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  1. Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization

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    Wang Wen-Quan

    2012-11-01

    Full Text Available Abstract Background Promotion of endothelial normalization restores tumor oxygenation and obstructs tumor cells invasion, intravasation, and metastasis. We therefore investigated whether a vasoactive drug, tanshinone IIA, could inhibit metastasis by inducing vascular normalization after palliative resection (PR of hepatocellular carcinoma (HCC. Methods A liver orthotopic double-tumor xenograft model in nude mouse was established by implantation of HCCLM3 (high metastatic potential and HepG2 tumor cells. After removal of one tumor by PR, the effects of tanshinone IIA administration on metastasis, tumor vascularization, and survival were evaluated. Tube formation was examined in mouse tumor-derived endothelial cells (TECs treated with tanshinone IIA. Results PR significantly accelerated residual hepatoma metastases. Tanshinone IIA did not inhibit growth of single-xenotransplanted tumors, but it did reduce the occurrence of metastases. Moreover, it inhibited PR-enhanced metastases and, more importantly, prolonged host survival. Tanshinone IIA alleviated residual tumor hypoxia and suppressed epithelial-mesenchymal transition (EMT in vivo; however, it did not downregulate hypoxia-inducible factor 1α (HIF-1α or reverse EMT of tumor cells under hypoxic conditions in vitro. Tanshinone IIA directly strengthened tube formation of TECs, associated with vascular endothelial cell growth factor receptor 1/platelet derived growth factor receptor (VEGFR1/PDGFR upregulation. Although the microvessel density (MVD of residual tumor tissue increased after PR, the microvessel integrity (MVI was still low. While tanshinone IIA did not inhibit MVD, it did dramatically increase MVI, leading to vascular normalization. Conclusions Our results demonstrate that tanshinone IIA can inhibit the enhanced HCC metastasis associated with PR. Inhibition results from promoting VEGFR1/PDGFR-related vascular normalization. This application demonstrates the potential clinical

  2. The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG.

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    Lv, Chao; Zeng, Hua-Wu; Wang, Jin-Xin; Yuan, Xing; Zhang, Chuang; Fang, Ting; Yang, Pei-Ming; Wu, Tong; Zhou, Yu-Dong; Nagle, Dale G; Zhang, Wei-Dong

    2018-02-07

    Tanshinone IIA (Tan IIA), the primary bioactive compound derived from the traditional Chinese medicine (TCM) Salvia miltiorrhiza Bunge, has been reported to possess antitumor activity. However, its antitumor mechanisms are not fully understood. To resolve the potential antitumor mechanism(s) of Tan IIA, its gene expression profiles from our database was analyzed by connectivity map (CMAP) and the CMAP-based mechanistic predictions were confirmed/validated in further studies. Specifically, Tan IIA inhibited total protein kinase C (PKC) activity and selectively suppressed the expression of cytosolic and plasma membrane PKC isoforms ζ and ε. The Ras/MAPK pathway that is closely regulated by the PKC signaling is also inhibited by Tan IIA. While Tan IIA did not inhibit heat shock protein 90 (Hsp90), it synergistically enhanced the antitumor efficacy of the Hsp90 inhibitors 17-AAG and ganetespib in human breast cancer MCF-7 cells. In addition, Tan IIA significantly inhibited PI3K/Akt/mTOR signaling, and induced both cell cycle arrest and autophagy. Collectively, these studies provide new insights into the molecular mechanisms responsible for antitumor activity of Tan IIA.

  3. Tanshinone IIA stimulates erythrocyte phosphatidylserine exposure

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    Zelenak, C.; Pasham, V.; Jilani, K.; Tripodi, P.M.; Rosaclerio, L.; Pathare, G.T.; Lupescu, A.; Faggio, C.; Qadri, S.M.; Lang, F.

    2012-01-01

    Tanshinone IIA, an antimicrobial, antioxidant, antianaphylactic, antifibrotic, vasodilating, antiatherosclerotic, organo-protective and antineoplastic component from the rhizome of Salvia miltiorrhiza, is known to trigger apoptosis of tumor cells. Tanshinone IIA is effective in part through

  4. Tanshinone IIA attenuates neuropathic pain via inhibiting glial activation and immune response.

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    Cao, Fa-Le; Xu, Min; Wang, Yan; Gong, Ke-Rui; Zhang, Jin-Tao

    2015-01-01

    Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose-dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-α and IL-1β in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord. Taken together, our study provides evidence that TIIA inhibited SNL-induced neuropathic pain through depressing microglial activation and immune response by the inhibition of mitogen-activated protein kinases (MAPKs) pathways. Our findings suggest that TIIA might be a promising agent in the treatment of neuropathic pain. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Tanshinone IIA Attenuates Diabetic Peripheral Neuropathic Pain in Experimental Rats via Inhibiting Inflammation

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    Baojian Zhang

    2018-01-01

    Full Text Available Diabetic peripheral neuropathic pain (DPNP is a common and intractable complication of diabetes. Conventional therapies are always not ideal; development of novel drugs is still needed to achieve better pain relief. Recent evidences have demonstrated that inflammation is involved in the onset and maintenance of DPNP. The anti-inflammatory property of Tanshinone IIA (TIIA makes it a promising candidate to block or alter the pain perception. This study was conducted to investigate whether TIIA could attenuate DPNP in streptozotocin- (STZ- induced rats model and its potential mechanisms. TIIA was administered to STZ-induced diabetic rats at the dose of 40 mg/kg once a day for 3 weeks. The effects of TIIA on thermal hyperalgesia and mechanical allodynia were investigated using behavioral tests. The mRNA level and expression of interleukin- (IL- 1β, interleukin- (IL- 6, tumor necrosis factor- (TNF- α, and interleukin- (IL- 10 in the fourth to sixth segments of the dorsal root ganglion (L4–6 DRG were detected by quantitative real-time PCR (qPCR and Western blot. TIIA treatment significantly attenuated mechanical allodynia and thermal hyperalgesia in diabetic rats. In addition, the expression of the proinflammatory cytokines IL-1β, IL-6, and TNF-α was inhibited, and the level of the anti-inflammatory cytokine IL-10 was increased by TIIA. This study demonstrated that TIIA has significant antiallodynic and antihyperalgesic effects in a rat model of STZ-induced DPNP, and the effect may be associated with its anti-inflammation property.

  6. Tanshinone IIA Inhibits Epithelial-Mesenchymal Transition in Bladder Cancer Cells via Modulation of STAT3-CCL2 Signaling

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    Sung-Ying Huang

    2017-07-01

    Full Text Available Tanshinone IIA (Tan-IIA is an extract from the widely used traditional Chinese medicine (TCM Danshen (Salvia miltiorrhiza, and has been found to attenuate the proliferation of bladder cancer (BCa cells (The IC50 were: 5637, 2.6 μg/mL; BFTC, 2 μg/mL; T24, 2.7 μg/mL, respectively.. However, the mechanism of the effect of Tan-IIA on migration inhibition of BCa cells remains unclear. This study investigates the anti-metastatic effect of Tan-IIA in human BCa cells and clarifies its molecular mechanism. Three human BCa cell lines, 5637, BFTC and T24, were used for subsequent experiments. Cell migration and invasion were evaluated by transwell assays. Real-time RT-PCR and western blotting were performed to detect epithelial-mesenchymal transition (EMT-related gene expression. The enzymatic activity of matrix metalloproteinases (MMP was evaluated by zymography assay. Tan-IIA inhibited the migration and invasion of human BCa cells. Tan-IIA suppressed both the protein expression and enzymatic activity of MMP-9/-2 in human BCa cells. Tan-IIA up-regulated the epithelial marker E-cadherin and down-regulated mesenchymal markers such as N-cadherin and Vimentin, along with transcription regulators such as Snail and Slug in BCa cells in a time- and dose-dependent manner. Mechanism dissection revealed that Tan-IIA-inhibited BCa cell invasion could function via suppressed chemokine (C-C motif ligand 2 (CCL2 expression, which could be reversed by the addition of CCL2 recombinant protein. Furthermore, Tan-IIA could inhibit the phosphorylation of the signal transducer and activator of transcription 3 (STAT3 (Tyr705, which cannot be restored by the CCL2 recombinant protein addition. These data implicated that Tan-IIA might suppress EMT on BCa cells through STAT3-CCL2 signaling inhibition. Tan-IIA inhibits EMT of BCa cells via modulation of STAT3-CCL2 signaling. Our findings suggest that Tan-IIA can serve as a potential anti-metastatic agent in BCa therapy.

  7. Inhibition of Tanshinone IIA, Salvianolic Acid A and Salvianolic Acid B on Areca Nut Extract-Induced Oral Submucous Fibrosis in Vitro

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    Jian-Ping Dai

    2015-04-01

    Full Text Available Salvia miltiorrhiza Bunge has been reported to possess excellent antifibrotic activity. In this study, we have investigated the effect and mechanism of tanshinone IIA (Tan-IIA, salvianolic acid A (Sal-A and salvianolic acid B (Sal-B, the important active compounds of Salvia miltiorrhiza Bunge, on areca nut extract (ANE-induced oral submucous fibrosis (OSF in vitro. Through human procollagen gene promoter luciferase reporter plasmid assay, hydroxyproline assay, gelatin zymography assay, qRT-PCR, ELISA and Western blot assay, the influence of these three compounds on ANE-stimulated cell viability, collagen accumulation, procollagen gene transcription, MMP-2/-9 activity, MMP-1/-13 and TIMP-1/-2 expression, cytokine secretion and the activation of PI3K/AKT, ERK/JNK/p38 MAPK and TGF-β/Smads pathways were detected. The results showed that Tan-IIA, Sal-A and Sal-B could significantly inhibit the ANE-stimulated abnormal viability and collagen accumulation of mice oral mucosal fibroblasts (MOMFs, inhibit the transcription of procollagen gene COL1A1 and COL3A1, increase MMP-2/-9 activity, decrease TIMP-1/-2 expression and inhibit the transcription and release of CTGF, TGF-β1, IL-6 and TNF-α; Tan-IIA, Sal-A and Sal-B also inhibited the ANE-induced activation of AKT and ERK MAPK pathways in MOMFs and the activation of TGF-β/Smads pathway in HaCaT cells. In conclusion, Tan-IIA, Sal-A and Sal-B possess excellent antifibrotic activity in vitro and can possibly be used to promote the rehabilitation of OSF patients.

  8. Inhibitory effect of tanshinone IIA on rat hepatic stellate cells.

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    Ya-Wei Liu

    Full Text Available Anti-inflammation via inhibition of NF-κB pathways in hepatic stellate cells (HSCs is one therapeutic approach to hepatic fibrosis. Tanshinone IIA (C19H18O3, Tan IIA is a lipophilic diterpene isolated from Salvia miltiorrhiza Bunge, with reported anti-inflammatory activity. We tested whether Tan IIA could inhibit HSC activation.The cell line of rat hepatic stellate cells (HSC-T6 was stimulated with lipopolysaccharide (LPS (100 ng/ml. Cytotoxicity was assessed by MTT assay. HSC-T6 cells were pretreated with Tan IIA (1, 3 and 10 µM, then induced by LPS (100 ng/ml. NF-κB activity was evaluated by the luciferase reporter gene assay. Western blotting analysis was performed to measure NF-κB-p65, and phosphorylations of MAPKs (ERK, JNK, p38. Cell chemotaxis was assessed by both wound-healing assay and trans-well invasion assay. Quantitative real-time PCR was used to detect gene expression in HSC-T6 cells.All concentrations of drugs showed no cytotoxicity against HSC-T6 cells. LPS stimulated NF-κB luciferase activities, nuclear translocation of NF-κB-p65, and phosphorylations of ERK, JNK and p38, all of which were suppressed by Tan IIA. In addition, Tan IIA significantly inhibited LPS-induced HSCs chemotaxis, in both wound-healing and trans-well invasion assays. Moreover, Tan IIA attenuated LPS-induced mRNA expressions of CCL2, CCL3, CCL5, IL-1β, TNF-α, IL-6, ICAM-1, iNOS, and α-SMA in HSC-T6 cells.Our results demonstrated that Tan IIA decreased LPS-induced HSC activation.

  9. Rescue therapy with Tanshinone IIA hinders transition of acute kidney injury to chronic kidney disease via targeting GSK3β

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    Jiang, Chunming; Zhu, Wei; Yan, Xiang; Shao, Qiuyuan; Xu, Biao; Zhang, Miao; Gong, Rujun

    2016-01-01

    Acute kidney injury (AKI) remains challenging for clinical practice and poses a risk of developing progressive chronic kidney disease (CKD) with no definitive treatment available yet. Tanshinone IIA, an active ingredient of Chinese herbal Salvia miltiorrhiza, has been widely used in Asia for the remarkable organoprotective activities. Its effect on established AKI, however, remains unknown. In mice with folic acid-induced AKI, delayed treatment with Tanshinone IIA, commenced early or late after injury, diminished renal expression of kidney injury markers, reduced apoptosis and improved kidney dysfunction, concomitant with mitigated histologic signs of AKI to CKD transition, including interstitial fibrosis and tubular atrophy, and with an ameliorated inflammatory infiltration in tubulointerstitium and a favored M2-skewed macrophage polarization. Mechanistically, Tanshinone IIA blunted glycogen synthase kinase (GSK)3β overactivity and hyperactivation of its downstream mitogen-activated protein kinases that are centrally implicated in renal fibrogenesis and inflammation. Inhibition of GSK3β is likely a key mechanism mediating the therapeutic activity of Tanshinone IIA, because sodium nitroprusside, a GSK3β activator, largely offset its renoprotective effect. In confirmatory studies, rescue treatment with Tanshinone IIA likewise ameliorated ischemia/reperfusion-induced kidney destruction in mice. Our data suggest that Tanshinone IIA represents a valuable treatment that improves post-AKI kidney salvage via targeting GSK3β. PMID:27857162

  10. Sodium Tanshinone IIA Sulfonate Ameliorates Bladder Fibrosis in a Rat Model of Partial Bladder Outlet Obstruction by Inhibiting the TGF-β/Smad Pathway Activation.

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    Xiaoxiao Jiang

    Full Text Available Transforming growth factor (TGF-β1 is known to play a pivotal role in a diverse range of biological systems including modulation of fibrosis in several organs. The precise role of TGF-β/Smad signaling in the progression of bladder fibrosis secondary to partial bladder outlet obstruction (PBOO is yet to be conclusively. Using a rat PBOO model, we investigated TGF-β1 expression and exaimined whether sodium tanshinone IIA sulfonate (STS could inhibit TGF-β/Smad signaling pathway activation and ameliorate bladder fibrosis. Forty-eight female Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 16, PBOO operation without STS treatment group (n = 16 and PBOO operation with STS treatment group (n = 16. Thirty-two rats underwent the operative procedure to create PBOO and subsequently received intraperitoneal injections of STS (10 mg/kg/d; n = 16 or vehicle (n = 16 two days after the surgery. Sham surgery was conducted on 16 rats, which received intraperitoneal vehicle injection two days later. In each of the three groups, an equal number of rats were sacrificed at weeks 4 and 8 after the PBOO or sham operation. The TGF-β/Smad signaling pathway was analyzed using western blotting, immunohistochemical staining and reverse transcriptase polymerase chain reaction (RT-PCR. One-way analysis of variance was conducted to draw statistical inferences. At 4 and 8 weeks, the expression of TGF-β1 and phosphorylated Smad2 and Smad3 in STS-treated PBOO rats was significantly lower than in the PBOO rats not treated with STS. Alpha smooth muscle actin (α-SMA, collagen I and collagen III expression at 4 and 8 weeks post PBOO was lower in STS-treated PBOO rats when compared to that in PBOO rats not treated with STS. Our findings indicate that STS ameliorates bladder fibrosis by inhibiting TGF-β/Smad signaling pathway activation, and may prove to be a potential therapeutic measure for preventing bladder fibrosis secondary to PBOO

  11. Analysis of tanshinone IIA induced cellular apoptosis in leukemia cells by genome-wide expression profiling

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    Liu Chang

    2012-01-01

    Full Text Available Abstract Background Tanshinone IIA (Tan IIA is a diterpene quinone extracted from the root of Salvia miltiorrhiza, a Chinese traditional herb. Although previous studies have reported the anti-tumor effects of Tan IIA on various human cancer cells, the underlying mechanisms are not clear. The current study was undertaken to investigate the molecular mechanisms of Tan IIA's apoptotic effects on leukemia cells in vitro. Methods The cytotoxicity of Tan IIA on different types of leukemia cell lines was evaluated by the 3-[4,5-dimethylthiazol-2,5]-diphenyl tetrazolium bromide (MTT assay on cells treated without or with Tan IIA at different concentrations for different time periods. Cellular apoptosis progression with and without Tan IIA treatment was analyzed by Annexin V and Caspase 3 assays. Gene expression profiling was used to identify the genes regulated after Tan IIA treatment and those differentially expressed among the five cell lines. Confirmation of these expression regulations was carried out using real-time quantitative PCR and ELISA. The antagonizing effect of a PXR inhibitor L-SFN on Tan IIA treatment was tested using Colony Forming Unit Assay. Results Our results revealed that Tan IIA had different cytotoxic activities on five types of leukemia cells, with the highest toxicity on U-937 cells. Tan IIA inhibited the growth of U-937 cells in a time- and dose-dependent manner. Annexin V and Caspase-3 assays showed that Tan IIA induced apoptosis in U-937 cells. Using gene expression profiling, 366 genes were found to be significantly regulated after Tan IIA treatment and differentially expressed among the five cell lines. Among these genes, CCL2 was highly expressed in untreated U-937 cells and down-regulated significantly after Tan IIA treatment in a dose-dependent manner. RT-qPCR analyses validated the expression regulation of 80% of genes. Addition of L- sulforaphane (L-SFN, an inhibitor of Pregnane × receptor (PXR significantly

  12. Tanshinone IIA protects against pulmonary arterial hypertension in broilers.

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    Hu, Guoliang; Song, Yalu; Ke, Shanlin; Cao, Huabin; Zhang, Caiying; Deng, Guangfu; Yang, Fei; Zhou, Sihui; Liu, Pei; Guo, Xiaoquan; Liu, Ping

    2017-05-01

    This investigation was conducted to study the effects of tanshinone IIA (TIIA) on pulmonary arterial hypertension (PAH) in broilers. Two-hundred newly hatched Arbor Acre commercial broilers were randomly divided into 3 groups. All groups, with the exception of the control group (tap water), were given NaCl water (0.3%) starting on the d 15, and broilers in the protected group were fed a diet supplemented with TIIA (2.5 g/kg) starting on the d 15. On d 28, 35, 42, and 49, the ratio of the right ventricular weight to the total ventricular weight (RV: TV) and the values of other biochemical indicators for each group chickens were determined. The concentrations of interleukin-6 (IL-6), interleukin-1β (IL-1β), nuclear factor kappa (NF-κB), and P38 (a mitogen-activated protein kinase) were measured using enzyme-linked immune sorbent assays (ELISA). The results showed that the proportion of chickens in the diseased group with an RV:TV ratio in the range of 0.250 to 0.299 (10%) was significantly higher (25 to 30%) compared to that of the other groups (P chickens was 28%. In addition, the IL-6, IL-1β, NF-κB, and P38 protein concentrations were higher in the diseased group, whereas there were no differences between the control group and the protected group. Moreover, the measurements of body weight, liver function, kidney function and electrolytes showed significant differences between the diseased group and the other groups. These findings suggest that tanshinone IIA may protect broilers from PAH, which is an important piece of information for the poultry industry. © 2016 Poultry Science Association Inc.

  13. Tanshinon IIA injection accelerates tissue expansion by reducing the formation of the fibrous capsule.

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    Yu, Qingxiong; Sheng, Lingling; Yang, Mei; Zhu, Ming; Huang, Xiaolu; Li, Qingfeng

    2014-01-01

    The tissue expansion technique has been applied to obtain new skin tissue to repair large defects in clinical practice. The implantation of tissue expander could initiate a host response to foreign body (FBR), which leads to fibrotic encapsulation around the expander and prolongs the period of tissue expansion. Tanshinon IIA (Tan IIA) has been shown to have anti-inflammation and immunoregulation effect. The rat tissue expansion model was used in this study to observe whether Tan IIA injection systematically could inhibit the FBR to reduce fibrous capsule formation and accelerate the process of tissue expansion. Forty-eight rats were randomly divided into the Tan IIA group and control group with 24 rats in each group. The expansion was conducted twice a week to maintain a capsule pressure of 60 mmHg. The expansion volume and expanded area were measured. The expanded tissue in the two groups was harvested, and histological staining was performed; proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and transforming growth factor-β (TGF-β) were examined. The expansion volume and the expanded area in the Tan IIA group were greater than that of the control group. The thickness of the fibrous capsule in the Tan IIA group was reduced with no influence on the normal skin regeneration. Decreased infiltration of macrophages, lower level of TNF-α, IL-6, IL-1β and TGF-β, less proliferating myofibroblasts and enhanced neovascularization were observed in the Tan IIA group. Our findings indicated that the Tan IIA injection reduced the formation of the fibrous capsule and accelerated the process of tissue expansion by inhibiting the FBR.

  14. Tanshinon IIA injection accelerates tissue expansion by reducing the formation of the fibrous capsule.

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    Qingxiong Yu

    Full Text Available The tissue expansion technique has been applied to obtain new skin tissue to repair large defects in clinical practice. The implantation of tissue expander could initiate a host response to foreign body (FBR, which leads to fibrotic encapsulation around the expander and prolongs the period of tissue expansion. Tanshinon IIA (Tan IIA has been shown to have anti-inflammation and immunoregulation effect. The rat tissue expansion model was used in this study to observe whether Tan IIA injection systematically could inhibit the FBR to reduce fibrous capsule formation and accelerate the process of tissue expansion. Forty-eight rats were randomly divided into the Tan IIA group and control group with 24 rats in each group. The expansion was conducted twice a week to maintain a capsule pressure of 60 mmHg. The expansion volume and expanded area were measured. The expanded tissue in the two groups was harvested, and histological staining was performed; proinflammatory cytokines such as tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6 and interleukin-1β (IL-1β and transforming growth factor-β (TGF-β were examined. The expansion volume and the expanded area in the Tan IIA group were greater than that of the control group. The thickness of the fibrous capsule in the Tan IIA group was reduced with no influence on the normal skin regeneration. Decreased infiltration of macrophages, lower level of TNF-α, IL-6, IL-1β and TGF-β, less proliferating myofibroblasts and enhanced neovascularization were observed in the Tan IIA group. Our findings indicated that the Tan IIA injection reduced the formation of the fibrous capsule and accelerated the process of tissue expansion by inhibiting the FBR.

  15. Anti-Inflammatory and Immunomodulatory Mechanism of Tanshinone IIA for Atherosclerosis

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    Zhuo Chen

    2014-01-01

    Full Text Available Tanshinone IIA (Tan II A is widely used in the treatment of cardiovascular diseases as an active component of Salvia miltiorrhiza Bunge. It has been demonstrated to have pleiotropic effects for atherosclerosis. From the anti-inflammatory and immunomodulatory mechanism perspective, this paper reviewed major progresses of Tan IIA in antiatherosclerosis research, including immune cells, antigens, cytokines, and cell signaling pathways.

  16. Potential Therapeutic Roles of Tanshinone IIA in Human Bladder Cancer Cells

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    Sheng-Chun Chiu

    2014-09-01

    Full Text Available Tanshinone IIA (Tan-IIA, one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae, has been found to exhibit anticancer activity in various cancer cells. We have demonstrated that Tan-IIA induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. Here we explored the anticancer effect of Tan-IIA in human bladder cancer cell lines. Our results showed that Tan-IIA caused bladder cancer cell death in a time- and dose-dependent manner. Tan-IIA induced apoptosis through the mitochondria-dependent pathway in these bladder cancer cells. Tan-IIA also suppressed the migration of bladder cancer cells as revealed by the wound healing and transwell assays. Finally, combination therapy of Tan-IIA with a lower dose of cisplatin successfully killed bladder cancer cells, suggesting that Tan-IIA can serve as a potential anti-cancer agent in bladder cancer.

  17. The antitumor effect of tanshinone IIA on anti-proliferation and decreasing VEGF/VEGFR2 expression on the human non-small cell lung cancer A549 cell line

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    Jun Xie

    2015-11-01

    Full Text Available The effects of tanshinone IIA on the proliferation of the human non-small cell lung cancer cell line A549 and its possible mechanism on the VEGF/VEGFR signal pathway were investigated. The exploration of the interaction between tanshinone IIA and its target proteins provides a feasible platform for studying the anticancer mechanism of active components of herbs. The CCK-8 assay was used to evaluate the proliferative activity of A549 cells treated with tanshinone IIA (2.5−80 μmol/L for 24, 48 and 72 h, respectively. Flow cytometry was used for the detection of cell apoptosis and cell cycle perturbation. VEGF and VEGFR2 expression were studied by Western blotting. The binding mode of tanshinone IIA within the crystal structure of the VEGFR2 protein was evaluated with molecular docking analysis by use of the CDOCKER algorithm in Discovery Studio 2.1. The CCK-8 results showed that tanshinone IIA can significantly inhibit A549 cell proliferation in a dose- and time-dependent manner. Flow cytometry results showed that the apoptosis rate of tested group was higher than the vehicle control, and tanshinone IIA-treated cells accumulated at the S phase, which was higher than the vehicle control. Furthermore, the expression of VEGF and VEGFR2 was decreased in Western blot. Finally, molecular docking analysis revealed that tanshinone IIA could be stably docked into the kinase domain of VEGFR2 protein with its unique modes to form H-bonds with Cys917 and π–π stacking interactions with Val848. In conclusion, tanshinone IIA may suppress A549 proliferation, induce apoptosis and cell cycle arrest at the S phase. This drug may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2.

  18. Anti-Inflammatory Effects of Tanshinone IIA on Atherosclerostic Vessels of Ovariectomized ApoE-/- Mice are Mediated by Estrogen Receptor Activation and Through the ERK Signaling Pathway

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    Xin Liu

    2015-03-01

    expression of p-ERK1/2. Tanshinone IIA had no effect of level of serum 17ß-estradiol levels. All of the effects of Tanshinone IIA were similar to estrogen and were inhibited by the estrogen receptor antagonist ICI182780. Conclusion: Tanshinone IIA may play an anti-inflammatory and anti-oxidative stress role in OVX atherosclerotic apoE-/- mice by activating the estrogen receptor through the ERK signaling pathway. Therefore, Tanshinone IIA, as a phytoestrogen, could be used for estrogen replacement therapy for cardiovascular disease of postmenopausal women.

  19. Tanshinone IIA ameliorates dextran sulfate sodium-induced inflammatory bowel disease via the pregnane X receptor

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    Zhang, Xianxie; Wang, Yuguang; Ma, Zengchun; Liang, Qiande; Tang, Xianglin; Hu, Donghua; Tan, Hongling; Xiao, Chengrong; Gao, Yue

    2015-01-01

    Tanshinone IIA (Tan IIA) (C19H18O3) is one of the major active lipophilic components in a conventional Chinese medicine called danshen, and it has long been used in the People’s Republic of China and other neighboring countries to treat patients suffering from inflammatory bowel disease (IBD). Previous experiments by many teams determined which mechanism of Tan IIA is relevant to the treatment of IBD associated with inflammation and the pregnane X receptor (PXR). The current study demonstrated that Tan IIA is an efficacious PXR agonist and its ability to induce CYP3A4 mRNA and protein expression was mediated by the transactivation of PXR, a known target of abrogating inflammation in IBD. Clinical symptoms in mice and histological assessment data suggested that administration of Tan IIA in mice demonstrated significant protection and showed that in DSS-induced IBD it acts in a concentration-dependent manner. PXR-silenced mice treated with Tan IIA demonstrated low protection against DSS-induced mouse IBD and exacerbated the severity of IBD compared with wild-type mice; PXR-silenced mice demonstrated the necessity for PXR in Tan IIA-mediated upregulation of xenobiotic metabolism genes. The IBD treatment effects of Tan IIA are partially due to PXR-mediated upregulation of xenobiotic metabolism and downregulation of inflammatory mediators. The novel findings reported here may contribute to the effective utilization of Tan IIA and its derivatives as a PXR ligand in the treatment of human IBD. This suggests that Tan IIA may have considerable clinical utility. PMID:26674743

  20. Tanshinone IIA Sodium Sulfonate Attenuates LPS-Induced Intestinal Injury in Mice

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    Xin-Jing Yang

    2018-01-01

    Full Text Available Background. Tanshinone IIA sodium sulfonate (TSS is known to possess anti-inflammatory effects and has exhibited protective effects in various inflammatory conditions; however, its role in lipopolysaccharide- (LPS- induced intestinal injury is still unknown. Objective. The present study is designed to explore the role and possible mechanism of TSS in LPS-induced intestinal injury. Methods. Male C57BL/6J mice, challenged with intraperitoneal LPS injection, were treated with or without TSS 0.5 h prior to LPS exposure. At 1, 6, and 12 h after LPS injection, mice were sacrificed, and the small intestine was excised. The intestinal tissue injury was analyzed by HE staining. Inflammatory factors (TNF-α, IL-1β, and IL-6 in the intestinal tissue were examined by ELISA and RT-PCR. In addition, expressions of autophagy markers (microtubule-associated light chain 3 (LC3 and Beclin-1 were detected by western blot and RT-PCR. A number of autophagosomes were also observed under electron microscopy. Results. TSS treatment significantly attenuated small intestinal epithelium injury induced by LPS. LPS-induced release of inflammatory mediators, including TNF-α, IL-1β, and IL-6, were markedly inhibited by TSS. Furthermore, TSS treatment could effectively upregulate LPS-induced decrease of autophagy levels, as evidenced by the increased expression of LC3 and Beclin-1, and more autophagosomes. Conclusion. The protective effect of TSS on LPS-induced small intestinal injury may be attributed to the inhibition of inflammatory factors and promotion of autophagy levels. The present study may provide novel insight into the molecular mechanisms of TSS on the treatment of intestinal injury.

  1. Prevention and Therapeutic Effects and Mechanisms of Tanshinone IIA Sodium Sulfonate on Acute Liver Injury Mice Model

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    Lunjie Lu

    2016-01-01

    Full Text Available Tanshinone IIA sodium sulfonate (TSS is a water-soluble derivative of tanshinone IIA, which is the main pharmacologically active component of Salvia miltiorrhiza. This study aimed to verify the preventive and therapeutic effects of TSS and its combined therapeutic effects with magnesium isoglycyrrhizinate (MI in D-galactosamine- (D-Gal- induced acute liver injury (ALI in mice. The potential regulatory mechanisms of TSS on ALI were also examined. Our results may provide a basis for the development of novel therapeutics for ALI.

  2. Anti-inflammatory effects of tanshinone IIA on radiation-induced microglia BV-2 cells inflammatory response

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    Dong, Xiaorong; Dong, Jihua; Zhang, Ruiguang

    2009-01-01

    AIM: The aim of this study was to explore the inhibitory effects of Tanshinone II(A) on the production of proinflammation cytokines in radiation-stimulated microglia. METHODS: Microglia cells were treated with 2, 4, 8, 16, and 32 Gy of irradiation or sham-irradiated in the presence or absence of ...

  3. TanshinoneIIA and cryptotanshinone protect against hypoxia-induced mitochondrial apoptosis in H9c2 cells.

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    Hyou-Ju Jin

    Full Text Available Mitochondrial apoptosis pathway is an important target of cardioprotective signalling. Tanshinones, a group of major bioactive compounds isolated from Salvia miltiorrhiza, have been reported with actions against inflammation, oxidative stress, and myocardial ischemia reperfusion injury. However, the actions of these compounds on the chronic hypoxia-related mitochondrial apoptosis pathway have not been investigated. In this study, we examined the effects and molecular mechanisms of two major tanshonones, tanshinone IIA (TIIA and cryptotanshinone (CT on hypoxia induced apoptosis in H9c2 cells. Cultured H9c2 cells were treated with TIIA and CT (0.3 and 3 μΜ 2 hr before and during an 8 hr hypoxic period. Chronic hypoxia caused a significant increase in hypoxia inducible factor 1α expression and the cell late apoptosis rate, which was accompanied with an increase in caspase 3 activity, cytochrome c release, mitochondria membrane potential and expression of pro-apoptosis proteins (Bax and Bak. TIIA and CT (0.3 and 3 μΜ, in concentrations without affecting the cell viability, significantly inhibited the late apoptosis and the changes of caspase 3 activity, cytochrome c release, and mitochondria membrane potential induced by chronic hypoxia. These compounds also suppressed the overexpression of Bax and reduced the ratio of Bax/Bcl-2. The results indicate that TIIA and CT protect against chronic hypoxia induced cell apoptosis by regulating the mitochondrial apoptosis signaling pathway, involving inhibitions of mitochondria hyperpolarization, cytochrome c release and caspase 3 activity, and balancing anti- and pro-apoptotic proteins in Bcl-2 family proteins.

  4. Tanshinone IIA suppresses FcεRI-mediated mast cell signaling and anaphylaxis by activation of the Sirt1/LKB1/AMPK pathway.

    Science.gov (United States)

    Li, Xian; Park, Soon Jin; Jin, Fansi; Deng, Yifeng; Yang, Ju Hye; Chang, Jae-Hoon; Kim, Dong-Young; Kim, Jung-Ae; Lee, Youn Ju; Murakami, Makoto; Son, Kun Ho; Chang, Hyeun Wook

    2018-06-01

    AMP-activated protein kinase (AMPK) and its upstream mediators liver kinase B1 (LKB1) and sirtuin 1 (Sirt1) are generally known as key regulators of metabolism. We have recently reported that the AMPK pathway negatively regulates mast cell activation and anaphylaxis. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza extract that is currently used for the treatment of cardiovascular and cerebrovascular diseases, shows anti-diabetic activity and improves insulin resistance in db/db mice through activation of AMPK. The aim of this study was to evaluate the anti-allergic activity of Tan IIA in vivo and to investigate the underlying mechanism in vitro in the context of AMPK signaling. The anti-allergic effect of Tan IIA was evaluated using mouse bone marrow-derived mast cells (BMMCs) from AMPKα2 -/- or Sirt1 -/- mice, or BMMCs transfected with siRNAs specific for AMPKα2, LKB1, or Sirt1. AMPKα2 -/- and Sirt1 -/- mice were used to confirm the anti-allergic effect of Tan IIA in anaphylaxis in vivo. Tan IIA dose-dependently inhibited FcεRI-mediated degranulation and production of eicosanoids and cytokines in BMMCs. These inhibitory effects were diminished by siRNA-mediated knockdown or genetic deletion of AMPKα2 or Sirt1. Moreover, Tan IIA inhibited a mast cell-mediated local passive anaphylactic reaction in wild-type mice, but not in AMPKα2 -/- or Sirt1 -/- mice. In conclusion, Tan IIA suppresses FcεRI-mediated mast cell activation and anaphylaxis through activation of the inhibitory Sirt1-LKB1-AMPK pathway. Thus, Tan IIA may be useful as a new therapeutic agent for mast cell-mediated allergic diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. The vascular effects of sodium tanshinone IIA sulphonate in rodent and human pregnancy.

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    Jude S Morton

    Full Text Available Danshen, in particular its derivative tanshinone IIA (TS, is a promising compound in the treatment of cardiovascular diseases and has been used for many years in traditional Chinese medicine. Although many actions of TS have been researched, its vasodilator effects in pregnancy remain unknown. There have been a few studies that have shown the ability of TS to reduce blood pressure in women with hypertensive pregnancies; however, there are no studies which have examined the vascular effects of TS in the pregnant state in either normal or complicated pregnancies. Our aim was to determine the vasoactive role of TS in multiple arteries during pregnancy including: rat resistance (mesenteric and uterine and conduit (carotid arteries. Further, we aimed to assess the ability of TS to improve uterine blood flow in a rodent model of intrauterine growth restriction. Wire myography was used to assess vascular responses to the water-soluble derivative, sodium tanshinone IIA sulphonate (STS or to the endothelium-dependent vasodilator, methylcholine. At mid-pregnancy, STS caused direct vasodilation of rat resistance (pEC50 mesenteric: 4.47±0.05 and uterine: 3.65±0.10 but not conduit (carotid arteries. In late pregnancy, human myometrial arteries responded with a similar sensitivity to STS (pEC50 myometrial: 3.26±0.13. STS treatment for the last third of pregnancy in eNOS-/- mice increased uterine artery responses to methylcholine (Emax eNOS-/-: 55.2±9.2% vs. eNOS-/- treated: 75.7±8.9%, p<0.0001. The promising vascular effects, however, did not lead to improved uterine or umbilical blood flow in vivo, nor to improved fetal biometrics; body weight and crown-rump length. Further, STS treatment increased the uterine artery resistance index and decreased offspring body weight in control mice. Further research would be required to determine the safety and efficacy of use of STS in pregnancy.

  6. Pharmacokinetics and atherosclerotic lesions targeting effects of tanshinone IIA discoidal and spherical biomimetic high density lipoproteins.

    Science.gov (United States)

    Zhang, Wenli; He, Hongliang; Liu, Jianping; Wang, Ji; Zhang, Suyang; Zhang, Shuangshuang; Wu, Zimei

    2013-01-01

    High density lipoproteins (HDL) have been successfully reconstructed to deliver a large number of lipophilic drugs. Here, discoidal and spherical recombinant HDL loaded with cardiovascular drug tanshinone IIA (TA) were constructed (TA-d-rHDL and TA-s-rHDL), respectively. And next their in vitro physiochemical and biomimetic properties were characterized. Furthermore, pharmacokinetics, atherosclerotic lesions targeting effects and antiatherogenic efficacies were elaborately performed and compared in atherosclerotic New Zealand White (NZW) rabbits. In vitro characterizations results showed that both TA-d-rHDL and TA-s-rHDL had nano-size diameter, high entrapment efficiency (EE) and drug-loading capacity (DL). Additionally, similar to their native counterparts, TA-d-rHDL maintained remodeling behaviors induced by lecithin cholesterol acyltransferase (LCAT), and TA leaked during remodeling behaviors. Pharmacokinetic studies manifested that both TA-d-rHDL and TA-s-rHDL markedly improved pharmacokinetic behaviors of TA in vivo. Ex vivo imaging demonstrated that both d-rHDL and s-rHDL bound more avidly to atherosclerotic lesions than to normal vessel walls, and s-rHDL had better targeting effect than d-rHDL. Pharmacodynamic tests illustrated that both TA-d-rHDL and TA-s-rHDL had much stronger antiatherogenic efficacies than conventional TA nanostructured lipid carriers (TA-NLC), TA liposomes (TA-L) and commercially available preparation Sulfotanshinone Sodium Injection (SSI). Moreover, TA-s-rHDL had more potent antiatherogenic efficacies than TA-d-rHDL. Collectively our studies indicated that rHDL could be exploited as potential delivery vehicles of TA targeting atherosclerotic lesions as well as synergistically improving efficacies, especially for s-rHDL. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Inhibition of bone resorption by Tanshinone VI isolated from Salvia miltiorrhiza Bunge

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    V. Nicolin

    2010-05-01

    Full Text Available During the last decade, a more detailed knowledge of molecular mechanisms involved in osteoclastogenesis has driven research efforts in the development and screening of compound libraries of several small molecules that specifically inhibit the pathway involved in the commitment of the osteoclast precursor cells. Natural compounds that suppress osteoclast differentiation may have therapeutic value in treating osteoporosis and other bone erosive diseases such as rheumatoid arthritis or metastasis associated with bone loss. In ongoing investigation into anti-osteoporotic compounds from natural products we have analyzed the effect of Tanshinone VI on osteoclasts differentiation, using a physiologic three-dimensional osteoblast/bone marrow model of cell co-culture. Tanshinone VI is an abietane diterpene extracted from the root of Salvia miltiorrhiza Bunge (Labiatae, a Chinese traditional crude drug, ‘’Tan-Shen’’. Tashinone has been widely used in clinical practice for the prevention of cardiac diseases, arthritis and other inflammation-related disorders based on its pharmacological actions in multiple tissues. Although Tanshinone VI A has been used as a medicinal agent in the treatment of many diseases, its role in osteoclast-related bone diseases remains unknown. We showed previously that Tanshinone VI greatly inhibits osteoclast differentiation and suppresses bone resorption through disruption of the actin ring; subsequently, we intended to examine the precise inhibitory mechanism of Tanshinone VI on osteoclast differentiating factor. This study shows, for the first time, that Tanshinone VI prevents osteoclast differentiation by inhibiting RANKL expression and NFkB induction.

  8. Tanshinone IIA protects PC12 cells from β-amyloid(25-35)-induced apoptosis via PI3K/Akt signaling pathway.

    Science.gov (United States)

    Dong, Huimin; Mao, Shanping; Mao, Shanpin; Wei, Jiajun; Liu, Baohui; Zhang, Zhaohui; Zhang, Qian; Yan, Mingmin

    2012-06-01

    For the aging populations of any nation, Dementia is becoming a primary problem and Alzheimer’s dementia (AD) is the most common type. However, until now, there is no effective treatment for AD. Tanshinone IIA (Tan IIA) has been reported for neuroprotective potential to against amyloid β peptides (Aβ)-induced cytotoxicity in the rat pheochromocytoma cell line PC-12, which is widely used as AD research model, but the mechanism still remains unclear. To investigate the effect of Tan IIA and the possible molecular mechanism in the apoptosis of PC12 cells, we induced apoptosis in PC12 cells with β-amyloid(25-35), and treated cells with Tan IIA. After 24 h treatment, we found that Tan IIA increased the cell viability and reduced the number of apoptotic cells induced by Aβ(25-35). However, neuroprotection of Tan IIA was abolished by PI3K inhibitor LY294002. Meanwhile, Treatment with lithium chloride, a phosphorylation inhibitor of GSK3β, which is a downstream target of PI3K/Akt, can block Aβ(25-35)-induced cell apoptosis in a Tan IIA-like manner. Our findings suggest that Tan IIA is an effective neuroprotective agent and a viable candidate in AD therapy and PI3K/Akt activation and GSK3β phosphorylation are involved in the neuroprotection of Tan IIA.

  9. Tanshinone IIA mitigates peritoneal fibrosis by inhibiting EMT via ...

    African Journals Online (AJOL)

    The expression levels of mRNA and protein of TGF-β, smad2, smad7, α-smooth muscle ... transition was alleviated, and the expression levels of EMT-related proteins were significantly ..... Expression in Peritoneum in a Peritoneal Dialysis Rat.

  10. MYBPH inhibits NM IIA assembly via direct interaction with NMHC IIA and reduces cell motility

    International Nuclear Information System (INIS)

    Hosono, Yasuyuki; Usukura, Jiro; Yamaguchi, Tomoya; Yanagisawa, Kiyoshi; Suzuki, Motoshi; Takahashi, Takashi

    2012-01-01

    Highlights: ► MYBPH inhibits NMHC IIA assembly and cell motility. ► MYBPH interacts to assembly-competent NM IIA. ► MYBPH inhibits RLC and NMHC IIA, independent components of NM IIA. -- Abstract: Actomyosin filament assembly is a critical step in tumor cell migration. We previously found that myosin binding protein H (MYBPH) is directly transactivated by the TTF-1 lineage-survival oncogene in lung adenocarcinomas and inhibits phosphorylation of the myosin regulatory light chain (RLC) of non-muscle myosin IIA (NM IIA) via direct interaction with Rho kinase 1 (ROCK1). Here, we report that MYBPH also directly interacts with an additional molecule, non-muscle myosin heavy chain IIA (NMHC IIA), which was found to occur between MYBPH and the rod portion of NMHC IIA. MYBPH inhibited NMHC IIA assembly and reduced cell motility. Conversely, siMYBPH-induced increased motility was partially, yet significantly, suppressed by blebbistatin, a non-muscle myosin II inhibitor, while more profound effects were attained by combined treatment with siROCK1 and blebbistatin. Electron microscopy observations showed well-ordered paracrystals of NMHC IIA reflecting an assembled state, which were significantly less frequently observed in the presence of MYBPH. Furthermore, an in vitro sedimentation assay showed that a greater amount of NMHC IIA was in an unassembled state in the presence of MYBPH. Interestingly, treatment with a ROCK inhibitor that impairs transition of NM IIA from an assembly-incompetent to assembly-competent state reduced the interaction between MYBPH and NMHC IIA, suggesting that MYBPH has higher affinity to assembly-competent NM IIA. These results suggest that MYBPH inhibits RLC and NMHC IIA, independent components of NM IIA, and negatively regulates actomyosin organization at 2 distinct steps, resulting in firm inhibition of NM IIA assembly.

  11. Tanshinone IIA increases the bystander effect of herpes simplex virus thymidine kinase/ganciclovir gene therapy via enhanced gap junctional intercellular communication.

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    Jianyong Xiao

    Full Text Available The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV. This effect is reported to be mediated by gap junctional intercellular communication (GJIC, and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA, a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy.

  12. Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain.

    Science.gov (United States)

    Sun, Shukai; Yin, Yue; Yin, Xin; Cao, Fale; Luo, Daoshu; Zhang, Ting; Li, Yunqing; Ni, Longxing

    2012-09-01

    Inflammatory pain is an important clinical symptom. The levels of extracellular signal-regulated kinases (ERKs) and the levels of cytokines such as interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play important roles in inflammatory pain. Tanshinone IIA (TIIA) is an important component of Danshen, a traditional Chinese medicine that has been commonly used to treat cardiovascular disease. In this study, we investigated the potential anti-inflammatory nociceptive effects of TIIA on complete Freund's adjuvant (CFA)-induced inflammation and inflammatory pain in rats. The effects of TIIA on CFA-induced thermal and mechanical hypersensitivity were investigated using behavioral tests. The levels of ERKs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transient receptor potential vanilloid 1 (TRPV1) in the fifth segment of the lumbar spinal cord (L5) ganglia were detected by Western blot, and the levels of mRNA and protein production of IL1-β, IL-6 and TNF-α were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immuno sorbent assay (ELISA). In this study, we found that TIIA attenuates the development of CFA-induced mechanical and thermal hypersensitivity. In addition, p-ERK and NF-κB expression levels were inhibited by TIIA, and the levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced. Finally, we found that the expression level of TRPV1 was significantly decreased after TIIA injection. This study demonstrated that TIIA has significant anti-nociceptive effects in a rat model of CFA-induced inflammatory pain. TIIA can inhibit the activation of ERK signaling pathways and the expression of pro-inflammatory cytokines. These results suggest that TIIA may be a potential anti-inflammatory and anti-nociceptive drug. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Tanshinone IIA attenuates the cerebral ischemic injury-induced increase in levels of GFAP and of caspases-3 and -8.

    Science.gov (United States)

    Zhou, L; Bondy, S C; Jian, L; Wen, P; Yang, F; Luo, H; Li, W; Zhou, Jun

    2015-03-12

    Tanshinone IIA (TSA) is a lipid soluble agent derived from the root of Salvia miltiorrhiza (Danshen). This plant is a traditional Chinese herb, which has been used widely in China especially for enhancing circulation. However mechanisms underlying its efficacy remain poorly understood. The present study was designed to illuminate events that may underlie the apparently neuroprotective effects of TSA following ischemic insult. Adult Sprague-Dawley rats were subjected to transient focal cerebral ischemia by use of a middle cerebral artery occlusion model. They were then randomly divided into a sham-operated control group, and cerebral ischemia/reperfusion groups receiving a two-hour occlusion. Further subsets of groups received the same durations of occlusion or were sham-operated but then received daily i.p. injections of high or low doses of TSA, for seven or 15days. Hematoxylin and eosin staining revealed lesions in the entorhinal cortex of both rats subject to ischemia and to a lesser extent to those receiving TSA after surgery. Levels of glial fibrillary acidic protein (GFAP), caspase-3 and caspase-8, were quantified by both immunohistochemistry and Western blotting. TSA treatment after middle cerebral artery occlusion, markedly reduced infarct size, and reduced the expression of caspase-3 and caspase-8. These changes were considered protective and were generally proportional to the dose of TSA used. These results suggest that TSA may effect neuroprotection by way of reduction of the extent of cell inflammation and death within affected regions. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Evaluation and SAR analysis of the cytotoxicity of tanshinones in colon cancer cells.

    Science.gov (United States)

    Wang, Lin; Liu, An; Zhang, Fei-Long; Yeung, John H K; Li, Xu-Qin; Cho, Chi-Hin

    2014-03-01

    This study was designed to evaluate the anti-cancer actions of tanshinone I and tanshinone IIA, and six derivatives of tanshinone IIA on normal and cancerous colon cells. Structure activity relationship (SAR) analysis was conducted to delineate the significance of the structural modifications of tanshinones for improved anti-cancer action. Tanshinone derivatives were designed and synthesized according to the literature. The cytotoxicity of different compounds on colon cancer cells was determined by the MTT assay. Apoptotic activity of the tanshinones was measured by flow cytometry (FCM). Tanshinone I and tanshinone IIA both exhibited significant cytotoxicity on colon cancer cells. They are more effective in p53(+/+) colon cancer cell line. It was also noted that the anti-cancer activity of tanshinone I was more potent and selective. Two of the derivatives of tanshinone IIA (N1 and N2) also exhibited cytotoxicity on colon cancer cells. The anti-colon cancer activity of tanshinone I was more potent and selective than tanshinone IIA, and is p53 dependent. The derivatives obtained by structural modifications of tanshinone IIA exhibited lower cytotoxicity on both normal and colon cancer cells. From steric and electronic characteristics point of view, it was concluded that structural modifications of ring A and furan or dihydrofuran ring D on the basic structure of tanshinones influences the activity. An increase of the delocalization of the A and B rings could enhance the cytotoxicity of such compounds, while a non-planar and small sized D ring region would provide improved anti-cancer activity. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  15. Inhibition of class IIa histone deacetylase activity by gallic acid, sulforaphane, TMP269, and panobinostat.

    Science.gov (United States)

    Choi, Sin Young; Kee, Hae Jin; Jin, Li; Ryu, Yuhee; Sun, Simei; Kim, Gwi Ran; Jeong, Myung Ho

    2018-05-01

    Histone deacetylase (HDAC) inhibitors are gaining increasing attention as potential therapeutics for cardiovascular diseases as well as cancer. We recently reported that the class II HDAC inhibitor, MC1568, and the phytochemical, gallic acid, lowered high blood pressure in mouse models of hypertension. We hypothesized that class II HDACs may be involved in the regulation of hypertension. The aim of this study was to determine and compare the effects of well-known HDAC inhibitors (TMP269, panobinostat, and MC1568), phytochemicals (gallic acid, sulforaphane, and piceatannol), and anti-hypertensive drugs (losartan, carvedilol, and furosemide) on activities of class IIa HDACs (HDAC4, 5, 7, and 9). The selective class IIa HDAC inhibitor, TMP269, and the pan-HDAC inhibitor, panobinostat, but not MC1568, clearly inhibited class IIa HDAC activities. Among the three phytochemicals, gallic acid showed remarkable inhibition, whereas sulforaphane presented mild inhibition of class IIa HDACs. Piceatannol inhibited only HDAC7 activity. As expected, the anti-hypertensive drugs losartan, carvedilol, and furosemide did not affect the activity of any class IIa HDAC. In addition, we evaluated the inhibitory effect of several compounds on the activity of class l HDACs (HDAC1, 2, 3, and 8) and class IIb HDAC (HDAC6). MC1568 did not affect the activities of HDAC1, HDAC2, and HDAC3, but it reduced the activity of HDAC8 at concentrations of 1 and 10 μM. Gallic acid weakly inhibited HDAC1 and HDAC6 activities, but strongly inhibited HDAC8 activity with effectiveness comparable to that of trichostatin A. Inhibition of HDAC2 activity by sulforaphane was stronger than that by piceatnnaol. These results indicated that gallic acid is a powerful dietary inhibitor of HDAC8 and class IIa/b HDAC activities. Sulforaphane may also be used as a dietary inhibitor of HDAC2 and class IIa HDAC. Our findings suggest that the class II HDAC inhibitor, MC1568, does not inhibit class IIa HDAC, but inhibits

  16. Active Component of Danshen (Salvia miltiorrhiza Bunge, Tanshinone I, Attenuates Lung Tumorigenesis via Inhibitions of VEGF, Cyclin A, and Cyclin B Expressions

    Directory of Open Access Journals (Sweden)

    Yu-Tang Tung

    2013-01-01

    Full Text Available Tanshinone I (T1 and tanshinone II (T2 are the major diterpenes isolated from Danshen (Salvia miltiorrhiza Bunge. Three human lung adenocarcinoma cell lines, A549, CL1-0, and CL1-5, were treated with T1 and T2 for the in vitro antitumor test. Results showed that T1 was more effective than T2 in inhibiting the growth of lung cancer cells via suppressing the expression of VEGF, Cyclin A, and Cyclin B proteins in a dose-dependent manner. Moreover, a transgenic mice model of the human vascular endothelial growth factor-A165 (hVEGF-A165 gene-induced pulmonary tumor was further treated with T1 for the in vivo lung cancer therapy test. T1 significantly attenuated hVEGF-A165 overexpression to normal levels of the transgenic mice (Tg that were pretreated with human monocytic leukemia THP-1 cell-derived conditioned medium (CM. It also suppressed the formation of lung adenocarcinoma tumors (16.7% compared with two placebo groups (50% for Tg/Placebo and 83.3% for Tg/CM/Placebo; P<0.01. This antitumor effect is likely to slow the progression of cells through the S and G2/M phases of the cell cycle. Blocking of the tumor-activated cell cycle pathway may be a critical mechanism for the observed antitumorigenic effects of T1 treatment on vasculogenesis and angiogenesis.

  17. Tanshinone II A Attenuates TNF-α-Induced Expression of VCAM-1 and ICAM-1 in Endothelial Progenitor Cells by Blocking Activation of NF-κB

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    Jin-Xiu Yang

    2016-11-01

    Full Text Available Background/Aims: Tanshinone IIA (Tan IIA is effective in the treatment of inflammation and atherosclerosis. The adhesion of inflammatory cells to vascular endothelium plays important role in atherogenic processes. This study examined the effects of Tan IIA on expression of adhesion molecules in tumor necrosis factor-α (TNF-α-induced endothelial progenitor cells (EPCs. Methods: EPCs were pretreated with Tan IIA and stimulated with TNF-α. Mononuclear cell (MNC adhesion assay was performed to assess the effects of Tan IIA on TNF-α-induced MNC adhesion. Expression of vascular cell adhesion molecule-1 (VCAM-1/intracellular adhesion molecule-1 (ICAM-1 and activation of Nuclear factor κB (NF-κB signaling pathway were measured. Results: The results showed that the adhesion of MNCs to TNF-α-induced EPCs and expression of VCAM-1/ICAM-1 in EPCs were promoted by TNF-α, which were reduced by Tan IIA. TNF-α increased the amount of phosphorylation of NF-κB, IκB-α and IKKα/β in cytosolic fractions and NF-κB p65 in nucleus, while Tan IIA reduced its amount. Conclusion: This study demonstrated a novel mechanism for the anti-inflammatory/anti-atherosclerotic activity of Tan IIA, which may involve down-regulation of VCAM-1 and ICAM-1 through partial blockage of TNF-α-induced NF-κB activation and IκB-α phosphorylation by the inhibition of IKKα/β pathway in EPCs.

  18. An Ectosteric Inhibitor of Cathepsin K Inhibits Bone Resorption in Ovariectomized Mice

    DEFF Research Database (Denmark)

    Panwar, Preety; Xue, Liming; Søe, Kent

    2017-01-01

    The potent cathepsin K (CatK) inhibitor, Tanshinone IIA sulfonic sodium (T06), was tested for its in vitro and in vivo antiresorptive activities. T06 binds in an ectosteric site of CatK remote from its active site and selectively inhibits collagen degradation with an IC50 value of 2.7±0.2μM (CatK...

  19. Simultaneous Determination of Four Tanshinones by UPLC-TQ/MS and Their Pharmacokinetic Application after Administration of Single Ethanol Extract of Danshen Combined with Water Extract in Normal and Adenine-Induced Chronic Renal Failure Rats

    Directory of Open Access Journals (Sweden)

    Hong-Die Cai

    2016-11-01

    Full Text Available Salvia miltiorrhiza, one of the major traditional Chinese medicines, is commonly used and the main active ingredients—tanshinones—possess the ability to improve renal function. In this paper, the UPLC-TQ/MS method of simultaneously determining four tanshinones—tanshinone IIA, dihydrotanshinone I, tanshinone I, and cryptotanshinone—was established and applied to assess the pharmacokinetics in normal and chronic renal failure (CRF rat plasma. The pharmacokinetics of tanshinones in rats were studied after separately intragastric administration of Salvia miltiorrhiza ethanol extract (SMEE (0.65 g/kg, SMEE (0.65 g/kg combined with Salvia miltiorrhiza water extract (SMWE (1.55 g/kg. The results showed Cmax and AUC0–t of tanshinone IIA, tanshinone I, cryptotanshinone reduced by 50%~80% and CLz/F increased by 2~4 times (p < 0.05 in model group after administrated with SMEE. Nevertheless, after intragastric administration of a combination of SMWE and SMEE, the Cmax and AUC0–t of four tanshinones were upregulated and CLz/F was downregulated, which undulated similarity from the model group to the normal group with compatibility of SMEE and SMWE. These results hinted that SMWE could improve the bioavailability of tanshinones in CRF rats, which provides scientific information for further exploration the mechanism of the combination of SMWE and SMEE and offers a reference for clinical administration of Salvia miltiorrhiza.

  20. Inhibition of Group IIA Secretory Phospholipase A2 and its Inflammatory Reactions in Mice by Ethanolic Extract of Andrographis paniculata, a Well-known Medicinal Food

    Science.gov (United States)

    Kishore, V.; Yarla, N. S.; Zameer, F.; Nagendra Prasad, M. N.; Santosh, M. S.; More, S. S.; Rao, D. G.; Dhananjaya, Bhadrapura Lakkappa

    2016-01-01

    Andrographis paniculata Nees is an important medicinal plant found in the tropical regions of the world, which has been traditionally used in Indian and Chinese medicinal systems. It is also used as medicinal food. A. paniculata is found to exhibit anti-inflammatory activities; however, its inhibitory potential on inflammatory Group IIA phospholipases A2 (PLA2) and its associated inflammatory reactions are not clearly understood. The aim of the present study is to evaluate the inhibitory/neutralizing potential of ethanolic extract of A. paniculata on the isolated inflammatory PLA2 (VRV-PL-VIIIa) from Daboii rusellii pulchella (belonging to Group IIA inflammatory secretory PLA2 [sPLA2]) and its associated edema-induced activities in Swiss albino mice. A. paniculata extract dose dependently inhibited the Group IIA sPLA2 enzymatic activity with an IC50 value of 10.3 ± 0.5 μg/ml. Further, the extract dose dependently inhibited the edema formation, when co-injected with enzyme indicating that a strong correlation exists between lipolytic and pro-inflammatory activities of the enzyme. In conclusion, results of this study shows that the ethanolic extract of A. paniculata effectively inhibits Group IIA sPLA2 and its associated inflammatory activities, which substantiate its anti-inflammatory properties. The results of the present study warranted further studies to develop bioactive compound (s) in ethanolic extract of A. paniculata as potent therapeutic agent (s) for inflammatory diseases. SUMMARY This study emphasis the anti-inflammatory effect of A. paniculata by inhibiting the inflammatory Group IIA sPLA2 and its associated inflammatory activities such as edema. It was found that there is a strong correlation between lipolytic activity and pro-inflammatory activity inhibition. Therefore, the study suggests that the extract processes potent anti-inflammatory agents, which could be developed as a potential therapeutic agent against inflammatory and related diseases

  1. The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV☆

    Science.gov (United States)

    Tao, Shasha; Justiniano, Rebecca; Zhang, Donna D.; Wondrak, Georg T.

    2013-01-01

    Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photocarcinogenesis and photoaging, and an urgent need exists for improved strategies for skin photoprotection. The redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defense against environmental electrophilic insult, has recently emerged as an important determinant of cutaneous damage from solar UV, and the concept of pharmacological activation of Nrf2 has attracted considerable attention as a novel approach to skin photoprotection. In this study, we examined feasibility of using tanshinones, a novel class of phenanthrenequinone-based cytoprotective Nrf2 inducers derived from the medicinal plant Salvia miltiorrhiza, for protection of cultured human skin cells and reconstructed human skin against solar simulated UV. Using a dual luciferase reporter assay in human Hs27 dermal fibroblasts pronounced transcriptional activation of Nrf2 by four major tanshinones [tanshinone I (T-I), dihydrotanshinone (DHT), tanshinone IIA (T-II-A) and cryptotanshinone (CT)] was detected. In fibroblasts, the more potent tanshinones T-I and DHT caused a significant increase in Nrf2 protein half-life via blockage of ubiquitination, ultimately resulting in upregulated expression of cytoprotective Nrf2 target genes (GCLC, NQO1) with the elevation of cellular glutathione levels. Similar tanshinone-induced changes were also observed in HaCaT keratinocytes. T-I and DHT pretreatment caused significant suppression of skin cell death induced by solar simulated UV and riboflavin-sensitized UVA. Moreover, feasibility of tanshinone-based cutaneous photoprotection was tested employing a human skin reconstruct exposed to solar simulated UV (80 mJ/cm2 UVB; 1.53 J/cm2 UVA). The occurrence of markers of epidermal solar insult (cleaved procaspase 3, pycnotic nuclei, eosinophilic cytoplasm, acellular cavities) was significantly attenuated in DHT

  2. The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV.

    Science.gov (United States)

    Tao, Shasha; Justiniano, Rebecca; Zhang, Donna D; Wondrak, Georg T

    2013-01-01

    Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photocarcinogenesis and photoaging, and an urgent need exists for improved strategies for skin photoprotection. The redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defense against environmental electrophilic insult, has recently emerged as an important determinant of cutaneous damage from solar UV, and the concept of pharmacological activation of Nrf2 has attracted considerable attention as a novel approach to skin photoprotection. In this study, we examined feasibility of using tanshinones, a novel class of phenanthrenequinone-based cytoprotective Nrf2 inducers derived from the medicinal plant Salvia miltiorrhiza, for protection of cultured human skin cells and reconstructed human skin against solar simulated UV. Using a dual luciferase reporter assay in human Hs27 dermal fibroblasts pronounced transcriptional activation of Nrf2 by four major tanshinones [tanshinone I (T-I), dihydrotanshinone (DHT), tanshinone IIA (T-II-A) and cryptotanshinone (CT)] was detected. In fibroblasts, the more potent tanshinones T-I and DHT caused a significant increase in Nrf2 protein half-life via blockage of ubiquitination, ultimately resulting in upregulated expression of cytoprotective Nrf2 target genes (GCLC, NQO1) with the elevation of cellular glutathione levels. Similar tanshinone-induced changes were also observed in HaCaT keratinocytes. T-I and DHT pretreatment caused significant suppression of skin cell death induced by solar simulated UV and riboflavin-sensitized UVA. Moreover, feasibility of tanshinone-based cutaneous photoprotection was tested employing a human skin reconstruct exposed to solar simulated UV (80 mJ/cm(2) UVB; 1.53 J/cm(2) UVA). The occurrence of markers of epidermal solar insult (cleaved procaspase 3, pycnotic nuclei, eosinophilic cytoplasm, acellular cavities) was significantly attenuated in DHT

  3. The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV

    Directory of Open Access Journals (Sweden)

    Shasha Tao

    2013-01-01

    Full Text Available Exposure to solar ultraviolet (UV radiation is a causative factor in skin photocarcinogenesis and photoaging, and an urgent need exists for improved strategies for skin photoprotection. The redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2, a master regulator of the cellular antioxidant defense against environmental electrophilic insult, has recently emerged as an important determinant of cutaneous damage from solar UV, and the concept of pharmacological activation of Nrf2 has attracted considerable attention as a novel approach to skin photoprotection. In this study, we examined feasibility of using tanshinones, a novel class of phenanthrenequinone-based cytoprotective Nrf2 inducers derived from the medicinal plant Salvia miltiorrhiza, for protection of cultured human skin cells and reconstructed human skin against solar simulated UV. Using a dual luciferase reporter assay in human Hs27 dermal fibroblasts pronounced transcriptional activation of Nrf2 by four major tanshinones [tanshinone I (T-I, dihydrotanshinone (DHT, tanshinone IIA (T-II-A and cryptotanshinone (CT] was detected. In fibroblasts, the more potent tanshinones T-I and DHT caused a significant increase in Nrf2 protein half-life via blockage of ubiquitination, ultimately resulting in upregulated expression of cytoprotective Nrf2 target genes (GCLC, NQO1 with the elevation of cellular glutathione levels. Similar tanshinone-induced changes were also observed in HaCaT keratinocytes. T-I and DHT pretreatment caused significant suppression of skin cell death induced by solar simulated UV and riboflavin-sensitized UVA. Moreover, feasibility of tanshinone-based cutaneous photoprotection was tested employing a human skin reconstruct exposed to solar simulated UV (80 mJ/cm2 UVB; 1.53 J/cm2 UVA. The occurrence of markers of epidermal solar insult (cleaved procaspase 3, pycnotic nuclei, eosinophilic cytoplasm, acellular cavities was significantly attenuated in DHT

  4. Isolation and Characterization of Plantaricin Produced by Lactobacillus plantarum Strains (IIA-1A5, IIA-1B1, IIA-2B2

    Directory of Open Access Journals (Sweden)

    I. I. Arief

    2013-08-01

    Full Text Available Bacteriocins produced by Indonesian lactic acid bacteria Lactobacillus plantarum IIA-1A5, IIA-1B1, IIA-2B2 were purified and characterized. Plantaricin W gene had been successfully amplified from all strains. This amplicon showed the expected 200 bp size of plantaricin W gene. This bacteriocins purified from L. plantarum IIA-1A5, IIA-1B1, and IIA-2B2 were named plantaricin IIA-1A5, IIA-1B1, and IIA-2B2. Purification by cation exchange chromatography increased the purity (fold and activity of plantaricins. Purity of plantaricin IIA-1A5 was increased by 3.13 fold with specific activity 13.40 AU/mg. Plantaricin IIA-1B1 had 2.98 fold purity with specific activity 5.12 AU/mg, while purity of plantaricin IIA-2B2 was 1.37 fold with specific activity 7.70 AU/mg. All plantaricins could inhibit the growth of pathogenic bacteria, such as Escherichia coli, Salmonella typhimurium, Bacillus cereus, and Staphylococcus aureus. Plantaricins could be digested by trypsin. Stability of plantaricins at 80 oC for 30 min and at 121 oC for 15 min were affected by type of plantaricin and species of pathogenic bacteria. Generally, plantaricin IIA-1A5 was better as antimicrobial agent than plantaricin IIA-1B1 and plantaricin IIA-2B2.

  5. [Preparation of panax notoginseng saponins-tanshinone H(A) composite method for pulmonary delivery with spray-drying method and its characterization].

    Science.gov (United States)

    Wang, Hua-Mei; Fu, Ting-Ming; Guo, Li-Wei

    2013-02-01

    To prepare panax notoginseng saponins-tanshinone II(A) composite particles for pulmonary delivery, in order to explore a dry powder particle preparation method ensuring synchronized arrival of multiple components of traditional Chinese medicine compounds at absorption sites. Panax notoginseng saponins-tanshinone II(A) composite particles were prepared with spray-drying method, and characterized by scanning electron microscopy (SEM), confocal laser scanning microscope (CLSM), X-ray diffraction (XRD), infrared analysis (IR), dry laser particle size analysis, high performance liquid chromatography (HPLC) and the aerodynamic behavior was evaluated by a Next Generation Impactor (NGI). The dry powder particles produced had narrow particle size distribution range and good aerodynamic behavior, and could realize synchronized administration of multiple components. The spray-drying method is used to combine traditional Chinese medicine components with different physical and chemical properties in the same particle, and product into traditional Chinese medicine compound particles in line with the requirements for pulmonary delivery.

  6. Expression profiles of genes involved in tanshinone biosynthesis of ...

    Indian Academy of Sciences (India)

    Expression profiles of genes involved in tanshinone biosynthesis of two. Salvia miltiorrhiza genotypes with different tanshinone contents. Zhenqiao Song, Jianhua Wang and Xingfeng Li. J. Genet. 95, 433–439. Table 1. S. miltiorrhiza genes and primer pairs used for qRT-PCR. Gene. GenBank accession. Primer name.

  7. Separation and Determination of Four Tanshinones in Danshen and Related Medicinal Plants by Micellar Electrokinetic Chromatography Using Ionic Liquids as Modifier.

    Science.gov (United States)

    Cao, Jiliang; Wei, Jinchao; Xiang, Cheng; Zhang, Mi; Li, Baocai; Wan, Jianbo; Su, Huanxing; Li, Peng

    2016-09-01

    A simple and fast micellar electrokinetic chromatography (MEKC) method using ionic liquids as modifier was established for simultaneous determination of four hydrophobic tanshinones, including dihydrotanshinone I ( 1: ), cryptotanshinone ( 2: ), tanshinone I ( 3: ) and tanshinone IIA ( 4: ), in Danshen and related medicinal plants. In normal MEKC using sodium dodecyl sulfate (SDS) as surfactant and organic solvents as additives, the four tanshinones, especially cryptotanshinone and tanshinone I, could not be well separated. Fortunately, further addition of ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) resulted in a baseline separation of these four analytes. After an optimization study, 10 mM borax-10 mM SDS-10 mM [bmim]BF4 containing 15% acetonitrile (v/v) at pH 9.6 was adopted as the running buffer to complete the separation within 16 min at the voltage of 25 kV, temperature of 25°C and detection wavelength of 254 nm. The relative standard deviations of migration time and peak area were in the range of 0.62-2.21 and 1.33-3.90%, respectively, indicating the good repeatability of the developed method. This method was extensively validated by evaluating the linearity (R(2) ≥ 0.9992), limits of detection (0.75-1.11 μg mL(-1)), limits of quantification (2.26-3.32 μg mL(-1)) and recovery (96.11-103.74%). Under the optimum conditions, samples of Danshen and related medicinal plants were well analyzed with high separation efficiency. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Leishmanicidal, antiplasmodial, and cytotoxic activity of novel diterpenoid 1,2-quinones from Perovskia abrotanoides: new source of tanshinones

    DEFF Research Database (Denmark)

    Sairafianpour, M; Christensen, J; Staerk, D

    2001-01-01

    provide a rationale for traditional use of the roots in Iran as a constituent of poultices for treatment of cutaneous leishmaniasis. The isolated tanshinones also inhibited growth of cultured malaria parasites (3D7 strain of Plasmodium falciparum), drug-sensitive KB-3-1 human carcinoma cell line...

  9. sPLA2-IIA

    Indian Academy of Sciences (India)

    67

    Recent research showed that maslinic acid interacts with sPLA2-IIA ... Further analysis revealed that sPLA2-IIA only induced modest LDL ..... MDA/mg protein) compared to native LDL (2.043 nmol MDA/mg protein) while .... to modify extracellular non-cellular lipid components such as lipoproteins, ... The main pathway for.

  10. Regulation of myosin IIA and filamentous actin during insulin-stimulated glucose uptake in 3T3-L1 adipocytes

    International Nuclear Information System (INIS)

    Stall, Richard; Ramos, Joseph; Kent Fulcher, F.; Patel, Yashomati M.

    2014-01-01

    Insulin stimulated glucose uptake requires the colocalization of myosin IIA (MyoIIA) and the insulin-responsive glucose transporter 4 (GLUT4) at the plasma membrane for proper GLUT4 fusion. MyoIIA facilitates filamentous actin (F-actin) reorganization in various cell types. In adipocytes F-actin reorganization is required for insulin-stimulated glucose uptake. What is not known is whether MyoIIA interacts with F-actin to regulate insulin-induced GLUT4 fusion at the plasma membrane. To elucidate the relationship between MyoIIA and F-actin, we examined the colocalization of MyoIIA and F-actin at the plasma membrane upon insulin stimulation as well as the regulation of this interaction. Our findings demonstrated that MyoIIA and F-actin colocalized at the site of GLUT4 fusion with the plasma membrane upon insulin stimulation. Furthermore, inhibition of MyoII with blebbistatin impaired F-actin localization at the plasma membrane. Next we examined the regulatory role of calcium in MyoIIA-F-actin colocalization. Reduced calcium or calmodulin levels decreased colocalization of MyoIIA and F-actin at the plasma membrane. While calcium alone can translocate MyoIIA it did not stimulate F-actin accumulation at the plasma membrane. Taken together, we established that while MyoIIA activity is required for F-actin localization at the plasma membrane, it alone is insufficient to localize F-actin to the plasma membrane. - Highlights: • Insulin induces colocalization of MyoIIA and F-actin at the cortex in adipocytes. • MyoIIA is necessary but not sufficient to localize F-actin at the cell cortex. • MyoIIA-F-actin colocalization is regulated by calcium and calmodulin

  11. Genomic survey of bZIP transcription factor genes related to tanshinone biosynthesis in Salvia miltiorrhiza

    Directory of Open Access Journals (Sweden)

    Yu Zhang

    2018-03-01

    Full Text Available Tanshinones are a class of bioactive components in the traditional Chinese medicine Salvia miltiorrhiza, and their biosynthesis and regulation have been widely studied. Current studies show that basic leucine zipper (bZIP proteins regulate plant secondary metabolism, growth and developmental processes. However, the bZIP transcription factors involved in tanshinone biosynthesis are unknown. Here, we conducted the first genome-wide survey of the bZIP gene family and analyzed the phylogeny, gene structure, additional conserved motifs and alternative splicing events in S. miltiorrhiza. A total of 70 SmbZIP transcription factors were identified and categorized into 11 subgroups based on their phylogenetic relationships with those in Arabidopsis. Moreover, seventeen SmbZIP genes underwent alternative splicing events. According to the transcriptomic data, the SmbZIP genes that were highly expressed in the Danshen root and periderm were selected. Based on the prediction of bZIP binding sites in the promoters and the co-expression analysis and co-induction patterns in response to Ag+ treatment via quantitative real-time polymerase chain reaction (qRT-PCR, we concluded that SmbZIP7 and SmbZIP20 potentially participate in the regulation of tanshinone biosynthesis. These results provide a foundation for further functional characterization of the candidate SmbZIP genes, which have the potential to increase tanshinone production. KEY WORDS: bZIP genes, Salvia miltiorrhiza, Phylogenetic analysis, Expression pattern analysis, Tanshinone biosynthesis

  12. Class IIa histone deacetylases are conserved regulators of circadian function.

    Science.gov (United States)

    Fogg, Paul C M; O'Neill, John S; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C; McIntosh, Rebecca L L; Elliott, Christopher J H; Sweeney, Sean T; Hastings, Michael H; Chawla, Sangeeta

    2014-12-05

    Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca(2+) and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Tanshinone I alleviates insulin resistance in type 2 diabetes mellitus rats through IRS-1 pathway.

    Science.gov (United States)

    Wei, Ying; Gao, Jiaqi; Qin, Lingling; Xu, Yunling; Wang, Dongchao; Shi, Haoxia; Xu, Tunhai; Liu, Tonghua

    2017-09-01

    Tanshinone I from tanshen has been used in traditional Chinese medicine for treating cardiovascular diseases and inflammatory diseases. Given the link between inflammation and Type 2 diabetes mellitus (T2DM), we suspect that tanshinone I may have a beneficial effect on T2DM. This study was to investigate the potential effects of tanshinone I on T2DM and its underlying mechanism. T2DM was thus induced in Sprague-Dawley (SD) rats using streptozotocin (STZ) and high-fat diet. It was observed that T2DM rats had higher levels of total cholesterol (TC), nonesterified fatty acids (NEFAs), total triglyceride (TG) and total low density lipoprotein cholesterol (LDL-C) compared with normal, healthy SD rats. Treatment with tanshinone I decreased these levels and lowered blood glucose level in T2DM rats. In addition, enzyme-linked immunosorbent assay (ELISA) analysis showed that T2DM rats had elevated levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Furthermore, Western blot analysis revealed that T2DM rats had enhanced nuclear translocation of NF-κB as well as elevated phosphorylation of Ser307 in IRS-1(insulin receptor substrate 1). Treatment by tanshinone I lowered the levels of IL-6 and TNF-α, decreased nuclear translocation of NF-κB as well as phosphorylation of Ser307 in IRS-1. These results demonstrated that tanshinone I could alleviate T2DM syndrome in rats. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Audiological findings in Usher syndrome types IIa and II (non-IIa).

    Science.gov (United States)

    Sadeghi, Mehdi; Cohn, Edward S; Kelly, William J; Kimberling, William J; Tranebjoerg, Lisbeth; Möller, Claes

    2004-03-01

    The aim was to define the natural history of hearing loss in Usher syndrome type IIa compared to non-IIa. People with Usher syndrome type II show moderate-to-severe hearing loss, normal balance and retinitis pigmentosa. Several genes cause Usher syndrome type II. Our subjects formed two genetic groups: (1) subjects with Usher syndrome type IIa with a mutation and/or linkage to the Usher IIa gene; (2) subjects with the Usher II phenotype with no mutation and/or linkage to the Usher IIa gene. Four hundred and two audiograms of 80 Usher IIa subjects were compared with 435 audiograms of 87 non-IIa subjects. Serial audiograms with intervals of > or = 5 years were examined for progression in 109 individuals Those with Usher syndrome type IIa had significantly worse hearing thresholds than those with non-IIa Usher syndrome after the second decade. The hearing loss in Usher syndrome type IIa was found to be more progressive, and the progression started earlier than in non-IIa Usher syndrome. This suggests an auditory phenotype for Usher syndrome type IIa that is different from that of other types of Usher syndrome II. Thus, this is to our knowledge one of the first studies showing a genotype-phenotype auditory correlation.

  15. In vivo angiogenesis screening and mechanism of action of novel tanshinone derivatives produced by one-pot combinatorial modification of natural tanshinone mixture from Salvia miltiorrhiza.

    Directory of Open Access Journals (Sweden)

    Zhe-Rui Zhang

    Full Text Available Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1-10 and one oxazole-tanshinone (Compound 11, the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors.Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great

  16. Salvia miltiorrhiza Bunge (Danshen) extract attenuates permanent cerebral ischemia through inhibiting platelet activation in rats.

    Science.gov (United States)

    Fei, Yu-Xiang; Wang, Si-Qi; Yang, Li-Jian; Qiu, Yan-Ying; Li, Yi-Ze; Liu, Wen-Yuan; Xi, Tao; Fang, Wei-Rong; Li, Yun-Man

    2017-07-31

    Danshen is a crude herbal drug isolated from dried roots of Salvia miltiorrhiza Bunge. This plant is widely used in oriental medicine for the treatment of cardiovascular and cerebrovascular diseases. The supercritical CO 2 extract from Danshen (SCED) (57.85%, 5.67% and 4.55% for tanshinone IIA, tanshinone I and cryptotanshinone respectively) was studied in this article, whose potential molecular mechanism remains unclear, especially in anti-thrombosis. The present study was designed to observe the protective effect of SCED on ischemic stroke in rats and to explore the underlying anti-thrombosis mechanism. Following induction of cerebral ischemia in rats by permanent middle cerebral artery occlusion (pMCAO). Neurological defect score, cerebral blood flow, infarct size, and brain edema were measured to evaluate the injury. Arteriovenous shunt thrombosis model and adenosine 5'-diphosphate (ADP) induced acute pulmonary embolism model were conducted to estimate the antithrombotic effect of SCED. In order to investigate the effects of SCED on platelet aggregation, rat platelet-rich-plasma (PRP) were incubated with SCED prior to the addition of the stimuli (ADP or 9, 11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619)). Aggregation was monitored in a light transmission aggregometer. Inhibitory effect of SCED on thromboxane A2 (TXA 2 ) release was detected by ELISA kit. Phospholipase C (PLC)/ Protein kinase C (PKC) signaling pathway was analyzed by a Western blot technique. The effect of the SCED was also studied in vivo on bleeding time in mice. SCED improved the neurological defect score, increased cerebral blood flow, reduced infarct size and alleviated brain edema in rats exposed to pMCAO. After administration of SCED, thrombosis formation in arteriovenous shunt was inhibited and recovery time in pulmonary embolism was shortened. The inhibitory effect of SCED on platelet activation was further confirmed by TXB 2 ELISA kit and Western blot analysis of PLC

  17. Efficiency of rat bone marrow-derived endothelial progenitor cells on VEGF and SDF-1 expression with the aid of Tanshinone ⅡA%丹参酮ⅡA增效大鼠骨髓源性内皮祖细胞VEGF、SDF-1表达

    Institute of Scientific and Technical Information of China (English)

    杨彦; 陈庆伟; 曹广煜; 李桂琼

    2012-01-01

    Objective:To investigate the effect of rat bone marrow-derived endothelial progenitor cells on VEGF expression with the aid of Tanshinone ⅡA.Methods:The mononuclear cells were isolated from rat femoral and tibial bone marrow using percoll density gradient centrifugation,then induced with vascular endothelial growth factor(VEGF),basic fibroblast growth factor(bFGF) and epidermal growth factor(EGF)for two weeks.The expression of cell markers was assessed by immunocytochemistry,and the attached cells were stained with Dil-acLDL and FITC-UEA-1.Then this study included two groups: EPCs and EPCs+ Tanshinone ⅡA groups.The expression levels of VEGF and SDF-1 was detected by fluorescent qRT-PCR and western blot.Results:Compared with the EPCs group,EPCs+ Tanshinone IIA group had a higher VEGF and SDF-1 expression(P0.05).Conclusions:EPCs can increase VEGF and SDF-1 expression with combination of Tanshinone IIA.Homing rate and repairing efficacy of EPCs can improve also with the aid of Tanshinone IIA.EPCs can increase VEGF and SDF-1 expression in injured myocardium after homing,thus improve angiogenesis efficiently.%目的:研究在丹参酮ⅡA的辅助下,骨髓源性内皮祖细胞(EPCs)VEGF与SDF-1表达是否能增强,从而促进细胞归巢。方法:Percoll密度梯度离心法分离SD大鼠骨髓单个核细胞,血管内皮生长因子(VEGF)、表皮生长因子((EGF)、碱性成纤维细胞生长因子(bFGF)诱导培养,并进行形态学、免疫学(免疫细胞化学染色)、功能学(Dil-acLDL与FITC-UEA-1双荧光染色)鉴定。将鉴定为EPCs的细胞分为单纯EPCs组(对照组)、EPCs+丹参酮ⅡA组(加药组)。细胞培养第9d,Western blot与实时荧光定量PCR检测各组VEGF、SDF-1基因与蛋白表达。结果:EPCs+丹参酮IIA组VEGF、SDF-1基因与蛋白表达均高于EPCs组(p均〈0.05)。结论:丹参酮ⅡA可上调大鼠骨

  18. Transcription Factor SmWRKY1 Positively Promotes the Biosynthesis of Tanshinones in Salvia miltiorrhiza

    Directory of Open Access Journals (Sweden)

    Wenzhi Cao

    2018-04-01

    Full Text Available Tanshinones, one group of bioactive diterpenes, were widely used in the treatment of cardiovascular diseases. WRKYs play important roles in plant metabolism, but their regulation mechanism in Salvia miltiorrhiza remains elusive. In this study, one WRKY transcription factor SmWRKY1 was isolated and functionally characterized from S. miltiorrhiza. Multiple sequence alignment and phylogenetic tree analysis showed SmWRKY1 shared high homology with other plant WRKYs such as CrWRKY1. SmWRKY1 was found predominantly expressed in leaves and stems, and was responsive to salicylic acid (SA, methyl jasmonate (MeJA, and nitric oxide (NO treatment. Subcellular localization analysis found that SmWRKY1 was localized in the nucleus. Over-expression of SmWRKY1 significantly elevated the transcripts of genes coding for enzymes in the MEP pathway especially 1-deoxy-D-xylulose-5-phosphate synthase (SmDXS and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (SmDXR, resulted in over fivefold increase in tanshinones production in transgenic lines (up to 13.7 mg/g DW compared with the control lines. A dual-luciferase (Dual-LUC assay showed that SmWRKY1 can positively regulate SmDXR expression by binding to its promoter. Our work revealed that SmWRKY1 participated in the regulation of tanshinones biosynthesis and acted as a positive regulator through activating SmDXR in the MEP pathway, thus provided a new insight to further explore the regulation mechanism of tanshinones biosynthesis.

  19. Crystal structure of MboIIA methyltransferase.

    Science.gov (United States)

    Osipiuk, Jerzy; Walsh, Martin A; Joachimiak, Andrzej

    2003-09-15

    DNA methyltransferases (MTases) are sequence-specific enzymes which transfer a methyl group from S-adenosyl-L-methionine (AdoMet) to the amino group of either cytosine or adenine within a recognized DNA sequence. Methylation of a base in a specific DNA sequence protects DNA from nucleolytic cleavage by restriction enzymes recognizing the same DNA sequence. We have determined at 1.74 A resolution the crystal structure of a beta-class DNA MTase MboIIA (M.MboIIA) from the bacterium Moraxella bovis, the smallest DNA MTase determined to date. M.MboIIA methylates the 3' adenine of the pentanucleotide sequence 5'-GAAGA-3'. The protein crystallizes with two molecules in the asymmetric unit which we propose to resemble the dimer when M.MboIIA is not bound to DNA. The overall structure of the enzyme closely resembles that of M.RsrI. However, the cofactor-binding pocket in M.MboIIA forms a closed structure which is in contrast to the open-form structures of other known MTases.

  20. Massive type IIA supergravity and E10

    International Nuclear Information System (INIS)

    Henneaux, M.; Kleinschmidt, A.; Persson, D.; Jamsin, E.

    2009-01-01

    In this talk we investigate the symmetry under E 10 of Romans' massive type IIA supergravity. We show that the dynamics of a spinning particle in a non-linear sigma model on the coset space E 10 /K(E 10 ) reproduces the bosonic and fermionic dynamics of massive IIA supergravity, in the standard truncation. In particular, we identify Romans' mass with a generator of E 10 that is beyond the realm of the generators of E 10 considered in the eleven-dimensional analysis, but using the same, underformed sigma model. As a consequence, this work provides a dynamical unification of the massless and massive versions of type IIA supergravity inside E 10 . (Abstract Copyright [2009], Wiley Periodicals, Inc.)

  1. Dynamical symmetry enhancement near IIA horizons

    International Nuclear Information System (INIS)

    Gran, University; Gutowski, J.; Kayani, University; Papadopoulos, G.

    2015-01-01

    We show that smooth type IIA Killing horizons with compact spatial sections preserve an even number of supersymmetries, and that the symmetry algebra of horizons with non-trivial fluxes includes an sl(2,ℝ) subalgebra. This confirms the conjecture of http://dx.doi.org/10.1007/JHEP11(2013)104 for type IIA horizons. As an intermediate step in the proof, we also demonstrate new Lichnerowicz type theorems for spin bundle connections whose holonomy is contained in a general linear group.

  2. Crystal structure of MboIIA methyltransferase

    OpenAIRE

    Osipiuk, Jerzy; Walsh, Martin A.; Joachimiak, Andrzej

    2003-01-01

    DNA methyltransferases (MTases) are sequence-specific enzymes which transfer a methyl group from S-adenosyl-l-methionine (AdoMet) to the amino group of either cytosine or adenine within a recognized DNA sequence. Methylation of a base in a specific DNA sequence protects DNA from nucleolytic cleavage by restriction enzymes recognizing the same DNA sequence. We have determined at 1.74 Å resolution the crystal structure of a β-class DNA MTase MboIIA (M·MboIIA) from the bacterium Moraxella bovis,...

  3. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis.

    Science.gov (United States)

    Mihaylova, Maria M; Vasquez, Debbie S; Ravnskjaer, Kim; Denechaud, Pierre-Damien; Yu, Ruth T; Alvarez, Jacqueline G; Downes, Michael; Evans, Ronald M; Montminy, Marc; Shaw, Reuben J

    2011-05-13

    Class IIa histone deacetylases (HDACs) are signal-dependent modulators of transcription with established roles in muscle differentiation and neuronal survival. We show here that in liver, class IIa HDACs (HDAC4, 5, and 7) are phosphorylated and excluded from the nucleus by AMPK family kinases. In response to the fasting hormone glucagon, class IIa HDACs are rapidly dephosphorylated and translocated to the nucleus where they associate with the promoters of gluconeogenic enzymes such as G6Pase. In turn, HDAC4/5 recruit HDAC3, which results in the acute transcriptional induction of these genes via deacetylation and activation of FOXO family transcription factors. Loss of class IIa HDACs in murine liver results in inhibition of FOXO target genes and lowers blood glucose, resulting in increased glycogen storage. Finally, suppression of class IIa HDACs in mouse models of type 2 diabetes ameliorates hyperglycemia, suggesting that inhibitors of class I/II HDACs may be potential therapeutics for metabolic syndrome. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Danshensu prevents hypoxic pulmonary hypertension in rats by inhibiting the proliferation of pulmonary artery smooth muscle cells via TGF-β-smad3-associated pathway.

    Science.gov (United States)

    Zhang, Ning; Dong, Mingqing; Luo, Ying; Zhao, Feng; Li, Yongjun

    2018-02-05

    Hypoxic pulmonary hypertension is characterized by the remodeling of pulmonary artery. Previously we showed that tanshinone IIA, one lipid-soluble component from the Chinese herb Danshen, ameliorated hypoxic pulmonary hypertension by inhibiting pulmonary artery remodeling. Here we explored the effects of danshensu, one water-soluble component of Danshen, on hypoxic pulmonary hypertension and its mechanism. Rats were exposed to hypobaric hypoxia for 4 weeks to develop hypoxic pulmonary hypertension along with administration of danshensu. Hemodynamics and pulmonary arterial remodeling index were measured. The effects of danshensu on the proliferation of primary pulmonary artery smooth muscle cells and transforming growth factor-β-smad3 pathway were assessed in vitro. Danshensu significantly decreased the right ventricle systolic pressure, the right ventricle hypertrophy and pulmonary vascular remodeling index in hypoxic pulmonary hypertension rats. Danshensu also reduced the increased expression of transforming growth factor-β and phosphorylation of smad3 in pulmonary arteries in hypoxic pulmonary hypertension rats. In vitro, danshensu inhibited the hypoxia- or transforming growth factor-β-induced proliferation of primary pulmonary artery smooth muscle cells. Moreover, danshensu decreased the hypoxia-induced expression and secretion of transforming growth factor in primary pulmonary adventitial fibroblasts and NR8383 cell line, inhibited the hypoxia or transforming growth factor-β-induced phosphorylation of smad3 in rat primary pulmonary artery smooth muscle cells. These results demonstrate that danshensu ameliorates hypoxic pulmonary hypertension in rats by inhibiting the hypoxia-induced proliferation of pulmonary artery smooth muscle cells, and the inhibition effects is associated with transforming growth factor-β-smad3 pathway. Therefore danshensu may be a potential treatment for hypoxic pulmonary hypertension. Copyright © 2017 Elsevier B.V. All rights

  5. Supersymmetric geometries of IIA supergravity III

    International Nuclear Information System (INIS)

    Gran, Ulf; Papadopoulos, George; Schultz, Christian von

    2016-01-01

    We find that (massive) IIA backgrounds that admit a G 2 ⋉ℝ 8 invariant Killing spinor must exhibit a null Killing vector field which leaves the Killing spinor invariant and that the rotation of the Killing vector field satisfies a certain g 2 instanton condition. This result together with those in http://dx.doi.org/10.1007/JHEP05(2014)024 and http://dx.doi.org/10.1007/JHEP12(2015)113 complete the classification of geometries of all (massive) IIA backgrounds that preserve one supersymmetry. We also explore the geometry of a class of backgrounds which admit a G 2 ⋉ℝ 8 invariant Killing spinor and where in addition an appropriate 1-form bilinear vanishes. In all cases, we express the fluxes of the theory in terms of the geometry.

  6. Alkali metals and group IIA metals

    International Nuclear Information System (INIS)

    Fenton, D.E.

    1987-01-01

    This chapter on the coordination complexes of the alkali metals of group IIA starts with a historical perspective of their chemistry, from simple monodentate ligands, metal-β-diketonates to the macrocyclic polyethers which act as ligands to the alkali and akaline earth metals. Other macrocyclic ligands include quarterenes, calixarenes, porphyrins, phthalocyanines and chlorophylls. A section on the naturally occurring ionophores and carboxylic ionophores is included. (UK)

  7. IIA/B, Wound and Wrapped

    International Nuclear Information System (INIS)

    Danielsson, Ulf H.; Guijosa, Alberto; Kruczenski, Martin

    2000-01-01

    We examine the T-duality relation between 1+1 NCOS and the DLCQ limit of type IIA string theory. We show that, as long as there is a compact dimension, one can meaningfully define an 'NCOS' limit of IIB/A string theory even in the absence of D-branes (and even if there is no B-field). This yields a theory of closed strings with strictly positive winding, which is T-dual to DLCQ IIA/B without any D-branes. We call this the Type IIB/A Wound String Theory. The existence of decoupled sectors can be seen directly from the energy spectrum, and mirrors that of the DLCQ theory. It becomes clear then that all of the different p+1 NCOS theories are simply different states of this single Wound IIA/B theory which contain D-branes. We study some of the properties of this theory. In particular, we show that upon toroidal compactification, Wound string theory is U-dual to various Wrapped Brane theories which contain OM theory and the ODp theories as special states. (author)

  8. Maslinic acid modulates secreted phospholipase A2-IIA (sPLA2-IIA ...

    Indian Academy of Sciences (India)

    Wei Hsum Yap

    2018-03-29

    Mar 29, 2018 ... Further analysis revealed that sPLA2-IIA only induced modest LDL oxidation and that inhibitory .... COX-2, was also reduced in primary human chondrocyte, primary rat .... oxidation (4.34 nmol MDA/mg protein) compared to native ..... rheumatoid fibroblast-like synoviocyte arachidonic acid meta- bolism.

  9. Secretory Phospholipase A2-IIA and Cardiovascular Disease

    DEFF Research Database (Denmark)

    Holmes, Michael V; Simon, Tabassome; Exeter, Holly J

    2013-01-01

    This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.......This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease....

  10. Secretory Phospholipase A(2)-IIA and Cardiovascular Disease

    NARCIS (Netherlands)

    Holmes, Michael V.; Simon, Tabassome; Exeter, Holly J.; Folkersen, Lasse; Asselbergs, Folkert W.; Guardiola, Montse; Cooper, Jackie A.; Palmen, Jutta; Hubacek, Jaroslav A.; Carruthers, Kathryn F.; Horne, Benjamin D.; Brunisholz, Kimberly D.; Mega, Jessica L.; Van Iperen, Erik P. A.; Li, Mingyao; Leusink, Maarten; Trompet, Stella; Verschuren, Jeffrey J. W.; Hovingh, G. Kees; Dehghan, Abbas; Nelson, Christopher P.; Kotti, Salma; Danchin, Nicolas; Scholz, Markus; Haase, Christiane L.; Rothenbacher, Dietrich; Swerdlow, Daniel I.; Kuchenbaecker, Karoline B.; Staines-Urias, Eleonora; Goel, Anuj; van 't Hooft, Ferdinand; Gertow, Karl; de Faire, Ulf; Panayiotou, Andrie G.; Tremoli, Elena; Baldassarre, Damiano; Veglia, Fabrizio; Holdt, Lesca M.; Beutner, Frank; Gansevoort, Ron T.; Navis, Gerjan J.; Mateo Leach, Irene; Breitling, Lutz P.; Brenner, Hermann; Thiery, Joachim; Dallmeier, Dhayana; Franco-Cereceda, Anders; Boer, Jolanda M. A.; Stephens, Jeffrey W.; Hofker, Marten H.; Tedgui, Alain; Hofman, Albert; Uitterlinden, Andre G.; Adamkova, Vera; Pitha, Jan; Onland-Moret, N. Charlotte; Cramer, Maarten J.; Nathoe, Hendrik M.; Spiering, Wilko; Klungel, Olaf H.; Kumari, Meena; Whincup, Peter H.; Morrow, David A.; Braund, Peter S.; Hall, Alistair S.; Olsson, Anders G.; Doevendans, Pieter A.; Trip, Mieke D.; Tobin, Martin D.; Hamsten, Anders; Watkins, Hugh; Koenig, Wolfgang; Nicolaides, Andrew N.; Teupser, Daniel; Day, Ian N. M.; Carlquist, John F.; Gaunt, Tom R.; Ford, Ian; Sattar, Naveed; Tsimikas, Sotirios; Schwartz, Gregory G.; Lawlor, Debbie A.; Morris, Richard W.; Sandhu, Manjinder S.; Poledne, Rudolf; Maitland-van der Zee, Anke H.; Khaw, Kay-Tee; Keating, Brendan J.; van der Harst, Pim; Price, Jackie F.; Mehta, Shamir R.; Yusuf, Salim; Witteman, Jaqueline C. M.; Franco, Oscar H.; Jukema, J. Wouter; de Knijff, Peter; Tybjaerg-Hansen, Anne; Rader, Daniel J.; Farrall, Martin; Samani, Nilesh J.; Kivimaki, Mika; Fox, Keith A. A.; Humphries, Steve E.; Anderson, Jeffrey L.; Boekholdt, S. Matthijs; Palmer, Tom M.; Eriksson, Per; Pare, Guillaume; Hingorani, Aroon D.; Sabatine, Marc S.; Mallat, Ziad; Casas, Juan P.; Talmud, Philippa J.

    2013-01-01

    Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. Background Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not

  11. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial.

    Science.gov (United States)

    Bissonnette, R; Papp, K A; Poulin, Y; Gooderham, M; Raman, M; Mallbris, L; Wang, C; Purohit, V; Mamolo, C; Papacharalambous, J; Ports, W C

    2016-11-01

    Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown. Tofacitinib, a small-molecule JAK inhibitor, was investigated for the topical treatment of AD. In this 4-week, phase IIa, randomized, double-blind, vehicle-controlled study (NCT02001181), 69 adults with mild-to-moderate AD were randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient-reported pruritus. Safety, local tolerability and pharmacokinetics were monitored. The mean percentage CFB at week 4 in EASI score was significantly greater (P tofacitinib (-81·7%) vs. vehicle (-29·9%). Patients treated with tofacitinib showed significant (P tofacitinib. Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD. © 2016 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

  12. Massive IIA string theory and Matrix theory compactification

    International Nuclear Information System (INIS)

    Lowe, David A.; Nastase, Horatiu; Ramgoolam, Sanjaye

    2003-01-01

    We propose a Matrix theory approach to Romans' massive Type IIA supergravity. It is obtained by applying the procedure of Matrix theory compactifications to Hull's proposal of the massive Type IIA string theory as M-theory on a twisted torus. The resulting Matrix theory is a super-Yang-Mills theory on large N three-branes with a space-dependent noncommutativity parameter, which is also independently derived by a T-duality approach. We give evidence showing that the energies of a class of physical excitations of the super-Yang-Mills theory show the correct symmetry expected from massive Type IIA string theory in a lightcone quantization

  13. Myosin IIA participates in docking of Glut4 storage vesicles with the plasma membrane in 3T3-L1 adipocytes

    International Nuclear Information System (INIS)

    Chung, Le Thi Kim; Hosaka, Toshio; Harada, Nagakatsu; Jambaldorj, Bayasgalan; Fukunaga, Keiko; Nishiwaki, Yuka; Teshigawara, Kiyoshi; Sakai, Tohru; Nakaya, Yutaka; Funaki, Makoto

    2010-01-01

    In adipocytes and myocytes, insulin stimulation translocates glucose transporter 4 (Glut4) storage vesicles (GSVs) from their intracellular storage sites to the plasma membrane (PM) where they dock with the PM. Then, Glut4 is inserted into the PM and initiates glucose uptake into these cells. Previous studies using chemical inhibitors demonstrated that myosin II participates in fusion of GSVs and the PM and increase in the intrinsic activity of Glut4. In this study, the effect of myosin IIA on GSV trafficking was examined by knocking down myosin IIA expression. Myosin IIA knockdown decreased both glucose uptake and exposures of myc-tagged Glut4 to the cell surface in insulin-stimulated cells, but did not affect insulin signal transduction. Interestingly, myosin IIA knockdown failed to decrease insulin-dependent trafficking of Glut4 to the PM. Moreover, in myosin IIA knockdown cells, insulin-stimulated binding of GSV SNARE protein, vesicle-associated membrane protein 2 (VAMP2) to PM SNARE protein, syntaxin 4 was inhibited. These data suggest that myosin IIA plays a role in insulin-stimulated docking of GSVs to the PM in 3T3-L1 adipocytes through SNARE complex formation.

  14. Session II-A. Site characterization

    International Nuclear Information System (INIS)

    McIntosh, W.

    1981-01-01

    Section II-A on Site Characterization consists of the following papers which describe the progress made during the past fiscal year toward identifying sites for high-level radioactive waste repositories in deep geologic formations: (1) progress in expanded studies for repository sites; (2) evaluation of geologic and hydrologic characteristics in the Basin and Range Province relative to high-level nuclear waste disposal; (3) siting progress: Permian region; (4) Paradox Basin site exploration: a progress report; (5) progress toward recommending a salt site for an exploratory shaft; (6) status of geologic investigations for nuclear waste disposal at the Nevada Test Site; (7) geohydrologic investigation of the Hanford Site, Washington: basalt waste isolation project. Highlights include: expanding studies in crystalline rocks, both in the Appalachian and Lake Superior regions; laying the ground work with the states in the Basin and Range Province to kick off a joint USGS-state province study; narrowing areas of the Permian and Paradox bedded salt regions to a few promising locations; issuing a Gulf Coast Salt Dome Evaluation report (ONWI-109) for public review and comment; narrowing the Nevada Test Site area and Hanford Site area to locations for detailed site investigations and exploratory shafts; progress in developing the subseabed and space disposals alternatives

  15. Japanese contributions to IAEA INTOR workshop, phase IIA

    International Nuclear Information System (INIS)

    Naruse, Yuji; Hiraoka, Toru; Tanaka, Kichizo

    1982-11-01

    Tritium breeding blanket is incorporated in the INTOR design based on economic and tritium availability considerations. In Phase IIA, critical issues on 'Tritium', which were identified during the Phase I Workshop, were investigated. Main objectives of Phase IIA are to develop a tritium breeding blanket and to evaluate tritium containment. Data base assessments of tritium containment were made. The design of the tritium breeding blanket was also revised. (author)

  16. Down-Regulation of the Na+-Coupled Phosphate Transporter NaPi-IIa by AMP-Activated Protein Kinase

    Directory of Open Access Journals (Sweden)

    Miribane Dërmaku-Sopjani

    2013-11-01

    Full Text Available Background/Aims: The Na+-coupled phosphate transporter NaPi-IIa is the main carrier accomplishing renal tubular phosphate reabsorption. It is driven by the electrochemical Na+ gradient across the apical cell membrane, which is maintained by Na+ extrusion across the basolateral cell membrane through the Na+/K+ ATPase. The operation of NaPi-IIa thus requires energy in order to avoid cellular Na+ accumulation and K+ loss with eventual decrease of cell membrane potential, Cl- entry and cell swelling. Upon energy depletion, early inhibition of Na+-coupled transport processes may delay cell swelling and thus foster cell survival. Energy depletion is sensed by the AMP-activated protein kinase (AMPK, a serine/threonine kinase stimulating several cellular mechanisms increasing energy production and limiting energy utilization. The present study explored whether AMPK influences the activity of NAPi-IIa. Methods: cRNA encoding NAPi-IIa was injected into Xenopus oocytes with or without additional expression of wild-type AMPK (AMPKα1-HA+AMPKβ1-Flag+AMPKγ1-HA, of inactive AMPKαK45R (AMPKα1K45R+AMPKβ1-Flag+AMPKγ1-HA or of constitutively active AMPKγR70Q (AMPKα1-HA+AMPKβ1-Flag+AMPKγ1R70Q. NaPi-IIa activity was estimated from phosphate-induced current in dual electrode voltage clamp experiments. Results: In NaPi-IIa-expressing, but not in water-injected Xenopus oocytes, the addition of phosphate (1 mM to the extracellular bath solution generated a current (Ip, which was significantly decreased by coexpression of wild-type AMPK and of AMPKγR70Q but not of AMPKαK45R. The phosphate-induced current in NaPi-IIa- and AMPK-expressing Xenopus ooocytes was significantly increased by AMPK inhibitor Compound C (20 µM. Kinetic analysis revealed that AMPK significantly decreased the maximal transport rate. Conclusion: The AMP-activated protein kinase AMPK is a powerful regulator of NaPi-IIa and thus of renal tubular phosphate transport.

  17. Effect of tanshinone combined with valsartan therapy on the renal injury and endothelial injury in patients with hypertensive nephropathy

    Directory of Open Access Journals (Sweden)

    Wen-Tao Ma1

    2017-04-01

    Full Text Available Objective: To study the effect of tanshinone combined with valsartan therapy on the renal injury and endothelial injury in patients with hypertensive nephropathy. Methods: A total of 72 patients with hypertensive nephropathy who were treated in our hospital between January 2013 and April 2016 were selected and randomly divided into the control group (n=36 who received conventional treatment + valsartan therapy and the observation group (n=36 who received conventional treatment + tanshinone combined with valsartan therapy, and both therapies lasted for 2 weeks. Before treatment and after 2 weeks of treatment, automatic biochemical analyzer was used to determine the renal function indexes in peripheral blood, enzyme-linked immunosorbent assay (ELISA was used to determine the levels of endothelial injury markers and inflammatory cytokines in peripheral blood, and RIA method was used to determine the serum levels of oxidative stress indexes. Results: Before treatment, the differences in the peripheral blood renal function indexes and endothelial injury markers as well as the serum inflammatory factors and oxidative stress indexes were not statistically significant between two groups of patients. After 2 weeks of treatment, peripheral blood renal function indexes Scr and BUN levels as well as urine mAlb level of observation group were lower than those of control group, and endothelial injury indexes E-selectin and ET levels were lower than those of control group while NOS and CGRP levels were higher than those of control group; serum inflammatory cytokines IL-1, IL-6, CRP and TNF-α levels of observation group were lower than those of control group, and oxidative stress index GSH-Px level was higher than that of control group while MDA and AOPP levels were lower than those of control group. Conclusion: Tanshinone combined with valsartan can reduce the renal injury and endothelial injury in patients with hypertensive nephropathy, and the specific

  18. Sulfotanshinone IIA Sodium Ameliorates Glucose Peritoneal Dialysis Solution-Induced Human Peritoneal Mesothelial Cell Injury via Suppression of ASK1-P38-mediated Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Yao Zhou

    2018-05-01

    Full Text Available Background/Aims: Long-term use of high-glucose peritoneal dialysis solution (PDS induces peritoneal mesothelial cell (PMC injury, peritoneal dysfunction, and peritoneal dialysis (PD failure in patients with end-stage renal disease. How to preserve PMCs in PD is a major challenge for nephrologists worldwide. In this study, we aimed to elucidate the efficacy and mechanisms of sulfotanshinone IIA sodium (Tan IIa in ameliorating high-glucose PDS-induced human PMC injury. Methods: The human PMC line HMrSV5 was incubated with 4.25% PDS in vitro to mimic the high-glucose conditions in PD. Cellular viability was measured by Cell Counting Kit 8. Generation of superoxide and reactive oxygen species (ROS was assessed using a Total ROS/Superoxide Detection Kit. Oxidative modification of protein was evaluated by OxyBlot Protein Oxidation Detection Kit. TUNEL (dT-mediated dUTP nick end labeling assay and DAPI (4,6-diamidino-2-phenylindole staining were used to evaluate apoptosis. Western blot analysis was performed to evaluate the efficacy and mechanisms of Tan IIa. Results: Tan IIa protected PMCs against PDS-induced injury as evidenced by alleviating changes in morphology and loss of cell viability. Consistent with their antioxidant properties, N-acetyl-L-cysteine (NAC and Tan IIa suppressed superoxide and ROS production, protein oxidation, and apoptosis elicited by PDS. Apoptosis signal-regulating kinase 1 (ASK1-p38 signaling was activated by PDS. Both Tan IIa and NAC suppressed ASK1 and p38 phosphorylation elicited by PDS. Moreover, genetic downregulation of ASK1 ameliorated cell injury and inhibited the phosphorylation of p38 and activation of caspase 3. Conclusion: Tan IIa protects PMCs against PDS-induced oxidative injury through suppression of ASK1-p38 signaling.

  19. Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease

    DEFF Research Database (Denmark)

    Pecci, A.; Panza, E.; Pujol-Moix, N.

    2008-01-01

    MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA). All patients present from birth with macrothrombocytopenia, but in infancy or adult life, some of them develop sensorineural deafness...... to 50 unrelated pedigrees. The risk of noncongenital manifestations associated with different genotypes was estimated over time by event-free survival analysis. We demonstrated that all subjects with mutations in the motor domain of NMMHC-IIA present with severe thrombocytopenia and develop nephritis...... and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. We also evaluated the clinical course of patients with mutations in the four most frequently affected residues of NMMHC...

  20. AMPK Signaling Involvement for the Repression of the IL-1β-Induced Group IIA Secretory Phospholipase A2 Expression in VSMCs.

    Directory of Open Access Journals (Sweden)

    Khadija El Hadri

    Full Text Available Secretory Phospholipase A2 of type IIA (sPLA2 IIA plays a crucial role in the production of lipid mediators by amplifying the neointimal inflammatory context of the vascular smooth muscle cells (VSMCs, especially during atherogenesis. Phenformin, a biguanide family member, by its anti-inflammatory properties presents potential for promoting beneficial effects upon vascular cells, however its impact upon the IL-1β-induced sPLA2 gene expression has not been deeply investigated so far. The present study was designed to determine the relationship between phenformin coupling AMP-activated protein kinase (AMPK function and the molecular mechanism by which the sPLA2 IIA expression was modulated in VSMCs. Here we find that 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleotide (AICAR treatment strongly repressed IL-1β-induced sPLA2 expression at least at the transcriptional level. Our study reveals that phenformin elicited a dose-dependent inhibition of the sPLA2 IIA expression and transient overexpression experiments of constitutively active AMPK demonstrate clearly that AMPK signaling is involved in the transcriptional inhibition of sPLA2-IIA gene expression. Furthermore, although the expression of the transcriptional repressor B-cell lymphoma-6 protein (BCL-6 was markedly enhanced by phenformin and AICAR, the repression of sPLA2 gene occurs through a mechanism independent of BCL-6 DNA binding site. In addition we show that activation of AMPK limits IL-1β-induced NF-κB pathway activation. Our results indicate that BCL-6, once activated by AMPK, functions as a competitor of the IL-1β induced NF-κB transcription complex. Our findings provide insights on a new anti-inflammatory pathway linking phenformin, AMPK and molecular control of sPLA2 IIA gene expression in VSMCs.

  1. Compactifications of IIA supergravity on SU(2)-structure manifolds

    Energy Technology Data Exchange (ETDEWEB)

    Spanjaard, B.

    2008-07-15

    In this thesis, we study compactifications of type IIA supergravity on six-dimensional manifolds with an SU(2)-structure. A general study of six-dimensional manifolds with SU(2)-structure shows that IIA supergravity compactified on such a manifold should yield a four-dimensional gauged N=4 supergravity. We explicitly derive the bosonic spectrum, gauge transformations and action for IIA supergravity compactified on two different manifolds with SU(2)-structure, one of which also has an H{sup (3)}{sub 10}-flux, and confirm that the resulting four-dimensional theories are indeed N=4 gauged supergravities. In the second chapter, we study an explicit construction of a set of SU(2)-structure manifolds. This construction involves a Scherk-Schwarz duality twist reduction of the half-maximal six-dimensional supergravity obtained by compactifying IIA supergravity on a K3. This reduction results in a gauged N=4 four-dimensional supergravity, where the gaugings can be divided into three classes of parameters. We relate two of the classes to parameters we found before, and argue that the third class of parameters could be interpreted as a mirror flux. (orig.)

  2. Japanese contributions to IAEA INTOR workshop, phase IIA

    International Nuclear Information System (INIS)

    Fujisawa, Noboru; Sugihara, Masayoshi; Shimada, Michiya; Saito, Seiji.

    1982-11-01

    This report corresponds to Chapter VI of Japanese contribution report to IAEA INTOR workshop, Phase IIA. Special emphasis is placed on pumped limiter analysis for comparative studies between limiter and divertor concepts. Pumping characteristics of divertor/limiter and radiation cooling of diverted plasmas by impurities are also intensively studied. (author)

  3. Japanese contributions to IAEA INTOR workshop, phase IIA

    International Nuclear Information System (INIS)

    Miyamoto, Kenro; Sugihara, Masayoshi; Kimura, Haruyuki

    1982-11-01

    This report corresponds to Chapter V of Japanese contribution report to IAEA INTOR workshop, Phase IIA. Physics studies for radio frequency heating are concentrated on heating to ignition by means of ion cyclotron and lower hybrid ranges of frequencies, and discharge start-up assist and current drive by lower hybrid range. Their system design studies are also performed. (author)

  4. Japanese contributions to IAEA INTOR workshop, phase IIA

    International Nuclear Information System (INIS)

    Tone, Tatsuzo; Shiraishi, Kensuke; Watanabe, Hitoshi

    1982-11-01

    This report describes the engineering testing to be carried out in INTOR, which has been presented for discussions of Group C in the Phase IIA of the INTOR Workshop. Structural material testing, blanket testing and long-term operation are covered. A design of test modules to be installed in the INTOR is proposed. (author)

  5. Superdualities, brane tensions and massive IIA/IIB duality

    International Nuclear Information System (INIS)

    Lavrinenko, I.V.; Lue, H.; Pope, C.N.; Stelle, K.S.

    1999-01-01

    The gauge transformations of p-form fields in supergravity theories acquire a non-commuting character when one introduces potentials both for the theory's original field strengths and for their duals. This has previously been shown in the 'doubled' formalism for maximal supergravities, where a generalised duality relation between original and dual field strengths replaces the equations of motion. In the doubled formalism, the gauge transformations generate a superalgebra, and the corresponding symmetries have accordingly been called 'superdualities'. The corresponding Noether charges form a representation of the cohomology ring on the space-time manifold. In this paper, we show that the gauge symmetry superalgebra implies certain non-trivial relations among the various p-brane tensions, which can straightforwardly be read off from the superalgebra commutation relations. This provides an elegant derivation of the brane-tension relations purely within a given theory, without the need to make use of duality relations between different theories, such as the type IIA/IIB T-duality, although the results are consistent with such dualities. We present the complete set of brane-tension relations in M-theory, in the type IIA and type IIB theories, and in all the lower-dimensional maximal supergravities. We also construct a doubled formalism for massive type IIA supergravity, and this enables us to obtain the brane-tension relations involving the D8-brane, purely within the framework of the massive IIA theory. We also obtain explicit transformations for the nine-dimensional T-duality between the massive type IIA theory and the Scherk-Schwarz reduced type IIB theory

  6. Characteristic of Lamb Sausages Fermented by Indonesian Meat-Derived Probiotic, Lactobacillus plantarum IIA-2C12 and Lactobacillus acidophilus IIA-2B4

    Directory of Open Access Journals (Sweden)

    Noraimah Binti Sulaiman

    2016-08-01

    Full Text Available Probiotic is a group of microorganism, mainly from lactic acid bacteria (LAB, widely used to increase functionality of various foodstuffs, including lamb which was limited by its goaty odor and short life issue. This study aimed to evaluate the characteristic of lamb sausages fermented by either Lactobacillus plantarum IIA-2C12 or L. acidophilus IIA-2B4 isolated from local cattle in Indonesia, and stored for 21 days at low temperature (4oC. Fermented lamb sausages were made with the addition of L. plantarum IIA-2C12 and L. acidophilus IIA-2B4 with three replications. The result showed that pH value, protein, and cholesterol contents of the sausages with addition of L. acidophilus IIA-2B4 were higher (P<0.05 than that of L. plantarum IIA-2C12. Meanwhile, the sausage fermented with L. plantarum IIA-2C12 had higher titratable acid (TA value, texture, and the content of fat, carbohydrate, tyrosine, lysine, myristoleic (C14:1, pentadecanoic (C15:0, heneicosanoic (C21:0 and cis-11-eicosatrienoic (C20:1 as compared to that of  L. acidophilus 2C12-2B4. Final population of LAB in the sausage fermented by L. plantarum IIA-2C12 was also higher than that of L. acidophilus IIA-2B4, yet both can be categorized as a probiotic. The differences between characteristics of the physicochemical traits and microbiological quality of the sausage fermentation associated with the addition of L. plantarum IIA-2C12 or L. acidophilus IIA-2B4. The 21 days of storage at cold temperatures with probiotics addition could extend shelf life and maintain quality of fermented sausage.

  7. Massive deformations of Type IIA theory within double field theory

    Science.gov (United States)

    Çatal-Özer, Aybike

    2018-02-01

    We obtain massive deformations of Type IIA supergravity theory through duality twisted reductions of Double Field Theory (DFT) of massless Type II strings. The mass deformation is induced through the reduction of the DFT of the RR sector. Such reductions are determined by a twist element belonging to Spin+(10, 10), which is the duality group of the DFT of the RR sector. We determine the form of the twists and give particular examples of twists matrices, for which a massive deformation of Type IIA theory can be obtained. In one of the cases, requirement of gauge invariance of the RR sector implies that the dilaton field must pick up a linear dependence on one of the dual coordinates. In another case, the choice of the twist matrix violates the weak and the strong constraints explicitly in the internal doubled space.

  8. Development of Class IIa Bacteriocins as Therapeutic Agents

    Directory of Open Access Journals (Sweden)

    Christopher T. Lohans

    2012-01-01

    Full Text Available Class IIa bacteriocins have been primarily explored as natural food preservatives, but there is much interest in exploring the application of these peptides as therapeutic antimicrobial agents. Bacteriocins of this class possess antimicrobial activity against several important human pathogens. Therefore, the therapeutic development of these bacteriocins will be reviewed. Biological and chemical modifications to both stabilize and increase the potency of bacteriocins are discussed, as well as the optimization of their production and purification. The suitability of bacteriocins as pharmaceuticals is explored through determinations of cytotoxicity, effects on the natural microbiota, and in vivo efficacy in mouse models. Recent results suggest that class IIa bacteriocins show promise as a class of therapeutic agents.

  9. Transcriptional Profiles of SmWRKY Family Genes and Their Putative Roles in the Biosynthesis of Tanshinone and Phenolic Acids in Salvia miltiorrhiza

    Directory of Open Access Journals (Sweden)

    Haizheng Yu

    2018-05-01

    Full Text Available Salvia miltiorrhiza Bunge is a Chinese traditional herb for treating cardiovascular and cerebrovascular diseases, and tanshinones and phenolic acids are the dominated medicinal and secondary metabolism constituents of this plant. WRKY transcription factors (TFs can function as regulators of secondary metabolites biosynthesis in many plants. However, studies on the WRKY that regulate tanshinones and phenolics biosynthesis are limited. In this study, 69 SmWRKYs were identified in the transcriptome database of S. miltiorrhiza, and phylogenetic analysis indicated that some SmWRKYs had closer genetic relationships with other plant WRKYs, which were involved in secondary metabolism. Hairy roots of S. miltiorrhiza were treated by methyl jasmonate (MeJA to detect the dynamic change trend of SmWRKY, biosynthetic genes, and medicinal ingredients accumulation. Base on those date, a correlation analysis using Pearson’s correlation coefficient was performed to construct gene-to-metabolite network and identify 9 SmWRKYs (SmWRKY1, 7, 19, 29, 45, 52, 56, 58, and 68, which were most likely to be involved in tanshinones and phenolic acids biosynthesis. Taken together, this study has provided a significant resource that could be used for further research on SmWRKY in S. miltiorrhiza and especially could be used as a cue for further investigating SmWRKY functions in secondary metabolite accumulation.

  10. Development of Class IIa Bacteriocins as Therapeutic Agents

    OpenAIRE

    Christopher T. Lohans; John C. Vederas

    2012-01-01

    Class IIa bacteriocins have been primarily explored as natural food preservatives, but there is much interest in exploring the application of these peptides as therapeutic antimicrobial agents. Bacteriocins of this class possess antimicrobial activity against several important human pathogens. Therefore, the therapeutic development of these bacteriocins will be reviewed. Biological and chemical modifications to both stabilize and increase the potency of bacteriocins are discussed, as well as ...

  11. Eupafolin inhibits PGE2 production and COX2 expression in LPS-stimulated human dermal fibroblasts by blocking JNK/AP-1 and Nox2/p47{sup phox} pathway

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, Ming-Horng [Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan (China); Lin, Zih-Chan [Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Liang, Chan-Jung [Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Yen, Feng-Lin [Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Institute of Biomedical Sciences, Sun Yat-Sen University, 70 Lienhai Rd., Kaohsiung, Taiwan (China); Chiang, Yao-Chang [Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung, Taiwan (China); China Medical University, Taichung, Taiwan (China); Lee, Chiang-Wen, E-mail: cwlee@gw.cgust.edu.tw [Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan (China); Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi, Taiwan (China); Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan (China)

    2014-09-01

    Eupafolin, a major active component found in the methanol extracts of Phyla nodiflora, has been used to treat inflammation of skin. We examined its effects on cyclooxygenase-2 (COX-2) expression in LPS-treated human dermal fibroblasts. Lipopolysaccharide (LPS) significantly increased prostaglandin-E2 (PGE2) production associated with increased COX-2 expression in Hs68 cells. This effect was blocked by eupafolin, TLR-4 antibody, antioxidants (APO and NAC), as well as inhibitors, including U0126 (ERK1/2), SB202190 (p38), SP600125 (JNK1/2), and Tanshinone IIA (AP-1). In gene regulation level, qPCR and promoter assays revealed that COX-2 expression was attenuated by eupafolin. In addition, eupafolin also ameliorated LPS-induced p47 phox activation and decreased reactive oxygen species (ROS) generation and NADPH oxidase (Nox) activity. Moreover, pretreatment with eupafolin and APO led to reduced LPS-induced phosphorylation of ERK1/2, JNK, and p38. Further, eupafolin attenuated LPS-induced increase in AP-1 transcription factor binding activity as well as the increase in the phosphorylation of c-Jun and c-Fos. In vivo studies have shown that in dermal fibroblasts of LPS treated mice, eupafolin exerted anti-inflammation effects by decreasing COX-2 protein levels. Our results reveal a novel mechanism for anti-inflammatory and anti-oxidative effects of eupafolin that involved inhibition of LPS-induced ROS generation, suppression of MAPK phosphorylation, diminished DNA binding activity of AP-1 and attenuated COX-2 expression leading to reduced production of prostaglandin E2 (PGE2). Our results demonstrate that eupafolin may be used to treat inflammatory responses associated with dermatologic diseases. - Highlights: • LPS activates the Nox2/p47{sup phox}/JNK/AP-1 and induces COX2 expression in Hs68 cells. • Eupafolin inhibits LPS-induced COX-2 expression via Nox2/p47{sup phox} inhibition. • Eupafolin may be used in the treatment of skin diseases involving inflammation.

  12. Eupafolin inhibits PGE2 production and COX2 expression in LPS-stimulated human dermal fibroblasts by blocking JNK/AP-1 and Nox2/p47phox pathway

    International Nuclear Information System (INIS)

    Tsai, Ming-Horng; Lin, Zih-Chan; Liang, Chan-Jung; Yen, Feng-Lin; Chiang, Yao-Chang; Lee, Chiang-Wen

    2014-01-01

    Eupafolin, a major active component found in the methanol extracts of Phyla nodiflora, has been used to treat inflammation of skin. We examined its effects on cyclooxygenase-2 (COX-2) expression in LPS-treated human dermal fibroblasts. Lipopolysaccharide (LPS) significantly increased prostaglandin-E2 (PGE2) production associated with increased COX-2 expression in Hs68 cells. This effect was blocked by eupafolin, TLR-4 antibody, antioxidants (APO and NAC), as well as inhibitors, including U0126 (ERK1/2), SB202190 (p38), SP600125 (JNK1/2), and Tanshinone IIA (AP-1). In gene regulation level, qPCR and promoter assays revealed that COX-2 expression was attenuated by eupafolin. In addition, eupafolin also ameliorated LPS-induced p47 phox activation and decreased reactive oxygen species (ROS) generation and NADPH oxidase (Nox) activity. Moreover, pretreatment with eupafolin and APO led to reduced LPS-induced phosphorylation of ERK1/2, JNK, and p38. Further, eupafolin attenuated LPS-induced increase in AP-1 transcription factor binding activity as well as the increase in the phosphorylation of c-Jun and c-Fos. In vivo studies have shown that in dermal fibroblasts of LPS treated mice, eupafolin exerted anti-inflammation effects by decreasing COX-2 protein levels. Our results reveal a novel mechanism for anti-inflammatory and anti-oxidative effects of eupafolin that involved inhibition of LPS-induced ROS generation, suppression of MAPK phosphorylation, diminished DNA binding activity of AP-1 and attenuated COX-2 expression leading to reduced production of prostaglandin E2 (PGE2). Our results demonstrate that eupafolin may be used to treat inflammatory responses associated with dermatologic diseases. - Highlights: • LPS activates the Nox2/p47 phox /JNK/AP-1 and induces COX2 expression in Hs68 cells. • Eupafolin inhibits LPS-induced COX-2 expression via Nox2/p47 phox inhibition. • Eupafolin may be used in the treatment of skin diseases involving inflammation

  13. de Sitter space from dilatino condensates in massive IIA supergravity

    Science.gov (United States)

    Souères, Bertrand; Tsimpis, Dimitrios

    2018-02-01

    We use the superspace formulation of (massive) IIA supergravity to obtain the explicit form of the dilatino terms, and we find that the quartic-dilatino term is positive. The theory admits a ten-dimensional de Sitter solution, obtained by assuming a nonvanishing quartic-dilatino condensate which generates a positive cosmological constant. Moreover, in the presence of dilatino condensates, the theory admits formal four-dimensional de Sitter solutions of the form d S4×M6, where M6 is a six-dimensional Kähler-Einstein manifold of positive scalar curvature.

  14. Is chloroplastic class IIA aldolase a marine enzyme?

    Science.gov (United States)

    Miyasaka, Hitoshi; Ogata, Takeru; Tanaka, Satoshi; Ohama, Takeshi; Kano, Sanae; Kazuhiro, Fujiwara; Hayashi, Shuhei; Yamamoto, Shinjiro; Takahashi, Hiro; Matsuura, Hideyuki; Hirata, Kazumasa

    2016-01-01

    Expressed sequence tag analyses revealed that two marine Chlorophyceae green algae, Chlamydomonas sp. W80 and Chlamydomonas sp. HS5, contain genes coding for chloroplastic class IIA aldolase (fructose-1, 6-bisphosphate aldolase: FBA). These genes show robust monophyly with those of the marine Prasinophyceae algae genera Micromonas, Ostreococcus and Bathycoccus, indicating that the acquisition of this gene through horizontal gene transfer by an ancestor of the green algal lineage occurred prior to the divergence of the core chlorophytes (Chlorophyceae and Trebouxiophyceae) and the prasinophytes. The absence of this gene in some freshwater chlorophytes, such as Chlamydomonas reinhardtii, Volvox carteri, Chlorella vulgaris, Chlorella variabilis and Coccomyxa subellipsoidea, can therefore be explained by the loss of this gene somewhere in the evolutionary process. Our survey on the distribution of this gene in genomic and transcriptome databases suggests that this gene occurs almost exclusively in marine algae, with a few exceptions, and as such, we propose that chloroplastic class IIA FBA is a marine environment-adapted enzyme. This hypothesis was also experimentally tested using Chlamydomonas W80, for which we found that the transcript levels of this gene to be significantly lower under low-salt (that is, simulated terrestrial) conditions. Expression analyses of transcriptome data for two algae, Prymnesium parvum and Emiliania huxleyi, taken from the Sequence Read Archive database also indicated that the expression of this gene under terrestrial conditions (low NaCl and low sulfate) is significantly downregulated. Thus, these experimental and transcriptome data provide support for our hypothesis. PMID:27058504

  15. Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A2, lipoxygenase and cyclooxygenase.

    Science.gov (United States)

    Joshi, Vikram; Umashankara, M; Ramakrishnan, Chandrasekaran; Nanjaraj Urs, Ankanahalli N; Suvilesh, Kanve Nagaraj; Velmurugan, Devadasan; Rangappa, Kanchugarakoppal S; Vishwanath, Bannikuppe Sannanaik

    2016-05-15

    Overproduction of arachidonic acid (AA) mediated by secretory phospholipase A2 group IIA (sPLA2IIA) is a hallmark of many inflammatory disorders. AA is subsequently converted into pro-inflammatory eicosanoids through 5-lipoxygenase (5-LOX) and cyclooxygenase-1/2 (COX-1/2) activities. Hence, inhibition of sPLA2IIA, 5-LOX and COX-1/2 activities is critical in regulating inflammation. We have previously reported unconjugated bilirubin (UCB), an endogenous antioxidant, as sPLA2IIA inhibitor. However, lipophilic UCB gets conjugated in liver with glucuronic acid into hydrophilic conjugated bilirubin (CB). Since hydrophobicity is pre-requisite for sPLA2IIA inhibition, conjugation reduces the efficacy of UCB. In this regard, UCB was chemically modified and derivatives were evaluated for sPLA2IIA, 5-LOX and COX-1/2 inhibition. Among the derivatives, BD1 (dimethyl ester of bilirubin) exhibited ∼ 3 fold greater inhibitory potency towards sPLA2IIA compared to UCB. Both UCB and BD1 inhibited human 5-LOX and COX-2 activities; however only BD1 inhibited AA induced platelet aggregation. Molecular docking studies demonstrated BD1 as better inhibitor of aforesaid enzymes than UCB and other endogenous antioxidants. These data suggest that BD1 exhibits strong anti-inflammatory activity through inhibition of AA cascade enzymes which is of great therapeutic importance. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study

    NARCIS (Netherlands)

    Holmes, Michael V.; Simon, Tabassome; Exeter, Holly J.; Folkersen, Lasse; Asselbergs, Folkert W.; Guardiola, Montse; Cooper, Jackie A.; Palmen, Jutta; Hubacek, Jaroslav A.; Carruthers, Kathryn F.; Horne, Benjamin D.; Brunisholz, Kimberly D.; Mega, Jessica L.; van Iperen, Erik P. A.; Li, Mingyao; Leusink, Maarten; Trompet, Stella; Verschuren, Jeffrey J. W.; Hovingh, G. Kees; Dehghan, Abbas; Nelson, Christopher P.; Kotti, Salma; Danchin, Nicolas; Scholz, Markus; Haase, Christiane L.; Rothenbacher, Dietrich; Swerdlow, Daniel I.; Kuchenbaecker, Karoline B.; Staines-Urias, Eleonora; Goel, Anuj; van 't Hooft, Ferdinand; Gertow, Karl; de Faire, Ulf; Panayiotou, Andrie G.; Tremoli, Elena; Baldassarre, Damiano; Veglia, Fabrizio; Holdt, Lesca M.; Beutner, Frank; Gansevoort, Ron T.; Navis, Gerjan J.; Mateo Leach, Irene; Breitling, Lutz P.; Brenner, Hermann; Thiery, Joachim; Dallmeier, Dhayana; Franco-Cereceda, Anders; Boer, Jolanda M. A.; Stephens, Jeffrey W.; Hofker, Marten H.; Tedgui, Alain; Hofman, Albert; Uitterlinden, André G.; Adamkova, Vera; Pitha, Jan; Onland-Moret, N. Charlotte; Cramer, Maarten J.; Nathoe, Hendrik M.; Spiering, Wilko; Klungel, Olaf H.; Kumari, Meena; Whincup, Peter H.; Morrow, David A.; Braund, Peter S.; Hall, Alistair S.; Olsson, Anders G.; Doevendans, Pieter A.; Trip, Mieke D.; Tobin, Martin D.; Hamsten, Anders; Watkins, Hugh; Koenig, Wolfgang; Nicolaides, Andrew N.; Teupser, Daniel; Day, Ian N. M.; Carlquist, John F.; Gaunt, Tom R.; Ford, Ian; Sattar, Naveed; Tsimikas, Sotirios; Schwartz, Gregory G.; Lawlor, Debbie A.; Morris, Richard W.; Sandhu, Manjinder S.; Poledne, Rudolf; Maitland-van der Zee, Anke H.; Khaw, Kay-Tee; Keating, Brendan J.; van der Harst, Pim; Price, Jackie F.; Mehta, Shamir R.; Yusuf, Salim; Witteman, Jaqueline C. M.; Franco, Oscar H.; Jukema, J. Wouter; de Knijff, Peter; Tybjaerg-Hansen, Anne; Rader, Daniel J.; Farrall, Martin; Samani, Nilesh J.; Kivimaki, Mika; Fox, Keith A. A.; Humphries, Steve E.; Anderson, Jeffrey L.; Boekholdt, S. Matthijs; Palmer, Tom M.; Eriksson, Per; Paré, Guillaume; Hingorani, Aroon D.; Sabatine, Marc S.; Mallat, Ziad; Casas, Juan P.; Talmud, Philippa J.

    2013-01-01

    This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is

  17. Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation

    Directory of Open Access Journals (Sweden)

    Vidhi Gaur

    2016-09-01

    Full Text Available Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.

  18. Value of urinary topoisomerase-IIA cell-free DNA for diagnosis of bladder cancer.

    Science.gov (United States)

    Kim, Ye-Hwan; Yan, Chunri; Lee, Il-Seok; Piao, Xuan-Mei; Byun, Young Joon; Jeong, Pildu; Kim, Won Tae; Yun, Seok-Joong; Kim, Wun-Jae

    2016-03-01

    Topoisomerase-II alpha (TopoIIA ), a DNA gyrase isoform that plays an important role in the cell cycle, is present in normal tissues and various human cancers, and can show altered expression in both. The aim of the current study was to examine the value of urinary TopoIIA cell-free DNA as a noninvasive diagnosis of bladder cancer (BC). Two patient cohorts were examined. Cohort 1 (73 BC patients and seven controls) provided bladder tissue samples, whereas cohort 2 (83 BC patients, 54 nonmalignant hematuric patients, and 61 normal controls) provided urine samples. Real-time quantitative polymerase chain reaction was used to measure expression of TopoIIA mRNA in tissues and TopoIIA cell-free DNA in urine samples. The results showed that expression of TopoIIA mRNA in BC tissues was significantly higher than that in noncancer control tissues (pbladder cancer (MIBC) when compared with nonmuscle invasive bladder cancer (NMIBC) (p=0.002). Receiver operating characteristics (ROC) curve analysis was performed to examine the sensitivity/specificity of urinary TopoIIA cell-free DNA for diagnosing BC, NMIBC, and MIBC. The areas under the ROC curve for BC, NMIBC, and MIBC were 0.741, 0.701, and 0.838, respectively. In summary, the results of this study provide evidence that cell-free TopoIIA DNA may be a potential biomarker for BC.

  19. Overexpressed human metallothionein IIA gene protects Chinese hamster ovary cells from killing by alkylating agents.

    OpenAIRE

    Kaina, B; Lohrer, H; Karin, M; Herrlich, P

    1990-01-01

    Experiments were designed to detect survival advantages that cells gain by overexpressing metallothionein (MT). Chinese hamster ovary K1-2 cells and an x-ray-sensitive derivative were transfected with a bovine papillomavirus (BPV)-linked construct carrying the human metallothionein IIA (hMT-IIA) gene. Transfectants survived 40-fold higher levels of cadmium chloride, harbored at least 30 copies of hMT-IIA, and contained 25- to 166-fold more MT than the parent cells. Even under conditions of re...

  20. Flipped and unflipped SU(5) as type IIA flux vacua

    Energy Technology Data Exchange (ETDEWEB)

    Chen Chingming [George P. and Cynthia W. Mitchell Institute for Fundamental Physics, Texas A and M University, College Station, TX 77843 (United States); Li Tianjun [Department of Physics and Astronomy, Rutgers University, Piscataway, NJ 08854 (United States) and Institute of Theoretical Physics, Chinese Academy of Sciences, Beijing 100080 (China)]. E-mail: tjli@physics.rutgers.edu; Nanopoulos, Dimitri V. [George P. and Cynthia W. Mitchell Institute for Fundamental Physics, Texas A and M University, College Station, TX 77843 (United States); Astroparticle Physics Group, Houston Advanced Research Center (HARC), Mitchell Campus, Woodlands, TX 77381 (United States); Academy of Athens, Division of Natural Sciences, 28 Panepistimiou Avenue, Athens 10679 (Greece)

    2006-09-04

    On type IIA orientifolds with flux compactifications in supersymmetric AdS vacua, we for the first time construct SU(5) models with three anti-symmetric 10 representations and without symmetric 15 representations. We show that all the pairs of the anti-fundamental 5-bar and fundamental 5 representations can obtain GUT/string-scale vector-like masses after the additional gauge symmetry breaking via supersymmetry preserving Higgs mechanism. Then we have exact three 5-bar , and no other chiral exotic particles that are charged under SU(5) due to the non-Abelian anomaly free condition. Moreover, we can break the SU(5) gauge symmetry down to the SM gauge symmetry via D6-brane splitting, and solve the doublet-triplet splitting problem. Assuming that the extra one (or several) pair(s) of Higgs doublets and adjoint particles obtain GUT/string-scale masses via high-dimensional operators, we only have the MSSM in the observable sector below the GUT scale. Then the observed low energy gauge couplings can be generated via RGE running if we choose the suitable grand unified gauge coupling by adjusting the string scale. Furthermore, we construct the first flipped SU(5) model with exact three 10, and the first flipped SU(5) model in which all the Yukawa couplings are allowed by the global U(1) symmetries.

  1. Type IIA flux compactifications. Vacua, effective theories and cosmological challenges

    International Nuclear Information System (INIS)

    Koers, Simon

    2009-01-01

    In this thesis, we studied a number of type IIA SU(3)-structure compactifications with 06-planes on nilmanifolds and cosets, which are tractable enough to allow for an explicit derivation of the low energy effective theory. In particular we calculated the mass spectrum of the light scalar modes, using N = 1 supergravity techniques. For the torus and the Iwasawa solution, we have also performed an explicit Kaluza-Klein reduction, which led to the same result. For the nilmanifold examples we have found that there are always three unstabilized moduli corresponding to axions in the RR sector. On the other hand, in the coset models, except for SU(2) x SU(2), all moduli are stabilized. We discussed the Kaluza-Klein decoupling for the supersymmetric AdS vacua and found that it requires going to the Nearly-Calabi Yau limited. We searched for non-trivial de Sitter minima in the original flux potential away from the AdS vacuum. Finally, in chapter 7, we focused on a family of three coset spaces and constructed non-supersymmetric vacua on them. (orig.)

  2. Type IIA orientifolds on SU(2)-structure manifolds

    Energy Technology Data Exchange (ETDEWEB)

    Danckaert, Thomas

    2010-11-15

    We investigate the possible supersymmetry-preserving orientifold projections of type IIA string theory on a six-dimensional background with SU(2)-structure. We find two categories of projections which preserve half of the low-energy supersymmetry, reducing the effective theory from an N=4 supergravity theory, to an N=2 supergravity. For these two cases, we impose the projection on the low-energy spectrum and reduce the effective N=4 supergravity action accordingly. We can identify the resulting gauged N=2 supergravity theory and bring the action into canonical form. We compute the scalar moduli spaces and characterize the gauged symmetries in terms of the geometry of these moduli spaces. Due to their origin in N=4 supergravity, which is a highly constrained theory, the moduli spaces are of a very simple form. We find that, for suitable background manifolds, isometries in all scalar sectors can become gauged. The obtained gaugings share many features with those of N=2 supergravities obtained previously from other G-structure compactifications. (orig.)

  3. Point of care testing of phospholipase A2 group IIA for serological diagnosis of rheumatoid arthritis

    Science.gov (United States)

    Liu, Nathan J.; Chapman, Robert; Lin, Yiyang; Mmesi, Jonas; Bentham, Andrew; Tyreman, Matthew; Abraham, Sonya; Stevens, Molly M.

    2016-02-01

    Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care.Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08423g

  4. Design of group IIA secreted/synovial phospholipase A(2 inhibitors: an oxadiazolone derivative suppresses chondrocyte prostaglandin E(2 secretion.

    Directory of Open Access Journals (Sweden)

    Jean-Edouard Ombetta

    Full Text Available Group IIA secreted/synovial phospholipase A(2 (GIIAPLA(2 is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E(2 (PGE(2, the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-ylpentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA(2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA(2, along with their chemical synthesis and results from PLA(2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA(2 affinities than did C1, and such predictions were confirmed by in vitro PLA(2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA(2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1beta-stimulated PGE(2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints.

  5. Increased expression and activity of group IIA and X secretory phospholipase A2 in peritumoral versus central colon carcinoma tissue

    DEFF Research Database (Denmark)

    Tribler, Line; Jensen, Lotte T.; Jørgensen, Kent

    2007-01-01

    Secretory phospholipase A2 (sPLA2) type IIA and X was analyzed in tumors from 22 patients with colon adenocarcinomas in order to determine the involvement and activity of sPLA2 in colon cancer. Evaluation of immunoreactive sPLA2 IIA by Western blotting showed a significantly higher level...... in the periphery of the tumors, compared to central tumor regions. Increased levels of sPLA2 IIA protein correlated with a two-fold increase in sPLA2 enzymatic activity in the peripheral regions compared to central regions. Nineteen out of 22 tumors showed high levels of sPLA2 IIA, whereas 7 out of the 22 tumors...... showed sPLA2 type X. These data demonstrate that both sPLA2 type IIA and X are present in human colon cancer and suggest a role for sPLA2 in colon cancer tumor immunology and tumorigenesis....

  6. Septin 7 reduces nonmuscle myosin IIA activity in the SNAP23 complex and hinders GLUT4 storage vesicle docking and fusion

    Energy Technology Data Exchange (ETDEWEB)

    Wasik, Anita A.; Dumont, Vincent [Department of Pathology, University of Helsinki, 00014 Helsinki (Finland); Tienari, Jukka [Department of Pathology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, 05850 Hyvinkää (Finland); Nyman, Tuula A. [Institute of Biotechnology, University of Helsinki, 00014 Helsinki (Finland); Fogarty, Christopher L.; Forsblom, Carol; Lehto, Markku [Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki (Finland); Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, 000290 Helsinki (Finland); Diabetes& Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki (Finland); Lehtonen, Eero [Department of Pathology, University of Helsinki, 00014 Helsinki (Finland); Laboratory Animal Centre, University of Helsinki, 00014 Helsinki (Finland); Groop, Per-Henrik [Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki (Finland); Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, 000290 Helsinki (Finland); Diabetes& Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki (Finland); Baker IDI Heart & Diabetes Institute, 3004 Melbourne (Australia); Lehtonen, Sanna, E-mail: sanna.h.lehtonen@helsinki.fi [Department of Pathology, University of Helsinki, 00014 Helsinki (Finland)

    2017-01-15

    Glomerular epithelial cells, podocytes, are insulin responsive and can develop insulin resistance. Here, we demonstrate that the small GTPase septin 7 forms a complex with nonmuscle myosin heavy chain IIA (NMHC-IIA; encoded by MYH9), a component of the nonmuscle myosin IIA (NM-IIA) hexameric complex. We observed that knockdown of NMHC-IIA decreases insulin-stimulated glucose uptake into podocytes. Both septin 7 and NM-IIA associate with SNAP23, a SNARE protein involved in GLUT4 storage vesicle (GSV) docking and fusion with the plasma membrane. We observed that insulin decreases the level of septin 7 and increases the activity of NM-IIA in the SNAP23 complex, as visualized by increased phosphorylation of myosin regulatory light chain. Also knockdown of septin 7 increases the activity of NM-IIA in the complex. The activity of NM-IIA is increased in diabetic rat glomeruli and cultured human podocytes exposed to macroalbuminuric sera from patients with type 1 diabetes. Collectively, the data suggest that the activity of NM-IIA in the SNAP23 complex plays a key role in insulin-stimulated glucose uptake into podocytes. Furthermore, we observed that septin 7 reduces the activity of NM-IIA in the SNAP23 complex and thereby hinders GSV docking and fusion with the plasma membrane. - Highlights: • Septin 7, nonmuscle myosin heavy chain IIA (NMHC-IIA) and SNAP23 form a complex. • Knockdown of septin 7 increases NM-IIA activity in the SNAP23 complex. • Insulin decreases septin 7 level and increases NM-IIA activity in the SNAP23 complex. • Septin 7 hinders GSV docking/fusion by reducing NM-IIA activity in the SNAP23 complex.

  7. Septin 7 reduces nonmuscle myosin IIA activity in the SNAP23 complex and hinders GLUT4 storage vesicle docking and fusion

    International Nuclear Information System (INIS)

    Wasik, Anita A.; Dumont, Vincent; Tienari, Jukka; Nyman, Tuula A.; Fogarty, Christopher L.; Forsblom, Carol; Lehto, Markku; Lehtonen, Eero; Groop, Per-Henrik; Lehtonen, Sanna

    2017-01-01

    Glomerular epithelial cells, podocytes, are insulin responsive and can develop insulin resistance. Here, we demonstrate that the small GTPase septin 7 forms a complex with nonmuscle myosin heavy chain IIA (NMHC-IIA; encoded by MYH9), a component of the nonmuscle myosin IIA (NM-IIA) hexameric complex. We observed that knockdown of NMHC-IIA decreases insulin-stimulated glucose uptake into podocytes. Both septin 7 and NM-IIA associate with SNAP23, a SNARE protein involved in GLUT4 storage vesicle (GSV) docking and fusion with the plasma membrane. We observed that insulin decreases the level of septin 7 and increases the activity of NM-IIA in the SNAP23 complex, as visualized by increased phosphorylation of myosin regulatory light chain. Also knockdown of septin 7 increases the activity of NM-IIA in the complex. The activity of NM-IIA is increased in diabetic rat glomeruli and cultured human podocytes exposed to macroalbuminuric sera from patients with type 1 diabetes. Collectively, the data suggest that the activity of NM-IIA in the SNAP23 complex plays a key role in insulin-stimulated glucose uptake into podocytes. Furthermore, we observed that septin 7 reduces the activity of NM-IIA in the SNAP23 complex and thereby hinders GSV docking and fusion with the plasma membrane. - Highlights: • Septin 7, nonmuscle myosin heavy chain IIA (NMHC-IIA) and SNAP23 form a complex. • Knockdown of septin 7 increases NM-IIA activity in the SNAP23 complex. • Insulin decreases septin 7 level and increases NM-IIA activity in the SNAP23 complex. • Septin 7 hinders GSV docking/fusion by reducing NM-IIA activity in the SNAP23 complex.

  8. Overexpressed human metallothionein IIA gene protects Chinese hamster ovary cells from killing by alkylating agents

    International Nuclear Information System (INIS)

    Kaina, B.; Lohrer, H.; Karin, M.; Herrlich, P.

    1990-01-01

    Experiments were designed to detect survival advantages that cells gain by overexpressing metallothionein (MT). Chinese hamster ovary K1-2 cells and an x-ray-sensitive derivative were transfected with a bovine papillomavirus (BPV)-linked construct carrying the human metallothionein IIA (hMT-IIA) gene. Transfectants survived 40-fold higher levels of cadmium chloride, harbored at least 30 copies of hMT-IIA, and contained 25- to 166-fold more MT than the parent cells. Even under conditions of reduced glutathione synthesis, the transfectants were not more resistant to the lethal effects of ionizing radiation and bleomycin than the parent cells. Thus free radicals generated by these agents cannot be scavenged efficiently by MT in vivo. The hMT-IIA transfectants, however, but not control transfectants harboring a BPV-MT promoter-neo construct, tolerated significantly higher doses of the alkylating agents N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine. Resistance and MT overexpression occurred irrespective of selection and cultivation in cadmium and zinc. There was no increase in resistance to methyl methanesulfonate and N-hydroxyethyl-N-chloroethylnitrosourea. MT did not affect the degree of overall DNA methylation after N-methyl-N-nitrosourea treatment nor the level of O6-methylguanine-DNA methyltransferase. The results suggest that MT participates as a cofactor or regulatory element in repair or tolerance of toxic alkylation lesions

  9. Hydroxyurea with Radiation Therapy of the Carcinoma of the Cervix IIA, IIB

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Hee; Youn, Seon Min; Kim, Ok Bae [Keimyung University College of Medicine, Taegu (Korea, Republic of)

    1995-12-15

    Purpose : To evaluate the efficacy of hydroxyurea with radiation in carcinoma of the cervix, huge exophytic or endophytic stage IIa and Iib. Materials and Methods : Sixty four patients with carcinoma of the cervix stage IIA(29 patients) with exophytic({>=}3cm in diameter) or huge endophytic mass and IIB(35 patients) treated with radiation and hydroxyurea at the Department of Radiation Oncology, Dongsan Hospital, Keimyung University, School of Medicine from Aug, 1989 to May, 1991. The maximum and mean follow up durations were 68 and 57 months respectively. The radiation therapy consisted of external irradiation to the whole pelvis(3600-5400cGy) shield (4X10 cm), and combined with intracavitary irradiation (3000-3500cGy to point A). Hydroxyurea was to be taken in a single oral dose of 1.0gm/day during radiation therapy. Results : The control rate was 89.1%. The actuarial overall five year survival rate was 78.8% for stage IIA and 72.8% for stage IIB. The overall recurrence rate was 25%(16/64). Twenty-three percent of the patients developed or greater thrombocytopenia. Grade 3 or greater GI, GU complication and anemia were not noted. There was no treatment related death noted. Conclusion : We considered that hydroxyurea and radiation therapy may improve survival rate in huge exophytic and endophytic stage IIa cervical carcinoma with acceptible morbidity.

  10. Hydroxyurea with Radiation Therapy of the Carcinoma of the Cervix IIA, IIB

    International Nuclear Information System (INIS)

    Kim, Jin Hee; Youn, Seon Min; Kim, Ok Bae

    1995-01-01

    Purpose : To evaluate the efficacy of hydroxyurea with radiation in carcinoma of the cervix, huge exophytic or endophytic stage IIa and Iib. Materials and Methods : Sixty four patients with carcinoma of the cervix stage IIA(29 patients) with exophytic(≥3cm in diameter) or huge endophytic mass and IIB(35 patients) treated with radiation and hydroxyurea at the Department of Radiation Oncology, Dongsan Hospital, Keimyung University, School of Medicine from Aug, 1989 to May, 1991. The maximum and mean follow up durations were 68 and 57 months respectively. The radiation therapy consisted of external irradiation to the whole pelvis(3600-5400cGy) shield (4X10 cm), and combined with intracavitary irradiation (3000-3500cGy to point A). Hydroxyurea was to be taken in a single oral dose of 1.0gm/day during radiation therapy. Results : The control rate was 89.1%. The actuarial overall five year survival rate was 78.8% for stage IIA and 72.8% for stage IIB. The overall recurrence rate was 25%(16/64). Twenty-three percent of the patients developed or greater thrombocytopenia. Grade 3 or greater GI, GU complication and anemia were not noted. There was no treatment related death noted. Conclusion : We considered that hydroxyurea and radiation therapy may improve survival rate in huge exophytic and endophytic stage IIa cervical carcinoma with acceptible morbidity

  11. Overexpressed human metallothionein IIA gene protects Chinese hamster ovary cells from killing by alkylating agents

    Energy Technology Data Exchange (ETDEWEB)

    Kaina, B.; Lohrer, H.; Karin, M.; Herrlich, P. (Kernforschungszentrum Karlsruhe, Karlsruhe (Germany, F.R.))

    1990-04-01

    Experiments were designed to detect survival advantages that cells gain by overexpressing metallothionein (MT). Chinese hamster ovary K1-2 cells and an x-ray-sensitive derivative were transfected with a bovine papillomavirus (BPV)-linked construct carrying the human metallothionein IIA (hMT-IIA) gene. Transfectants survived 40-fold higher levels of cadmium chloride, harbored at least 30 copies of hMT-IIA, and contained 25- to 166-fold more MT than the parent cells. Even under conditions of reduced glutathione synthesis, the transfectants were not more resistant to the lethal effects of ionizing radiation and bleomycin than the parent cells. Thus free radicals generated by these agents cannot be scavenged efficiently by MT in vivo. The hMT-IIA transfectants, however, but not control transfectants harboring a BPV-MT promoter-neo construct, tolerated significantly higher doses of the alkylating agents N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine. Resistance and MT overexpression occurred irrespective of selection and cultivation in cadmium and zinc. There was no increase in resistance to methyl methanesulfonate and N-hydroxyethyl-N-chloroethylnitrosourea. MT did not affect the degree of overall DNA methylation after N-methyl-N-nitrosourea treatment nor the level of O6-methylguanine-DNA methyltransferase. The results suggest that MT participates as a cofactor or regulatory element in repair or tolerance of toxic alkylation lesions.

  12. Overexpressed human metallothionein IIA gene protects Chinese hamster ovary cells from killing by alkylating agents.

    Science.gov (United States)

    Kaina, B; Lohrer, H; Karin, M; Herrlich, P

    1990-01-01

    Experiments were designed to detect survival advantages that cells gain by overexpressing metallothionein (MT). Chinese hamster ovary K1-2 cells and an x-ray-sensitive derivative were transfected with a bovine papillomavirus (BPV)-linked construct carrying the human metallothionein IIA (hMT-IIA) gene. Transfectants survived 40-fold higher levels of cadmium chloride, harbored at least 30 copies of hMT-IIA, and contained 25- to 166-fold more MT than the parent cells. Even under conditions of reduced glutathione synthesis, the transfectants were not more resistant to the lethal effects of ionizing radiation and bleomycin than the parent cells. Thus free radicals generated by these agents cannot be scavenged efficiently by MT in vivo. The hMT-IIA transfectants, however, but not control transfectants harboring a BPV-MT promoter-neo construct, tolerated significantly higher doses of the alkylating agents N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine. Resistance and MT overexpression occurred irrespective of selection and cultivation in cadmium and zinc. There was no increase in resistance to methyl methanesulfonate and N-hydroxyethyl-N-chloroethylnitrosourea. MT did not affect the degree of overall DNA methylation after N-methyl-N-nitrosourea treatment nor the level of O6-methylguanine-DNA methyltransferase. The results suggest that MT participates as a cofactor or regulatory element in repair or tolerance of toxic alkylation lesions. Images PMID:2320583

  13. Expression of Dihydropyridine and Ryanodine Receptors in Type IIA Fibers of Rat Skeletal Muscle

    International Nuclear Information System (INIS)

    Anttila, Katja; Mänttäri, Satu; Järvilehto, Matti

    2007-01-01

    In this study, the fiber type specificity of dihydropyridine receptors (DHPRs) and ryanodine receptors (RyRs) in different rat limb muscles was investigated. Western blot and histochemical analyses provided for the first time evidence that the expression of both receptors correlates to a specific myosin heavy chain (MHC) composition. We observed a significant (p=0.01) correlation between DHP as well as Ry receptor density and the expression of MHC IIa (correlation factor r=0.674 and r=0.645, respectively) in one slow-twitch, postural muscle (m. soleus), one mixed, fast-twitch muscle (m. gastrocnemius) and two fast-twitch muscles (m. rectus femoris, m. extensor digitorum longus). The highest DHP and Ry receptor density was found in the white part of m. rectus femoris (0.058±0.0060 and 0.057±0.0158 ODu, respectively). As expected, the highest relative percentage of MHC IIa was also found in the white part of m. rectus femoris (70.0±7.77%). Furthermore, histochemical experiments revealed that the IIA fibers stained most strongly for the fluorophore-conjugated receptor blockers. Our data clearly suggest that the expression of DHPRs and RyRs follows a fiber type-specific pattern, indicating an important role for these proteins in the maintenance of an effective Ca 2+ cycle in the fast contracting fiber type IIA

  14. Type IIA2 urethral duplication: report of an unusual case | Gupta ...

    African Journals Online (AJOL)

    This report describes a rare case of type IIA2 sagittal urethral duplication. The presentation, investigation, and management of this rare anomaly are briefly discussed. A 3½-year-old boy presented with urinary obstruction and recurrent urinary tract infection due to a stenosed dorsal urethra and segmental stenosis of the ...

  15. Cochlear Implantation in Patients With Usher Syndrome Type IIa Increases Performance and Quality of Life

    NARCIS (Netherlands)

    Hartel, B.P.; Nierop, J.W.I. van; Huinck, W.J.; Rotteveel, L.J.C.; Mylanus, E.A.M.; Snik, A.F.M.; Kunst, H.P.M.; Pennings, R.J.E.

    2017-01-01

    OBJECTIVES: Usher syndrome type IIa (USH2a) is characterized by congenital moderate to severe hearing impairment and retinitis pigmentosa. Hearing rehabilitation starts in early childhood with the application of hearing aids. In some patients with USH2a, severe progression of hearing impairment

  16. Effects of starch synthase IIa gene dosage on grain, protein and starch in endosperm of wheat.

    Science.gov (United States)

    Konik-Rose, Christine; Thistleton, Jenny; Chanvrier, Helene; Tan, Ihwa; Halley, Peter; Gidley, Michael; Kosar-Hashemi, Behjat; Wang, Hong; Larroque, Oscar; Ikea, Joseph; McMaugh, Steve; Regina, Ahmed; Rahman, Sadequr; Morell, Matthew; Li, Zhongyi

    2007-11-01

    Starch synthases (SS) are responsible for elongating the alpha-1,4 glucan chains of starch. A doubled haploid population was generated by crossing a line of wheat, which lacks functional ssIIa genes on each genome (abd), and an Australian wheat cultivar, Sunco, with wild type ssIIa alleles on each genome (ABD). Evidence has been presented previously indicating that the SGP-1 (starch granule protein-1) proteins present in the starch granule in wheat are products of the ssIIa genes. Analysis of 100 progeny lines demonstrated co-segregation of the ssIIa alleles from the three genomes with the SGP-1 proteins, providing further evidence that the SGP-1 proteins are the products of the ssIIa genes. From the progeny lines, 40 doubled haploid lines representing the eight possible genotypes for SSIIa (ABD, aBD, AbD, ABd, abD, aBd, Abd, abd) were characterized for their grain weight, protein content, total starch content and starch properties. For some properties (chain length distribution, pasting properties, swelling power, and gelatinization properties), a progressive change was observed across the four classes of genotypes (wild type, single nulls, double nulls and triple nulls). However, for other grain properties (seed weight and protein content) and starch properties (total starch content, granule morphology and crystallinity, granule size distribution, amylose content, amylose-lipid dissociation properties), a statistically significant change only occurred for the triple nulls, indicating that all three genes had to be missing or inactive for a change to occur. These results illustrate the importance of SSIIa in controlling grain and starch properties and the importance of amylopectin fine structure in controlling starch granule properties in wheat.

  17. Domain-induced activation of human phospholipase A2 type IIA: Local versus global lipid composition

    DEFF Research Database (Denmark)

    Leidy, C.; Linderoth, L.; Andresen, T.L.

    2006-01-01

    , we show that local enrichment of anionic lipids into fluid domains triggers PLA(2)-IIA activity. In addition, the compositional range of enzyme activity is shown to be related to the underlying lipid phase diagram. A comparison is done between PLA(2)-IIA and snake venom PLA(2), which in contrast...... to PLA(2)-IIA hydrolyzes both anionic and zwitterionic membranes. In general, this work shows that PLA(2)-IIA activation can be accomplished through local enrichment of anionic lipids into domains, indicating a mechanism for PLA(2)-IIA to target perturbed native membranes with low global anionic lipid...

  18. Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design

    Science.gov (United States)

    Lättig, Jens; Böhl, Markus; Fischer, Petra; Tischer, Sandra; Tietböhl, Claudia; Menschikowski, Mario; Gutzeit, Herwig O.; Metz, Peter; Pisabarro, M. Teresa

    2007-08-01

    The human secretory phospholipase A2 group IIA (PLA2-IIA) is a lipolytic enzyme. Its inhibition leads to a decrease in eicosanoids levels and, thereby, to reduced inflammation. Therefore, PLA2-IIA is of high pharmacological interest in treatment of chronic diseases such as asthma and rheumatoid arthritis. Quercetin and naringenin, amongst other flavonoids, are known for their anti-inflammatory activity by modulation of enzymes of the arachidonic acid cascade. However, the mechanism by which flavonoids inhibit Phospholipase A2 (PLA2) remained unclear so far. Flavonoids are widely produced in plant tissues and, thereby, suitable targets for pharmaceutical extractions and chemical syntheses. Our work focuses on understanding the binding modes of flavonoids to PLA2, their inhibition mechanism and the rationale to modify them to obtain potent and specific inhibitors. Our computational and experimental studies focused on a set of 24 compounds including natural flavonoids and naringenin-based derivatives. Experimental results on PLA2-inhibition showed good inhibitory activity for quercetin, kaempferol, and galangin, but relatively poor for naringenin. Several naringenin derivatives were synthesized and tested for affinity and inhibitory activity improvement. 6-(1,1-dimethylallyl)naringenin revealed comparable PLA2 inhibition to quercetin-like compounds. We characterized the binding mode of these compounds and the determinants for their affinity, selectivity, and inhibitory potency. Based on our results, we suggest C(6) as the most promising position of the flavonoid scaffold to introduce chemical modifications to improve affinity, selectivity, and inhibition of PLA2-IIA by flavonoids.

  19. Differential diagnosis of gastric adenoma and type IIa early gastric cancer

    International Nuclear Information System (INIS)

    Tsuchigame, T.; Ogata, Y.; Sumi, M.; Fukui, K.; Saito, R.; Nakashima, K.; Urata, J.; Arakawa, A.; Saito, Y.; Takahashi, M.

    1991-01-01

    The endoscopic and radiographic findings of 45 gastric adenomas in 39 patients were followed for 6 months to 13 years and compared with type IIa early gastric cancer observed in 9 patients. Difficulties in the diffential diagnosis of these disorders were evaluated. The following features were suggestive of gastric adenomas: clustered lesions; protuberance with gentle slope; smooth surface; and relatively young patients. Discrimination of adenoma from type IIa early gastric cancer is often difficult by visual observation alone; biopsy was essential in most patients. A group III adenoma verified on biopsy should be followed closely because the lesion may harbor a cancer (so-called carcinoma-in-adenoma) or a cancer may later develop. (orig.)

  20. Deformed N = 8 supergravity from IIA strings and its Chern-Simons duals

    Energy Technology Data Exchange (ETDEWEB)

    Guarino, Adolfo [Nikhef Theory Group, Amsterdam (Netherlands); Jafferis, Daniel L. [Center for the Fundamental Laws of Nature, Harvard University, Cambridge, MA (United States); Varela, Oscar [Center for the Fundamental Laws of Nature, Harvard University, Cambridge, MA (United States); Centre de Physique Theorique, Ecole Polytechnique, CNRS UMR 7644, Palaiseau (France)

    2016-04-15

    Do electric/magnetic deformations of N = 8 supergravity enjoy a string/M-theory origin, or are they just a fourdimensional artefact? We address this question for the gauging of a group closely related to SO(8): its contraction ISO(7). We argue that the deformed ISO(7) supergravity arises from consistent truncation of massive IIA supergravity on S{sup 6}, and its electric/magnetic deformation parameter descends directly from the Romans mass. The critical points of the supergravity uplift to AdS{sub 4} massive type IIA vacua and the corresponding CFT{sub 3} duals are identified as super-Chern-Simons-matter theories with gauge group SU(N) and level k given also by the Romans mass. (copyright 2015 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  1. Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer

    Science.gov (United States)

    2018-04-06

    Ductal Breast Carcinoma; Invasive Breast Carcinoma; Lobular Breast Carcinoma; Medullary Breast Carcinoma; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Tubular Breast Carcinoma

  2. 10D massive type IIA supergravities as the uplift of parabolic M2-brane torus bundles

    Energy Technology Data Exchange (ETDEWEB)

    Garcia del Moral, Maria Pilar [Universidad de Antofagasta (Chile). Dept. de Fisica; Restuccia, Alvaro [Universidad de Antofagasta (Chile). Dept. de Fisica; Universidad Simon Bolivar, Caracas (Venezuela, Bolivarian Republic of). Dept. de Fisica

    2016-04-15

    We remark that the two 10D massive deformations of the N = 2 maximal type IIA supergravity (Romans and HLW supergravity) are associated to the low energy limit of the uplift to 10D of M2-brane torus bundles with parabolic monodromy linearly and non-linearly realized respectively. Romans supergravity corresponds to M2-brane compactified on a twice-punctured torus bundle. (copyright 2015 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  3. Focal cortical dysplasia type IIa and IIb: MRI aspects in 118 cases proven by histopathology

    Energy Technology Data Exchange (ETDEWEB)

    Colombo, Nadia; Citterio, Alberto [Ospedale Ca Granda Niguarda, Department of Neuroradiology, Milano (Italy); Tassi, Laura; Mai, Roberto; Sartori, Ivana; Cardinale, Francesco; Lo Russo, Giorgio [Ospedale Niguarda, Claudio Munari Epilepsy Surgery Center, Milano (Italy); Deleo, Francesco; Spreafico, Roberto [IRCCS Foundation Neurological Institute ' ' C. Besta' ' , Department of Epilepsy Clinic and Experimental Neurophysiology, Milano (Italy); Bramerio, Manuela [Ospedale Niguarda, Department of Pathology, Milano (Italy)

    2012-10-15

    This study aims to review the magnetic resonance imaging (MRI) aspects of a large series of patients with focal cortical dysplasia type II (FCD II) and attempt to identify distinctive features in the two histopathological subtypes IIa and IIb. We retrospectively reviewed the MRI scans of 118 patients with histological proven FCD IIa (n = 37) or IIb (n = 81) who were surgically treated for intractable epilepsy. MRI was abnormal in 93 patients (79 %) and unremarkable in 25 (21 %). A dysplastic lesion was identified in 90 cases (97 %) and classified as FCD II in 83 and FCD non-II in seven cases. In three cases, the MRI diagnosis was other than FCD. There was a significant association between the presence of cortical thickening (p = 0.002) and the ''transmantle sign'' (p < 0.001) and a correct MRI diagnosis of FCD II. MRI positivity was more frequent in the patients with FCD IIb than in those with FCD IIa (91 % vs. 51 %), and the detection rate of FCD II was also better in the patients with type IIb (88 % vs. 32 %). The transmantle sign was significantly more frequent in the IIb subgroup (p = 0.003). The rates of abnormal MRI results and correct MRI diagnoses of FCD II were significantly higher in the IIb subgroup. Although other MRI stigmata may contribute to the diagnosis, the only significant correlation was between the transmantle sign and FCD IIb. (orig.)

  4. Surgery or radiation therapy for Stage I and IIA carcinoma of the cervix

    International Nuclear Information System (INIS)

    Brady, L.W.

    1979-01-01

    The choice of treatment in carcinoma of the cervix is best decided after careful individual appraisal has been carried out. For best results, a long-term view must be agreed upon initially and careful followup by the same team is obligatory. At present, surgery, radiation therapy, and a combination of these two modalities have been employed successfully to manage carcinoma of the cervix. To a great extent, the facilities, the experience, and the interest of the personnel involved influence the type of therapy that will be employed. Generally speaking, the choice of treatment is determined primarily by the stage of the disease process. Radical surgery in the management of patients with Stage I and Stage II-A carcinoma of the cervix must be planned to include within the en bloc dissection the uterus, tubes, ovaries, and regional lymph node drainage from those organs. Therefore, a radical lymphadnectomy is an integral and important part of the overall management program when radical surgery is performed. In most institutions, radiation therapy is used most frequently to treat carcinoma of the cervix in Stages I and II-A. The data from various institutions indicate significant survival potential from radiation therapy treatment programs that are appropriately devised. In Stages I and II-A the complications are minimal in character (primarily proctitis and cystitis); generally, they involve a potential incidence of about six percent

  5. A counterselection method for Lactococcus lactis genome editing based on class IIa bacteriocin sensitivity.

    Science.gov (United States)

    Wan, Xing; Usvalampi, Anne M; Saris, Per E J; Takala, Timo M

    2016-11-01

    In this paper, we present a new counterselection method for deleting fragments from Lactococcus lactis chromosome. The method uses a non-replicating plasmid vector, which integrates into the chromosome and makes the cell sensitive to bacteriocins. The integration vector carries pUC ori functional in Escherichia coli but not in L. lactis, an erythromycin resistance gene for selecting single crossover integrants, and two fragments from L. lactis chromosome for homologous recombinations. In addition, the integration vector is equipped with the Listeria monocytogenes gene mptC encoding the mannose-phosphotransferase system component IIC, the receptor for class IIa bacteriocins. Expression of mptC from the integration vector renders the naturally resistant L. lactis sensitive to class IIa bacteriocins. This sensitivity is then used to select the double crossover colonies on bacteriocin agar. Only the cells which have regained the endogenous bacteriocin resistance through the loss of the mptC plasmid will survive. The colonies carrying the desired deletion can then be distinguished from the wild-type revertants by PCR. By using the class IIa bacteriocins leucocin A, leucocin C or pediocin AcH as the counterselective agents, we deleted 22- and 33-kb chromosomal fragments from the wild-type nisin producing L. lactis strain N8. In conclusion, this counterselection method presented here is a convenient, efficient and inexpensive technique to generate successive deletions in L. lactis chromosome.

  6. A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells.

    Directory of Open Access Journals (Sweden)

    Rubén Martín

    Full Text Available Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA. Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.

  7. 30 CFR 57.22208 - Auxiliary fans (I-A, II-A, III, and V-A mines).

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Auxiliary fans (I-A, II-A, III, and V-A mines... fans (I-A, II-A, III, and V-A mines). (a) Auxiliary fans, except fans used in shops and other areas... applicable requirements of 30 CFR part 18, and be operated so that recirculation is minimized. Auxiliary fans...

  8. Moduli Potentials in Type IIA Compactifications with RR and NS Flux

    Energy Technology Data Exchange (ETDEWEB)

    Kachru, S.

    2004-12-01

    We describe a simple class of type IIA string compactifications on Calabi-Yau manifolds where background fluxes generate a potential for the complex structure moduli, the dilaton, and the Kaehler moduli. This class of models corresponds to gauged {Nu} = 2 supergravities, and the potential is completely determined by a choice of gauging and by data of the {Nu} = 2 Calabi-Yau model--the prepotential for vector multiplets and the quaternionic metric on the hypermultiplet moduli space. Using mirror symmetry, one can determine many (though not all) of the quantum corrections which are relevant in these models.

  9. Development of pop-up Langmuir probe system for the JET MkIIa divertor

    International Nuclear Information System (INIS)

    Davies, S.J.; Tellier, X.; Matthews, G.F.; Wilson, C.H.

    1999-01-01

    The successful operation of a pop-up Langmuir probe system, which was installed in the JET MkIIa divertor, is described. The system utilises the ambient magnetic field in tokamak plasmas to act on a current carrying coil and pop up a rail containing Langmuir probes. Measurements were made using pin-plate probes which, owing to their relatively large exposed area, are ideally suited for use with such a system. Details of the design, testing, measurements and potential applications of JET's pop-up system are given. (orig.)

  10. Development of 'popup' Langmuir probe system for the JET MkIIa divertor

    International Nuclear Information System (INIS)

    Davies, S.; Tellier, X.; Matthews, G.

    1999-01-01

    The successful operation of a 'popup' Langmuir probe system, which was installed in the JET MkIIa divertor, is described. The system utilises the ambient magnetic field in tokamak plasmas to act on a current carrying coil and pop up a rail containing Langmuir probes. Measurements were made using 'Pin-Plate' probes which, owing to their relatively large exposed area, are ideally suited for use with such a system. Details of the design, testing, measurements and potential applications of JET's 'popup' system are given. (author)

  11. Non-perturbative scalar potential inspired by type IIA strings on rigid CY

    Energy Technology Data Exchange (ETDEWEB)

    Alexandrov, Sergei [Laboratoire Charles Coulomb (L2C), UMR 5221, CNRS-Université de Montpellier,F-34095, Montpellier (France); Ketov, Sergei V. [Department of Physics, Tokyo Metropolitan University,1-1 Minami-ohsawa, Hachioji-shi, Tokyo 192-0397 (Japan); Kavli Institute for the Physics and Mathematics of the Universe (IPMU), The University of Tokyo,Chiba 277-8568 (Japan); Institute of Physics and Technology, Tomsk Polytechnic University,30 Lenin Ave., Tomsk 634050 (Russian Federation); Wakimoto, Yuki [Department of Physics, Tokyo Metropolitan University,1-1 Minami-ohsawa, Hachioji-shi, Tokyo 192-0397 (Japan)

    2016-11-10

    Motivated by a class of flux compactifications of type IIA strings on rigid Calabi-Yau manifolds, preserving N=2 local supersymmetry in four dimensions, we derive a non-perturbative potential of all scalar fields from the exact D-instanton corrected metric on the hypermultiplet moduli space. Applying this potential to moduli stabilization, we find a discrete set of exact vacua for axions. At these critical points, the stability problem is decoupled into two subspaces spanned by the axions and the other fields (dilaton and Kähler moduli), respectively. Whereas the stability of the axions is easily achieved, numerical analysis shows instabilities in the second subspace.

  12. Type IIA photosensitivity and formation of pores in optical fibers under intense ultraviolet irradiation

    International Nuclear Information System (INIS)

    Kukushkin, S. A.; Shlyagin, M. G.; Swart, P. L.; Chtcherbakov, A. A.; Osipov, A. V.

    2007-01-01

    Formation of the type IIA Bragg gratings in germanosilicate optical fibers is studied. We report the observation of such a type of gratings in the standard single-mode fiber (Corning SMF-28) under different experimental conditions. A mechanism for the type IIA photosensitivity in optical fibers is proposed which is based on nucleation and evolution of pores from vacancy-type defects in fiber areas where a high level of mechanical stress is induced under intense ultraviolet (UV) light. Evolution of fiber core temperature under influence of a single 20 ns light pulse from a KrF excimer laser was measured and compared with theoretical calculations. It was shown that transient thermoinduced stress in the fiber core can achieve a level sufficient for effective nucleation of pores. A theory describing formation of pores in optical fibers has been developed and was used to estimate the pore nucleation rate, concentration, and other parameters of pore evolution for different levels of UV fluence and fiber core stress

  13. PENGGUNAAN BAHAN AJAR TEMATIK PEMBAGIAN UNTUK MENINGKATKAN HASIL BELAJAR DI KELAS IIA MI AHLIYAH II PALEMBANG

    Directory of Open Access Journals (Sweden)

    Luvi Antari

    2015-12-01

    Full Text Available This study aims to look at improving student learning outcomes in the materials division using a thematic approach based teaching materials. This research is a classroom action research (Claassroom Action Research with a research subject graders IIA MI Ahliyah 2 Palembang, the second semester of 2014/2015 the number of students 28 people, consisting of 14 male students and 14 female students. This study was conducted by two cycles following the model of a Class Action Research & McTaggart Kemmis models which consists of four stages: planning, implementation, observation, and reflection. The process of collecting data by using observation and tests. Based on this research, the data obtained in the first cycle who scored ≥ 70 there were 17 students with learning completeness percentage amounted to 60.71% of students had reached the indicators of success and the second cycle there are 23 students who reached a value ≥ 70 on the percentage of students learning completeness by 82 , 14% had reached an indicator of success. With the student response rate reached 76.56% in the first cycle and the second cycle reaches 81.25%. It can be concluded that learning by using a thematic approach based teaching materials division performed in this research was effective, because it can improve student learning outcomes in the distribution of matter in class IIA MI Ahliyah II Palembang

  14. The N=1 effective actions of D-branes in Type IIA and IIB orientifolds

    International Nuclear Information System (INIS)

    Grimm, Thomas W.; Vieira Lopes, Daniel

    2012-01-01

    We discuss the four-dimensional N=1 effective actions of single space-time filling Dp-branes in general Type IIA and Type IIB Calabi-Yau orientifold compactifications. The effective actions depend on an infinite number of normal deformations and gauge connection modes. For D6-branes the N=1 Kähler potential, the gauge-coupling function, the superpotential and the D-terms are determined as functions of these fields. They can be expressed as integrals over chains which end on the D-brane cycle and a reference cycle. The infinite deformation space will reduce to a finite dimensional moduli space of special Lagrangian submanifolds upon imposing F- and D-term supersymmetry conditions. We show that the Type IIA moduli space geometry is captured by three real functionals encoding the deformations of special Lagrangian submanifolds, holomorphic three-forms and Kähler two-forms of Calabi-Yau manifolds. These elegantly combine in the N=1 Kähler potential, which reduces after applying mirror symmetry to the results previously determined for space-time filling D3-, D5- and D7-branes. We also propose general chain integral expressions for the Kähler potentials of Type IIB D-branes.

  15. An adhesome comprising laminin, dystroglycan and myosin IIA is required during notochord development in Xenopus laevis.

    Science.gov (United States)

    Buisson, Nicolas; Sirour, Cathy; Moreau, Nicole; Denker, Elsa; Le Bouffant, Ronan; Goullancourt, Aline; Darribère, Thierry; Bello, Valérie

    2014-12-01

    Dystroglycan (Dg) is a transmembrane receptor for laminin that must be expressed at the right time and place in order to be involved in notochord morphogenesis. The function of Dg was examined in Xenopus laevis embryos by knockdown of Dg and overexpression and replacement of the endogenous Dg with a mutated form of the protein. This analysis revealed that Dg is required for correct laminin assembly, for cell polarization during mediolateral intercalation and for proper differentiation of vacuoles. Using mutations in the cytoplasmic domain, we identified two sites that are involved in cell polarization and are required for mediolateral cell intercalation, and a site that is required for vacuolation. Furthermore, using a proteomic analysis, the cytoskeletal non-muscle myosin IIA has been identified for the first time as a molecular link between the Dg-cytoplasmic domain and cortical actin. The data allowed us to identify the adhesome laminin-Dg-myosin IIA as being required to maintain the cortical actin cytoskeleton network during vacuolation, which is crucial to maintain the shape of notochordal cells. © 2014. Published by The Company of Biologists Ltd.

  16. Radiation therapy for stage IIA and IIB testicular seminoma: peripheral dose calculations and risk assessments

    Science.gov (United States)

    Mazonakis, Michalis; Berris, Theocharris; Lyraraki, Efrossyni; Damilakis, John

    2015-03-01

    This study was conducted to calculate the peripheral dose to critical structures and assess the radiation risks from modern radiotherapy for stage IIA/IIB testicular seminoma. A Monte Carlo code was used for treatment simulation on a computational phantom representing an average adult. The initial treatment phase involved anteroposterior and posteroanaterior modified dog-leg fields exposing para-aortic and ipsilateral iliac lymph nodes followed by a cone-down phase for nodal mass irradiation. Peripheral doses were calculated using different modified dog-leg field dimensions and an extended conventional dog-leg portal. The risk models of the BEIR-VII report and ICRP-103 were combined with dosimetric calculations to estimate the probability of developing stochastic effects. Radiotherapy for stage IIA seminoma with a target dose of 30 Gy resulted in a range of 23.0-603.7 mGy to non-targeted peripheral tissues and organs. The corresponding range for treatment of stage IIB disease to a cumulative dose of 36 Gy was 24.2-633.9 mGy. A dose variation of less than 13% was found by altering the field dimensions. Radiotherapy with the conventional instead of the modern modified dog-leg field increased the peripheral dose up to 8.2 times. The calculated heart doses of 589.0-632.9 mGy may increase the risk for developing cardiovascular diseases whereas the testicular dose of more than 231.9 mGy may lead to a temporary infertility. The probability of birth abnormalities in the offspring of cancer survivors was below 0.13% which is much lower than the spontaneous mutation rate. Abdominoplevic irradiation may increase the lifetime intrinsic risk for the induction of secondary malignancies by 0.6-3.9% depending upon the site of interest, patient’s age and tumor dose. Radiotherapy for stage IIA/IIB seminoma with restricted fields and low doses is associated with an increased morbidity. These data may allow the definition of a risk-adapted follow-up scheme for long

  17. The Yang monopole in IIA superstring: multi-charge disease and enhançon cure

    International Nuclear Information System (INIS)

    Belhaj, Adil; Diaz, Pablo; Segui, Antonio

    2012-01-01

    A brane picture in type IIA superstring for the Yang monopole is reconsidered. It makes use of D2 and D4-branes wrapped on cycles in the K3 surface. When the model was first presented, some problems concerning the charges of the monopoles arose. In this paper, they are shown to be cured by the model itself. Surprisingly, the incompatibility between the multi-charge configuration and the spherical symmetry of the Yang monopole is seen in the brane description as the emergence of the enhançon shell and the fuzzy geometry. This consistency is deep and surprising, and is the point that triggered this work. It nontrivially relates a purely geometrical problem in ordinary spacetime with the emergence of noncommutative geometries. Besides, this paper includes an extended model for SO(4)-monopoles and a T-dual model in type IIB superstring. (paper)

  18. Stability of high-beta tokamak equilibria and transport in Belt-Pinch IIa

    Energy Technology Data Exchange (ETDEWEB)

    Becker, G; Gruber, O; Krause, H; Mast, F; Wilhelm, R [Association Euratom-Max-Planck-Institut fuer Plasmaphysik, Garching (Germany, F.R.)

    1978-01-01

    In Belt-Pinch IIa, highly elongated equilibria with poloidal beta values up to the aspect ratio have been achieved. In these tokamak-like configurations, no fast-growing MHD instabilities such as external kink and ballooning modes have been observed. Rigid displacement instabilities have been stabilized by an appropriate poloidal magnetic field configuration and by a conducting shell. By comparing simulation experiments using the Garching high-beta transport code with measurements, it has been found that in the collision-dominated plasma no anomalously enhanced transport occurs. Transport theory in the Pfirsch-Schlueter regime, which includes elongation and high-beta effects, has been confirmed by the experiment. In particular, it has been shown that the perpendicular electrical conductivity is also classical. Detailed investigations of oxygen and carbon impurity losses demonstrated that the impurity subprograms commonly used for tokamaks underestimate the radiation losses in the range Tsub(e)=10 to 30 eV.

  19. Structural characterization of the PTS IIA and IIB proteins associated with pneumococcal fucose utilization.

    Science.gov (United States)

    Higgins, Melanie A; Hamilton, Aileen M; Boraston, Alisdair B

    2017-05-01

    Streptococcus pneumoniae harbors a significant number of transporters, including phosphotransferase (PTS) systems, allowing the bacterium to utilize a number of different carbohydrates for metabolic and other purposes. The genes encoding for one PTS transport system in particular (EII fuc ) are found within a fucose utilization operon in S. pneumoniae TIGR4. Here, we report the three-dimensional structures of IIA fuc and IIB fuc providing evidence that this PTS system belongs to the EII man family. Additionally, the predicted metabolic pathway for this distinctive fucose utilization system suggests that EII fuc transports the H-disaccharide blood group antigen, which would represent a novel PTS transporter specificity. Proteins 2017; 85:963-968. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  20. Enterocin T, a novel class IIa bacteriocin produced by Enterococcus sp. 812.

    Science.gov (United States)

    Chen, Yi-Sheng; Yu, Chi-Rong; Ji, Si-Hua; Liou, Min-Shiuan; Leong, Kun-Hon; Pan, Shwu-Fen; Wu, Hui-Chung; Lin, Yu-Hsuan; Yu, Bi; Yanagida, Fujitoshi

    2013-09-01

    Enterococcus sp. 812, isolated from fresh broccoli, was previously found to produce a bacteriocin active against a number of Gram-positive bacteria, including Listeria monocytogenes. Bacteriocin activity decreased slightly after autoclaving (121 °C for 15 min), but was inactivated by protease K. Mass spectrometry analysis revealed the bacteriocin mass to be approximately 4,521.34 Da. N-terminal amino acid sequencing yielded a partial sequence, NH2-ATYYGNGVYXDKKKXWVEWGQA, by Edman degradation, which contained the consensus class IIa bacteriocin motif YGNGV in the N-terminal region. The obtained partial sequence showed high homology with some enterococcal bacteriocins; however, no identical peptide or protein was found. This peptide was therefore considered to be a novel bacteriocin produced by Enterococcus sp. 812 and was termed enterocin T.

  1. More supersymmetric standardlike models from intersecting D6-branes on type IIA orientifolds

    International Nuclear Information System (INIS)

    Cvetic, Mirjam; Papadimitriou, Ioannis

    2003-01-01

    We present new classes of supersymmetric standardlike models from a type IIA T 6 /(Z 2 xZ 2 ) orientifold with intersecting D6-branes. D6-branes can wrap general supersymmetric three-cycles of T 6 =T 2 xT 2 xT 2 , and any T 2 is allowed to be tilted. The models still suffer from additional exotics; however, we obtain solutions with fewer Higgs doublets, as well as models with all three families of left-handed quarks and leptons arising from the same intersecting sector, and examples of a genuine left-right symmetric model with three copies of left-handed and right-handed families of quarks and leptons

  2. KK-monopoles and G-structures in M-theory/type IIA reductions

    International Nuclear Information System (INIS)

    Danielsson, Ulf; Dibitetto, Giuseppe; Guarino, Adolfo

    2015-01-01

    We argue that M-theory/massive IIA backgrounds including KK-monopoles are suitably described in the language of G-structures and their intrinsic torsion. To this end, we study classes of minimal supergravity models that admit an interpretation as twisted reductions in which the twist parameters are not restricted to satisfy the Jacobi constraints ω ω=0 required by an ordinary Scherk-Schwarz reduction. We first derive the correspondence between four-dimensional data and torsion classes of the internal space and, then, check the one-to-one correspondence between higher-dimensional and four-dimensional equations of motion. Remarkably, the whole construction holds regardless of the Jacobi constraints, thus shedding light upon the string/M-theory interpretation of (smeared) KK-monopoles.

  3. On (orientifold of) type IIA on a compact Calabi-Yau

    International Nuclear Information System (INIS)

    Misra, A.

    2004-01-01

    We study the gauged sigma model and its mirror Landau-Ginsburg model corresponding to type IIA on the Fermat degree-24 hypersurface in WCP 4 [1,1,2,8,12] (whose blow-up gives the smooth CY 3 (3,243)) away from the orbifold singularities, and its orientifold by a freely-acting antiholomorphic involution. We derive the Picard-Fuchs equation obeyed a period integral of a parent N=2 type IIA theory. We obtain the Meijer's basis of solutions to the equation in the large and small complex structure limits (on the mirror Landau-Ginsburg side) of the abovementioned Calabi-Yau, and make some remarks about the monodromy properties associated at the same and another MATHEMATICAlly interesting point. Based on a recently shown N=1 four-dimensional triality between Heterotic on the self-mirror Calabi-Yau CY 3 (11,11), M theory on CY 3 (3,243) x S 1 /(Z 2 ) and F-theory on an elliptically fibered CY 4 with the base given by CP 1 x Enriques surface, we first give a heuristic argument that there can be no superpotential generated in the orientifold of of CY 3 (3,243), and then explicitly verify the same using a mirror symmetry formulation for the abovementioned hypersurface away from its orbifold singularities. We then discuss briefly the sigma model and the mirror Landau-Ginsburg model corresponding to the resolved Calabi-Yau as well. (Abstract Copyright [2004], Wiley Periodicals, Inc.)

  4. Hearing aid fitting for visual and hearing impaired patients with Usher syndrome type IIa.

    Science.gov (United States)

    Hartel, B P; Agterberg, M J H; Snik, A F; Kunst, H P M; van Opstal, A J; Bosman, A J; Pennings, R J E

    2017-08-01

    Usher syndrome is the leading cause of hereditary deaf-blindness. Most patients with Usher syndrome type IIa start using hearing aids from a young age. A serious complaint refers to interference between sound localisation abilities and adaptive sound processing (compression), as present in today's hearing aids. The aim of this study was to investigate the effect of advanced signal processing on binaural hearing, including sound localisation. In this prospective study, patients were fitted with hearing aids with a nonlinear (compression) and linear amplification programs. Data logging was used to objectively evaluate the use of either program. Performance was evaluated with a speech-in-noise test, a sound localisation test and two questionnaires focussing on self-reported benefit. Data logging confirmed that the reported use of hearing aids was high. The linear program was used significantly more often (average use: 77%) than the nonlinear program (average use: 17%). The results for speech intelligibility in noise and sound localisation did not show a significant difference between type of amplification. However, the self-reported outcomes showed higher scores on 'ease of communication' and overall benefit, and significant lower scores on disability for the new hearing aids when compared to their previous hearing aids with compression amplification. Patients with Usher syndrome type IIa prefer a linear amplification over nonlinear amplification when fitted with novel hearing aids. Apart from a significantly higher logged use, no difference in speech in noise and sound localisation was observed between linear and nonlinear amplification with the currently used tests. Further research is needed to evaluate the reasons behind the preference for the linear settings. © 2016 The Authors. Clinical Otolaryngology Published by John Wiley & Sons Ltd.

  5. The secretory phospholipase A2 group IIA: a missing link between inflammation, activated renin-angiotensin system, and atherogenesis?

    Directory of Open Access Journals (Sweden)

    Dimitar Divchev

    2008-06-01

    Full Text Available Dimitar Divchev, Bernhard SchiefferDepartment of Cardiology and Angiology, Medizinische Hochschule Hannover, GermanyAbstract: Inflammation, lipid peroxidation and chronic activation of the renin–angiotensin system (RAS are hallmarks of the development of atherosclerosis. Recent studies have suggested the involvement of the pro-inflammatory secretory phospholipase A2 (sPLA2-IIA in atherogenesis. This enzyme is produced by different cell types through stimulation by proinflammatory cytokines. It is detectable in the intima and in media smooth muscle cells, not only in atherosclerotic lesions but also in the very early stages of atherogenesis. sPLA2-IIA can hydrolyse the phospholipid monolayers of low density lipoproteins (LDL. Such modified LDL show increased affinity to proteoglycans. The modified particles have a greater tendency to aggregate and an enhanced ability to insert cholesterol into cells. This modification may promote macrophage LDL uptake leading to the formation of foam cells. Furthermore, sPLA2-IIA is not only a mediator for localized inflammation but may be also used as an independent predictor of adverse outcomes in patients with stable coronary artery disease or acute coronary syndromes. An interaction between activated RAS and phospholipases has been indicated by observations showing that inhibitors of sPLA2 decrease angiotensin (Ang II-induced macrophage lipid peroxidation. Meanwhile, various interactions between Ang II and oxLDL have been demonstrated suggesting a central role of sPLA2-IIA in these processes and offering a possible target for treatment. The role of sPLA2-IIA in the perpetuation of atherosclerosis appears to be the missing link between inflammation, activated RAS and lipidperoxidation.Keywords: secretory phospholipase A2, lipoproteins, renin-angiotensin system, inflammation, atherosclerosis

  6. Molecular cloning, expression and characterization of albolamin: a type P-IIa snake venom metalloproteinase from green pit viper (Cryptelytrops albolabris).

    Science.gov (United States)

    Jangprasert, Panchalee; Rojnuckarin, Ponlapat

    2014-03-01

    Snake venom metalloproteinases (SVMPs) can damage vessel wall, degrade clotting factors, inhibit integrins and block platelet functions. Studying them not only gives us deeper insights in pathogenesis of snakebites, but also potentially yields novel therapeutic agents. Here, we discovered a clone of an RGD-containing SVMP from the green pit viper (Cryptelytrops albolabris) venom gland cDNA library. Sequence analysis revealed that it belonged to the P-IIa subclass of SVMP comprising signal peptide, prodomain, metalloproteinase and disintegrin. Compared with other P-II SVMPs, it contained 2 additional conserved cysteines that were predicted to prevent the release of disintegrin from the metalloproteinase domain in the mature protein. The N-terminal histidine-tagged construct of metalloproteinase and disintegrin domains of albolamin was inserted into the pPICZαA vector and expressed in Pichia pastoris. The recombinant protein molecular weight was approximately 35 kDa on Western blot probed with anti-polyhistidine antibody. The recombinant albolamin could digest human type IV collagen starting within 15 min after incubation. In addition, it dose-dependently inhibited collagen-induced platelet aggregation with the IC50 of 1.8 μM. However, there was no effect on ADP-induced platelet aggregation. Therefore, the inhibition mechanism is probably through blocking collagen receptor(s). Albolamin activities probably contributed to pathology of green pit viper bites. Its disintegrin domain deserves further studies for the potential to be a useful agent affecting platelet functions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection.

    Directory of Open Access Journals (Sweden)

    Wakako Furuyama

    2016-12-01

    Full Text Available Antibody-dependent enhancement (ADE of Ebola virus (EBOV infection has been demonstrated in vitro, raising concerns about the detrimental potential of some anti-EBOV antibodies. ADE has been described for many viruses and mostly depends on the cross-linking of virus-antibody complexes to cell surface Fc receptors, leading to enhanced infection. However, little is known about the molecular mechanisms underlying this phenomenon. Here we show that Fcγ-receptor IIa (FcγRIIa-mediated intracellular signaling through Src family protein tyrosine kinases (PTKs is required for ADE of EBOV infection. We found that deletion of the FcγRIIa cytoplasmic tail abolished EBOV ADE due to decreased virus uptake into cellular endosomes. Furthermore, EBOV ADE, but not non-ADE infection, was significantly reduced by inhibition of the Src family protein PTK pathway, which was also found to be important to promote phagocytosis/macropinocytosis for viral uptake into endosomes. We further confirmed a significant increase of the Src phosphorylation mediated by ADE. These data suggest that antibody-EBOV complexes bound to the cell surface FcγRIIa activate the Src signaling pathway that leads to enhanced viral entry into cells, providing a novel perspective for the general understanding of ADE of virus infection.

  8. Geology and mineral resources of central Antioquia Department (Zone IIA), Colombia

    Science.gov (United States)

    Hall, R.B.; Alvarez A., Jairo; Rico H., Hector

    1973-01-01

    Antioquian batholith. Displacement along the great Romeral wrench fault may have begun in the Cretaceous. Plutonism continued into the Cenozoic, exemplified by the hornblende-diorite Sabanalarga pluton. Intermontane basins were filled with molasse derived from the erosion of adjacent highlands; Tertiary sedimentation in marshy areas included organic carboniferous matter subsequently converted to lignite or subbituminous coal. The Sabanalarga fault system originated in the Late Tertiary; intermittent displacement continued on the older wrench faults such as the Romeral. Epeirogenic uplift, which probably began in the Pliocene and continued through the Pleistocene and Holocene, brought on renewed erosion which has sculptured the mountains into their present form. Mineral resources in subzone IIA are varied but not of outstanding importance. Gold and silver mining, significant in past centuries, is minor today. Ferruginous laterite on serpentinite once considered as a potential source of iron ore is not economically exploitable. IMN has explored nickeliferous laterite at the extreme northwest corner of subzone IIA; this is a potential resource, exploitable only after exhaustion of the larger and richer nickel laterite deposit at Cerro Matoso, farther to the north and outside the boundaries of Zone If. Known deposits of mercury, chromium, manganese, and copper are small, with limited economic potential. Nonmetallic resources include raw materials for cement, including portland cement. Saprolite clay is widely used in making common red brick and tile, still a dominant construction material in all but the most modern multistory buildings. Aggregate materials are varied and abundant. Kaolin of good quality near La Union is important as a ceramic raw mineral filler. Tertiary subbituminous coal beds are an important energy resource in western subzone IIA, and have a good potential for greater development. Deposits of sodic feldspar, talc, decorative stone, and silica a

  9. HPHT growth and x-ray characterization of high-quality type IIa diamond.

    Science.gov (United States)

    Burns, R C; Chumakov, A I; Connell, S H; Dube, D; Godfried, H P; Hansen, J O; Härtwig, J; Hoszowska, J; Masiello, F; Mkhonza, L; Rebak, M; Rommevaux, A; Setshedi, R; Van Vaerenbergh, P

    2009-09-09

    The trend in synchrotron radiation (x-rays) is towards higher brilliance. This may lead to a very high power density, of the order of hundreds of watts per square millimetre at the x-ray optical elements. These elements are, typically, windows, polarizers, filters and monochromators. The preferred material for Bragg diffracting optical elements at present is silicon, which can be grown to a very high crystal perfection and workable size as well as rather easily processed to the required surface quality. This allows x-ray optical elements to be built with a sufficient degree of lattice perfection and crystal processing that they may preserve transversal coherence in the x-ray beam. This is important for the new techniques which include phase-sensitive imaging experiments like holo-tomography, x-ray photon correlation spectroscopy, coherent diffraction imaging and nanofocusing. Diamond has a lower absorption coefficient than silicon, a better thermal conductivity and lower thermal expansion coefficient which would make it the preferred material if the crystal perfection (bulk and surface) could be improved. Synthetic HPHT-grown (high pressure, high temperature) type Ib material can readily be produced in the necessary sizes of 4-8 mm square and with a nitrogen content of typically a few hundred parts per million. This material has applications in the less demanding roles such as phase plates: however, in a coherence-preserving beamline, where all elements must be of the same high quality, its quality is far from sufficient. Advances in HPHT synthesis methods have allowed the growth of type IIa diamond crystals of the same size as type Ib, but with substantially lower nitrogen content. Characterization of this high purity type IIa material has been carried out with the result that the crystalline (bulk) perfection of some of the HPHT-grown materials is approaching the quality required for the more demanding applications such as imaging applications and imaging

  10. Multiple Authorisation: The Legal Complexity of Desentralisasi in Indonesia and the Potential Contribution of IIAs in Reducing Confusion

    Directory of Open Access Journals (Sweden)

    Michael Ewing-Chow

    2015-12-01

    Full Text Available Decentralisation system in Indonesia was introduced after the fall of the former President Soeharto with the objective of ensuring good governance and equitable development across all regions in the country. Unfortunately, the implementation of desentralisasi has been complicated. Some scholars have suggested that the model was flawed as it did not consider Indonesia’s context of less developed administrative institutions in the regions. Not only did desentralisasi cause headaches for the government, it also created confusion for foreign investors. Consequently, it affects the investment climate in the country and undermines the perception of Indonesia as an attractive place to invest in. In certain cases, desentralisasi has also led to claims by foreign investors for investor-State arbitration under Indonesia’s international investment agreements (IIAs. This paper analyses the problems of desentralisasi in Indonesia, its effects to foreign investors and suggests ways to alleviate the problems by modifying and using Indonesia’s IIAs effectively.

  11. Hypermultiplet gaugings and supersymmetric solutions from 11D and massive IIA supergravity on H^{(p,q)} spaces

    Science.gov (United States)

    Guarino, Adolfo

    2018-03-01

    Supersymmetric {AdS}4, {AdS}2 × Σ 2 and asymptotically AdS4 black hole solutions are studied in the context of non-minimal N=2 supergravity models involving three vector multiplets (STU-model) and Abelian gaugings of the universal hypermultiplet moduli space. Such models correspond to consistent subsectors of the {SO}(p,q) and {ISO}(p,q) gauged maximal supergravities that arise from the reduction of 11D and massive IIA supergravity on {H}^{(p,q)} spaces down to four dimensions. A unified description of all the models is provided in terms of a square-root prepotential and the gauging of a duality-hidden symmetry pair of the universal hypermultiplet. Some aspects of M-theory and massive IIA holography are mentioned in passing.

  12. Generation of transgenic corn-derived Actinobacillus pleuropneumoniae ApxIIA fused with the cholera toxin B subunit as a vaccine candidate

    Science.gov (United States)

    Shin, Min-Kyoung; Jung, Myung Hwan; Lee, Won-Jung; Choi, Pil Son; Jang, Yong-Suk

    2011-01-01

    Corn, one of the most important forage crops worldwide, has proven to be a useful expression vehicle due to the availability of established transformation procedures for this well-studied plant. The exotoxin Apx, a major virulence factor, is recognized as a common antigen of Actinobacillus (A.) pleuropneumoniae, the causative agent of porcine pleuropneumonia. In this study, a cholera toxin B (CTB)-ApxIIA#5 fusion protein and full-size ApxIIA expressed in corn seed, as a subunit vaccine candidate, were observed to induce Apx-specific immune responses in mice. These results suggest that transgenic corn-derived ApxIIA and CTB-ApxIIA#5 proteins are potential vaccine candidates against A. pleuropneumoniae infection. PMID:22122907

  13. First-principle approach based bandgap engineering for cubic boron nitride doped with group IIA elements

    Science.gov (United States)

    Li, Yubo; Wang, Pengtao; Hua, Fei; Zhan, Shijie; Wang, Xiaozhi; Luo, Jikui; Yang, Hangsheng

    2018-03-01

    Electronic properties of cubic boron nitride (c-BN) doped with group IIA elements were systematically investigated using the first principle calculation based on density functional theory. The electronic bandgap of c-BN was found to be narrowed when the impurity atom substituted either the B (IIA→B) or the N (IIA→N) atom. For IIA→B, a shallow accept level degenerated into valence band (VB); while for IIA→N, a shallow donor level degenerated conduction band (CB). In the cases of IIBe→N and IIMg→N, deep donor levels were also induced. Moreover, a zigzag bandgap narrowing pattern was found, which is in consistent with the variation pattern of dopants' radius of electron occupied outer s-orbital. From the view of formation energy, the substitution of B atom under N-rich conditions and the substitution of N atom under B-rich conditions were energetically favored. Our simulation results suggested that Mg and Ca are good candidates for p-type dopants, and Ca is the best candidate for n-type dopant.

  14. Water Dancer II-A: A Non-Tethered Telecontrollable Water Strider Robot

    Directory of Open Access Journals (Sweden)

    Licheng Wu

    2011-09-01

    Full Text Available Water Strider Robot (WSR is a kind of bio-inspired micro robot that can stand and move on water surface via surface tension. In this paper, a design method is presented with algorithms for designing driving leg. Structure, control system and software of the robot are also discussed in details. A prototype Water Dancer II-a that is driven with two electric motors is presented as successfully tested in lab. The proposed WSR is tele-controlled with infrared signals and has the capability of turning and speed regulation with features of light tiny volume and low power consumption. Experimental results are reported and discussed to show practical feasibility of the presented WSR prototype. The new results in the paper are related also to the WSR prototype design with a robot body of less than 30 × 30 mm size and with ten leg rods of 90 mm length and 0.2 diameter that are able to provide lifting force for a water walk of the 6.0 grams robot at a forward speed of 20 cm/s or angular velocity of 9 degree/s with two micro DC motors(RoomFlight 4 × 8 mm, 28 Ohm.

  15. Type IIA on a compact Calabi-Yau and D=11 supergravity uplift of its orientifold

    International Nuclear Information System (INIS)

    Misra, A.

    2004-01-01

    Using the prescription of K. Hori and C. Vafa for defining period integrals in the Landau-Ginsburg theory for compact Calabi-Yau's, we obtain the Picard-Fuchs equation and the Meijer basis of solutions for the compact Calabi-Yau CY 3 (3,243) expressed as a degree-24 Fermat hypersurface after resolution of the orbifold singularities. The importance of the method lies in the ease with which one can consider the large and small complex structure limits, as well as the ability to get the ''ln''-terms in the periods without having to parametrically differentiate infinite series. We consider in detail the evaluation of the monodromy matrix in the large and small complex structure limits. We also consider the action of the freely acting antiholomorphic involution on D=11 supergravity compactified on CY 3 (3,243) x S 1 and obtain the Kaehler potential for the same in the limit of large volume of the Calabi-Yau. As a by-product, we also give a conjecture for the action of the orientation-reversing antiholomorphic involution on the periods, given its action on the cohomology, using a canonical (co)homology basis. Finally, we also consider showing a null superpotential on the orientifold of type IIA on CY 3 (3,243), having taken care of the orbifold singularities. (Abstract Copyright [2004], Wiley Periodicals, Inc.)

  16. Cochlear Implantation in Patients With Usher Syndrome Type IIa Increases Performance and Quality of Life.

    Science.gov (United States)

    Hartel, Bas P; van Nierop, Josephine W I; Huinck, Wendy J; Rotteveel, Liselotte J C; Mylanus, Emmanuel A M; Snik, Ad F; Kunst, Henricus P M; Pennings, Ronald J E

    2017-07-01

    Usher syndrome type IIa (USH2a) is characterized by congenital moderate to severe hearing impairment and retinitis pigmentosa. Hearing rehabilitation starts in early childhood with the application of hearing aids. In some patients with USH2a, severe progression of hearing impairment leads to insufficient speech intelligibility with hearing aids and issues with adequate communication and safety. Cochlear implantation (CI) is the next step in rehabilitation of such patients. This study evaluates the performance and benefit of CI in patients with USH2a. Retrospective case-control study to evaluate the performance and benefit of CI in 16 postlingually deaf adults (eight patients with USH2a and eight matched controls). Performance and benefit were evaluated by a speech intelligibility test and three quality-of-life questionnaires. Patients with USH2a with a mean age of 59 years at implantation exhibited good performance after CI. The phoneme scores improved significantly from 41 to 87% in patients with USH2a (p = 0.02) and from 30 to 86% in the control group (p = 0.001). The results of the questionnaire survey demonstrated a clear benefit from CI. There were no differences in performance or benefit between patients with USH2a and control patients before and after CI. CI increases speech intelligibility and improves quality of life in patients with USH2a.

  17. Expressivity of hearing loss in cases with Usher syndrome type IIA.

    Science.gov (United States)

    Sadeghi, André M; Cohn, Edward S; Kimberling, William J; Halvarsson, Glenn; Möller, Claes

    2013-12-01

    The purpose of this study was to compare the genotype/phenotype relationship between siblings with identical USH2A pathologic mutations and the consequent audiologic phenotypes, in particular degree of hearing loss (HL). Decade audiograms were also compared among two groups of affected subjects with different mutations of USH2A. DNA samples from patients with Usher syndrome type II were analysed. The audiological features of patients and affected siblings with USH2A mutations were also examined to identify genotype-phenotype correlations. Genetic and audiometric examinations were performed in 18 subjects from nine families with Usher syndrome type IIA. Three different USH2A mutations were identified in the affected subjects. Both similarities and differences of the auditory phenotype were seen in families with several affected siblings. A variable degree of hearing loss, ranging from mild to profound, was observed among affected subjects. No significant differences in hearing thresholds were found the group of affected subjects with different pathological mutations. Our results indicate that mutations in the USH2A gene and the resulting phenotype are probably modulated by other variables, such as modifying genes, epigenetics or environmental factors which may be of importance for better understanding the etiology of Usher syndrome.

  18. Development and clinical application in arthritis of a new immunoassay for serum type IIA procollagen NH2 propeptide.

    Science.gov (United States)

    Rousseau, Jean-Charles; Sandell, Linda J; Delmas, Pierre D; Garnero, Patrick

    2004-01-01

    Type II collagen, the most abundant protein of cartilage matrix, is synthesized as a procollagen molecule including the N-(PIINP) and C-(PIICP) propeptides at each end. Type II procollagen is produced in two forms as the result of alternative RNA splicing. One form (IIA) includes and the other form (IIB) excludes a 69-amino acid cysteine-rich globular domain encoded by exon 2 in PIINP. During the process of synthesis, these N-propeptides are removed by specific proteases and released in the circulation, and their levels are believed to reflect type II collagen synthesis. In this chapter we describe the development of a specific enzyme-linked immunosorbent assay (ELISA) for the measurement of the IIA form of PIINP (PIIANP) in serum based on a polyclonal antibody raised against recombinant human exon 2 fusion protein of type II procollagen. We show that this ELISA is highly specific for circulating PIIANP and has adequate technical precision. In patients with knee osteoarthritis and rheumatoid arthritis, serum PIIANP was decreased by 53% (p type IIA collagen synthesis is altered in these arthritic diseases. The measurement of serum PIIANP may be useful for the clinical investigation of patients with joint diseases.

  19. Value of diffusion-weighted imaging in predicting parametrial invasion in stage IA2-IIA cervical cancer

    International Nuclear Information System (INIS)

    Park, Jung Jae; Kim, Chan Kyo; Park, Sung Yoon; Park, Byung Kwan; Kim, Bohyun

    2014-01-01

    To investigate the value of diffusion-weighted imaging (DWI) in evaluating parametrial invasion (PMI) in stage IA2-IIA cervical cancer. A total of 117 patients with stage IA2-IIA cervical cancer who underwent preoperative MRI and radical hysterectomy were included in this study. Preoperative clinical variables and MRI variables were analysed and compared between the groups with and without pathologically proven PMI. All variables except age were significantly different between patients with and without pathologic PMI (P < 0.05). All variables except squamous cell carcinoma (SCC) antigen were also significantly correlated with pathologic PMI on univariate analysis (P < 0.05). Multivariate analysis indicated that PMI on MRI (P < 0.001) and tumour apparent diffusion coefficient (ADC) (P = 0.029) were independent predictors of pathologic PMI. Area under the curve of PMI on MRI increased significantly from 0.793 to 0.872 when combined with tumour ADC (P = 0.002). When PMI on MRI was further stratified by tumour ADC, the false negative rate was 2.0 % (1/49). In stage IA2-IIA cervical cancer, tumour ADC and PMI on MRI seem to be independent predictors of pathologic PMI. Combining the two predictors improved the diagnostic performance of identifying patients at low risk of pathologic PMI. (orig.)

  20. Nonmuscle myosin heavy chain IIA is a critical factor contributing to the efficiency of early infection of severe fever with thrombocytopenia syndrome virus.

    Science.gov (United States)

    Sun, Yinyan; Qi, Yonghe; Liu, Chenxuan; Gao, Wenqing; Chen, Pan; Fu, Liran; Peng, Bo; Wang, Haimin; Jing, Zhiyi; Zhong, Guocai; Li, Wenhui

    2014-01-01

    Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus in the Bunyaviridae family. Most patients infected by SFTSV present with fever and thrombocytopenia, and up to 30% die due to multiple-organ dysfunction. The mechanisms by which SFTSV enters multiple cell types are unknown. SFTSV contains two species of envelope glycoproteins, Gn (44.2 kDa) and Gc (56 kDa), both of which are encoded by the M segment and are cleaved from a precursor polypeptide (about 116 kDa) in the endoplasmic reticulum (ER). Gn fused with an immunoglobulin Fc tag at its C terminus (Gn-Fc) bound to multiple cells susceptible to the infection of SFTSV and blocked viral infection of human umbilical vein endothelial cells (HUVECs). Immunoprecipitation assays following mass spectrometry analysis showed that Gn binds to nonmuscle myosin heavy chain IIA (NMMHC-IIA), a cellular protein with surface expression in multiple cell types. Small interfering RNA (siRNA) knockdown of NMMHC-IIA, but not the closely related NMMHC-IIB or NMMHC-IIC, reduced SFTSV infection, and NMMHC-IIA specific antibody blocked infection by SFTSV but not other control viruses. Overexpression of NMMHC-IIA in HeLa cells, which show limited susceptivity to SFTSV, markedly enhanced SFTSV infection of the cells. These results show that NMMHC-IIA is critical for the cellular entry of SFTSV. As NMMHC-IIA is essential for the normal functions of platelets and human vascular endothelial cells, it is conceivable that NMMHC-IIA directly contributes to the pathogenesis of SFTSV and may be a useful target for antiviral interventions against the viral infection.

  1. 30 CFR 57.22204 - Main fan operation and inspection (I-A, II-A, III, and V-A mines).

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Main fan operation and inspection (I-A, II-A, III, and V-A mines). 57.22204 Section 57.22204 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION... Main fan operation and inspection (I-A, II-A, III, and V-A mines). Main fans shall be— (a) Provided...

  2. 30 CFR 57.22205 - Doors on main fans (I-A, II-A, III, and V-A mines).

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Doors on main fans (I-A, II-A, III, and V-A... main fans (I-A, II-A, III, and V-A mines). In mines ventilated by multiple main fans, each main fan... reversal through the fan. The doors shall be located so that they are not in direct line with explosive...

  3. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V... Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). (a) Main fans shall be— (1) Installed on the... mines, provided with an automatic signal device to give an alarm when the fan stops. The signal device...

  4. Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi's sarcoma-associated herpesvirus.

    Directory of Open Access Journals (Sweden)

    Mohanan Valiya Veettil

    2010-12-01

    Full Text Available KSHV is etiologically associated with Kaposi's sarcoma (KS, an angioproliferative endothelial cell malignancy. Macropinocytosis is the predominant mode of in vitro entry of KSHV into its natural target cells, human dermal microvascular endothelial (HMVEC-d cells. Although macropinocytosis is known to be a major route of entry for many viruses, the molecule(s involved in the recruitment and integration of signaling early during macropinosome formation is less well studied. Here we demonstrate that tyrosine phosphorylation of the adaptor protein c-Cbl is required for KSHV induced membrane blebbing and macropinocytosis. KSHV induced the tyrosine phosphorylation of c-Cbl as early as 1 min post-infection and was recruited to the sites of bleb formation. Infection also led to an increase in the interaction of c-Cbl with PI3-K p85 in a time dependent manner. c-Cbl shRNA decreased the formation of KSHV induced membrane blebs and macropinocytosis as well as virus entry. Immunoprecipitation of c-Cbl followed by mass spectrometry identified the interaction of c-Cbl with a novel molecular partner, non-muscle myosin heavy chain IIA (myosin IIA, in bleb associated macropinocytosis. Phosphorylated c-Cbl colocalized with phospho-myosin light chain II in the interior of blebs of infected cells and this interaction was abolished by c-Cbl shRNA. Studies with the myosin II inhibitor blebbistatin demonstrated that myosin IIA is a biologically significant component of the c-Cbl signaling pathway and c-Cbl plays a new role in the recruitment of myosin IIA to the blebs during KSHV infection. Myosin II associates with actin in KSHV induced blebs and the absence of actin and myosin ubiquitination in c-Cbl ShRNA cells suggested that c-Cbl is also responsible for the ubiquitination of these proteins in the infected cells. This is the first study demonstrating the role of c-Cbl in viral entry as well as macropinocytosis, and provides the evidence that a signaling complex

  5. Binding of methacycline to human serum albumin at subdomain IIA using multispectroscopic and molecular modeling methods.

    Science.gov (United States)

    Dong, Chengyu; Lu, Ningning; Liu, Ying

    2013-01-01

    This study was designed to examine the interaction of methacyline (METC) with human serum albumin (HSA) by multispectroscopy and a molecular modeling method under simulative physiological conditions. The quenching mechanism was suggested to be static quenching based on fluorescence and ultraviolet-visible (UV-Vis) spectroscopy. According to the Vant' Hoff equation, the values of enthalpy (∆H) and entropy change (∆S) were calculated to be -95.29 kJ/mol and -218.13 J/mol/K, indicating that the main driving force of the interaction between HSA and METC were hydrogen bonds and van der Waals's forces. By performing displacement measurements, the specific binding of METC in the vicinity of Sudlow's site I of HSA was clarified. An apparent distance of 3.05 nm between Trp214 and METC was obtained via the fluorescence resonance energy transfer (FRET) method. Furthermore, the binding details between METC and HSA were further confirmed by molecular docking studies, which revealed that METC was bound at subdomain IIA through multiple interactions, such as hydrophobic effect, polar forces, hydrogen bonding, etc. The results of three-dimensional fluorescence and Fourier transform infrared (FTIR) spectroscopy showed that METC caused conformational and some microenvironmental changes in HSA and reduced the α-helix significantly in the range of 52.3-40.4% in HSA secondary structure. Moreover, the coexistence of metal ions such as Ca(2+), Al(3+), Fe(3+), Zn(2+), Cu(2+), Cr(3+) and Cd(2+) can decrease the binding constants of METC-HSA. Copyright © 2012 John Wiley & Sons, Ltd.

  6. The Development of IIA Method and the Application on the 1661 Luermen event

    Science.gov (United States)

    Wu, T. R.; Wu, H.; Hu, S. K.; Tsai, Y. L.

    2016-12-01

    In 1661, Chinese navy led by General Koxinga at the end of Ming Dynasty had a naval battle against the Netherlands. This battle was not only the first official sea warfare that China confronted the Western world, but also the only naval battle won by Chinese Navy so far. This case was significant because it altered the fate of Taiwan until today. Ace of the critical points that General Zheng won the battle was entering Lakjemuyse bay unexpected. Luermen bay was and is an extremely shallow bay with a 2.1m maximum water depth during the high tide, which was not possible for a fleet of 20,000 marines to cross. Hence, no defense was deployed from the Netherlands side. However, plenty of historical literatures mentioned a strange phenomenon that helped Chinese warships entered the Luermen bay, the rise of water level. In this study, we will discuss the possible causes that might rise the water level, e.g. Tsunami, storm surge, and high tide. We analyzed it based on the knowledge of hydrodynamics. We performed the newly developed Impact Intensify Analysis (IIA) for finding the potential tsunami sources, and the COMCOT tsunami model was adopted for the nonlinear scenario simulations, associated with the high resolution bathymetry data. Both earthquake and mudslide tsunamis were inspected. Other than that, we also collected the information of tide and weather for identifying the effects from high tide and storm surge. After the thorough study, a scenario that satisfies most of the descriptions in the historical literatures will be presented. The results will explain the cause of mysterious event that changed the destiny of Taiwan.

  7. Adjuvant radiotherapy following radical hysterectomy for patients with stage IB and IIA cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Soisson, A.P.; Soper, J.T.; Clarke-Pearson, D.L.; Berchuck, A.; Montana, G.; Creasman, W.T. (Duke Univ. Medical Center, Durham, NC (USA))

    1990-06-01

    From 1971 through 1984, 320 women underwent radical hysterectomy as primary therapy of stage IB and IIA cervical cancer. Two hundred forty-eight patients (78%) were treated with surgery alone and 72 patients (22%) received adjuvant postoperative external-beam radiotherapy. Presence of lymph node metastasis, large lesion (greater than 4 cm in diameter), histologic grade, race (noncaucasian), and age (greater than 40 years) were significant poor prognostic factors for the entire group of patients. Patients treated with surgery alone had a better disease-free survival than those who received combination therapy (P less than 0.001). However, patients receiving adjuvant radiation therapy had a higher incidence of lymphatic metastases, tumor involvement of the surgical margin, and large cervical lesions. Adjuvant pelvic radiation therapy did not improve the survival of patients with unilateral nodal metastases or those who had a large cervical lesion with free surgical margins and the absence of nodal involvement. Radiation therapy appears to reduce the incidence of pelvic recurrences. Unfortunately, 84% of patients who developed recurrent tumor after combination therapy had a component of distant failure. The incidence of severe gastrointestinal or genitourinary tract complications was not different in the two treatment groups. However, the incidence of lymphedema was increased in patients who received adjuvant radiation therapy. Although adjuvant radiation therapy appears to be tolerated without a significant increase in serious complications, the extent to which it may improve local control rates and survival in high-risk patients appears to be limited. In view of the high incidence of distant metastases in high-risk patients, consideration should be given to adjuvant systemic chemotherapy in addition to radiation therapy.

  8. Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa.

    Science.gov (United States)

    Pierrache, Laurence H M; Hartel, Bas P; van Wijk, Erwin; Meester-Smoor, Magda A; Cremers, Frans P M; de Baere, Elfride; de Zaeytijd, Julie; van Schooneveld, Mary J; Cremers, Cor W R J; Dagnelie, Gislin; Hoyng, Carel B; Bergen, Arthur A; Leroy, Bart P; Pennings, Ronald J E; van den Born, L Ingeborgh; Klaver, Caroline C W

    2016-05-01

    USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. Clinic-based, longitudinal, multicenter study. Consecutive patients with Usher syndrome type IIa (n = 152) and nonsyndromic RP (n = 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium. Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow-up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis. Low vision and blindness. Participant groups had similar distributions of gender (48% vs. 45% males in Usher syndrome type IIa vs. nonsydromic RP; P = 0.8), ethnicity (97% vs. 99% European; P = 0.3), and median follow-up time (6.5 years vs. 3 years; P = 0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25%) and nonsyndromic RP (19%): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations. Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  9. A snake venom group IIA PLA2 with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ2 in macrophages.

    Science.gov (United States)

    Giannotti, Karina Cristina; Leiguez, Elbio; Carvalho, Ana Eduarda Zulim de; Nascimento, Neide Galvão; Matsubara, Márcio Hideki; Fortes-Dias, Consuelo Latorre; Moreira, Vanessa; Teixeira, Catarina

    2017-06-22

    Crotoxin B (CB) is a catalytically active group IIA sPLA 2 from Crotalus durissus terrificus snake venom. In contrast to most GIIA sPLA 2 s, CB exhibits anti-inflammatory effects, including the ability to inhibit leukocyte functions. Lipid droplets (LDs) are lipid-rich organelles associated with inflammation and recognized as a site for the synthesis of inflammatory lipid mediators. Here, the ability of CB to induce formation of LDs and the mechanisms involved in this effect were investigated in isolated macrophages. The profile of CB-induced 15-d-PGJ 2 (15-Deoxy-Delta-12,14-prostaglandin J 2 ) production and involvement of LDs in 15-d-PGJ 2 biosynthesis were also investigated. Stimulation of murine macrophages with CB induced increased number of LDs and release of 15-d-PGJ 2 . LDs induced by CB were associated to PLIN2 recruitment and expression and required activation of PKC, PI3K, MEK1/2, JNK, iPLA 2 and PLD. Both 15-d-PGJ 2 and COX-1 were found in CB-induced LDs indicating that LDs contribute to the inhibitory effects of CB by acting as platform for synthesis of 15-d-PGJ 2 , a pro-resolving lipid mediator. Together, our data indicate that an immunomodulatory GIIA sPLA 2 can directly induce LD formation and production of a pro-resolving mediator in an inflammatory cell and afford new insights into the roles of LDs in resolution of inflammatory processes.

  10. Class IIa bacteriocin resistance in Enterococcus faecalis V583: The mannose PTS operon mediates global transcriptional responses

    Directory of Open Access Journals (Sweden)

    Opsata Mona

    2010-08-01

    Full Text Available Abstract Background The class IIa bacteriocin, pediocin PA-1, has clear potential as food preservative and in the medical field to be used against Gram negative pathogen species as Enterococcus faecalis and Listeria monocytogenes. Resistance towards class IIa bacteriocins appear in laboratory and characterization of these phenotypes is important for their application. To gain insight into bacteriocin resistance we studied mutants of E. faecalis V583 resistant to pediocin PA-1 by use of transcriptomic analyses. Results Mutants of E. faecalis V583 resistant to pediocin PA-1 were isolated, and their gene expression profiles were analyzed and compared to the wild type using whole-genome microarray. Significantly altered transcription was detected from about 200 genes; most of them encoding proteins involved in energy metabolism and transport. Glycolytic genes were down-regulated in the mutants, but most of the genes showing differential expression were up-regulated. The data indicate that the mutants were relieved from glucose repression and putative catabolic responsive elements (cre could be identified in the upstream regions of 70% of the differentially expressed genes. Bacteriocin resistance was caused by reduced expression of the mpt operon encoding the mannose-specific phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS, and the same transcriptional changes were seen in a mptD-inactivated mutant. This mutant also had decreased transcription of the whole mpt operon, showing that the PTS is involved in its own transcriptional regulation. Conclusion Our data confirm the important role of mannose PTS in class IIa bacteriocin sensitivity and we demonstrate its importance involving global carbon catabolite control.

  11. A Precision Measurement of the W Boson Mass with 1 Inverse Femtobarn of DZero Run IIa Data

    Energy Technology Data Exchange (ETDEWEB)

    Osta, Jyotsna [Univ. of Notre Dame, IN (United States)

    2009-12-01

    This thesis is a detailed presentation of a precision measurement of the mass of the W boson. It has been obtained by analyzing W → ev decays. The data used for this analysis was collected from 2002 to 2006 with the D0 detector, during Run IIa of the Fermilab Tevatron collider. It corresponds to a total integrated luminosity of 1 fb-1. With a sample of 499,830 W → ev candidate events, we obtain a mass measurement of MW = 80.401 ± 0.043 GeV. This is the most precise measurement from a single experiment to date.

  12. Role of acetate in production of an autoinducible Class IIa Bacteriocin in Carnobacterium piscicola A9b

    DEFF Research Database (Denmark)

    Nilsson, Lilian; Nielsen, Michael Krogsgaard; Ng, Yin

    2002-01-01

    was to purify the compound and describe factors affecting its production, with particular emphasis on food-relevant factors. Amino acid sequencing showed that the compound is a class IIa bacteriocin with an N-terminal amino acid sequence identical to that of carnobacteriocin B2. The production....... The induction of bacteriocin production showed a dose-dependent relationship at acetate concentrations of up to 10 to 20 mM (depending on the growth medium) and at a concentration of 1.9 x 10(-8) M for the bacteriocin itself; a saturation level of bacteriocin specific activity was reached...

  13. Functional analysis of two PLA2G2A variants associated with secretory phospholipase A2-IIA levels.

    Directory of Open Access Journals (Sweden)

    Holly J Exeter

    Full Text Available Secretory phospholipase A2 group IIA (sPLA2-IIA has been identified as a biomarker of atherosclerosis in observational and animal studies. The protein is encoded by the PLA2G2A gene and the aim of this study was to test the functionality of two PLA2G2A non-coding SNPs, rs11573156 C>G and rs3767221 T>G where the rare alleles have been previously associated with higher and lower sPLA2-IIA levels respectively.Luciferase assays, electrophoretic mobility shift assays (EMSA, and RNA expression by RT-PCR were used to examine allelic differences. For rs3767221 the G allele showed ∼55% lower luciferase activity compared to the T allele (T = 62.1 (95% CI 59.1 to 65.1 G = 27.8 (95% CI 25.0 to 30.6, p = 1.22×10⁻³⁵, and stronger EMSA binding of a nuclear protein compared to the T-allele. For rs11573156 C >G there were no luciferase or EMSA allelic differences seen. In lymphocyte cell RNA, from individuals of known rs11573156 genotype, there was no allelic RNA expression difference for exons 5 and 6, but G allele carriers (n = 7 showed a trend to lower exon 1-2 expression compared to CC individuals. To take this further, in the ASAP study (n = 223, an rs11573156 proxy (r² = 0.91 showed ∼25% higher liver expression of PLA2G2A (1.67×10⁻¹⁷ associated with the G allele. However, considering exon specific expression, the association was greatly reduced for exon 2 (4.5×10⁻⁵ compared to exons 3-6 (10⁻¹⁰ to 10⁻²⁰, suggesting rs11573156 G allele-specific exon 2 skipping.Both SNPs are functional and provide useful tools for Mendelian Randomisation to determine whether the relationship between sPLA2-IIA and coronary heart disease is causal.

  14. A densitometric analysis of IIaO film flown aboard the space shuttle transportation system STS #3, 7, and 8

    Science.gov (United States)

    Hammond, Ernest C., Jr.

    1989-01-01

    Since the United States of America is moving into an age of reusable space vehicles, both electronic and photographic materials will continue to be an integral part of the recording techniques available. Film as a scientifically viable recording technique in astronomy is well documented. There is a real need to expose various types of films to the Shuttle environment. Thus, the main objective was to look at the subtle densitometric changes of canisters of IIaO film that was placed aboard the Space Shuttle 3 (STS-3).

  15. Retrospective case-control study of surgical treatment of stage IB-IIA cervical carcinomas after neoadjuvant radiotherapy

    International Nuclear Information System (INIS)

    Cigriejiene, V. M.; Kajenas, S.; Balnys, M.; Mikuckaite, L.

    2004-01-01

    To evaluate if preoperative radiotherapy influences course of operation (radical hysterectomy and lymphadenectomy) and postoperative period in series of stage IB-IIA cervical carcinomas. Retrospective comparative study was performed. During the study we analyzed 101 case histories of patients who underwent radical type II hysterectomy with lymphadenectomy in Kaunas University of Medicine Hospital and Kaunas Hospital of Oncology between 1995 and 2002. Mean operation time was shorter, hemoglobin and hematocrit values after operation were better, stay in hospital was longer, demand for narcotic analgetics was bigger, function of ovaries was maintained more rarely (p 0.05). In our study, preoperative radiotherapy did not seem to complicate course of radical hysterectomy. (author)

  16. Advanced Start of Combustion Sensor Phases I and II-A: Feasibility Demonstration, Design and Optimization

    Energy Technology Data Exchange (ETDEWEB)

    Chad Smutzer

    2010-01-31

    Homogeneous Compressed Charge Ignition (HCCI) has elevated the need for Start of Combustion (SOC) sensors. HCCI engines have been the exciting focus of engine research recently, primarily because HCCI offers higher thermal efficiency than the conventional Spark Ignition (SI) engines and significantly lower NOx and soot emissions than conventional Compression Ignition (CI) engines, and could be fuel neutral. HCCI has the potential to unify all the internal combustion engine technology to achieve the high-efficiency, low-emission goal. However, these advantages do not come easy. It is well known that the problems encountered with HCCI combustion center on the difficulty of controlling the Start of Combustion. TIAX has an SOC sensor under development which has shown promise. In previous work, including a DOE-sponsored SBIR project, TIAX has developed an accelerometer-based method which was able to determine SOC within a few degrees crank angle for a range of operating conditions. A signal processing protocol allows reconstruction of the combustion pressure event signal imbedded in the background engine vibration recorded by the accelerometer. From this reconstructed pressure trace, an algorithm locates the SOC. This SOC sensor approach is nonintrusive, rugged, and is particularly robust when the pressure event is strong relative to background engine vibration (at medium to high engine load). Phase I of this project refined the previously developed technology with an engine-generic and robust algorithm. The objective of the Phase I research was to answer two fundamental questions: Can the accelerometer-based SOC sensor provide adequate SOC event capture to control an HCCI engine in a feedback loop? And, will the sensor system meet cost, durability, and software efficiency (speed) targets? Based upon the results, the answer to both questions was 'YES'. The objective of Phase II-A was to complete the parameter optimization of the SOC sensor prototype in order

  17. Genetic organization of ascB-dapE internalin cluster serves as a potential marker for Listeria monocytogenes sublineages IIA, IIB, and IIC.

    Science.gov (United States)

    Chen, Jianshun; Fang, Chun; Zhu, Ningyu; Lv, Yonghui; Cheng, Changyong; Bei, Yijiang; Zheng, Tianlun; Fang, Weihuan

    2012-05-01

    Listeria monocytogenes is an important foodborne pathogen that comprises four genetic lineages: I, II, III, and IV. Of these, lineage II is frequently recovered from foods and environments and responsible for the increasing incidence of human listeriosis. In this study, the phylogenetic structure of lineage II was determined through sequencing analysis of the ascB-dapE internalin cluster. Fifteen sequence types proposed by multilocus sequence typing based on nine housekeeping genes were grouped into three distinct sublineages, IIA, IIB, and IIC. Organization of the ascBdapE internalin cluster could serve as a molecular marker for these sublineages, with inlGHE, inlGC2DE, and inlC2DE for IIA, IIB, and IIC, respectively. These sublineages displayed specific genetic and phenotypic characteristics. IIA and IIC showed a higher frequency of recombination (rho/theta). However, recombination events had greater effect (r/m) on IIB, leading to its high nucleotide diversity. Moreover, IIA and IIB harbored a wider range of internalin and stress-response genes, and possessed higher nisin tolerance, whereas IIC contained the largest portion of low-virulent strains owing to premature stop codons in inlA. The results of this study indicate that IIA, IIB, and IIC might occupy different ecological niches, and IIB might have a better adaptation to a broad range of environmental niches.

  18. An Amperometric Biosensor for the Determination of Bacterial Sepsis Biomarker, Secretory Phospholipase Group 2-IIA Using a Tri-Enzyme System

    Directory of Open Access Journals (Sweden)

    Nik Nurhanan Nik Mansor

    2018-02-01

    Full Text Available A tri-enzyme system consisting of choline kinase/choline oxidase/horseradish peroxidase was used in the rapid and specific determination of the biomarker for bacterial sepsis infection, secretory phospholipase Group 2-IIA (sPLA2-IIA. These enzymes were individually immobilized onto the acrylic microspheres via succinimide groups for the preparation of an electrochemical biosensor. The reaction of sPLA2-IIA with its substrate initiated a cascading enzymatic reaction in the tri-enzyme system that led to the final production of hydrogen peroxide, which presence was indicated by the redox characteristics of potassium ferricyanide, K3Fe(CN6. An amperometric biosensor based on enzyme conjugated acrylic microspheres and gold nanoparticles composite coated onto a carbon-paste screen printed electrode (SPE was fabricated and the current measurement was performed at a low potential of 0.20 V. This enzymatic biosensor gave a linear range 0.01–100 ng/mL (R2 = 0.98304 with a detection limit recorded at 5 × 10−3 ng/mL towards sPLA2-IIA. Moreover, the biosensor showed good reproducibility (relative standard deviation (RSD of 3.04% (n = 5. The biosensor response was reliable up to 25 days of storage at 4 °C. Analysis of human serum samples for sPLA2-IIA indicated that the biosensor has potential for rapid bacterial sepsis diagnosis in hospital emergency department.

  19. Influence of fast and slow alkali myosin light chain isoforms on the kinetics of stretch-induced force transients of fast-twitch type IIA fibres of rat.

    Science.gov (United States)

    Andruchov, Oleg; Galler, Stefan

    2008-03-01

    This study contributes to understand the physiological role of slow myosin light chain isoforms in fast-twitch type IIA fibres of skeletal muscle. These isoforms are often attached to the myosin necks of rat type IIA fibres, whereby the slow alkali myosin light chain isoform MLC1s is much more frequent and abundant than the slow regulatory myosin light chain isoform MLC2s. In the present study, single-skinned rat type IIA fibres were maximally Ca(2+) activated and subjected to stepwise stretches for causing a perturbation of myosin head pulling cycles. From the time course of the resulting force transients, myosin head kinetics was deduced. Fibres containing MLC1s exhibited slower kinetics independently of the presence or absence of MLC2s. At the maximal MLC1s concentration of about 75%, the slowing was about 40%. The slowing effect of MLC1s is possibly due to differences in the myosin heavy chain binding sites of the fast and slow alkali MLC isoforms, which changes the rigidity of the myosin neck. Compared with the impact of myosin heavy chain isoforms in various fast-twitch fibre types, the influence of MLC1s on myosin head kinetics of type IIA fibres is much smaller. In conclusion, the physiological role of fast and slow MLC isoforms in type IIA fibres is a fine-tuning of the myosin head kinetics.

  20. Phase IIA and IIB experiments of JAERI/U.S.DOE collaborative program on fusion blanket neutronics

    International Nuclear Information System (INIS)

    Oyama, Yukio

    1989-12-01

    Phase IIA and IIB experiments on fusion blanket neutronics has been performed on a basis of JAERI/USDOE collaborative program. In the Phase II experimental series, a D-T neutron source and a test blanket were contained by a lithium-carbonate enclosure to adjust the incident neutron spectrum to the test blanket so as to simulate that of a fusion reactor. First two series of the Phase II, IIA and IIB, focused especially on influences of beryllium configurations for neutron multiplying zone to neutronic parameters. Measured parameters were tritium production rate using Li-glass and NE213 scintillators, and Li-metal foil and Lithium-oxide block with liquid scintillation technique; neutron spectrum using NE213 scintillator and proton recoil proportional counter; reaction rate using foil activation technique. These parameters were compared among six different beryllium configurations of the experimental system. Consistency between different techniques for each measured parameter was also tested among different experimental systems and confirmed to be within experimental errors. This report describes, in detail, experimental conditions, assemblies, equipments and neutron source in Part I. The part II compiles all information required for a calculational analysis of this experiment, e.g., dimensions of the target room, target assembly, experimental assembly, their material densities and numerical data of experimental results. This compilation provides benchmark data to test calculation models and computing code systems used for a nuclear design of a fusion reactor. (author)

  1. The novel kasugamycin 2'-N-acetyltransferase gene aac(2')-IIa, carried by the IncP island, confers kasugamycin resistance to rice-pathogenic bacteria.

    Science.gov (United States)

    Yoshii, Atsushi; Moriyama, Hiromitsu; Fukuhara, Toshiyuki

    2012-08-01

    Kasugamycin (KSM), a unique aminoglycoside antibiotic, has been used in agriculture for many years to control not only rice blast caused by the fungus Magnaporthe grisea but also rice bacterial grain and seedling rot or rice bacterial brown stripe caused by Burkholderia glumae or Acidovorax avenae subsp. avenae, respectively. Since both bacterial pathogens are seed-borne and cause serious injury to rice seedlings, the emergence of KSM-resistant B. glumae and A. avenae isolates highlights the urgent need to understand the mechanism of resistance to KSM. Here, we identified a novel gene, aac(2')-IIa, encoding a KSM 2'-N-acetyltransferase from both KSM-resistant pathogens but not from KSM-sensitive bacteria. AAC(2')-IIa inactivates KSM, although it reveals no cross-resistance to other aminoglycosides. The aac(2')-IIa gene from B. glumae strain 5091 was identified within the IncP genomic island inserted into the bacterial chromosome, indicating the acquisition of this gene by horizontal gene transfer. Although excision activity of the IncP island and conjugational gene transfer was not detected under the conditions tested, circular intermediates containing the aac(2')-IIa gene were detected. These results indicate that the aac(2')-IIa gene had been integrated into the IncP island of a donor bacterial species. Molecular detection of the aac(2')-IIa gene could distinguish whether isolates are resistant or susceptible to KSM. This may contribute to the production of uninfected rice seeds and lead to the effective control of these pathogens by KSM.

  2. Preoperatively Assessable Clinical and Pathological Risk Factors for Parametrial Involvement in Surgically Treated FIGO Stage IB-IIA Cervical Cancer.

    Science.gov (United States)

    Canaz, Emel; Ozyurek, Eser Sefik; Erdem, Baki; Aldikactioglu Talmac, Merve; Yildiz Ozaydin, Ipek; Akbayir, Ozgur; Numanoglu, Ceyhun; Ulker, Volkan

    2017-10-01

    Determining the risk factors associated with parametrial involvement (PMI) is of paramount importance to decrease the multimodality treatment in early-stage cervical cancer. We investigated the preoperatively assessable clinical and pathological risk factors associated with PMI in surgically treated stage IB1-IIA2 cervical cancer. A retrospective cohort study of women underwent Querleu-Morrow type C hysterectomy for cervical cancer stage IB1-IIA2 from 2001 to 2015. All patients underwent clinical staging examination under anesthesia by the same gynecological oncologists during the study period. Evaluated variables were age, menopausal status, body mass index, smoking status, FIGO (International Federation of Obstetrics and Gynecology) stage, clinically measured maximal tumor diameter, clinical presentation (exophytic or endophytic tumor), histological type, tumor grade, lymphovascular space invasion, clinical and pathological vaginal invasion, and uterine body involvement. Endophytic clinical presentation was defined for ulcerative tumors and barrel-shaped morphology. Two-dimensional transvaginal ultrasonography was used to measure tumor dimensions. Of 127 eligible women, 37 (29.1%) had PMI. On univariate analysis, endophytic clinical presentation (P = 0.01), larger tumor size (P PMI. In multivariate analysis endophytic clinical presentation (odds ratio, 11.34; 95% confidence interval, 1.34-95.85; P = 0.02) and larger tumor size (odds ratio, 32.31; 95% confidence interval, 2.46-423.83; P = 0.008) were the independent risk factors for PMI. Threshold of 31 mm in tumor size predicted PMI with 71% sensitivity and 75% specificity. We identified 18 patients with tumor size of more than 30 mm and endophytic presentation; 14 (77.7%) of these had PMI. Endophytic clinical presentation and larger clinical tumor size (>3 cm) are independent risk factors for PMI in stage IB-IIA cervical cancer. Approximately 78% of the patients with a tumor size of more than 3 cm and endophytic

  3. ATP6V0A2 mutations present in two Mexican Mestizo children with an autosomal recessive cutis laxa syndrome type IIA

    Directory of Open Access Journals (Sweden)

    D. Bahena-Bahena

    2014-01-01

    Full Text Available Patients with ARCL-IIA harbor mutations in ATP6V0A2 that codes for an organelle proton pump. The ARCL-IIA syndrome characteristically presents a combined glycosylation defect affecting N-linked and O-linked glycosylations, differentiating it from other cutis laxa syndromes and classifying it as a Congenital Disorder of Glycosylation (ATP6V0A2-CDG. We studied two Mexican Mestizo patients with a clinical phenotype corresponding to an ARCL-IIA syndrome. Both patients presented abnormal transferrin (N-linked glycosylation but Patient 1 had a normal ApoCIII (O-linked glycosylation profile. Mutational screening of ATP6V0A2 using cDNA and genomic DNA revealed in Patient 1 a previously reported homozygous nonsense mutation c.187C>T (p.R63X associated with a novel clinical finding of a VSD. In Patient 2 we found a homozygous c.2293C>T (p.Q765X mutation that had been previously reported but found that it also altered RNA processing generating a novel transcript not previously identified (r.2176_2293del; p.F726Sfs*10. This is the first report to describe Mestizo patients with molecular diagnosis of ARCL-IIA/ATP6V0A2-CDG and to establish that their mutations are the first to be found in patients from different regions of the world and with different genetic backgrounds.

  4. A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa

    NARCIS (Netherlands)

    Hartel, B.P.; Lofgren, M.; Huygen, P.L.; Guchelaar, I.; Lo, A.N.K.N.; Sadeghi, A.M.; van Wijk, E.; Tranebjaerg, L.; Kremer, H.; Kimberling, W.J.; Cremers, C.W.R.J.; Moller, C.; Pennings, R.J.

    2016-01-01

    OBJECTIVES: Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates

  5. Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa

    NARCIS (Netherlands)

    Pierrache, Laurence H. M.; Hartel, Bas P.; van Wijk, Erwin; Meester-Smoor, Magda A.; Cremers, Frans P. M.; de Baere, Elfride; de Zaeytijd, Julie; van Schooneveld, Mary J.; Cremers, Cor W. R. J.; Dagnelie, Gislin; Hoyng, Carel B.; Bergen, Arthur A.; Leroy, Bart P.; Pennings, Ronald J. E.; van den Born, L. Ingeborgh; Klaver, Caroline C. W.

    2016-01-01

    USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. Clinic-based, longitudinal, multicenter study.

  6. Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa

    NARCIS (Netherlands)

    Pierrache, Laurence H M; Hartel, Bas P; van Wijk, Erwin; Meester-Smoor, Magda A; Cremers, Frans P M; de Baere, Elfride; de Zaeytijd, Julie; van Schooneveld, Mary J; Cremers, Cor W R J; Dagnelie, Gislin; Hoyng, Carel B; Bergen, Arthur A; Leroy, Bart P; Pennings, Ronald J E; van den Born, L Ingeborgh; Klaver, Caroline C W

    2016-01-01

    PURPOSE: USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. DESIGN: Clinic-based, longitudinal,

  7. Differential impacts of clinical variables and 5-fluorouracil-based adjuvant chemotherapy on 5-year disease-free survival of patients with stage IIa and IIb colon cancer

    Directory of Open Access Journals (Sweden)

    Yi-Hung Kuo

    2018-01-01

    Conclusion: Different predictors of DFS were observed in stage IIa and IIb colon cancer; adjuvant chemotherapy could provide a survival benefit for patients with stage IIb colon cancer who have one of the four factors that were studied in our hospital-based analysis.

  8. Comparative analysis of the long-term results of treatment in patients with Stages I-IIa breast cancer in relation to major prognostic factors

    Directory of Open Access Journals (Sweden)

    Yu. V. Efimkina

    2010-01-01

    Full Text Available The analysis of the long-term results of treatment in patients with Stages I-IIa breast cancer in relation to major prognostic factors re- vealed poor morphological factors that greatly influenced the lifespan of female patients, such as tumor invasion along the neural fibers, tumor necrosis, cancer emboli in the lymph gaps and vessels, vascular tumor invasion.

  9. One-point functions of non-SUSY operators at arbitrary genus in a matrix model for type IIA superstrings

    International Nuclear Information System (INIS)

    Kuroki, Tsunehide; Sugino, Fumihiko

    2017-01-01

    In the previous paper, the authors pointed out correspondence between a supersymmetric double-well matrix model and two-dimensional type IIA superstring theory on a Ramond–Ramond background from the viewpoint of symmetry and spectrum. This was confirmed by agreement between planar correlation functions in the matrix model and tree-level amplitudes in the superstring theory. In order to investigate the correspondence further, in this paper we compute correlation functions to all order of genus expansion in the double scaling limit of the matrix model. One-point functions of operators protected by supersymmetry terminate at some finite order, whereas those of unprotected operators yield non-Borel summable series. The behavior of the latter is characteristic in string perturbation series, providing further evidence that the matrix model describes a string theory. Moreover, instanton corrections to the planar one-point functions are also computed, and universal logarithmic scaling behavior is found for non-supersymmetric operators.

  10. One-point functions of non-SUSY operators at arbitrary genus in a matrix model for type IIA superstrings

    Energy Technology Data Exchange (ETDEWEB)

    Kuroki, Tsunehide, E-mail: kuroki@dg.kagawa-nct.ac.jp [General Eduction, National Institute of Technology, Kagawa College, 551 Kohda, Takuma-cho, Mitoyo, Kagawa 769-1192 (Japan); Sugino, Fumihiko, E-mail: fusugino@gmail.com [Okayama Institute for Quantum Physics, Furugyocho 1-7-36, Naka-ku, Okayama 703-8278 (Japan)

    2017-06-15

    In the previous paper, the authors pointed out correspondence between a supersymmetric double-well matrix model and two-dimensional type IIA superstring theory on a Ramond–Ramond background from the viewpoint of symmetry and spectrum. This was confirmed by agreement between planar correlation functions in the matrix model and tree-level amplitudes in the superstring theory. In order to investigate the correspondence further, in this paper we compute correlation functions to all order of genus expansion in the double scaling limit of the matrix model. One-point functions of operators protected by supersymmetry terminate at some finite order, whereas those of unprotected operators yield non-Borel summable series. The behavior of the latter is characteristic in string perturbation series, providing further evidence that the matrix model describes a string theory. Moreover, instanton corrections to the planar one-point functions are also computed, and universal logarithmic scaling behavior is found for non-supersymmetric operators.

  11. Intraoperative validation of CT-based lymph nodal levels, sublevels IIa and IIb: Is it of clinical relevance in selective radiation therapy?

    International Nuclear Information System (INIS)

    Levendag, Peter; Gregoire, Vincent; Hamoir, Marc; Voet, Peter; Est, Henrie van der; Heijmen, Ben; Kerrebijn, Jeroen

    2005-01-01

    Purpose: The objectives of this study are to discuss the intraoperative validation of CT-based boundaries of lymph nodal levels in the neck, and in particular the clinical relevance of the delineation of sublevels IIa and IIb in case of selective radiation therapy (RT). Methods and Materials: To validate the radiologically defined level contours, clips were positioned intraoperatively at the level boundaries defined by surgical anatomy. In 10 consecutive patients, clips were placed, at the time of a neck dissection being performed, at the most cranial border of the neck. Anterior-posterior and lateral X-ray films were obtained intraoperatively. Next, in 3 patients, neck levels were contoured on preoperative contrast-enhanced CT scans according to the international consensus guidelines. From each of these 3 patients, an intraoperative CT scan was also obtained, with clips placed at the surgical-anatomy-based level boundaries. The preoperative (CT-based) and intraoperative (surgery-defined) CT scans were matched. Results: Clips placed at the most cranial part of the neck lined up at the caudal part of the transverse process of the cervical vertebra C-I. The posterior border of surgical level IIa (spinal accessory nerve [SAN]) did not match with the posterior border of CT-based level IIa (internal jugular vein [IJV]). Other surgical boundaries and CT-based contours were in good agreement. Conclusions: The cranial border of the neck, i.e., the cranial border of level IIa/IIb, corresponds to the caudal edge of the lateral process of C-I. Except for the posterior border between level IIa and level IIb, a perfect match was observed between the other surgical-clip-identified levels II-V boundaries (surgical-anatomy) and the CT-based delineation contours. It is argued that (1) because of the parotid gland overlapping part of level II, and (2) the frequent infestation of occult metastatic cells in the lymph channels around the IJV, the division of level II into radiologic

  12. Maltaricin CPN, a new class IIa bacteriocin produced by Carnobacterium maltaromaticum CPN isolated from mould-ripened cheese.

    Science.gov (United States)

    Hammi, I; Delalande, F; Belkhou, R; Marchioni, E; Cianferani, S; Ennahar, S

    2016-11-01

    The purpose of this study was to isolate, characterize and determine the structure and the antibacterial activities of a bacteriocin produced by Carnobacterium maltaromaticum CPN, a strain isolated from unpasteurized milk Camembert cheese. This bacteriocin, termed maltaricin CPN, was produced at higher amounts in MRS broth at temperatures between 15°C and 25°C. It was purified to homogeneity from culture supernatant by using a simple method consisting of cation-exchange and reversed-phase chromatographies. Mass spectrometry showed that maltaricin was a 4427·29 Da bacteriocin. Its amino acid sequence was determined by Edman degradation which showed that it had close similarity with bacteriocins of the class IIa. Maltaricin CPN consisted in fact of 44 unmodified amino acids including two cysteine residues at positions 9 and 14 linked by a disulphide bond. The antimicrobial activity of maltaricin CPN covered a range of bacteria, with strong activity against many species of Gram-positive bacteria, especially the food-borne pathogen Listeria monocytogenes, but no activity against Gram-negative ones. In the studied conditions, C. maltaromaticum CPN produced a new class IIa bacteriocin with strong anti-Listeria activity. The study covers the purification and the structural characterization of a new bacteriocin produced by strain C. maltaromaticum CPN isolated from Camembert cheese. Its activity against strains of L. monocytogenes and higher production rates at relatively low temperatures show potential technological applications to improve the safety of refrigerated food. © 2016 The Society for Applied Microbiology.

  13. Involvement of P-glycoprotein and multidrug resistance associated protein 1 in the transport of tanshinone IIB, a primary active diterpenoid quinone from the roots of Salvia miltiorrhiza, across the blood-brain barrier.

    Science.gov (United States)

    Zhou, Zhi-Wei; Chen, Xiao; Liang, Jun; Yu, Xi-Yong; Wen, Jing-Yuan; Zhou, Shu-Feng

    2007-08-01

    Tanshinone IIB (TSB) is a major constituent of Salvia miltiorrhiza, which is widely used in treatment of cardiovascular and central nervous system (CNS) diseases such as coronary heart disease and stroke. This study aimed to investigate the role of various drug transporters in the brain penetration of TSB using several in vitro and in vivo mouse and rat models. The uptake and efflux of TSB in rat primary microvascular endothelial cells (RBMVECs) were ATP-dependent and significantly altered in the presence of a P-glycoprotein (P-gp) or multidrug resistance associated protein (Mrp1/2) inhibitor. A polarized transport of TSB was found in RBMVEC monolayers with facilitated efflux from the abluminal to luminal side. Addition of a P-gp inhibitor (e.g. verapamil) in both abluminal and luminal sides attenuated the polarized transport. In an in situ rat brain perfusion model, TSB crossed the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier at a greater rate than that for sucrose, and the brain penetration was increased in the presence of a P-gp or Mrp1/2 inhibitor. The brain levels of TSB were only about 30% of that in the plasma and it could be increased to up to 72% of plasma levels when verapamil, quinidine, or probenecid was co-administered in rats. The entry of TSB to CNS increased by 67-97% in rats subjected to middle cerebral artery occlusion or treatment with the neurotoxin, quinolinic acid, compared to normal rats. Furthermore, The brain levels of TSB in mdr1a(-/-) and mrp1(-/-) mice were 28- to 2.6-fold higher than those in the wild-type mice. TSB has limited brain penetration through the BBB due to the contribution of P-gp and to a lesser extent of Mrp1 in rodents. Further studies are needed to confirm whether these corresponding transporters in humans are involved in limiting the penetration of TSB across the BBB and the clinical relevance.

  14. Inhibition of B cell proliferation by antisense DNA to both alpha and beta forms of Fc epsilon R II.

    Science.gov (United States)

    Bhatti, L; Behle, K; Stevens, R H

    1992-10-01

    Epstein-Barr Virus (EBV) infection activates B lymphocyte proliferation through partially understood mechanisms, resulting in phenotypic changes, including the appearance of new antigens. One such antigen is Fc epsilon R II/CD-23 which may be relevant for B cell proliferation. We have used anti-sense oligonucleotides to study the importance of the two forms of this molecule for proliferation in the EBV-transformed, Fc epsilon R II +ve lymphoblastoid B cell line, RPMI 8866. Anti-sense oligodeoxynucleotides were generated to the two forms of Fc epsilon R II; Fc epsilon R IIa (alpha) and IIb (beta) which differ only in their intracytoplasmic domains. Addition of increasing concentrations of anti-sense oligonucleotides, ranging from 1 to 30 microM, significantly decreased cellular proliferation as measured by the incorporation of [3H]thymidine (inhibition range 8-88%). Optimum inhibition of cellular proliferation was apparent at 15 microM concentration of both anti-sense Fc epsilon R IIa and IIb (Fc epsilon R IIa, mean +/- SE = 75 +/- 7% inhibition, p less than 0.001; Fc epsilon R IIb, mean +/- SE = 71 +/- 7% inhibition, p less than 0.001). Anti-sense oligonucleotides complementary to the common part of Fc epsilon R II resulted in a similar inhibition of proliferation. Sense oligonucleotides did not induce significant inhibition. Preincubation of sense and anti-sense oligonucleotides resulted in an abrogation of proliferation inhibition. Moreover, none of these oligonucleotides had any effect on a Fc epsilon R II -ve cell line. Incubation with both anti-sense IIa and IIb resulted in additive, but not synergistic inhibition of proliferation. Addition of soluble Fc epsilon R II did not reverse inhibition of proliferation, suggesting that membrane-bound or intracellular rather than soluble Fc epsilon R II was important for the induced proliferation. Analysis of cell surface expression for Fc epsilon II indicated that while there was a pronounced effect on cell number

  15. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  16. Preoperative radium therapy and radical hysterectomy in the treatment of cervical cancer stage IB, IIA, and initial IIB.; Radiumterapia pre-operatoria e histerectomia radical no tratamento do cancer do colo uterino IB, IIA e IIB inicial

    Energy Technology Data Exchange (ETDEWEB)

    Salum, Resalla; Lopes, Edison R.; Souza, Maria A.H. de [Faculdade de Medicina do Triangulo Mineiro, Uberaba, MG (Brazil). Hospital Escola

    1995-07-01

    Patients with IB, IIa and in initial IIb cervical cancer were randomized for combined therapy, consisting of one or two radium insertion followed by Wertheim Meigs operation performed 40 days later. We look for the early and late complications of the treatment, residual cancer after radiotherapy and survival without recurrence. The project begin in 1965 and ended in 1986. All the operations were done by one of the investigators and 116 patients were analysed. The age ranged from 21 to 75 years with an average of 4.18 years. During the operations 31 (26.72%) patients needed 1.500 cc or greater amount of blood transfusion and we have 3 iliac veins lesions. Managing the ureters, we do our best to leave the posterior fascia as intact as possible. Post operative complications ranged from minor (fever, localised pelvic infections, temporary popliteal nerve paralysis) to evisceration (3 patients) deep venous thrombosis (3 patients) and two early urinary fistulas. Late complications were seen in patients submitted to sequential teletherapy irradiation. One uretrovaginal fistula occurred 10 month after treatment, another one, 7 years later and the third one 24 years later. One patient develop hydronefrosis and enterocolite after 7.000 rads of teletherapy and another one rectovaginal fistula 13 years after initial therapy. The shortening of the vagina making impossible the intercourse was seen in 7 patients. By the histological examination, the cervix was sterilized in 73.3 % of the patients. Residual cancer was found according the original size of the tumour and the stage of the disease. Studying different combinations between the existence of residual cervical cancer with positive or negative limphnodes and making a correlation with survival, we found the critical points is to have positive cervix and positive lymphonodes. The five years survival (life table methodology) for stage 1 lesion was 96%; stage II, 67%. At ten years survival was slighted different. With positive

  17. Primary radiotherapy of stage IIA/B-IIIB cervical carcinoma. A comparison of continuous versus sequential regimens

    International Nuclear Information System (INIS)

    Mayer, A.; Nemeskeri, C.; Petnehazi, C.; Varga, S.; Naszaly, A.; Borgulya, G.

    2004-01-01

    Background: comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B-IIIB cervical carcinoma. Patients and methods: 210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 x 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 x 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68-70 Gy to point A and 52-54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i.e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5-4.2) years. Results: progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837). Conclusion: for the patients included in this study, no advantage has been found so far in using CRT, i.e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per

  18. Preoperative radium therapy and radical hysterectomy in the treatment of cervical cancer stage IB, IIA, and initial IIB

    International Nuclear Information System (INIS)

    Salum, Resalla; Lopes, Edison R.; Souza, Maria A.H. de

    1995-01-01

    Patients with IB, IIa and in initial IIb cervical cancer were randomized for combined therapy, consisting of one or two radium insertion followed by Wertheim Meigs operation performed 40 days later. We look for the early and late complications of the treatment, residual cancer after radiotherapy and survival without recurrence. The project begin in 1965 and ended in 1986. All the operations were done by one of the investigators and 116 patients were analysed. The age ranged from 21 to 75 years with an average of 4.18 years. During the operations 31 (26.72%) patients needed 1.500 cc or greater amount of blood transfusion and we have 3 iliac veins lesions. Managing the ureters, we do our best to leave the posterior fascia as intact as possible. Post operative complications ranged from minor (fever, localised pelvic infections, temporary popliteal nerve paralysis) to evisceration (3 patients) deep venous thrombosis (3 patients) and two early urinary fistulas. Late complications were seen in patients submitted to sequential teletherapy irradiation. One uretrovaginal fistula occurred 10 month after treatment, another one, 7 years later and the third one 24 years later. One patient develop hydronefrosis and enterocolite after 7.000 rads of teletherapy and another one rectovaginal fistula 13 years after initial therapy. The shortening of the vagina making impossible the intercourse was seen in 7 patients. By the histological examination, the cervix was sterilized in 73.3 % of the patients. Residual cancer was found according the original size of the tumour and the stage of the disease. Studying different combinations between the existence of residual cervical cancer with positive or negative limphnodes and making a correlation with survival, we found the critical points is to have positive cervix and [positive lymphonodes. The five years survival (life table methodology) for stage 1 lesion was 96%; stage II, 67%. At ten years survival was slighted different. With positive

  19. A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa

    DEFF Research Database (Denmark)

    Hartel, Bas P.; Lofgren, Maria; Huygen, Patrick L. M.

    2016-01-01

    Objectives Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates...... the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations. Design...... A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA...

  20. Correlation between tumor size and surveillance of lymph node metastasis for IB and IIA cervical cancer by magnetic resonance images

    International Nuclear Information System (INIS)

    Kim, See Hyung; Lee, Hee Jung; Kim, Young Whan

    2012-01-01

    Purpose: To assess the feasibility of preoperative MRI based measurement of tumor size with regard to lymph node (LN) metastasis in early uterine cervical cancer. Material and Methods: A retrospective review of patients with FIGO stage IB–IIA cervical cancer who underwent lymphadenectomy was performed. Diagnostic accuracy of MRI in detecting LN metastasis and rate of LN recurrence in terms of tumor size (≤4 cm versus >4 cm) were analyzed. ROC curve analysis was used to determine LN size for differentiating LN metastasis in terms of tumor size. P 4 cm revealed higher diagnostic accuracy of MRI in detecting LN metastasis (85.4% versus 50.6%, P = 0.023) and rate of LN recurrence (20.0% versus 6.4%, P = 0.031) in than those with size with ≤4 cm, the differences were statistically significant. Discriminant analysis of LN size for the differentiation of metastasis from non-metastasis resulted in cut-off values (11.8 mm; size with >4 cm versus 8.3 mm; size with ≤4 cm) and diagnostic accuracy (84.0% of size with >4 cm versus 72.0% of size with ≤4 cm). Conclusion: MRI has limited sensitivity, but high specificity in predicting surveillance of LN metastasis in the preoperative early cervical cancer, especially useful tool for patients with tumor size with >4 cm.

  1. Dlc1 interaction with non-muscle myosin heavy chain II-A (Myh9 and Rac1 activation

    Directory of Open Access Journals (Sweden)

    Mohammad G. Sabbir

    2016-04-01

    Full Text Available The Deleted in liver cancer 1 (Dlc1 gene codes for a Rho GTPase-activating protein that also acts as a tumour suppressor gene. Several studies have consistently found that overexpression leads to excessive cell elongation, cytoskeleton changes and subsequent cell death. However, none of these studies have been able to satisfactorily explain the Dlc1-induced cell morphological phenotypes and the function of the different Dlc1 isoforms. Therefore, we have studied the interacting proteins associated with the three major Dlc1 transcriptional isoforms using a mass spectrometric approach in Dlc1 overexpressing cells. We have found and validated novel interacting partners in constitutive Dlc1-expressing cells. Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9, plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. These data support a role for Dlc1 in induced cell elongation morphology and provide some molecular targets for further analysis of this phenotype.

  2. One-point functions of non-SUSY operators at arbitrary genus in a matrix model for type IIA superstrings

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    Tsunehide Kuroki

    2017-06-01

    Full Text Available In the previous paper, the authors pointed out correspondence between a supersymmetric double-well matrix model and two-dimensional type IIA superstring theory on a Ramond–Ramond background from the viewpoint of symmetry and spectrum. This was confirmed by agreement between planar correlation functions in the matrix model and tree-level amplitudes in the superstring theory. In order to investigate the correspondence further, in this paper we compute correlation functions to all order of genus expansion in the double scaling limit of the matrix model. One-point functions of operators protected by supersymmetry terminate at some finite order, whereas those of unprotected operators yield non-Borel summable series. The behavior of the latter is characteristic in string perturbation series, providing further evidence that the matrix model describes a string theory. Moreover, instanton corrections to the planar one-point functions are also computed, and universal logarithmic scaling behavior is found for non-supersymmetric operators.

  3. Classification of criticality calculations with correlation coefficient method and its application to OECD/NEA burnup credit benchmarks phase III-A and II-A

    International Nuclear Information System (INIS)

    Okuno, Hiroshi

    2003-01-01

    A method for classifying benchmark results of criticality calculations according to similarity was proposed in this paper. After formulation of the method utilizing correlation coefficients, it was applied to burnup credit criticality benchmarks Phase III-A and II-A, which were conducted by the Expert Group on Burnup Credit Criticality Safety under auspices of the Nuclear Energy Agency of the Organisation for Economic Cooperation and Development (OECD/NEA). Phase III-A benchmark was a series of criticality calculations for irradiated Boiling Water Reactor (BWR) fuel assemblies, whereas Phase II-A benchmark was a suite of criticality calculations for irradiated Pressurized Water Reactor (PWR) fuel pins. These benchmark problems and their results were summarized. The correlation coefficients were calculated and sets of benchmark calculation results were classified according to the criterion that the values of the correlation coefficients were no less than 0.15 for Phase III-A and 0.10 for Phase II-A benchmarks. When a couple of benchmark calculation results belonged to the same group, one calculation result was found predictable from the other. An example was shown for each of the Benchmarks. While the evaluated nuclear data seemed the main factor for the classification, further investigations were required for finding other factors. (author)

  4. Platelet half-life in patients with primary hyperlipoproteinemia type IIa, IIb, and IV according to Fredrickson with and without clinical signs of atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Jaeger, E; Sinzinger, H; Widhalm, K; Kaliman, J; Hoefer, R [Vienna Univ. (Austria). 2. Medizinische Klinik; Ludwig Boltzmann-Institut fuer Nuklearmedizin, Vienna (Austria); Vienna Univ. (Austria). Kinderklinik; Vienna Univ. (Austria). Kardiologische Klinik)

    1982-09-01

    It is generally accepted that platelet half-life is shortened in atherosclerotic vascular diseases. Concerning changes due to hyperlipoproteinemia (HLP), however, there exist only few data. Therefore, we examined the platelet-half life in 60 patients with recently discovered HLP type IIa, IIb and IV according to Fredrickson before treatment in comparison to 60 controls. 33 of the HLP-patients had no clinical symptoms of angiopathy. 27 patients suffered from peripheral vascular disease or from coronary heart disease as verified by angiography. The labelling of autologous platelets was performed with 100..mu..Ci of /sup 111/Indium-oxine-sulfate at 37/sup 0/C for 5 minutes. The mean labelling efficiency was 90%, the recovery after 2 hours about 70%. Serum lipoproteins were estimated by means of ultracentrifugation and polyanionprecipitation according to Lipid Research Clinic Methods. In the patients with HLP platelet half-life was significantly shortened in comparison to the control group (p < 0.01). These changes were most pronounced in patients with HLP-type IIa and with atherosclerotic lesions, respectively. In patients with HLP-type IIa a very close correlation could be demonstrated between platelet half-life and LDL-cholesterol (r = -0.72; p < 0.001) as well as total cholesterol (r = -0.73; p < 0.001). These data prove that in HLP in-vivo platelet function as measured by platelet survival is significantly influenced even before the occurrence of clinically relevant symptoms of atherosclerosis.

  5. Randomized study of preoperative radiation and surgery or irradiation alone in the treatment of Stage IB and IIA carcinoma of the uterine cervix

    International Nuclear Information System (INIS)

    Perez, C.A.; Camel, H.M.; Kao, M.S.; Askin, F.

    1980-01-01

    A prospective randomized study in selected patients with Stage IB and IIA carcinoma of the uterine cervix was carried out. Patients were randomized to be treated with 1) irradiation alone consisting of 1000 rad whole pelvis, additional 4000 rads to the parametria with a step wedge midline block, and two intracavitary insertions for 7500 mgh; and 2) irradiation and surgery, consisting of 2000 rad whole pelvis irradiation, one intracavitary insertion for 5000 to 6000 mgh followed in two to six weeks later by a radical hysterectomy with pelvic lymphadenectomy. The five-year, tumor-free actuarial survival for Stage IB patients treated with radiation was 87% and with preoperative radiation and surgery 82%. In Stage IIA, the actuarial five-year survival NED was 57% for the irradiation alone group and 71% for the patients treated with preoperative radiation and radical hysterectomy. Major complications of therapy were slightly higher in the patients trated with radiation alone (9.4%, consisting of one recto-vaginal fistula and one vesico-vaginal fistula and a combined recto-vesico-vaginal fistula in another patient). In the preoperative radiation group, only two ureteral strictures (4.1%) were noted. The present study shows no significant difference in therapeutic results or morbidity for invasive carcinoma of the uterine cervix Stage IB or IIA treated with irradiation alone or combined with a radical hysterectomy

  6. A National-Level Validation of the New American Joint Committee on Cancer 8th Edition Subclassification of Stage IIA and B Anal Squamous Cell Cancer.

    Science.gov (United States)

    Goffredo, Paolo; Garancini, Mattia; Robinson, Timothy J; Frakes, Jessica; Hoshi, Hisakazu; Hassan, Imran

    2018-06-01

    The 8th edition of the American Joint Committee on Cancer (AJCC) updated the staging system of anal squamous cell cancer (ASCC) by subdividing stage II into A (T2N0M0) and B (T3N0M0) based on a secondary analysis of the RTOG 98-11 trial. We aimed to validate this new subclassification utilizing two nationally representative databases. The National Cancer Database (NCDB) [2004-2014] and the Surveillance, Epidemiology, and End Results (SEER) database [1988-2013] were queried to identify patients with stage II ASCC. A total of 6651 and 2579 stage IIA (2-5 cm) and 1777 and 641 stage IIB (> 5 cm) patients were identified in the NCDB and SEER databases, respectively. Compared with stage IIB patients, stage IIA patients within the NCDB were more often females with fewer comorbidities. No significant differences were observed between age, race, receipt of chemotherapy and radiation, and mean radiation dose. Demographic, clinical, and pathologic characteristics were comparable between patients in both datasets. The 5-year OS was 72% and 69% for stage IIA versus 57% and 50% for stage IIB in the NCDB and SEER databases, respectively (p  5 cm) in the general ASCC population. AJCC stage IIB patients represent a higher risk category that should be targeted with more aggressive/novel therapies.

  7. A densitometric analysis of IIaO film flown aboard the space shuttle transportation system STS-3, STS-8, and STS-7

    Science.gov (United States)

    Hammond, E. C., Jr.; Peters, K. A.; Atkinson, P. F.

    1986-01-01

    Three canisters of IIaO film were prepared along with packets of color film from the National Geographic Society, which were then placed on the Space Shuttle #3. The ultimate goal was to obtain reasonably accurate data concerning the background fogging effects on IIaO film as it relates to the film's total environmental experience. This includes: the ground based packing, and loading of the film from Goddard Space Flight Center to Cape Kennedy; the effects of the solar wind, humidity, and cosmic rays; the Van Allen Belt radiation exposure; various thermal effect; reentry and off-loading of the film during take off, and 8 day, 3 hour 15 minutes orbits. The total densitometric change caused by all of the above factors were examined. The results of these studies have implications for the utilization of IIaO spectroscopic film on the future shuttle and space lab missions. These responses to standard photonic energy sources will have immediate application for the uneven responses of the film photographing a star field in a terrestrial or extraterrestrial environment with associated digital imaging equipment.

  8. Co-Circulation of Canine Coronavirus I and IIa/b with High Prevalence and Genetic Diversity in Heilongjiang Province, Northeast China.

    Directory of Open Access Journals (Sweden)

    Xinyu Wang

    Full Text Available To trace the evolution of canine coronavirus (CCoV, 201 stool samples from diarrheic dogs in northeast China were subjected to reverse transcription-polymerase chain reactions (RT-PCRs targeting the partial M and S genes of CCoV, followed by an epidemiological analysis. M gene RT-PCRs showed that 28.36% (57/201 of the samples were positive for CCoV; of the 57 positive samples, CCoV-I and CCoV-II accounted for 15.79% (9/57 and 84.21% (48/57, respectively. A sequence comparison of the partial M gene revealed nucleotide homologies of 88.4%-100% among the 57 CCoV strains, and 88.7%-96.2% identity between the 57 CCoV strains and the Chinese reference strain HF3. The CCoV-I and CCoV-II strains exhibited genetic diversity when compared with reference strains from China and other countries. The 57 CCoV strains exhibited high co-infection rates with canine kobuvirus (CaKV (33.33% and canine parvovirus-2 (CPV-2 (31.58%. The CCoV prevalence in diarrheic dogs differed significantly with immunization status, regions, seasons, and ages. Moreover, 28 S genes were amplified from the 57 CCoV-positive samples, including 26 CCoV-IIa strains, one CCoV-IIb strain, and one CCoV-I strain. A sequence comparison of the partial S gene revealed 86.3%-100% nucleotide identity among the 26 CCoV-IIa strains, and 89.6%-92.2% identity between the 26 CCoV-IIa strains and the Chinese reference strain V1. The 26 CCoV-IIa strains showed genetic diversity when compared with reference strains from China and other countries. Our data provide evidence that CCoV-I, CCoV-IIa, and CCoV-IIb strains co-circulate in the diarrhoetic dogs in northeast China, high co-infection rates with CaKV and CPV-2 were observed, and the CCoV-II strains exhibited high prevalence and genetic diversity.

  9. Elevated tumor-to-liver uptake ratio (TLR) from 18F-FDG-PET/CT predicts poor prognosis in stage IIA colorectal cancer following curative resection

    International Nuclear Information System (INIS)

    Huang, Jun; Huang, Liang; Zhou, Jiaming; Huang, Pinzhu; Tan, Shuyun; Wang, Jianping; Huang, Meijin; Duan, Yinghua; Zhang, Zhanwen; Hu, Ping; Wang, Xiaoyan

    2017-01-01

    The prognostic value of the tumor-to-liver uptake ratio (TLR) from 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) in the early stage of colorectal cancer (CRC) is unclear. Notably, some stage IIA CRC patients experience early recurrence even after curative resection and might benefit from neoadjuvant or adjuvant chemotherapy. This study aims to evaluate whether elevated TLR from 18 F-FDG-PET/CT can predict poor prognosis in stage IIA CRC patients undergoing curative resection. From April 2010 to December 2013, 504 consecutive CRC patients with different TNM stages (I-IV) underwent 18 F-FDG-PET/CT scans at the 6th Affiliated Hospital of Sun Yat-Sen University. Among the patients, 118 with stage IIA CRC who accepted preoperative 18 F-FDG-PET/CT scanning and were treated with curative surgery alone were reviewed retrospectively. The maximum standardized uptake value (SUVmax) in the primary tumor, TLR, and demographic, clinical, histopathological, and laboratory data were analyzed. Receiver operating characteristic (ROC) curve, univariate and multivariate analyses were performed to identify prognostic factors associated with patient disease-free survival (DFS) and overall survival (OS). ROC curve analysis demonstrated that TLR was superior to primary tumor SUVmax in predicting the risk of recurrence in stage IIA CRC. The optimal TLR cutoff was 6.2. Univariate analysis indicated that elevated TLR, tumor size, and lymphovascular/neural invasion correlated with DFS (P = 0.001, P = 0.002, and P = 0.001, respectively) and OS (P = 0.001, P = 0.003, and P < 0.001, respectively). The 1-, 3-, and 5-year DFS rates were 98.4%, 96.9%, and 96.9% for stage IIA CRC patients with lower TLR (≤6.2) versus 77.8%, 60.6%, and 60.6% for those with elevated TLR (>6.2), respectively. The 1-, 3-, and 5-year OS rates were 100.0%, 100.0%, and 98.3% for the patients with lower TLR versus 98.1%, 83.3%, and 74.3% for those with elevated TLR. Cox

  10. Elevated tumor-to-liver uptake ratio (TLR) from {sup 18}F-FDG-PET/CT predicts poor prognosis in stage IIA colorectal cancer following curative resection

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Jun; Huang, Liang; Zhou, Jiaming; Huang, Pinzhu; Tan, Shuyun; Wang, Jianping; Huang, Meijin [6th Affiliated Hospital, Sun Yat-sen University, Department of Colorectal Surgery, Guangzhou, Guangdong (China); Duan, Yinghua [1st Affiliated Hospital, Sun Yat-sen University, Department of Traditional Chinese Medicine, Guangzhou (China); Zhang, Zhanwen; Hu, Ping [6th Affiliated Hospital, Sun Yat-sen University, Department of Nuclear Medicine, Guangzhou (China); Wang, Xiaoyan [1st Affiliated Hospital, Sun Yat-sen University, Department of Nuclear Medicine, Guangzhou (China)

    2017-11-15

    The prognostic value of the tumor-to-liver uptake ratio (TLR) from 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG-PET/CT) in the early stage of colorectal cancer (CRC) is unclear. Notably, some stage IIA CRC patients experience early recurrence even after curative resection and might benefit from neoadjuvant or adjuvant chemotherapy. This study aims to evaluate whether elevated TLR from {sup 18}F-FDG-PET/CT can predict poor prognosis in stage IIA CRC patients undergoing curative resection. From April 2010 to December 2013, 504 consecutive CRC patients with different TNM stages (I-IV) underwent {sup 18}F-FDG-PET/CT scans at the 6th Affiliated Hospital of Sun Yat-Sen University. Among the patients, 118 with stage IIA CRC who accepted preoperative {sup 18}F-FDG-PET/CT scanning and were treated with curative surgery alone were reviewed retrospectively. The maximum standardized uptake value (SUVmax) in the primary tumor, TLR, and demographic, clinical, histopathological, and laboratory data were analyzed. Receiver operating characteristic (ROC) curve, univariate and multivariate analyses were performed to identify prognostic factors associated with patient disease-free survival (DFS) and overall survival (OS). ROC curve analysis demonstrated that TLR was superior to primary tumor SUVmax in predicting the risk of recurrence in stage IIA CRC. The optimal TLR cutoff was 6.2. Univariate analysis indicated that elevated TLR, tumor size, and lymphovascular/neural invasion correlated with DFS (P = 0.001, P = 0.002, and P = 0.001, respectively) and OS (P = 0.001, P = 0.003, and P < 0.001, respectively). The 1-, 3-, and 5-year DFS rates were 98.4%, 96.9%, and 96.9% for stage IIA CRC patients with lower TLR (≤6.2) versus 77.8%, 60.6%, and 60.6% for those with elevated TLR (>6.2), respectively. The 1-, 3-, and 5-year OS rates were 100.0%, 100.0%, and 98.3% for the patients with lower TLR versus 98.1%, 83.3%, and 74.3% for those with

  11. Reappraisal of VAChT-Cre: Preference in slow motor neurons innervating type I or IIa muscle fibers.

    Science.gov (United States)

    Misawa, Hidemi; Inomata, Daijiro; Kikuchi, Miseri; Maruyama, Sae; Moriwaki, Yasuhiro; Okuda, Takashi; Nukina, Nobuyuki; Yamanaka, Tomoyuki

    2016-11-01

    VAChT-Cre.Fast and VAChT-Cre.Slow mice selectively express Cre recombinase in approximately one half of postnatal somatic motor neurons. The mouse lines have been used in various studies with selective genetic modifications in adult motor neurons. In the present study, we crossed VAChT-Cre lines with a reporter line, CAG-Syp/tdTomato, in which synaptophysin-tdTomato fusion proteins are efficiently sorted to axon terminals, making it possible to label both cell bodies and axon terminals of motor neurons. In the mice, Syp/tdTomato fluorescence preferentially co-localized with osteopontin, a recently discovered motor neuron marker for slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) types. The fluorescence did not preferentially co-localize with matrix metalloproteinase-9, a marker for fast-twitch fatigable (FF) motor neurons. In the neuromuscular junctions, Syp/tdTomato fluorescence was detected mainly in motor nerve terminals that innervate type I or IIa muscle fibers. These results suggest that the VAChT-Cre lines are Cre-drivers that have selectivity in S and FR motor neurons. In order to avoid confusion, we have changed the mouse line names from VAChT-Cre.Fast and VAChT-Cre.Slow to VAChT-Cre.Early and VAChT-Cre.Late, respectively. The mouse lines will be useful tools to study slow-type motor neurons, in relation to physiology and pathology. © 2016 Wiley Periodicals, Inc.

  12. High resolution melting analysis for the detection of EMS induced mutations in wheat SbeIIa genes

    Directory of Open Access Journals (Sweden)

    Botticella Ermelinda

    2011-11-01

    Full Text Available Abstract Background Manipulation of the amylose-amylopectin ratio in cereal starch has been identified as a major target for the production of starches with novel functional properties. In wheat, silencing of starch branching enzyme genes by a transgenic approach reportedly caused an increase of amylose content up to 70% of total starch, exhibiting novel and interesting nutritional characteristics. In this work, the functionality of starch branching enzyme IIa (SBEIIa has been targeted in bread wheat by TILLING. An EMS-mutagenised wheat population has been screened using High Resolution Melting of PCR products to identify functional SNPs in the three homoeologous genes encoding the target enzyme in the hexaploid genome. Results This analysis resulted in the identification of 56, 14 and 53 new allelic variants respectively for SBEIIa-A, SBEIIa-B and SBEIIa-D. The effects of the mutations on protein structure and functionality were evaluated by a bioinformatic approach. Two putative null alleles containing non-sense or splice site mutations were identified for each of the three homoeologous SBEIIa genes; qRT-PCR analysis showed a significant decrease of their gene expression and resulted in increased amylose content. Pyramiding of different single null homoeologous allowed to isolate double null mutants showing an increase of amylose content up to 21% compared to the control. Conclusion TILLING has successfully been used to generate novel alleles for SBEIIa genes known to control amylose content in wheat. Single and double null SBEIIa genotypes have been found to show a significant increase in amylose content.

  13. Inulin based glutathione-responsive delivery system for colon cancer treatment.

    Science.gov (United States)

    Wang, Dongdong; Sun, Feifei; Lu, Chunbo; Chen, Peng; Wang, Zhaojie; Qiu, Yuanhao; Mu, Haibo; Miao, Zehong; Duan, Jinyou

    2018-05-01

    Colorectal cancer is one of the most common types of tumor in the world. Here we developed a lipoic acid esterified polysaccharide (inulin) delivery system for tanshinone IIA to treat colorectal cancer in vitro. The release of tanshinone IIA in the system was highly responsive to glutathione, which is commonly abundant in cancer cells. In addition, this drug delivery system was proliferative to Bifidobacterium longum, the common inhabitant of human intestine. Thus, this strategy might be useful to improve colon cancer therapy efficacy of anticancer drugs and meanwhile promote the growth of beneficial commensal flora in the gut. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Metabolic profiles and cDNA-AFLP analysis of Salvia miltiorrhiza and Salvia castanea Diel f. tomentosa Stib.

    Directory of Open Access Journals (Sweden)

    Dongfeng Yang

    Full Text Available Plants of the genus Salvia produce various types of phenolic compounds and tanshinones which are effective for treatment of coronary heart disease. Salvia miltiorrhiza and S. castanea Diels f. tomentosa Stib are two important members of the genus. In this study, metabolic profiles and cDNA-AFLP analysis of four samples were employed to identify novel genes potentially involved in phenolic compounds and tanshinones biosynthesis, including the red roots from the two species and two tanshinone-free roots from S. miltiorrhiza. The results showed that the red roots of S. castanea Diels f. tomentosa Stib produced high contents of rosmarinic acid (21.77 mg/g and tanshinone IIA (12.60 mg/g, but low content of salvianolic acid B (1.45 mg/g. The red roots of S. miltiorrhiza produced high content of salvianolic acid B (18.69 mg/g, while tanshinones accumulation in this sample was much less than that in S. castanea Diels f. tomentosa Stib. Tanshinones were not detected in the two tanshinone-free samples, which produced high contents of phenolic compounds. A cDNA-AFLP analysis with 128 primer pairs revealed that 2300 transcript derived fragments (TDFs were differentially expressed among the four samples. About 323 TDFs were sequenced, of which 78 TDFs were annotated with known functions through BLASTX searching the Genbank database and 14 annotated TDFs were assigned into secondary metabolic pathways through searching the KEGGPATHWAY database. The quantitative real-time PCR analysis indicated that the expression of 9 TDFs was positively correlated with accumulation of phenolic compounds and tanshinones. These TDFs additionally showed coordinated transcriptional response with 6 previously-identified genes involved in biosynthesis of tanshinones and phenolic compounds in S. miltiorrhiza hairy roots treated with yeast extract. The sequence data in the present work not only provided us candidate genes involved in phenolic compounds and tanshinones biosynthesis

  15. Analysis of the type II-A CRISPR-Cas system of Streptococcus agalactiae reveals distinctive features according to genetic lineages

    Science.gov (United States)

    Lier, Clément; Baticle, Elodie; Horvath, Philippe; Haguenoer, Eve; Valentin, Anne-Sophie; Glaser, Philippe; Mereghetti, Laurent; Lanotte, Philippe

    2015-01-01

    CRISPR-Cas systems (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) are found in 90% of archaea and about 40% of bacteria. In this original system, CRISPR arrays comprise short, almost unique sequences called spacers that are interspersed with conserved palindromic repeats. These systems play a role in adaptive immunity and participate to fight non-self DNA such as integrative and conjugative elements, plasmids, and phages. In Streptococcus agalactiae, a bacterium implicated in colonization and infections in humans since the 1960s, two CRISPR-Cas systems have been described. A type II-A system, characterized by proteins Cas9, Cas1, Cas2, and Csn2, is ubiquitous, and a type I–C system, with the Cas8c signature protein, is present in about 20% of the isolates. Unlike type I–C, which appears to be non-functional, type II-A appears fully functional. Here we studied type II-A CRISPR-cas loci from 126 human isolates of S. agalactiae belonging to different clonal complexes that represent the diversity of the species and that have been implicated in colonization or infection. The CRISPR-cas locus was analyzed both at spacer and repeat levels. Major distinctive features were identified according to the phylogenetic lineages previously defined by multilocus sequence typing, especially for the sequence type (ST) 17, which is considered hypervirulent. Among other idiosyncrasies, ST-17 shows a significantly lower number of spacers in comparison with other lineages. This characteristic could reflect the peculiar virulence or colonization specificities of this lineage. PMID:26124774

  16. Radioactive waste disposal implications of extending Part IIA of the Environmental Protection Act to cover radioactively contaminated land.

    Science.gov (United States)

    Nancarrow, D J; White, M M

    2004-03-01

    A short study has been carried out of the potential radioactive waste disposal issues associated with the proposed extension of Part IIA of the Environmental Protection Act 1990 to include radioactively contaminated land, where there is no other suitable existing legislation. It was found that there is likely to be an availability problem with respect to disposal at landfills of the radioactive wastes arising from remediation. This is expected to be principally wastes of high volume and low activity (categorised as low level waste (LLW) and very low level waste (VLLW)). The availability problem results from a lack of applications by landfill operators for authorisation to accept LLW wastes for disposal. This is apparently due to perceived adverse publicity associated with the consultation process for authorisation coupled with uncertainty over future liabilities. Disposal of waste as VLLW is limited both by questions over volumes that may be acceptable and, more fundamentally, by the likely alpha activity of wastes (originating from radium and thorium operations). Authorised on-site disposal has had little attention in policy and guidance in recent years, but may have a part to play, especially if considered commercially attractive. Disposal at BNFL's near surface disposal facility for LLW at Drigg is limited to wastes for which there are no practical alternative disposal options (and preference has been given to operational type wastes). Therefore, wastes from the radioactively contaminated land (RCL) regime are not obviously attractive for disposal to Drigg. Illustrative calculations have been performed based on possible volumes and activities of RCL arisings (and assuming Drigg's future volumetric disposal capacity is 950,000 m3). These suggest that wastes arising from implementing the RCL regime, if all disposed to Drigg, would not represent a significant fraction of the volumetric capacity of Drigg, but could have a significant impact on the radiological

  17. Radioactive waste disposal implications of extending Part IIA of the Environmental Protection Act to cover radioactively contaminated land

    International Nuclear Information System (INIS)

    Nancarrow, D J; White, M M

    2004-01-01

    A short study has been carried out of the potential radioactive waste disposal issues associated with the proposed extension of Part IIA of the Environmental Protection Act 1990 to include radioactively contaminated land, where there is no other suitable existing legislation. It was found that there is likely to be an availability problem with respect to disposal at landfills of the radioactive wastes arising from remediation. This is expected to be principally wastes of high volume and low activity (categorised as low level waste (LLW) and very low level waste (VLLW)). The availability problem results from a lack of applications by landfill operators for authorisation to accept LLW wastes for disposal. This is apparently due to perceived adverse publicity associated with the consultation process for authorisation coupled with uncertainty over future liabilities. Disposal of waste as VLLW is limited both by questions over volumes that may be acceptable and, more fundamentally, by the likely alpha activity of wastes (originating from radium and thorium operations). Authorised on-site disposal has had little attention in policy and guidance in recent years, but may have a part to play, especially if considered commercially attractive. Disposal at BNFL's near surface disposal facility for LLW at Drigg is limited to wastes for which there are no practical alternative disposal options (and preference has been given to operational type wastes). Therefore, wastes from the radioactively contaminated land (RCL) regime are not obviously attractive for disposal to Drigg. Illustrative calculations have been performed based on possible volumes and activities of RCL arisings (and assuming Drigg's future volumetric disposal capacity is 950 000 m 3 ). These suggest that wastes arising from implementing the RCL regime, if all disposed to Drigg, would not represent a significant fraction of the volumetric capacity of Drigg, but could have a significant impact on the radiological

  18. Risk strata-based therapy and outcome in stage Ib-IIa carcinoma cervix: single-centre ten-year experience.

    Science.gov (United States)

    Kundargi, Rajshekar S; Guruprasad, B; Rathod, Praveen Shankar; Shakuntala, Pn; Shobha, K; Pallavi, Vr; Uma Devi, K; Bafna, Ud

    2013-01-01

    To review the outcome of stage (Ib, IIa), cervical cancer patients were primarily treated with radical hysterectomy and risk-based postoperative therapy. Between January 2001 and December 2011, 601 cases underwent surgery followed by tailored therapy. Patients were classified into low risk (pelvic lymph node negative, tumour less than 4 cm, no evidence of lympho-vascular invasion, less than one-third of thickness of surgical stoma involved), intermediate risk (positive lympho-vascular space invasion, tumour size more than 4 cm, and deep invasion of cervical stroma), and high risk (pelvic lymph node involved, positive parametrial, or vaginal margins) groups. Postoperative adju-vant therapy in the form of radiotherapy alone to those with intermediate risk and chemo-radiotherapy to those with high risk was given to patients. The median follow-up was 60 months. The majority of patients had intermediate risk. The overall event-free survival (EFS) at five years was 74.37%, with EFS of 86.5% in those from the low-risk group, 73% in those from the intermediate-risk group, and 64% in those from the high-risk group. In conclusion, risk strata-based adjuvant postoperative therapy is able to provide a favourable outcome in patients with stage Ib-IIa cervical cancer with a nearly 11% improvement in survival compared with historical control.

  19. Is vitamin D hypothesis for schizophrenia valid? Independent segregation of psychosis in a family with vitamin-D-dependent rickets type IIA.

    Science.gov (United States)

    Ozer, Suzan; Uluşahin, Aylin; Ulusoy, Semra; Okur, Hamza; Coşkun, Turgay; Tuncali, Timur; Göğüş, Ahmet; Akarsu, A Nurten

    2004-03-01

    The vitamin D hypothesis of schizophrenia is a recent concept bringing together old observations on environmental risk factors and new findings on the neurodevelopmental effects of vitamin D. Candidate genes related to the vitamin D endocrine system have not yet been fully explored for this purpose. The coexistence of vitamin-D-dependent-rickets type II with alopecia (VDDR IIA) and different forms of psychosis in the same inbred family has provided us with an opportunity to investigate the presumed relationship between vitamin D deficiency and psychosis. Psychiatric examination and molecular genetic studies were performed in this family overloaded with psychotic disorders and VDDR IIA. Forty members were evaluated in order to describe their phenotypic features. The family was tested for a linkage to the chromosome 12q12-q14 region where the vitamin D receptor (VDR) gene is located. Psychosis was the common phenotype in the 18 psychiatrically affected members. Pedigree analysis did not show a cosegregation of psychosis and rickets. Lod scores were not significant to prove a linkage between psychosis and VDR locus. The authors concluded that (1) the neurodevelopmental consequences of vitamin D deficiency do not play a causative role in psychotic disorders, (2) these two syndromes are inherited independently, and (3) vitamin D deficiency does not act as a risk factor in subjects susceptible to psychosis.

  20. Detection of HTLV-IIa in blood donors in an urban area of the Amazon Region of Brazil (Belém, PA

    Directory of Open Access Journals (Sweden)

    Ishak R.

    1998-01-01

    Full Text Available The human lymphotropic viruses type I (HTLV-I and type II (HTLV-II are members of a group of mammalian retroviruses with similar biological properties, and blood transfusion is an important route of transmission. HTLV-I is endemic in a number of different geographical areas and is associated with several clinical disorders. HTLV-II is endemic in several Indian groups of the Americas and intravenous drug abusers in North and South America, Europe and Southeast Asia. During the year of 1995, all blood donors tested positive to HTLV-I/II in the State Blood Bank (HEMOPA, were directed to a physician and to the Virus Laboratory at the Universidade Federal do Pará for counselling and laboratory diagnosis confirmation. Thirty-five sera were tested by an enzyme immune assay, and a Western blot that discriminates HTLV-I and HTLV-II infection. Two HTLV-II positive samples were submitted to PCR analysis of pX and env genomic region, and confirmed to be of subtype IIa. This is the first detection in Belém of the presence of HTLV-IIa infection among blood donors. This result emphasizes that HTLV-II is also present in urban areas of the Amazon region of Brazil and highlights the need to include screening tests that are capable to detect antibodies for both types of HTLV.

  1. The Novel Kasugamycin 2′-N-Acetyltransferase Gene aac(2′)-IIa, Carried by the IncP Island, Confers Kasugamycin Resistance to Rice-Pathogenic Bacteria

    Science.gov (United States)

    Moriyama, Hiromitsu; Fukuhara, Toshiyuki

    2012-01-01

    Kasugamycin (KSM), a unique aminoglycoside antibiotic, has been used in agriculture for many years to control not only rice blast caused by the fungus Magnaporthe grisea but also rice bacterial grain and seedling rot or rice bacterial brown stripe caused by Burkholderia glumae or Acidovorax avenae subsp. avenae, respectively. Since both bacterial pathogens are seed-borne and cause serious injury to rice seedlings, the emergence of KSM-resistant B. glumae and A. avenae isolates highlights the urgent need to understand the mechanism of resistance to KSM. Here, we identified a novel gene, aac(2′)-IIa, encoding a KSM 2′-N-acetyltransferase from both KSM-resistant pathogens but not from KSM-sensitive bacteria. AAC(2′)-IIa inactivates KSM, although it reveals no cross-resistance to other aminoglycosides. The aac(2′)-IIa gene from B. glumae strain 5091 was identified within the IncP genomic island inserted into the bacterial chromosome, indicating the acquisition of this gene by horizontal gene transfer. Although excision activity of the IncP island and conjugational gene transfer was not detected under the conditions tested, circular intermediates containing the aac(2′)-IIa gene were detected. These results indicate that the aac(2′)-IIa gene had been integrated into the IncP island of a donor bacterial species. Molecular detection of the aac(2′)-IIa gene could distinguish whether isolates are resistant or susceptible to KSM. This may contribute to the production of uninfected rice seeds and lead to the effective control of these pathogens by KSM. PMID:22660700

  2. Altered inhibition in Tuberous Sclerosis and Type IIb cortical dysplasia

    Science.gov (United States)

    Talos, Delia M.; Sun, Hongyu; Kosaras, Bela; Joseph, Annelise; Folkerth, Rebecca D.; Poduri, Annapurna; Madsen, Joseph R.; Black, Peter M.; Jensen, Frances E.

    2012-01-01

    Objective The most common neurological symptom of tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) is early-life refractory epilepsy. As previous studies have shown enhanced excitatory glutamatergic neurotransmission in TSC and FCD brains, we hypothesized that neurons associated with these lesions may also express altered GABAA receptor (GABAAR)-mediated inhibition. Methods Expression of the GABAAR subunitsα1 and α4, the Na+-K+-2Cl− (NKCC1), and the K+−Cl− (KCC2) transporters in human TSC and FCD Type II specimens were analyzed by Western blot and double label immunocytochemistry. GABAAR responses in dysplastic neurons from a single case of TSC were measured by perforated-patch recording and compared to normal-appearing cortical neurons from a non-TSC epilepsy case. Results TSC and FCD Type IIb lesions demonstrated decreased expression of the GABAAR α1, increased NKCC1 and decreased KCC2 levels. In contrast, FCD Type IIa lesions showed decreased α4, and increased expression of both NKCC1 and KCC2 transporters. Patch clamp recordings from dysplastic neurons in acute slices from TSC tubers demonstrated excitatory GABAAR responses that were significantly attenuated by the NKCC1 inhibitor bumetanide, in contrast to hyperpolarizing GABAAR-mediated currents in normal neurons from non-TSC cortical slices. Interpretation Expression and function of GABAARs in TSC and FCD IIb suggests the relative benzodiazepine insensitivity and more excitatory action of GABA compared to FCD IIa. These factors may contribute to resistance of seizure activity to anticonvulsants that increase GABAergic function, and may justify add-on trials of the NKCC1 inhibitor bumetanide for the treatment of TSC and FCD Type IIb related epilepsy. PMID:22447678

  3. The calibration of photographic and spectroscopic films. A densitometric analysis of IIaO film flown aboard the space shuttle transportation system STS3, STS8, and STS7

    Science.gov (United States)

    Hammond, Ernest C., Jr.

    1987-01-01

    The results of these studies have implications for the utilization of the IIaO spectroscopic film on the future shuttle and space lab missions. These responses to standard photonic energy sources will have immediate application for the uneven responses of the film photographing a star field in a terrestrial or extraterrestrial environment with associated digital imaging equipment.

  4. Serum protein profiling using an aptamer array predicts clinical outcomes of stage IIA colon cancer: A leave-one-out crossvalidation

    Science.gov (United States)

    Huh, Jung Wook; Kim, Sung Chun; Sohn, Insuk; Jung, Sin-Ho; Kim, Hee Cheol

    2016-01-01

    Background In this study, we established and validated a model for predicting prognosis of stage IIA colon cancer patients based on expression profiles of aptamers in serum. Methods Bloods samples were collected from 227 consecutive patients with pathologic T3N0M0 (stage IIA) colon cancer. We incubated 1,149 serum molecule-binding aptamer pools of clinical significance with serum from patients to obtain aptamers bound to serum molecules, which were then amplified and marked. Oligonucleotide arrays were constructed with the base sequences of the 1,149 aptamers, and the marked products identified above were reacted with one another to produce profiles of the aptamers bound to serum molecules. These profiles were organized into low- and high-risk groups of colon cancer patients based on clinical information for the serum samples. Cox proportional hazards model and leave-one-out cross-validation (LOOCV) were used to evaluate predictive performance. Results During a median follow-up period of 5 years, 29 of the 227 patients (11.9%) experienced recurrence. There were 212 patients (93.4%) in the low-risk group and 15 patients (6.6%) in the high-risk group in our aptamer prognosis model. Postoperative recurrence significantly correlated with age and aptamer risk stratification (p = 0.046 and p = 0.001, respectively). In multivariate analysis, aptamer risk stratification (p recurrence. Disease-free survival curves calculated according to aptamer risk level predicted through a LOOCV procedure and age showed significant differences (p < 0.001 from permutations). Conclusion Aptamer risk stratification can be a valuable prognostic factor in stage II colon cancer patients. PMID:26908450

  5. Phase IIa Clinical Trial of Trans-1-Amino-3-18F-Fluoro- Cyclobutane Carboxylic Acid in Metastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Yusuke Inoue

    2014-10-01

    Full Text Available Objective(s: We performed a phase IIa clinical trial of trans-1-amino-3-18Ffluoro-cyclobutane carboxylic acid (anti-18F-FACBC, a synthetic amino acid analog for PET, in patients with metastatic prostate cancer. Methods: The study subjects consisted of 10 untreated prostate cancer patients having lymph node and/or bone metastasis. Five patients underwent whole-body PET 5 and 30 min after intravenous injection of anti-18F-FACBC. The other five patients underwent 60 min dynamic PET of the pelvis. Safety assessment was performed before and 24 h after injection. PET/CT images were assessed visually, and time courses of anti-18F-FACBC uptake were evaluated from dynamic imaging. Results: Two mild adverse events were observed and resolved without treatment. All 10 patients showed increased accumulation of anti-18F-FACBC in the primary prostate lesion. CT revealed five enlarged lymph nodes indicating metastasis, and all showed increased uptake. Additionally, anti-18F-FACBC PET delineated unenlarged lymph nodes as hot spots. Anti-18F-FACBC PET demonstrated metastatic bone lesions, similar to conventional imaging. In one of two patients with lung metastasis, some lesions showed increased uptake. Regarding the time course, increased uptake of anti-18F-FACBC in the lesion was demonstrated immediately after injection, followed by gradual washout. Conclusion: The results of this phase IIa clinical trial indicated the safety of anti-18F-FACBC in patients with prostate cancer and the potential of anti-18F-FACBC PET to delineate primary prostate lesions and metastatic lesions. This clinical trial was registered as JapicCTI-101326.

  6. Characteristics of the anti-dementia drug system of Zisu Fang preparations based on pharmacokinetic and pharmacodynamic analysis

    Directory of Open Access Journals (Sweden)

    Jianye Quan

    2017-04-01

    Conclusions: Based on the PK and PD correlation analysis, baicalin, rosmarinic acid, salvianolic acid B, matrine, and tanshinone IIA are the main active ingredients of Zisu Fang preparations with regard to its anti-dementia effects, and represent the basic characteristics of drug system: natures, synergy, and affinity.

  7. Insight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cell lines by molecular docking.

    Science.gov (United States)

    Taskin, T; Yilmaz, S; Yildiz, I; Yalcin, I; Aki, E

    2012-01-01

    Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti-tumour drug candidates that should be further studied.

  8. INHIBITION IN SPEAKING PERFORMANCE

    OpenAIRE

    Humaera, Isna

    2015-01-01

    The most common problem encountered by the learner in the languageacquisition process is learner inhibition. Inhibition refers to a temperamentaltendency to display wariness, fearfulness, or restrain in response tounfamiliar people, objects, and situations. There are some factors that causeinhibition, such as lack of motivation, shyness, self-confidence, self-esteem,and language ego. There are also levels of inhibition, it refers to kinds ofinhibition and caused of inhibition itself. Teacher ...

  9. Postoperative low-pelvic irradiation for stage I-IIA cervical cancer patients with risk factors other than pelvic lymph node metastasis

    International Nuclear Information System (INIS)

    Hong, J.-H.; Tsai, C.-S.; Lai, C.-H.; Chang, T.-C.; Wang, C.-C.; Lee, Steve P.; Tseng, C.-J.; Hsueh, Swei

    2002-01-01

    Purpose: To retrospectively investigate whether postoperative low-pelvic radiotherapy (RT) is an appropriate treatment for node-negative, high-risk Stage I-IIA cervical cancer patients. Methods and Materials: A total of 228 Stage I-IIA cervical cancer patients treated by radical surgery and postoperative RT were included in this study. All patients had histopathologically negative pelvic node metastasis, but at least one of the following risk factors: parametrial involvement, positive or close resection margins, invasion depth two-thirds or greater cervical stromal thickness. Seventy-nine patients (35%) received 30-50 Gy (median 44) to whole pelvis and a boost dose to the low pelvis (whole-pelvic RT group); the other 149 patients (65%) received low-pelvic RT only (low-pelvic RT group). For both groups, the total external RT dose to the low pelvis ranged from 40 to 60 Gy (median 50). The potential factors associated with survival, small bowel (gastrointestinal) complications, and leg lymphedema were analyzed, and patients who had a relapse in the upper pelvis were identified. Results: The 5-year overall and disease-specific survival rate was 84% and 86%, respectively. After multivariate analysis, only bulky tumor (≥4 cm) and non-squamous cell carcinoma were significantly associated with survival. Parametrial involvement, lymph-vascular invasion, ≤50.4 Gy to the low pelvis, positive or close margins, and low-pelvic RT alone did not significantly affect survival. Grade I-V small bowel complications occurred in 33 patients (15%). Whole pelvic RT and >50.4 Gy to the low pelvis, but not old age and treatment technique (AP-PA vs. box), were significantly associated with gastrointestinal complications. Three patients (2%) in the low-pelvic RT group and 6 patients (8%) in the whole-pelvic RT group were found to have Grade III or higher small bowel complications (p=0.023). Thirty-one percent of patients developed lymphedema of the leg. A dose to the low pelvis >50.4 Gy

  10. The protective effect of Transhinone II A in radiation-induced pulmonary fibrosis

    International Nuclear Information System (INIS)

    Li Guanghu; Li Zhiping; Xu Yong; Xu Feng; Wang Jin

    2006-01-01

    Objective: To investigate the protective effect and it's possible mechanism of Tanshinone II A in radiation-induced pulmonary fibrosis. Methods: Having the right hemithorax of female Wistar rats irradiated 30 Gy in 10 fractions within 14 days by 6 MV photons, the radiation-induced pulmonary fibrosis animal model was established. In the treatment group, sodium Tanshinone II A sulfonate (15 mg/kg) was given by intraperitoneal injection 1 hour before each fraction of irradiation. Five months after irradiation, the difference of the histopathological changes, the hyckoxyproline content and expression of TGF-β1 between the radiation alone group, tanshinone plus radiation and control group were analyzed by HE stain, Massion stain, immunohistochemical methor and reverse transcriptase polymerase chain reaction(RT-PCR) method. Results: The histopathological comparison revealed the protective effect of Tanshinone II A. The content of hydroxyproline was (21.99±3.96), (38.25± 7.18), (28.94±4.29) μg/g in the control group, radiation alone group and radiation plus Tanshinone II A. The expression of TGF-β1 (mRNA and protein) was reduced by Tanshinone II A. Pathological changes of the pulmonary fibrosis was reduced by Tanshinone II A yet. Conclusions: Our study shows that Tanshinone II A can inhibit radiation-induced pulmonary fibrosis, and the possible mechanism of its may be made possible through down-regulating the expression of TGF-β1 in the irritated lung tissue. (authors)

  11. A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa.

    Science.gov (United States)

    Hartel, Bas P; Löfgren, Maria; Huygen, Patrick L M; Guchelaar, Iris; Lo-A-Njoe Kort, Nicole; Sadeghi, Andre M; van Wijk, Erwin; Tranebjærg, Lisbeth; Kremer, Hannie; Kimberling, William J; Cremers, Cor W R J; Möller, Claes; Pennings, Ronald J E

    2016-09-01

    Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations. A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA) and a method to evaluate the difference in the degree of HI developed throughout life between subgroups. Cross-sectional linear regression analysis of last-visit audiograms for the best hearing ear demonstrated a gradual decline of hearing over decades. The congenital level of HI was in the range of 16-33 dB at 0.25-0.5 kHz, and in the range of 51-60 dB at 1-8 kHz. The annual threshold deterioration was in the range of 0.4-0.5 dB/year at 0.25-2 kHz and in the range of 0.7-0.8 dB/year at 4-8 kHz. Patients with two truncating mutations, including homozygotes for the common c.2299delG mutation, developed significantly more severe HI throughout life than patients with one truncating mutation combined with one nontruncating mutation, and patients with two nontruncating mutations. The results have direct implications for patient counselling in terms of prognosis of hearing and may serve as baseline measures for future (genetic) therapeutic interventions. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Molecular Characterization of Methicillin-Resistant Staphylococcus aureus from Outpatients in Northern Japan: Increasing Tendency of ST5/ST764 MRSA-IIa with Arginine Catabolic Mobile Element.

    Science.gov (United States)

    Aung, Meiji Soe; Kawaguchiya, Mitsuyo; Urushibara, Noriko; Sumi, Ayako; Ito, Masahiko; Kudo, Kenji; Morimoto, Shigeo; Hosoya, Shino; Kobayashi, Nobumichi

    2017-07-01

    Arginine catabolic mobile element (ACME) is a genomic island of staphylococcus and is considered to confer enhanced ability to survive and growth on host bacterial cells. ACME has been typically identified in Panton-Valentine Leukocidin (PVL)-positive ST8 methicillin-resistant Staphylococcus aureus (MRSA) with SCCmec type IVa (USA300 clone), and it is also found in other lineages at low frequency. Prevalence and molecular characteristics of PVL + and/or ACME + MRSA were investigated for 624 clinical isolates collected from outpatients in northern Japan from 2013 to 2014. Both PVL genes and ACME type I were detected in nine isolates (1.4%), which were ST8-MRSA-SCCmec IVa/spa type t008/agr-I; whereas solely PVL genes were positive in two isolates, ST30-MRSA-SCCmec IV and ST59-MRSA-SCCmec V. ACME type II' (previously referred to as ACME ΔII) was detected in 36 isolates (5.8%) with SCCmec II and V (32 and 4 isolates, respectively), exhibiting an increased rate within SCCmec II-MRSA (7.1%) compared with our previous studies (0.86-4.5%, 2008-2011). ACME II'-positive MRSA strains were classified into ST5-SCCmec IIa/V or ST764-SCCmec IIa belonging to five different spa types, with t002 being dominant. They harbored mostly enterotoxin gene clusters (seg-sei-sem-sen-seo-seu) and some more enterotoxin genes (seb1, seb2, sec3, sel, sep), showing resistance to more antimicrobials than ST8-MRSA-SCCmec IVa. ACME-SCCmec composite island (CI) of the 36 ACME II'-positive MRSA was classified into five types (ii)-(vi), among which type (ii) (orfX-ΨSCC ΔJ1 SCCmec I -ACME II'-SCCmec II) was dominant and subdivided into the A3 variant and the less common A2 variant. CI types (v) and (vi) were considered novel genetic organizations having speG (acetyltransferase genes for polyamines) in inserted SCC4610/SCC266-like genetic elements. The present study revealed increased prevalence and genetic diversity of the ST5/ST764-MRSA-SCCmec II with ACME II' in northern Japan.

  13. Disparities in Adherence to National Comprehensive Cancer Network Treatment Guidelines and Survival for Stage IB-IIA Cervical Cancer in California.

    Science.gov (United States)

    Pfaendler, Krista S; Chang, Jenny; Ziogas, Argyrios; Bristow, Robert E; Penner, Kristine R

    2018-05-01

    To evaluate the association of sociodemographic and hospital characteristics with adherence to National Comprehensive Cancer Network treatment guidelines for stage IB-IIA cervical cancer and to analyze the relationship between adherent care and survival. This is a retrospective population-based cohort study of patients with stage IB-IIA invasive cervical cancer reported to the California Cancer Registry from January 1, 1995, through December 31, 2009. Adherence to National Comprehensive Cancer Network guideline care was defined by year- and stage-appropriate surgical procedures, radiation, and chemotherapy. Multivariate logistic regression, Kaplan-Meier estimate, and Cox proportional hazard models were used to examine associations between patient, tumor, and treatment characteristics and National Comprehensive Cancer Network guideline adherence and cervical cancer-specific 5-year survival. A total of 6,063 patients were identified. Forty-seven percent received National Comprehensive Cancer Network guideline-adherent care, and 18.8% were treated in high-volume centers (20 or more patients/year). On multivariate analysis, lowest socioeconomic status (adjusted odds ratio [OR] 0.69, 95% CI 0.57-0.84), low-middle socioeconomic status (adjusted OR 0.76, 95% CI 0.64-0.92), and Charlson-Deyo comorbidity score 1 or higher (adjusted OR 0.78, 95% CI 0.69-0.89) were patient characteristics associated with receipt of nonguideline care. Receiving adherent care was less common in low-volume centers (45.9%) than in high-volume centers (50.9%) (effect size 0.90, 95% CI 0.84-0.96). Death from cervical cancer was more common in the nonadherent group (13.3%) than in the adherent group (8.6%) (effect size 1.55, 95% CI 1.34-1.80). Black race (adjusted hazard ratio 1.56, 95% CI 1.08-2.27), Medicaid payer status (adjusted hazard ratio 1.47, 95% CI 1.15-1.87), and Charlson-Deyo comorbidity score 1 or higher (adjusted hazard ratio 2.07, 95% CI 1.68-2.56) were all associated with increased

  14. Hydrolysis of lipoproteins by sPLA2's enhances mitogenesis and eicosanoid release from vascular smooth muscle cells: Diverse activity of sPLA2's IIA, V and X.

    Science.gov (United States)

    Pruzanski, Waldemar; Kopilov, Julia; Kuksis, Arnis

    2016-01-01

    Mitogenesis of Vascular Smooth Muscle Cells (VSMC) plays an important role in atherogenesis. Until recently, the effect of lipid subfractions has not been clarified. Secretory phospholipases A2 (sPLA2's) hydrolyse glycerophospholipids and release pro-inflammatory lyso-lipids, oxidized and non-oxidized fatty acids and isoprostanes. They localize in the vascular wall. We hypothesized that structurally similar sPLA2's may exert different impact on VSMC. The influence of sPLA2's, IIA, V, X, HDL, LDL, and hydrolysis products was tested on mitogenesis of VSMC, i.e., the early effect on the cell membrane phospholipids, and on PGE2 and LTB4 release, i.e., late effect of Cyclooxygenase and 5-lipooxygenase activity in VSMC. Mitogenesis was significantly enhanced by HDL and LDL, and by products of sPLA2 hydrolysis. Hydrolysis of HDL or LDL enhanced mitogenic activity in order V>X>IIA. The release of PGE2 was enhanced by group X sPLA2 and by HDL hydrolyzed by groups V and X. LDL and its hydrolysis products enhanced the release of PGE2 in order X>V>IIA. The release of LTB4 was markedly increased by LDL and HDL, and by hydrolytic products of group V and X, but not group IIA sPLA2. Our study demonstrates a diverse interaction of pro-inflammatory sPLA2's with HDL and LDL affecting both mitogenesis and eicosanoid release from VSMC, therefore potentially enhancing their pro-atherogenic activity. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. On the worldsheet theory of the type IIA {text{Ad}}{{text{S}}_4} × mathbb{C}{mathbb{P}_3} superstring

    Science.gov (United States)

    Sundin, Per

    2010-04-01

    We perform a detailed study of the type IIA superstring in {text{Ad}}{{text{S}}_4} × mathbb{C}{mathbb{P}_3} . After introducing suitable bosonic light-cone and fermionic kappa worldsheet gauges we derive the pure boson and fermion SU(2|2)×U(1) covariant light-cone Hamiltonian up to quartic order in fields. As a first application of our derivation we calculate energy shifts for string configurations in a closed fermionic subsector and successfully match these with a set of light-cone Bethe equations. We then turn to investigate the mismatch between the degrees of freedom of scattering states and oscillatory string modes. Since only light string modes appear as fundamental Bethe roots in the scattering theory, the physical role of the remaining 4 F + 4 B massive oscillators is rather unclear. By continuing a line of research initiated by Zarembo, we shed light on this question by calculating quantum corrections for the propagators of the bosonic massive fields. We show that, once loop corrections are incorporated, the massive coordinates dissolve in a continuum state of two light particles.

  16. A soluble activin type IIA receptor mitigates the loss of femoral neck bone strength and cancellous bone mass in a mouse model of disuse osteopenia.

    Science.gov (United States)

    Lodberg, Andreas; Eijken, Marco; van der Eerden, Bram C J; Okkels, Mette Wendelboe; Thomsen, Jesper Skovhus; Brüel, Annemarie

    2018-05-01

    Disuse causes a rapid and substantial bone loss distinct in its pathophysiology from the bone loss associated with cancers, age, and menopause. While inhibitors of the activin-receptor signaling pathway (IASPs) have been shown to prevent ovariectomy- and cancer-induced bone loss, their application in a model of disuse osteopenia remains to be tested. Here, we show that a soluble activin type IIA receptor (ActRIIA-mFc) increases diaphyseal bone strength and cancellous bone mass, and mitigates the loss of femoral neck bone strength in the Botulinum Toxin A (BTX)-model of disuse osteopenia in female C57BL/6J mice. We show that ActRIIA-mFc treatment preferentially stimulates a dual-effect (anabolic-antiresorptive) on the periosteal envelope of diaphyseal bone, demonstrating in detail the effects of ActRIIA-mFc on cortical bone. These observations constitute a previously undescribed feature of IASPs that mediates at least part of their ability to mitigate detrimental effects of unloading on bone tissue. The study findings support the application of IASPs as a strategy to combat bone loss during disuse. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Type IIA string theory on T"6/(Z_2 x Z_6 x ΩR). Model building and string phenomenology with intersecting D6-branes

    International Nuclear Information System (INIS)

    Ecker, Jill

    2016-01-01

    In this doctoral thesis, various aspects of string model building and phenomenology are investigated within the framework of Type IIA string theory on the T"6/(Z_2 x Z_6 x ΩR) orbifold with discrete torsion. The aim is the reproduction of supersymmetric versions of well-known particle physics models using intersecting rigid D6-branes wrapped on fractional three-cycles. The models analyzed include the minimal supersymmetric Standard Model as well as supersymmetric Pati-Salam models, left-right symmetric models and SU(5) models. Systematic computer scans test numerous combinations of intersecting D6-branes in order to detect those that give rise to the correct chiral particle content of the considered models. For each type of the afore mentioned models, concrete examples will be found which satisfy the constraints on the particle spectrum and fulfill all consistency conditions. Finally, the thesis focuses on phenomenological aspects of the particle physics models found, including the detection of massless U(1) combinations, discrete Z_n-symmetries and cubic couplings such as the Yukawa couplings.

  18. Stadium IB - IIA cervical cancer patient’s survival rate after receiving definitive radiation and radical operation therapy followed by adjuvant radiation therapy along with analysis of factors affecting the patient’s survival rate

    Science.gov (United States)

    Ruslim, S. K.; Purwoto, G.; Widyahening, I. S.; Ramli, I.

    2017-08-01

    To evaluate the characteristics and overall survival rates of early stage cervical cancer (FIGO IB-IIA) patients who receive definitive radiation therapy and those who are prescribed adjuvant postoperative radiation and to conduct a factors analysis of the variables that affect the overall survival rates in both groups of therapy. The medical records of 85 patients with cervical cancer FIGO stages IB-IIA who were treated at the Department of Radiotherapy of Cipto Mangunkusumo Hospital were reviewed and analyzed to determine their overall survival and the factors that affected it between a definitive radiation group and an adjuvant postoperative radiation group. There were 25 patients in the definitive radiation and 60 patients in the adjuvant radiation group. The overall survival rates in the adjuvant radiation group at years one, two, and three were 96.7%, 95%, and 93.3%, respectively. Negative lymph node metastasis had an average association with overall survival (p 12 g/dl was a factor with an average association with the overall survival (p cervical cancer FIGO stage IB-IIA patients who received definitive radiation or adjuvant postoperative radiation. Negative lymph node metastasis had an effect on the overall survival rate in the adjuvant postoperative radiation group, while a preradiation Hb level >12 g/dl tended to affect the overall survival in the definitive radiation group patients.

  19. Impairment of the class IIa bacteriocin receptor function and membrane structural changes are associated to enterocin CRL35 high resistance in Listeria monocytogenes.

    Science.gov (United States)

    Masias, Emilse; Dupuy, Fernando G; da Silva Sanches, Paulo Ricardo; Farizano, Juan Vicente; Cilli, Eduardo; Bellomio, Augusto; Saavedra, Lucila; Minahk, Carlos

    2017-07-01

    Enterocin CRL35 is a class IIa bacteriocin with anti-Listeria activity. Resistance to these peptides has been associated with either the downregulation of the receptor expression or changes in the membrane and cell walls. The scope of the present work was to characterize enterocin CRL35 resistant Listeria strains with MICs more than 10,000 times higher than the MIC of the WT sensitive strain. Listeria monocytogenes INS7 resistant isolates R2 and R3 were characterized by 16S RNA gene sequencing and rep-PCR. Bacterial growth kinetic was studied in different culture media. Plasma membranes of sensitive and resistant bacteria were characterized by FTIR and Langmuir monolayer techniques. The growth kinetic of the resistant isolates was slower as compared to the parental strain in TSB medium. Moreover, the resistant isolates barely grew in a glucose-based synthetic medium, suggesting that these cells had a major alteration in glucose transport. Resistant bacteria also had alterations in their cell wall and, most importantly, membrane lipids. In fact, even though enterocin CRL35 was able to bind to the membrane-water interface of both resistant and parental sensitive strains, this peptide was only able to get inserted into the latter membranes. These results indicate that bacteriocin receptor is altered in combination with membrane structural modifications in enterocin CRL35-resistant L. monocytogenes strains. Highly enterocin CRL35-resistant isolates derived from Listeria monocytogenes INS7 have not only an impaired glucose transport but also display structural changes in the hydrophobic core of their plasma membranes. Copyright © 2017. Published by Elsevier B.V.

  20. The ISRU Field Tests 2010 and 2012 at Mauna Kea, Hawaii: Results from the Miniaturised Mossbauer Spectrometers Mimos II and Mimos IIA

    Science.gov (United States)

    Klingelhoefer, G.; Morris, R. V.; Blumers, M; Bernhardt, B.; Graff, T.

    2014-01-01

    The 2010 and 2012 In-Situ Resource Utilization Analogue Test (ISRU) [1] on the Mauna Kea volcano in Hawai'i was coordinated by the Northern Centre for Advanced Technology (NORCAT) in collaboration with the Canadian Space Agency (CSA), the German Aerospace Center (DLR), and the National Aeronautics and Space Administration (NASA), through the PISCES program. Several instruments were tested as reference candidates for future analogue testing at the new field test site at the Mauna Kea volcano in Hawai'i. The fine-grained, volcanic nature of the material is a suitable lunar and martian analogue, and can be used to test excavation, site preparation, and resource utilization techniques. The 2010 location Pu'u Hiwahine, a cinder cone located below the summit of Mauna Kea (19deg45'39.29" N, 155deg28'14.56" W) at an elevation of 2800 m, provides a large number of slopes, rock avalanches, etc. to perform mobility tests, site preparation or resource prospecting. Besides hardware testing of technologies and systems related to resource identification, also in situ science measurements played a significant role in integration of ISRU and science instruments. For the advanced Mössbauer instrument MIMOS IIA, the new detector technologies and electronic components increase sensitivity and performance significantly. In combination with the high energy resolution of the SDD it is possible to perform Xray fluorescence analysis simultaneously to Mössbauer spectroscopy. In addition to the Fe-mineralogy, information on the sample's elemental composition will be gathered. The 2010 and 2012 field campaigns demonstrated that in-situ Mössbauer spectroscopy is an effective tool for both science and feedstock exploration and process monitoring. Engineering tests showed that a compact nickel metal hydride battery provided sufficient power for over 12 hr of continuous operation for the MIMOS instruments.

  1. Preoperative Concurrent Radiation Therapy and Chemotherapy for Bulky Stage IB2, IIA, and IIB Carcinoma of the Uterine Cervix With Proximal Parametrial Invasion

    International Nuclear Information System (INIS)

    Huguet, Florence; Cojocariu, Oana-Maria; Levy, Pierre; Lefranc, Jean-Pierre; Darai, Emile; Jannet, Denis; Ansquer, Yan; Lhuillier, Pierre-Eugene; Benifla, Jean-Louis; Seince, Nathalie; Touboul, Emmanuel

    2008-01-01

    Purpose: To evaluate toxicity, local tumor control, and survival after preoperative chemoradiation for operable bulky cervical carcinoma. Methods and Materials: Between December 1991 and July 2006, 92 patients with operable bulky stage IB2, IIA, and IIB cervical carcinoma without pelvic or para-aortic nodes on pretreatment imaging were treated. Treatment consisted of preoperative external beam pelvic radiation therapy (EBRT) and concomitant chemotherapy (CT) during the first and fourth weeks of radiation combining 5-fluorouracil and cisplatin. The pelvic radiation dose was 40.5 Gy over 4.5 weeks. EBRT was followed by low-dose rate uterovaginal brachytherapy with a total dose of 20 Gy in 62 patients. After a median rest period of 44 days, all patients underwent Class II modified radical hysterectomy with bilateral pelvic lymphadenectomy. Thirty patients who had not received preoperative uterovaginal brachytherapy underwent postoperative low-dose-rate vaginal brachytherapy at a dose of 20 Gy. The mean follow-up was 46 months. Results: Pathologic residual tumor was observed in 43 patients. After multivariate analysis, additional preoperative uterovaginal brachytherapy was the single significant predictive factor for pathologic complete response rate (p = 0.019). The 2- and 5-year disease-free survival (DFS) rates were 80.4% and 72.2%, respectively. Pathologic residual cervical tumor was the single independent factor decreasing the probability of DFS (p = 0.020). Acute toxicities were moderate. Two severe ureteral complications requiring surgical intervention were observed. Conclusions: Concomitant chemoradiation followed by surgery for operable bulky stage I-II cervical carcinoma without clinical lymph node involvement can be used with acceptable toxicity. Pathologic complete response increases the probability of DFS

  2. Randomized Phase IIA Trial of Gemcitabine Compared With Bleomycin Plus Vincristine for Treatment of Kaposi’s Sarcoma in Patients on Combination Antiretroviral Therapy in Western Kenya

    Directory of Open Access Journals (Sweden)

    Naftali W. Busakhala

    2018-01-01

    Full Text Available Purpose: Kaposi’s sarcoma (KS is a spindle cell tumor resulting from growth dysregulation in the setting of infection with human herpes virus-8 (also called KS herpes virus. Advanced KS is characterized by poor responses to antiretroviral therapy and some of the chemotherapy readily accessible to patients in low-resource areas. Gemcitabine induced partial and complete regression of AIDS-associated KS (AIDS-KS in 11 of 24 patients in a pilot study. The current study compares the antimetabolite gemcitabine with the standard care bleomycin and vincristine (BV in the treatment of chemotherapy-naïve patients with AIDS-KS in a resource-limited setting. Patients and Methods: Patients with persistent or progressive KS despite treatment with combined antiretroviral therapy were randomly assigned to receive gemcitabine 1,000 mg/m2 or bleomycin 15 IU/ m2 and vincristine 1.4 mg/m2 given twice weekly. The main end point was objective response by bidirectional measurement, adverse events, and quality of life after three cycles of chemotherapy. Results: Of 70 participants enrolled, 36 received gemcitabine and 34 received BV. Complete response was achieved in 12 patients (33.3% in the gemcitabine arm and six (17.6% in the BV arm (P = .175. The partial response rate was 52.8% (n = 19 in the gemcitabine arm and 58.8% (n = 20 in the BV arm. Both study arms reported similar neurologic and hematologic adverse events; there was statistically significant baseline to post-treatment improvement in health-related quality-of-life scores. Conclusion: The results of this randomized, phase IIA trial demonstrate gemcitabine activity in chemotherapy-naïve patients with AIDS-KS, on the basis of response rates, adverse events, and health-related quality-of-life scores.

  3. Inhibition of lactation.

    Science.gov (United States)

    Llewellyn-Jones, D

    1975-01-01

    The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

  4. More Accurate Definition of Clinical Target Volume Based on the Measurement of Microscopic Extensions of the Primary Tumor Toward the Uterus Body in International Federation of Gynecology and Obstetrics Ib-IIa Squamous Cell Carcinoma of the Cervix

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Wen-Jia [Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province (China); Wu, Xiao [Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province (China); Xue, Ren-Liang; Lin, Xiang-Ying [Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province (China); Kidd, Elizabeth A. [Department of Radiation Oncology, Stanford University, Stanford, California (United States); Yan, Shu-Mei [Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province (China); Zhang, Yao-Hong [Department of Radiation Oncology, Chaozhou Hospital of Chaozhou City, Guangdong Province (China); Zhai, Tian-Tian; Lu, Jia-Yang; Wu, Li-Li; Zhang, Hao [Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province (China); Huang, Hai-Hua [Department of Pathology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong Province (China); Chen, Zhi-Jian; Li, De-Rui [Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province (China); Xie, Liang-Xi, E-mail: xieliangxi1@qq.com [Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong Province (China)

    2015-01-01

    Purpose: To more accurately define clinical target volume for cervical cancer radiation treatment planning by evaluating tumor microscopic extension toward the uterus body (METU) in International Federation of Gynecology and Obstetrics stage Ib-IIa squamous cell carcinoma of the cervix (SCCC). Patients and Methods: In this multicenter study, surgical resection specimens from 318 cases of stage Ib-IIa SCCC that underwent radical hysterectomy were included. Patients who had undergone preoperative chemotherapy, radiation, or both were excluded from this study. Microscopic extension of primary tumor toward the uterus body was measured. The association between other pathologic factors and METU was analyzed. Results: Microscopic extension toward the uterus body was not common, with only 12.3% of patients (39 of 318) demonstrating METU. The mean (±SD) distance of METU was 0.32 ± 1.079 mm (range, 0-10 mm). Lymphovascular space invasion was associated with METU distance and occurrence rate. A margin of 5 mm added to gross tumor would adequately cover 99.4% and 99% of the METU in the whole group and in patients with lymphovascular space invasion, respectively. Conclusion: According to our analysis of 318 SCCC specimens for METU, using a 5-mm gross tumor volume to clinical target volume margin in the direction of the uterus should be adequate for International Federation of Gynecology and Obstetrics stage Ib-IIa SCCC. Considering the discrepancy between imaging and pathologic methods in determining gross tumor volume extent, we recommend a safer 10-mm margin in the uterine direction as the standard for clinical practice when using MRI for contouring tumor volume.

  5. Rapid healing of cutaneous leishmaniasis by high-frequency electrocauterization and hydrogel wound care with or without DAC N-055: a randomized controlled phase IIa trial in Kabul.

    Directory of Open Access Journals (Sweden)

    Ahmad Fawad Jebran

    2014-02-01

    Full Text Available Anthroponotic cutaneous leishmaniasis (CL due to Leishmania (L. tropica infection is a chronic, frequently disfiguring skin disease with limited therapeutic options. In endemic countries healing of ulcerative lesions is often delayed by bacterial and/or fungal infections. Here, we studied a novel therapeutic concept to prevent superinfections, accelerate wound closure, and improve the cosmetic outcome of ACL.From 2004 to 2008 we performed a two-armed, randomized, double-blinded, phase IIa trial in Kabul, Afghanistan, with patients suffering from L. tropica CL. The skin lesions were treated with bipolar high-frequency electrocauterization (EC followed by daily moist-wound-treatment (MWT with polyacrylate hydrogel with (group I or without (group II pharmaceutical sodium chlorite (DAC N-055. Patients below age 5, with facial lesions, pregnancy, or serious comorbidities were excluded. The primary, photodocumented outcome was the time needed for complete lesion epithelialization. Biopsies for parasitological and (immunohistopathological analyses were taken prior to EC (1(st, after wound closure (2(nd and after 6 months (3(rd. The mean duration for complete wound closure was short and indifferent in group I (59 patients, 43.1 d and II (54 patients, 42 d; p = 0.83. In patients with Leishmania-positive 2(nd biopsies DAC N-055 caused a more rapid wound epithelialization (37.2 d vs. 58.3 d; p = 0.08. Superinfections occurred in both groups at the same rate (8.8%. Except for one patient, reulcerations (10.2% in group I, 18.5% in group II; p = 0.158 were confined to cases with persistent high parasite loads after healing. In vitro, DAC N-055 showed a leishmanicidal effect on pro- and amastigotes.Compared to previous results with intralesional antimony injections, the EC plus MWT protocol led to more rapid wound closure. The tentatively lower rate of relapses and the acceleration of wound closure in a subgroup of patients with parasite persistence warrant

  6. Efficacy, tolerability and consumer acceptability of terbinafine topical spray versus terbinafine topical solution: a phase IIa, randomised, observer-blind, comparative study.

    Science.gov (United States)

    Brown, Marc; Evans, Charles; Muddle, Andrew; Turner, Rob; Lim, Sian; Reed, Jessica; Traynor, Matt

    2013-10-01

    Tinea pedis is one of the world's most prevalent dermatophyte infections. MedSpray™ tinea pedis 1 % w/w (topical spray) is a novel, easy-to-use propellant-based spray formulation containing 1 % w/w terbinafine, requiring no manipulation at the site of infection. This is in contrast to the only formulation currently approved in Europe for single application (none are approved in the USA for single use), which is Lamisil(®) Once 1 % w/w (topical solution), containing 1 % w/w terbinafine hydrochloride, which requires manipulation on the affected area. The aim of this study was to evaluate the efficacy, tolerability and consumer acceptability of a topical spray versus a topical solution in the treatment of tinea pedis. This study is a phase IIa, randomised, observer-blind, non-inferiority comparative study of the topical spray compared with the topical solution over a 12-week study period. The study was conducted at Bioskin GmbH, Hamburg and Berlin. Patients (n = 120) who presented with the presence of interdigital tinea pedis caused by dermatophytes on one or both feet were enrolled in the study. Patients were randomly assigned between the two treatment groups. Either the topical spray or the topical solution was administered by the study nurse and consisted of a single application (equivalent to 20 mg of terbinafine per foot) on day 1 of the study. No further applications were made for the duration of the study. The hypothesis formulated before commencement of the study was that the topical spray would prove to be non-inferior to the topical solution. Efficacy assessments, including clinical signs and symptoms, mycology and microscopy were performed at baseline and 1, 6 and 12 weeks after treatment. The rate of mycological cure at week 1 was statistically equivalent for both treatments. There was a significant reduction in the overall clinical score as assessed by the Physician's Global Assessment of signs and symptoms for both treatment groups. The topical

  7. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  8. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  9. Cooperation for Better Inhibiting.

    Science.gov (United States)

    Novoa, Eva Maria; Ribas de Pouplana, Lluís

    2015-06-18

    Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Plant density-dependent variations in bioactive markers and root yield in Australian-grown Salvia miltiorrhiza Bunge.

    Science.gov (United States)

    Li, Chun Guang; Sheng, Shu Jun; Pang, Edwin C K; May, Brian; Xue, Charlie Chang Li

    2011-04-01

    The plant density-dependent variations in the root yield and content, and the yield of biomarkers in Australian grown Salvia miltiorrhiza Bunge, a commonly used Chinese medicinal herb for the treatment of cardiovascular diseases, were investigated in a field trial involving six different plant densities. The key biomarker compounds cryptotanshinone, tanshinone I, tanshinone IIA, and salvianolic acid B were quantified by a validated RP-HPLC method, and the root yields were determined per plant pair or unit area. There were significant variations (pplant densities. Positive linear correlations were observed between the contents of the three tanshinones, whereas negative linear correlations were revealed between the contents of the tanshinones and salvianolic acid B. The highest root yield per plant pair was achieved when the plants were grown at 45×30 cm or 45×40 cm, whereas the highest root production par unit area was obtained for a plant density of 30×30 cm. The highest contents of the three tanshinones and the most abundant production of these tanshinones per unit area were achieved when the plants were grown at 30×30 cm. However, the highest content of salvianolic acid B was found for a density of 45×40 cm, while its highest yield per unit area was obtained for densities of 30×40 cm or 45×30 cm. The findings suggest that the plant density distinctly affects the root yield and content and the yield of tanshinones and salvianolic acid B in Australian grown S. miltiorrhiza, which may be used as a guide for developing optimal agricultural procedures for cultivating this herb. Copyright © 2011 Verlag Helvetica Chimica Acta AG, Zürich.

  11. Exploration of pH-dependent behavior of the anion receptor pocket of subdomain IIA of HSA: determination of effective pocket charge using the Debye-Hückel limiting law.

    Science.gov (United States)

    Bolel, Priyanka; Datta, Shubhashis; Mahapatra, Niharendu; Halder, Mintu

    2014-01-09

    Protein-ligand electrostatic interaction can be looked upon as ion receptor-ligand interaction, and the binding cavity of protein can be either an anion or cation receptor depending on the charge of the guest. Here we focus on the exploration of pH-modulated binding of a number of anionic ligands, specific to the subdomain IIA cavity of HSA, such as carmoisine, tartrazine, cochineal red, and warfarin. The logarithm of the binding constant is found to vary linearly with the square-root of ionic strength, indicating applicability of the Debye-Hückel limiting law to protein-ligand electrostatic binding equilibrium, and concludes that the subdomain IIA cavity is an anion receptor. The present approach is very unique that one can calculate the effective charge of the protein-based anion receptor pocket, and the calculated charge has been found to vary between +1 and +3 depending on the pH and ligand itself. The study also indicates that in such cases of specific ligand binding the pocket charge rather than the overall or surface charge of the macromolecule seems to have a paramount role in determining the strength of interaction. For the first time, it is demonstrated that the Debye-Hückel interionic interaction model can be successfully applied to understand the protein-based receptor-ligand electrostatic interaction in general.

  12. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  13. Inhibiting the inevitable

    DEFF Research Database (Denmark)

    Shashoua, Yvonne

    2006-01-01

    conservation is to ‘buy time’ for the object. Inhibitive conservation of plastics involves the removal or reduction of factors causing or accelerating degradation including light, oxygen, acids, relative humidity and acidic breakdown products. Specific approaches to conservation have been developed......Once plastics objects are registered in museum collections, the institution becomes responsible for their long term preservation, until the end of their useful lifetime. Plastics appear to deteriorate faster than other materials in museum collections and have a useful lifetime between 5 and 25...... years. Preventive or inhibitive conservation involves controlling the environments in which objects are placed during storage and display, with the aim of slowing the major deterioration reactions. Once in progress, degradation of plastics cannot be stopped or reversed, so the aim of preventive...

  14. Expression profiles of genes involved in tanshinone biosynthesis of ...

    Indian Academy of Sciences (India)

    1State Key Laboratory of Crop Biology, Shandong Key Laboratory of Crop Biology, and 2Agronomy College,. Shandong ... other clinical benefits have been reported, but not limited to antibacterial .... tute for Control of Pharmaceuticals and Biological Products. (Beijing, China). ... The quality and concentrations of RNAs were.

  15. Tanshinones as Effective Therapeutic Agents for Prostate Cancer

    Science.gov (United States)

    2011-06-01

    Y. Tian, T.-F. Chen, W. Ye, L. Li, F. Ni, J.-R. Zhou: Construction and screening of fractional library of Salvia Miltiorrhiza for the rapid...glutathione perturbation. Food Chem Toxicol 2008;46: 328–38. 19. Singh AV, Franke AA, Blackburn GL, Zhou JR. Soy phytochemicals prevent orthotopic growth and

  16. Differential association of the N-propeptide of collagen IIA (PIIANP) and collagen II C-telopeptide (CTX-II) with synovitis and erosions in early and longstanding rheumatoid arthritis

    DEFF Research Database (Denmark)

    Christensen, A F; Lottenburger, T; Lindegaard, H

    2009-01-01

    OBJECTIVES: To determine the N-terminal propeptide of collagen IIA (PIIANP) in early and established rheumatoid arthritis (RA) and to study the association with collagen II degradation assessed by its C-telopeptide (CTX-II), x-ray status and disease activity measures. METHODS: Two cohorts of RA......-ray progression (p=0.84). There was no correlation between PIIANP and CTX-II. CONCLUSION: Declining PIIANP with increasing RA duration and persistently increased CTX-II indicate that cartilage anabolic and degradative pathways are unbalanced from clinical RA onset. Furthermore, that collagen II depletion in RA...... is both mediated by anti-anabolic effects unassociated with synovitis (decreased PIIANP) and by excess collagen II degradation linked to synovitis (increased CTX-II)....

  17. Anxiety and retrieval inhibition: support for an enhanced inhibition account.

    Science.gov (United States)

    Nuñez, Mia; Gregory, Josh; Zinbarg, Richard E

    2017-02-01

    Retrieval inhibition of negative associations is important for exposure therapy for anxiety, but the relationship between memory inhibition and anxiety is not well understood-anxiety could either be associated with enhanced or deficient inhibition. The present study tested these two competing hypotheses by measuring retrieval inhibition of negative stimuli by related neutral stimuli. Non-clinically anxious undergraduates completed measures of trait and state anxiety and completed a retrieval induced forgetting task. Adaptive forgetting varied with state anxiety. Low levels of state anxiety were associated with no evidence for retrieval inhibition for either threatening or non-threatening categories. Participants in the middle tertile of state anxiety scores exhibited retrieval inhibition for non-threatening categories but not for threatening categories. Participants in the highest tertile of state anxiety, however, exhibited retrieval inhibition for both threatening and non-threatening categories with the magnitude of retrieval inhibition being greater for threatening than non-threatening categories. The data are in line with the avoidance aspect of the vigilance-avoidance theory of anxiety and inhibition. Implications for cognitive behavioural therapy practices are discussed.

  18. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine

    Science.gov (United States)

    Okazaki, Taku; Maeda, Akito; Nishimura, Hiroyuki; Kurosaki, Tomohiro; Honjo, Tasuku

    2001-01-01

    PD-1 is an immunoreceptor that belongs to the immunoglobulin (Ig) superfamily and contains two tyrosine residues in the cytoplasmic region. Studies on PD-1-deficient mice have shown that PD-1 plays critical roles in establishment and/or maintenance of peripheral tolerance, but the mode of action is totally unknown. To study the molecular mechanism for negative regulation of lymphocytes through the PD-1 receptor, we generated chimeric molecules composed of the IgG Fc receptor type IIB (FcγRIIB) extracellular region and the PD-1 cytoplasmic region and expressed them in a B lymphoma cell line, IIA1.6. Coligation of the cytoplasmic region of PD-1 with the B cell receptor (BCR) in IIA1.6 transformants inhibited BCR-mediated growth retardation, Ca2+ mobilization, and tyrosine phosphorylation of effector molecules, including Igβ, Syk, phospholipase C-γ2 (PLCγ2), and ERK1/2, whereas phosphorylation of Lyn and Dok was not affected. Mutagenesis studies indicated that these inhibitory effects do not require the N-terminal tyrosine in the immunoreceptor tyrosine-based inhibitory motif-like sequence, but do require the other tyrosine residue in the C-terminal tail. This tyrosine was phosphorylated and recruited src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) on coligation of PD-1 with BCR. These results show that PD-1 can inhibit BCR signaling by recruiting SHP-2 to its phosphotyrosine and dephosphorylating key signal transducers of BCR signaling. PMID:11698646

  19. Inhibition of polyphenoloxidase by sulfite

    International Nuclear Information System (INIS)

    Sayavedra-Soto, L.A.; Montgomery, M.W.

    1986-01-01

    When polyphenoloxidase (PPO) was exposed to sulfite prior to substrate addition, inhibition was irreversible. Trials to regenerate PPO activity, using extensive dialysis, column chromatography, and addition of copper salts were not successful. Increased concentrations of sulfite and pH levels less than 5 enhanced the inhibition of PPO by sulfite. At pH 4, concentrations greater than 0.04 mg/mL completely inhibited 1000 units of PPO activity almost instantaneously. This suggested that the HSO 3 - molecule was the main component in the sulfite system inhibiting PPO. Column chromatography, extensive dialysis, and gel electrophoresis did not demonstrate 35 SO 2 bound to purified pear PPO protein. Formation of extra protein bands of sulfite inhibited purified pear PPO fractions on gel electrophoresis was demonstrated. This and other evidence suggested that the major mode of direct irreversible inhibition of PPO was modification of the protein structure, with retention of its molecular unity

  20. Molecular Signaling Pathways Behind the Biological Effects of Salvia Species Diterpenes in Neuropharmacology and Cardiology.

    Science.gov (United States)

    Akaberi, M; Iranshahi, M; Mehri, S

    2016-06-01

    The genus Salvia, from the Lamiaceae family, has diverse biological properties that are primarily attributable to their diterpene contents. There is no comprehensive review on the molecular signaling pathways of these active components. In this review, we investigated the molecular targets of bioactive Salvia diterpenes responsible for the treatment of nervous and cardiovascular diseases. The effects on different pathways, including apoptosis signaling, oxidative stress phenomena, the accumulation of amyloid beta plaques, and tau phosphorylation, have all been considered to be mechanisms of the anti-Alzheimer properties of Salvia diterpenes. Additionally, effects on the benzodiazepine and kappa opioid receptors and neuroprotective effects are noted as neuropharmacological properties of Salvia diterpenes, including tanshinone IIA, salvinorin A, cryptotanshinone, and miltirone. Tanshinone IIA, as the primary diterpene of Salvia miltiorrhiza, has beneficial activities in heart diseases because of its ability to scavenge free radicals and its effects on transcription factors, such as nuclear transcription factor-kappa B (NF-κB) and the mitogen-activated protein kinases (MAPKs). Additionally, tanshinone IIA has also been proposed to have cardioprotective properties including antiarrhythmic activities and effects on myocardial infarction. With respect to the potential therapeutic effects of Salvia diterpenes, comprehensive clinical trials are warranted to evaluate these valuable molecules as lead compounds. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  1. [Influence of different original processing methods on quality of Salvia Miltiorrhizae Radix et Rhizoma from Shandong].

    Science.gov (United States)

    Zhao, Zhi-Gang; Gao, Shu-Rui; Hou, Jun-Ling; Wang, Wen-Quan; Xu, Zhen-Guang; Song, Yan; Zhang, Xian-Ming; Li, Jun

    2014-04-01

    In this paper the contents of rosmarinic acid, salvianolic acid B, crytotanshinone, tanshinone II(A) in samples of different original processed Salvia Miltiorrhizae Radix et Rhizoma were determined by HPLC. Different processing methods have varied influences on four active ingredients in Salvia Miltiorrhizae Radix et Rhizoma. Sun-drying reduced the content of crytotanshinone, tanshi-none II(A) and rosmarinic acid, integralsamples were better than those cut into segments. Oven dry method had great influence on water--soluble ingredients, high temperature (80-100 degrees C) could easily cause big loss of rosmarinic acid and salvianolic acid B. The role of traditional processing method "fahan: was complicated, the content of rosmarinic acid decreased, crytotanshinone and tanshinone II(A) increased, and salvianolic acid B showed no difference after "fahan". Drying in the shade and oven dry under low temperatrure (40-60 degrees C) were all effective to keep active ingredients of Salvia Miltiorrhizae Radix et Rhizoma, and, there was no difference between integral samples and samples cut into segments. Therefore, considering comprehensively the content of active ingredients in Salvia Miltiorrhizae Radix et Rhizoma, and processing costing etc., shade-drying or oven dry underlow temperature (40-60 degrees C) should be the most suitable original processing method.

  2. Rho-kinase signaling controls nucleocytoplasmic shuttling of class IIa Histone Deacetylase (HDAC7) and transcriptional activation of orphan nuclear receptor NR4A1

    Energy Technology Data Exchange (ETDEWEB)

    Compagnucci, Claudia; Barresi, Sabina [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome (Italy); Petrini, Stefania [Research Laboratories, Confocal Microscopy Core Facility, Bambino Gesù Children’s Hospital, IRCCS, Rome (Italy); Bertini, Enrico [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome (Italy); Zanni, Ginevra, E-mail: ginevra.zanni@opbg.net [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome (Italy)

    2015-04-03

    Rho-kinase (ROCK) has been well documented to play a key role in RhoA-induced actin remodeling. ROCK activation results in myosin light chain (MLC) phosphorylation either by direct action on MLC kinase (MLCK) or by inhibition of MLC phosphatase (MLCP), modulating actin–myosin contraction. We found that inhibition of the ROCK pathway in induced pluripotent stem cells, leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1 while in cells with constitutive ROCK hyperactivity due to loss of function of the RhoGTPase activating protein Oligophrenin-1 (OPHN1), the orphan nuclear receptor NR4A1 is downregulated. Our study identify a new target of ROCK signaling via myosin phosphatase subunit (MYPT1) and Histone Deacetylase (HDAC7) at the nuclear level and provide new insights in the cellular functions of ROCK. - Highlights: • ROCK regulates nucleocytoplasmic shuttling of HDAC7 via phosphorylation of MYPT1. • Nuclear export of HDAC7 and upregulation of NR4A1 occurs with low ROCK activity. • High levels of ROCK activity due to OPHN1 loss of function downregulate NR4A1.

  3. Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction

    Directory of Open Access Journals (Sweden)

    Takahiro Ochiya

    Full Text Available The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4-binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy.

  4. Modeling intentional inhibition of actions

    NARCIS (Netherlands)

    Thilakarathne, D.J.; Treur, J.

    2015-01-01

    Inspired by cognitive and neurological literature on action ownership and action awareness, in this paper a computational cognitive model for intentional inhibition (i.e.; the capacity to voluntarily suspend or inhibit an action) is introduced. The interplay between (positive) potential selection of

  5. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  6. Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

    International Nuclear Information System (INIS)

    Geletneky, Karsten; Hajda, Jacek; Huesing, Johannes; Rommelaere, Jean; Schlehofer, Joerg R; Leuchs, Barbara; Dahm, Michael; Krebs, Ottheinz; Knebel Doeberitz, Magnus von; Huber, Bernard

    2012-01-01

    The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application

  7. Frequency of anti-glycoprotein Ia/IIa (anti-HPA-5b,-5a and anti-glycoprotein IIb/IIIa (anti-HPA-1a,-3a,-4a alloantibodies in multiparous women of African descent

    Directory of Open Access Journals (Sweden)

    Zaccheaus A Jeremiah

    2010-05-01

    Full Text Available Zaccheaus A Jeremiah1, Justina E Oburu2, Osaro Erhabor1, Fiekumo I Buseri1, Teddy C Adias31Haematology and Blood Transfusion Science Unit, Department of Medical Laboratory Sciences, College of Health Sciences, Niger Delta University, Wilberforce Island, Nigeria; 2Department of Haematology and Blood Transfusion, University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria; 3Rivers State University of Science and Technology, Port Harcourt, NigeriaBackground: Human platelet antibodies are often implicated in some disease conditions, such as neonatal alloimmune thrombocytopenia (NAIT, idiopathic thrombocytopenic purpura (ITP and platelet refractoriness. The frequencies of these alloantibodies have not been reported in Nigeria and West Africa.Methods: Screening for allontibodies to human platelet antigens (HPA was undertaken using the GTI PakPlus® qualitative solid phase ELISA reagent. Platelet count was done using the ICSH approved procedure using 1% ammonium oxalate reagent.Study design: A cross-section of apparently healthy adult Nigerian multiparous non-pregnant women, who were staff of a tertiary health facility in the Niger Delta, Nigeria, were screened for alloantibodies to human platelet antigens.Results: Of the one hundred (100 women screened, the prevalence of anti-glycoprotein IIb/IIIa (anti-HPA-Ia,-3a,-4a was zero percent (0%, anti-glycoprotein Ia/IIa (anti-HPA-5b accounted for 30% of results, while anti-glycoprotein Ia/IIa (anti-HPA-5a was 18%. Parity was found to exert significant influence on the development to HPA antibodies (Fisher’s Exact Test = 11.683, P < 0.05; 13.577, P < 0.01. The platelet count of the women did not appear to exert any influence on the development of the antibodies (P > 0.05.Conclusion: This study has observed a high prevalence of anti-HPA-5b in our sample population. The prevalence of alloantibodies to HPA antigens was found to associate strongly with parity. These results indicate that there is a

  8. Selective inhibition of distracting input.

    Science.gov (United States)

    Noonan, MaryAnn P; Crittenden, Ben M; Jensen, Ole; Stokes, Mark G

    2017-10-16

    We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  9. [Concepts of inhibition in psychiatry].

    Science.gov (United States)

    Auroux, Y; Bourrat, M M; Brun, J P

    1978-01-01

    Following a historical approach, the authors first describe the original development of the concept of inhibition in neurophysiology and then analyze the subsequent adaptations made in psychiatry around such concept including those of: -- Pavlov, Hull, Watson and the behaviorists, -- Freud and the Freudian School, -- clinicians and psychopharmacologists. The concept of inhibition has thus various meanings in psychiatry. Although some unity is achieved on the semiological level, this aspect cannot explain the extent of the process.

  10. Inhibition of MMPs by alcohols

    Science.gov (United States)

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  11. Calibration of photographic and spectroscopic films. 1: Film batch variations of reciprocity failure in IIaO film. 2: Thermal and aging effects in relationship to reciprocity failure. 3: Shifting of reciprocity failure points as a function of thermal and aging effects. Semiannual report, December 1986

    International Nuclear Information System (INIS)

    Peters, K.A.; Atkinson, P.F.; Hammond, E.C. Jr.

    1986-01-01

    Reciprocity failure was examined for IIaO spectroscopic film. Three separate experiments were performed in order to study film batch variations, thermal and aging effects in relationship to reciprocity failure, and shifting of reciprocity failure points as a function of thermal and aging effects. The failure was examined over ranges of time between 5 and 60 seconds. The variation to illuminance was obtained by using thirty neutral density filters. A standard sensitometer device imprinted the wedge pattern on the film as exposure time was subjected to variation. The results indicate that film batch differences, temperature, and aging play an important role in reciprocity failure of IIaO spectroscopic film. A shifting of the failure points was also observed in various batches of film

  12. Methanol Extract of Myelophycus caespitosus Inhibits the ...

    African Journals Online (AJOL)

    Methanol Extract of Myelophycus caespitosus Inhibits the Inflammatory Response in Lipopolysaccharidestimulated BV2 Microglial Cells by Downregulating NF-kB via Inhibition of the Akt Signaling Pathway.

  13. Homo economicus belief inhibits trust.

    Directory of Open Access Journals (Sweden)

    Ziqiang Xin

    Full Text Available As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  14. Homo Economicus Belief Inhibits Trust

    Science.gov (United States)

    Xin, Ziqiang; Liu, Guofang

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners’ benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals’ homo economicus belief and inhibit their trust. It seems that people’s increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID:24146907

  15. Inhibition of Retinoblastoma Protein Inactivation

    Science.gov (United States)

    2017-11-01

    CONTRACT NUMBER Inhibition of Retinoblastoma Protein Inactivation 5b. GRANT NUMBER W81XWH-14-1-0329 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Seth M...confirmed 108 compounds as giving a dose-response curve with at least 30% inhibition at 10 µM. The flowchart of hit progression is shown on the...Cancer Research Program under Award No. W81XWH-14-1-0329 to S.M.R. Opinions, interpretations, conclusions, and recommendations are those of the author

  16. In vitro study of the PLA2 inhibition and antioxidant activities of Aloe vera leaf skin extracts

    Directory of Open Access Journals (Sweden)

    Gargouri Youssef

    2011-02-01

    Full Text Available Abstract Background In the present work we determined the total phenolic content of Aloe vera leaf skin (AVLS extracts by using various solvents (hexane, chloroform-ethanol (1/1, ethyl acetate, butanol and water. We have also evaluated the antioxidant and the anti-PLA2 properties of these extracts by measuring their inhibition potency on the human pro-inflammatory phospholipase A2 (group IIA. Results The water extract exhibits the highest inhibitory effect with an IC50 = 0.22 mg/ml and interestingly no effect was observed on the digestive phospholipase A2 (group IB even at a concentration of 5 mg/ml. Antioxidant activities were also analyzed and the most active extracts were observed when using chloroform ethanol (1/1 and ethyl acetate (IC50 = 0.274 and 0.326 mg/ml, respectively. Analysis of the total phenolic content reveals that the water extract, with the best anti-PLA2 effect, was poor in phenolic molecules (2 mg GAE/g. This latter value has to be compared with the chloroform-ethanol and the ethyl acetate extracts (40 and 23.8 mg GAE/g, respectively, mostly responsible for the antioxidant activity. Conclusion A significant correlation was established between the total phenolic content and the antioxidant capacity but not with the anti PLA2 activity. Results from phytochemical screening suggest that the anti PLA2 molecules were probably catechin tannins compounds.

  17. Is forgetting caused by inhibition?

    NARCIS (Netherlands)

    Raaijmakers, J.G.W.; Jakab, E.

    2013-01-01

    A well-known finding in memory research is the forgetting effect that occurs because of practicing some Item A on the recall of a related Item B. The traditional explanation for such interference effects is based on the notion of competition. According to the inhibition theory of forgetting,

  18. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup

    2003-01-01

    The main purpose of this course is to examine a newly developed biologically inhibiting material with regards to galvanic corrosion and electrochemical properties. More in detail, the concern was how the material would react when exposed to cleaning agents, here under CIP cleaning (Cleaning...

  19. Clinical efficacy of FDG-PET scan as preoperative diagnostic tool in cervical cancer stage Ib and IIa: comparison between the results of FDG-PET scan and operative findings

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jong Hoon

    1999-12-01

    This study was done to evaluate the clinical feasibility of FDG-PET scan for routine preoperative diagnostic methods in cervical carcinoma. PET-scans were performed from March, 1999 to November, 1999. There were 6 stage Ib and 7 IIa patients and all patients were performed radical hysterectomy and bilateral pelvic lymph node dissections and were evaluated by FDG-PET scan before operation. The mean age of the patients were 50.3 years old. Six cases had lymph node metastases by pelvis MRI, and three cases by FDG-PET scan. We could not find any lymph node metastases at surgery in 3 patients (50.0%) among 6 patients who were diagnosed by nodal metastases by pelvis MRI. And we found 1 patients with nodal metastases who had negative findings by pelvis MRI. By FDG-PET scan, we could find metastases in all positive patients. But we also found 2 additional metastatic cases in the patients with negative findings. In this study, the comparison was very difficult due to the individual differences in the comparison would be made by site-specific not person. The sensitivity of MRI and FDG-PET scan were 50.0% and 30.0%. The specificity were 94.1 % and 95.6%. The positive predictive value were 55.6 % and 50.0 %. In conclusion, we could find any superiority of FDG-PET scan in the diagnosis of lymph node metastases the pelvis MRI. So there are limitations to use the FDG-PET scan in the routine preoperative diagnostic tools in cervical cancer. But if we have more experiences to use the FDG-PET scan such as precise cut-off value of SUV and combination of other imaging technique, the FDG-PET scan are still promising diagnostic tools in cervical cancer.

  20. Molecular characterization and epidemiological investigation of Cryptosporidium hominis IkA18G1 and C. hominis monkey genotype IiA17, two unusual subtypes diagnosed in Swedish patients.

    Science.gov (United States)

    Lebbad, Marianne; Winiecka-Krusnell, Jadwiga; Insulander, Mona; Beser, Jessica

    2018-05-01

    Cryptosporidium hominis is considered a strictly human-adapted species, and it is only occasionally diagnosed in animals. However, two variants, C. hominis monkey genotype and C. hominis Ik, were originally described in non-human hosts, monkeys and horses, respectively. During a Swedish national Cryptosporidium study, where all samples were analyzed at the small subunit rRNA and the 60 kDa (gp60) glycoprotein loci, we identified two patients infected with C. hominis monkey genotype (subtype IiA17) and two infected with C. hominis subtype IkA18G1. The isolates were further analyzed at the actin and the 70 kDa heat shock protein loci, and these analyses showed that these two subtype families are closely related to each other and to human-adapted C. hominis as well as to Cryptosporidium cuniculus. The two patients with C. hominis monkey genotype infection (a father and son) had visited a monkey farm in Thailand prior to infection, while the two cases with C. hominis Ik were unrelated, both probably infected in Sweden. This is the first time that a monkey genotype infection in humans has been related to contact with monkeys and where the gp60 subtype was identified. It is also the first time that human infection caused by C. hominis subtype Ik is described. Even though we were not able to detect any parasites in the animal samples, zoonotic transmission cannot be ruled out in any of these cases because both subtype families are regarded as animal adapted. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Inhibiting cancer cell hallmark features through nuclear export inhibition.

    Science.gov (United States)

    Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

    2016-01-01

    Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

  2. On inhibition of dental erosion.

    Science.gov (United States)

    Rölla, Gunnar; Jonski, Grazyna; Saxegaard, Erik

    2013-11-01

    To examine the erosion-inhibiting effect of different concentrations of hydrofluoric acid. Thirty-six human molars were individually treated with 10 ml of 0.1 M citric acid for 30 min (Etch 1), acid was collected and stored until analysis. The teeth were randomly divided into six groups and then individually treated with 10 ml of one of six dilutions (from 0.1-1%) of hydrofluoric acid. The teeth were then again treated with citric acid (Etch 2). The individual acid samples from Etch 1 and 2 were analyzed for calcium by flame atomic absorption spectroscopy and difference in calcium loss was calculated. The highest erosion inhibiting effect was obtained in groups with the highest concentrations of hydrofluoric acid, where the pH was lowest, below pKa of 3.17, thus the hydrofluoric acids being mainly in an undissociated state. Diluted hydrofluoric acid is present in aqueous solution of SnF2 and TiF4 (which are known to inhibit dental erosion): SnF2 + 3H2O = Sn(OH)2 + 2HF + H2O and TiF4 + 5H2O = Ti(OH)4 + 4HF + H2O. It is also known that pure, diluted hydrofluoric acid can inhibit dental erosion. Teeth treated with hydrofluoric acid are covered by a layer of CaF2-like mineral. This mineral is acid resistant at pH acid resistant mineral, initiated by tooth enamel treatment with hydrofluoric acid. Hydrofluoric acid is different in having fluoride as a conjugated base, which provides this acid with unique properties.

  3. Entanglement and inhibited quantum evolution

    International Nuclear Information System (INIS)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W

    2003-01-01

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal

  4. Inhibition Performance in Children with Math Disabilities

    OpenAIRE

    Winegar, Kathryn Lileth

    2013-01-01

    This study examined the inhibition deficit hypothesis in children with math disabilities (MD). Children with and without MD were compared on two inhibition tasks that included the random generation of numbers and letters. The results addressed three hypotheses. Weak support was found for the first hypothesis which stated difficulties related to inhibition are significantly related to math performance. I found partial support for this hypothesis in that inhibition was related to math problem s...

  5. Circuit II--A Conversational Graphical Interface.

    Science.gov (United States)

    Singer, Ronald A.

    1993-01-01

    Provides an overview of Circuit II, an interactive system that provides users with a graphical representation of an electronic circuit within which questions may be posed and manipulated, and discusses how mouse selections have analogous roles to certain natural language features, such as anaphora, deixis, and ellipsis. (13 references) (EA)

  6. Entanglement and inhibited quantum evolution

    Energy Technology Data Exchange (ETDEWEB)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W [Universitaet Hamburg, Institut fuer Laser-Physik, Jungiusstrasse 9, D-20355 Hamburg (Germany)

    2003-03-14

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal.

  7. Behavioral inhibition and obsessive-compulsive disorder.

    Science.gov (United States)

    Coles, Meredith E; Schofield, Casey A; Pietrefesa, Ashley S

    2006-01-01

    Behavioral inhibition is frequently cited as a vulnerability factor for development of anxiety. However, few studies have examined the unique relationship between behavioral inhibition and obsessive-compulsive disorder (OCD). Therefore, the current study addressed the relationship between behavioral inhibition and OCD in a number of ways. In a large unselected student sample, frequency of current OC symptoms was significantly correlated with retrospective self-reports of total levels of childhood behavioral inhibition. In addition, frequency of current OC symptoms was also significantly correlated with both social and nonsocial components of behavioral inhibition. Further, there was evidence for a unique relationship between behavioral inhibition and OC symptoms beyond the relationship of behavioral inhibition and social anxiety. In addition, results showed that reports of childhood levels of behavioral inhibition significantly predicted levels of OCD symptoms in adulthood. Finally, preliminary evidence suggested that behavioral inhibition may be more strongly associated with some types of OC symptoms than others, and that overprotective parenting may moderate the impact of behavioral inhibition on OC symptoms. The current findings suggest the utility of additional research examining the role of behavioral inhibition in the etiology of OCD.

  8. Self-regulation, ego depletion, and inhibition.

    Science.gov (United States)

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Graphene: corrosion-inhibiting coating.

    Science.gov (United States)

    Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I

    2012-02-28

    We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating.

  10. Action inhibition in Tourette syndrome.

    Science.gov (United States)

    Ganos, Christos; Kühn, Simone; Kahl, Ursula; Schunke, Odette; Feldheim, Jan; Gerloff, Christian; Roessner, Veit; Bäumer, Tobias; Thomalla, Götz; Haggard, Patrick; Münchau, Alexander

    2014-10-01

    Tourette syndrome is a neuropsychiatric disorder characterized by tics. Tic generation is often linked to dysfunction of inhibitory brain networks. Some previous behavioral studies found deficiencies in inhibitory motor control in Tourette syndrome, but others suggested normal or even better-than-normal performance. Furthermore, neural correlates of action inhibition in these patients are poorly understood. We performed event-related functional magnetic resonance imaging during a stop-signal reaction-time task in 14 uncomplicated adult Tourette patients and 15 healthy controls. In patients, we correlated activations in stop-signal reaction-time task with their individual motor tic frequency. Task performance was similar in both groups. Activation of dorsal premotor cortex was stronger in the StopSuccess than in the Go condition in healthy controls. This pattern was reversed in Tourette patients. A significant positive correlation was present between motor tic frequency and activations in the supplementary motor area during StopSuccess versus Go in patients. Inhibitory brain networks differ between healthy controls and Tourette patients. In the latter the supplementary motor area is probably a key relay of inhibitory processes mediating both suppression of tics and inhibition of voluntary action. © 2014 International Parkinson and Movement Disorder Society.

  11. STIR: Assessing and Training Response Inhibition Abilities

    Science.gov (United States)

    2014-07-30

    Learning to stop responding to alcohol cues reduces alcohol intake via reduced affective associations rather than increased response inhibition. Addiction ...requires an abstract application of the core learning principle1,2, and viable examples are often hard to find and/or assess. If exposure to non...inhibition training that expands upon previous successful “near transfer” response inhibition training efforts—such as treating alcohol addictions by

  12. Inhibition of cortiocosteroidogenesis by delta-9-tetrahydrocannabinol.

    Science.gov (United States)

    Warner, W; Harris, L S; Carchman, R A

    1977-12-01

    ACTH, cholera toxin, cyclic AMP but not pregnenolone-induced steroidogenesis in Y-1 functional mouse adrenal tumor cells was significantly inhibited by delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol. The inhibition of steroidogenesis could not be correlated with a general depression in cell function or viability. The data suggest that cannabinoids inhibit corticosteroidogenesis at a site between the synthesis of cAMP and of pregnenolone.

  13. Inhibition of apparent photosynthesis by nitrogen oxides

    Energy Technology Data Exchange (ETDEWEB)

    Hill, A C; Bennett, J H

    1970-01-01

    The nitrogen oxides (NO/sub 2/ and NO) inhibited apparent photosynthesis of oats and alfalfa at concentrations below those required to cause visible injury. There appeared to be a threshold concentration of about 0.6 ppm for each pollutant. An additive effect in depressing apparent photosynthesis occurred when the plants were exposed to a mixture of NO and NO/sub 2/. Although NO produced a more rapid effect on the plants, lower concentrations of NO/sub 2/ were required to cause a given inhibition after 2 hour of exposure. Inhibition by nitric oxide was more closely related to its partial pressure than was inhibition by NO/sub 2/.

  14. Inhibition of photosynthesis by carbon monoxide and suspension of the carbon monoxide inhibition by light

    Energy Technology Data Exchange (ETDEWEB)

    Gewitz, H S; Voelker, W

    1963-08-01

    The experimental subject was the autotroph Chlorella pyrenoidosa. It was found that growth conditions determine whether the alga is inhibited by carbon monoxide or not. Respiration and photosynthesis are inhibited by carbon monoxide if the cells have grown rapidly under high light intensities. The inhibition of respiration and photosynthesis found in such cells is completely reversible. The inhibition depends not only on carbon monoxide pressure, but also on the oxygen pressure prevailing at the same time. 5 references, 1 figure, 3 tables.

  15. 7-Piperazinethylchrysin inhibits melanoma cell proliferation by ...

    African Journals Online (AJOL)

    In B16F10 and A375 cells, treatment with PEC caused the inhibition ... Conclusion: PEC inhibited melanoma cell proliferation, apparently by blocking the cell cycle at G0/G1 .... all statistical analyses. .... Financial support from the Department of.

  16. A Qualitative Approach to Enzyme Inhibition

    Science.gov (United States)

    Waldrop, Grover L.

    2009-01-01

    Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K[subscript m] and V[subscript max] are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the…

  17. Inhibition: Mental Control Process or Mental Resource?

    Science.gov (United States)

    Im-Bolter, Nancie; Johnson, Janice; Ling, Daphne; Pascual-Leone, Juan

    2015-01-01

    The current study tested 2 models of inhibition in 45 children with language impairment and 45 children with normally developing language; children were aged 7 to 12 years. Of interest was whether a model of inhibition as a mental-control process (i.e., executive function) or as a mental resource would more accurately reflect the relations among…

  18. The pharmacology of visuospatial attention and inhibition

    NARCIS (Netherlands)

    Logemann, H.N.A.

    2013-01-01

    Attention and inhibition are of vital importance in everyday functioning. Problems of attention and inhibition are central to disorders such as Attention Deficit/Hyperactivity Disorder (ADHD). Both bias and disengagement key components of visuospatial attention. Bias refers to neuronal signals that

  19. Inhibition of ethylene production by cobaltous ion

    International Nuclear Information System (INIS)

    Lau, O.L; Yang, S.F.

    1976-01-01

    The effect of Co 2+ on ethylene production by mung bean (Phaseolus aureus Roxb.) and by apple tissues was studied. Co 2+ , depending on concentrations applied, effectively inhibited ethylene production by both tissues. It also strongly inhibited the ethylene production induced by IAA, kinetin, IAA plus kinetin, Ca 2+ , kinetin plus Ca 2+ , or Cu 2+ treatments in mung bean hypocotyl segments. While Co 2+ greatly inhibited ethylene production, it had little effect on the respiration of apple tissue, indicating that Co 2+ does not exert its inhibitory effect as a general metabolic inhibitor. Ni 2+ , which belongs to the same group as Co 2+ in the periodic table, also markedly curtailed both the basal and the induced ethylene production by apple and mung bean hypocotyl tissues. In a system in which kinetin and Ca 2+ were applied together, kinetin greatly enhanced Ca 2+ uptake, thus enhancing ethylene production. Co 2+ , however, slightly inhibited the uptake of Ca 2+ but appreciably inhibited ethylene production, either in the presence or in the absence of kinetin. Tracer experiments using apple tissue indicated that Co 2+ strongly inhibited the in vivo conversion of L-[U-- 14 C]methionine to 14 C-ethylene. These data suggested that Co 2+ inhibited ethylene production by inhibiting the conversion of methionine to ethylene, a common step which is required for ethylene formation by higher plants. Co 2+ is known to promote elongation, leaf expansion, and hook opening in excised plant parts in response to applied auxins or cytokinins.Since ethylene is known to inhibit those growth phenomena, it is suggested that Co 2+ exerts its promotive effect, at least in part, by inhibiting ethylene formation

  20. Lysophospholipase inhibition by organophosphorus toxicants

    International Nuclear Information System (INIS)

    Quistad, Gary B.; Casida, John E.

    2004-01-01

    Lysophospholipases (LysoPLAs) are a large family of enzymes for removing lysophospholipids from cell membranes. Potent inhibitors are needed to define the importance of LysoPLAs as targets for toxicants and potential therapeutics. This study considers organophosphorus (OP) inhibitors with emphasis on mouse brain total LysoPLA activity relative to the mipafox-sensitive neuropathy target esterase (NTE)-LysoPLA recently established as 17% of the total activity and important in the action of OP delayed toxicants. The most potent inhibitors of total LysoPLA in mouse brain are isopropyl dodecylphosphonofluoridate (also for LysoPLA of Vibrio bacteria), ethyl octylphosphonofluoridate (EOPF), and two alkyl-benzodioxaphosphorin 2-oxides (BDPOs)[(S)-octyl and dodecyl] (IC50 2-8 nM). OP inhibitors acting in vitro and in vivo differentiate a more sensitive portion but not a distinct NTE-LysoPLA compared with total LysoPLA activity. For 10 active inhibitors, NTE-LysoPLA is 17-fold more sensitive than total LysoPLA, but structure-activity comparisons give a good correlation (r 2 = 0.94) of IC50 values, suggesting active site structural similarity or identity. In mice 4 h after intraperitoneal treatment with discriminating doses, EOPF, tribufos (a plant defoliant), and dodecanesulfonyl fluoride inhibit 41-57% of the total brain LysoPLA and 85-99% of the NTE-LysoPLA activity. Total LysoPLA as well as NTE-LysoPLA is decreased in activity in Nte +/- -haploinsufficient mice compared to their Nte +/+ littermates. The lysolecithin level of spinal cord but not brain is elevated significantly following EOPF treatment (3 mg/kg), thereby focusing attention on localized rather than general alterations in lysophospholipid metabolism in OP-induced hyperactivity and toxicity

  1. Regulation of spatial selectivity by crossover inhibition.

    Science.gov (United States)

    Cafaro, Jon; Rieke, Fred

    2013-04-10

    Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or "crossover" inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell's spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.

  2. Fear inhibition in high trait anxiety.

    Directory of Open Access Journals (Sweden)

    Merel Kindt

    Full Text Available Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear. Sixty undergraduate students participated in the study--High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms or with current anxiety symptoms, we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.

  3. Bivariate Correlation Analysis of the Chemometric Profiles of Chinese Wild Salvia miltiorrhiza Based on UPLC-Qqq-MS and Antioxidant Activities

    Directory of Open Access Journals (Sweden)

    Xiaodan Zhang

    2018-02-01

    Full Text Available To better understand the mechanisms underlying the pharmacological actions of Salvia miltiorrhiza, correlation between the chemical profiles and in vitro antioxidant activities in 50 batches of wild S. miltiorrhiza samples was analyzed. Our ultra-performance liquid chromatography–tandem mass spectrometry analysis detected twelve phenolic acids and five tanshinones and obtained various chemical profiles from different origins. In a principal component analysis (PCA and cluster analysis, the tanshinones cryptotanshinone, tanshinone IIA and dihydrotanshinone I exhibited higher weights in PC1, whereas the phenolic acids danshensu, salvianolic acids A and B and lithospermic acid were highly loaded in PC2. All components could be optimized as markers of different locations and might be suitable for S. miltiorrhiza quality analyses. Additionally, the DPPH and ABTS assays used to comprehensively evaluate antioxidant activities indicated large variations, with mean DPPH and ABTS scavenging potencies of 32.24 and 23.39 μg/mL, respectively, among S. miltiorrhiza extract solutions. Notably, samples that exceeded the mean IC50 values had higher phenolic acid contents. A correlation analysis indicated a strong correlation between the antioxidant activities and phenolic acid contents. Caffeic acid, danshensu, rosmarinic acid, lithospermic acid and salvianolic acid B were major contributors to antioxidant activity. In conclusion, phenolic compounds were the predominant antioxidant components in the investigated plant species. These plants may be sources of potent natural antioxidants and beneficial chemopreventive agents.

  4. Should we stop thinking about inhibition? Searching for individual and age differences in inhibition ability.

    Science.gov (United States)

    Rey-Mermet, Alodie; Gade, Miriam; Oberauer, Klaus

    2018-04-01

    Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  5. Inhibition of urinary calculi -- a spectroscopic study

    Science.gov (United States)

    Manciu, Felicia; Govani, Jayesh; Durrer, William; Reza, Layra; Pinales, Luis

    2008-10-01

    Although a considerable number of investigations have already been undertaken and many causes such as life habits, metabolic disorders, and genetic factors have been noted as sources that accelerate calculi depositions and aggregations, there are still plenty of unanswered questions regarding efficient inhibition and treatment mechanisms. Thus, in an attempt to acquire more insights, we propose here a detailed scientific study of kidney stone formation and growth inhibition based on a traditional medicine approach with Rotula Aquatica Lour (RAL) herbal extracts. A simplified single diffusion gel growth technique was used for synthesizing the samples for the present study. The unexpected Zn presence in the sample with RAL inhibitor, as revealed by XPS measurements, explains the inhibition process and the dramatic reflectance of the incident light observed in the infrared transmission studies. Raman data demonstrate potential binding of the inhibitor with the oxygen of the kidney stone. Photoluminescence results corroborate to provide additional evidence of Zn-related inhibition.

  6. Exogenously triggered response inhibition in developmental stuttering.

    Science.gov (United States)

    Eggers, Kurt; De Nil, Luc F; Van den Bergh, Bea R H

    2018-06-01

    The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Hypnotic suggestibility, cognitive inhibition, and dissociation.

    Science.gov (United States)

    Dienes, Zoltán; Brown, Elizabeth; Hutton, Sam; Kirsch, Irving; Mazzoni, Giuliana; Wright, Daniel B

    2009-12-01

    We examined two potential correlates of hypnotic suggestibility: dissociation and cognitive inhibition. Dissociation is the foundation of two of the major theories of hypnosis and other theories commonly postulate that hypnotic responding is a result of attentional abilities (including inhibition). Participants were administered the Waterloo-Stanford Group Scale of Hypnotic Susceptibility, Form C. Under the guise of an unrelated study, 180 of these participants also completed: a version of the Dissociative Experiences Scale that is normally distributed in non-clinical populations; a latent inhibition task, a spatial negative priming task, and a memory task designed to measure negative priming. The data ruled out even moderate correlations between hypnotic suggestibility and all the measures of dissociation and cognitive inhibition overall, though they also indicated gender differences. The results are a challenge for existing theories of hypnosis.

  8. Corrosion inhibition by lithium zinc phosphate pigment

    International Nuclear Information System (INIS)

    Alibakhshi, E.; Ghasemi, E.; Mahdavian, M.

    2013-01-01

    Highlights: •Synthesis of lithium zinc phosphate (LZP) by chemical co-precipitation method. •Corrosion inhibition activity of pigments compare with zinc phosphate (ZP). •LZP showed superior corrosion inhibition effect in EIS measurements. •Evaluation of adhesion strength and dispersion stability. -- Abstract: Lithium zinc phosphate (LZP) has been synthesized through a co-precipitation process and characterized by XRD and IR spectroscopy. The inhibitive performances of this pigment for corrosion of mild steel have been discussed in comparison with the zinc phosphate (ZP) in the pigment extract solution by means of EIS and in the epoxy coating by means of salt spray. The EIS and salt spray results revealed the superior corrosion inhibitive effect of LZP compared to ZP. Moreover, adhesion strength and dispersion stability of the pigmented epoxy coating showed the advantage of LZP compared to ZP

  9. Human milk glycoconjugates that inhibit pathogens.

    Science.gov (United States)

    Newburg, D S

    1999-02-01

    Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory IgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycoproteins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae and of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by S-fimbriated E. coli. The ganglioside, GM1, reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants.

  10. Inhibition in the Human Auditory Cortex.

    Directory of Open Access Journals (Sweden)

    Koji Inui

    Full Text Available Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful.

  11. Heme Oxygenase-1 Induction by Carbon Monoxide Releasing Molecule-3 Suppresses Interleukin-1β-Mediated Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Chih-Chung Lin

    2017-11-01

    Full Text Available Neurodegenerative disorders and brain damage are initiated by excessive production of reactive oxygen species (ROS, which leads to tissue injury, cellular death and inflammation. In cellular anti-oxidant systems, heme oxygenase-1 (HO-1 is an oxidative-sensor protein induced by ROS generation or carbon monoxide (CO release. CO releasing molecules (CORMs, including CORM-3, exert anti-oxidant and anti-inflammatory effects. However, the molecular mechanisms of CORM-3-induced HO-1 expression and protection against interleukin (IL-1β-induced inflammatory responses have not been fully elucidated in rat brain astrocytes (RBA-1. To study the regulation of CORM-3-induced HO-1 expression, signaling pathways, promoter activity, mRNA and protein expression were assessed following treatment with pharmacological inhibitors and gene-specific siRNA knockdown. We found that CORM-3 mediated HO-1 induction via transcritional and translational processes. Furthermore, CORM-3-induced HO-1 expression was mediated by phosphorylation of several protein kinases, such as c-Src, Pyk2, protein kinase Cα (PKCα and p42/p44 mitogen-activated protein kinase (MAPK, which were inhibited by respective pharmacological inhibitors or by gene-specific knockdown with siRNA transfections. Next, we found that CORM-3 sequentially activated the c-Src/Pyk2/PKCα/p42/p44 MAPK pathway, thereby up-regulating mRNA for the activator protein (AP-1 components c-Jun and c-Fos; these effects were attenuated by an AP-1 inhibitor (Tanshinone IIA; TSIIA and other relevant inhibitors. Moreover, CORM-3-induced upregulation of HO-1 attenuated the IL-1β-induced cell migration and matrix metallopeptidase-9 mRNA expression in RBA-1 cells. These effects were reversed by an matrix metalloproteinase (MMP2/9 inhibitor or by transfection with HO-1 siRNA.

  12. Characterization of acetylcholinesterase-inhibition by itopride.

    Science.gov (United States)

    Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

    1994-11-01

    Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

  13. Aspartate inhibits Staphylococcus aureus biofilm formation.

    Science.gov (United States)

    Yang, Hang; Wang, Mengyue; Yu, Junping; Wei, Hongping

    2015-04-01

    Biofilm formation renders Staphylococcus aureus highly resistant to conventional antibiotics and host defenses. Four D-amino acids (D-Leu, D-Met, D-Trp and D-Tyr) have been reported to be able to inhibit biofilm formation and disassemble established S. aureus biofilms. We report here for the first time that both D- and L-isoforms of aspartate (Asp) inhibited S. aureus biofilm formation on tissue culture plates. Similar biofilm inhibition effects were also observed against other staphylococcal strains, including S. saprophyticus, S. equorum, S. chromogenes and S. haemolyticus. It was found that Asp at high concentrations (>10 mM) inhibited the growth of planktonic N315 cells, but at subinhibitory concentrations decreased the cellular metabolic activity without influencing cell growth. The decreased cellular metabolic activity might be the reason for the production of less protein and DNA in the matrix of the biofilms formed in the presence of Asp. However, varied inhibition efficacies of Asp were observed for biofilms formed by clinical staphylococcal isolates. There might be mechanisms other than decreasing the metabolic activity, e.g. the biofilm phenotypes, affecting biofilm formation in the presence of Asp. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Simvastatin inhibits Candida albicans biofilm in vitro.

    Science.gov (United States)

    Liu, Geoffrey; Vellucci, Vincent F; Kyc, Stephanie; Hostetter, Margaret K

    2009-12-01

    By inhibiting the conversion of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to mevalonate, statins impair cholesterol metabolism in humans. We reasoned that statins might similarly interfere with the biosynthesis of ergosterol, the major sterol of the yeast cell membrane. As assessed by spectrophotometric and microscopic analysis, significant inhibition of biofilm production was noted after 16-h incubation with 1, 2.5, and 5 muM simvastatin, concentrations that did not affect growth, adhesion, or hyphal formation by C. albicans in vitro. Higher concentrations (10, 20, and 25 muM simvastatin) inhibited biofilm by >90% but also impaired growth. Addition of exogenous ergosterol (90 muM) overcame the effects of 1 and 2.5 muM simvastatin, suggesting that at least one mechanism of inhibition is interference with ergosterol biosynthesis. Clinical isolates from blood, skin, and mucosal surfaces produced biofilms; biofilms from bloodstream isolates were similarly inhibited by simvastatin. In the absence of fungicidal activity, simvastatin's interruption of a critical step in an essential metabolic pathway, highly conserved from yeast to man, has unexpected effects on biofilm production by a eukaryotic pathogen.

  15. Terbinafine inhibits gap junctional intercellular communication

    International Nuclear Information System (INIS)

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-01-01

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca 2+ concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca 2+ concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.

  16. Terbinafine inhibits gap junctional intercellular communication

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ju Yeun, E-mail: whitewndus@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Yoon, Sei Mee, E-mail: sei_mee@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Department of Integrated OMICS for Biomedical Sciences, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Choi, Eun Ju, E-mail: yureas@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Lee, Jinu, E-mail: jinulee@yonsei.ac.kr [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of)

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca{sup 2+} concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca{sup 2+} concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.

  17. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    Science.gov (United States)

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  18. Silver-Palladium Surfaces Inhibit Biofilm Formation

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Schroll, Casper; Hilbert, Lisbeth Rischel

    2009-01-01

    Undesired biofilm formation is a major concern in many areas. In the present study, we investigated biofilm-inhibiting properties of a silver-palladium surface that kills bacteria by generating microelectric fields and electrochemical redox processes. For evaluation of the biofilm inhibition...... efficacy and study of the biofilm inhibition mechanism, the silver-sensitive Escherichia coli J53 and the silver-resistant E. coli J53[pMG101] strains were used as model organisms, and batch and flow chamber setups were used as model systems. In the case of the silver-sensitive strain, the silver......-palladium surfaces killed the bacteria and prevented biofilm formation under conditions of low or high bacterial load. In the case of the silver-resistant strain, the silver-palladium surfaces killed surface-associated bacteria and prevented biofilm formation under conditions of low bacterial load, whereas under...

  19. Inhibition of melanogenesis by Xanthium strumarium L.

    Science.gov (United States)

    Li, Hailan; Min, Young Sil; Park, Kyoung-Chan; Kim, Dong-Seok

    2012-01-01

    Xanthium strumarium L. (Asteraceae) is traditionally used in Korea to treat skin diseases. In this study, we investigated the effects of a X. strumarium stem extract on melanin synthesis. It inhibited melanin synthesis in a concentration-dependent manner, but it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, and instead downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase expression. MITF, the master regulator of pigmentation, is a target of the Wnt signaling pathway, which includes glycogen synthase kinase 3β (GSK3β) and β-catenin. Hence, the influence of X. strumarium stem extract on GSK3β and β-catenin was further investigated. X. strumarium induced GSK3β phosphorylation (inactivation), but the level of β-catenin did not change. Moreover, a specific GSK3β inhibitor restored X. strumarium-induced melanin reduction. Hence, we suggest that X. strumarium inhibits melanin synthesis through downregulation of tyrosinase via GSK3β phosphorylation.

  20. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    Directory of Open Access Journals (Sweden)

    Susan Skanderup Falkenberg

    2012-01-01

    Full Text Available 12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM and collagen- (2.0 μg/mL induced aggregations in human blood. These four species in respective extracts (in brackets were Blechnum chilense (MeOH, Luma apiculata (H2O, Amomyrtus luma (DCM : MeOH 1 : 1 and Cestrum parqui (DCM : MeOH 1 : 1. The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1, and L. apiculata (H2O were substantial and confirmed by inhibition of platelet surface activation markers.

  1. Distractor inhibition: Evidence from lateralized readiness potentials.

    Science.gov (United States)

    Pramme, Lisa; Dierolf, Angelika M; Naumann, Ewald; Frings, Christian

    2015-08-01

    The present study investigated distractor inhibition on the level of stimulus representation. In a sequential distractor-to-distractor priming task participants had to respond to target letters flanked by distractor digits. Reaction time and stimulus-locked lateralized readiness potentials (S-LRPs) of probe responses were measured. Distractor-target onset asynchrony was varied. For RTs responses to probe targets were faster in the case of prime-distractor repetition compared to distractor changes indicating distractor inhibition. Benefits in RTs and the latency of S-LRP onsets for distractor repetition were also modulated by distractor-target onset asynchrony. For S-LRPs distractor inhibition was only present with a simultaneous onset of distractors and target. The results confirm previous results indicating inhibitory mechanisms of object-based selective attention on the level of distractor representations. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Terbinafine inhibits gap junctional intercellular communication.

    Science.gov (United States)

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca(2+) concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Inhibition of aluminum corrosion using Opuntia extract

    International Nuclear Information System (INIS)

    El-Etre, A.Y.

    2003-01-01

    The inhibitive action of the mucilage extracted from the modified stems of prickly pears, toward acid corrosion of aluminum, is tested using weight loss, thermometry, hydrogen evolution and polarization techniques. It was found that the extract acts as a good corrosion inhibitor for aluminum corrosion in 2.0 M HCl solution. The inhibition action of the extract was discussed in view of Langmuir adsorption isotherm. It was found that the adsorption of the extract on aluminum surface is a spontaneous process. The inhibition efficiency (IE) increases as the extract concentration is increased. The effect of temperature on the IE was studied. It was found that the presence of extract increases the activation energy of the corrosion reaction. Moreover, the thermodynamic parameters of the adsorption process were calculated. It was found also that the Opuntia extract provides a good protection to aluminum against pitting corrosion in chloride ion containing solutions

  4. Mapuche herbal medicine inhibits blood platelet aggregation.

    Science.gov (United States)

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM) and collagen- (2.0 μg/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H(2)O), Amomyrtus luma (DCM : MeOH 1 : 1) and Cestrum parqui (DCM : MeOH 1 : 1). The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1), and L. apiculata (H(2)O) were substantial and confirmed by inhibition of platelet surface activation markers.

  5. Inhibition of intestinal disaccharidase activity by pentoses

    DEFF Research Database (Denmark)

    Halschou-Jensen, Kia

    on carbohydrate- ingesting enzymes activity in vitro and possible effects on human postprandial blood response. In paper 1 the effects of sugar beet polyphenols from molasses and the potential inhibition of sucrase activity in vitro, was investigated. Two different polyphenol-rich fractions from chromatographic...... separation of molasses from sugar beets and pure ferulic acid were tested. We found no effects of the two fractions of molasses. The pure ferulic acid indicated an inhibition of sucrase in vitr. Both in vitro and in vivo studies have investigated the effects of L-arabinose and D-xylose on carbohydrate...

  6. Sprout inhibition in roots, tubers and bulbs

    International Nuclear Information System (INIS)

    Luna C, P.C.

    1992-05-01

    The treatment with ionizing radiations to low dose impedes that appear sprouts in the tubers (potatoes); bulbs (onion and garlic) and in roots like the ginger and the yucca. The purpose is to inhibit the germination during the process of manipulation and storage, and this way to avoid the lost ones post crop of these products. The radiation dose required to inhibit the germination goes to depend of: the development conditions, the differences of variety, of the storage state of the bulbs and the conditions of cured and storage. (Author)

  7. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    OpenAIRE

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0??M) and collagen- (2.0??g/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H2O), Amomyrtus l...

  8. Peptide inhibition of human cytomegalovirus infection

    Directory of Open Access Journals (Sweden)

    Morris Cindy A

    2011-02-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB, a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS, several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF were infected with the Towne-GFP strain of HCMV (0.5 MOI, preincubated with peptides at a range of concentrations (78 nm to 100 μM, and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 μM, and 51% and 62% inhibition at concentrations of 5 μM and 2.5 μM, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100

  9. Improved Oral Bioavailability Using a Solid Self-Microemulsifying Drug Delivery System Containing a Multicomponent Mixture Extracted from Salvia miltiorrhiza

    Directory of Open Access Journals (Sweden)

    Xiaolin Bi

    2016-04-01

    Full Text Available The active ingredients of salvia (dried root of Salvia miltiorrhiza include both lipophilic (e.g., tanshinone IIA, tanshinone I, cryptotanshinone and dihydrotanshinone I and hydrophilic (e.g., danshensu and salvianolic acid B constituents. The low oral bioavailability of these constituents may limit their efficacy. A solid self-microemulsifying drug delivery system (S-SMEDDS was developed to load the various active constituents of salvia into a single drug delivery system and improve their oral bioavailability. A prototype SMEDDS was designed using solubility studies and phase diagram construction, and characterized by self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. Furthermore, the S-SMEDDS was prepared by dispersing liquid SMEDDS containing liposoluble extract into a solution containing aqueous extract and hydrophilic polymer, and then freeze-drying. In vitro release of tanshinone IIA, salvianolic acid B, cryptotanshinone and danshensu from the S-SMEDDS was examined, showing approximately 60%–80% of each active component was released from the S-SMEDDS in vitro within 20 min. In vivo bioavailability of these four constituents indicated that the S-SMEDDS showed superior in vivo oral absorption to a drug suspension after oral administration in rats. It can be concluded that the novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of both lipophilic and hydrophilic constituents of salvia. Thus, the S-SMEDDS can be regarded as a promising new method by which to deliver salvia extract, and potentially other multicomponent drugs, by the oral route.

  10. Inhibition of barley grain germination by light

    NARCIS (Netherlands)

    Roth-Bejerano, N.; Meulen, R.M. van der; Wang, M.

    1996-01-01

    Intact grains of barley (Hordeum distichum cv. Triumph) germinated rapidly in the dark or when exposed to brief daily light breaks in the temperature range 15-25°C, although germination proceeded less rapidly at low temperatures. Prolonged illumination (16 h/day) or continuous light inhibited

  11. Probenazole treatment inhibits anthocyanins biosynthesis via ...

    African Journals Online (AJOL)

    It has been found that anthocyanins were accumulated in Arabidopsis under drought or salt stress. In this study, such accumulation was found to be inhibited by external applied probenazole (3-allyloxy-1, 2-benzisothiazole-1,1-dioxide, PBZ), which is the active ingredient in oryzemate used for the protection of rice from ...

  12. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    International Nuclear Information System (INIS)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-01-01

    Highlights: ► Salinomycin inhibits preadipocyte differentiation into adipocytes. ► Salinomycin inhibits transcriptional regulation of adipogenesis. ► Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  13. Illustrating Enzyme Inhibition Using Gibbs Energy Profiles

    Science.gov (United States)

    Bearne, Stephen L.

    2012-01-01

    Gibbs energy profiles have great utility as teaching and learning tools because they present students with a visual representation of the energy changes that occur during enzyme catalysis. Unfortunately, most textbooks divorce discussions of traditional kinetic topics, such as enzyme inhibition, from discussions of these same topics in terms of…

  14. Microbial Metabolism and Inhibition Studies of Phenobarbital

    African Journals Online (AJOL)

    Erah

    techniques, high performance liquid chromatography (HPLC), mass spectrometry (MS) ... Keywords: Microbial metabolism, Phenobarbital, Inhibition studies, Rhizopus stolonifer, CYP 2C9, .... 24 h of incubation 0.5 ml of drug solution was ... mode, positive: spray voltage, 3.5 KV: ... Rhizopus stolonifer showed an extra peak at.

  15. Luteoloside Inhibits Proliferation of Human Chronic Myeloid ...

    African Journals Online (AJOL)

    Purpose: To investigate the effects of luteoloside on the proliferation of human chronic ..... Zhang N, Wang D, Zhu Y, Wang J, Lin H. Inhibition ... Han X. Protection of Luteolin-7-O-Glucoside Against ... Hwang YJ, Lee EJ, Kim HR, Hwang KA.

  16. Nickel Inhibits Mitochondrial Fatty Acid Oxidation

    Science.gov (United States)

    Uppala, Radha; McKinney, Richard W.; Brant, Kelly A.; Fabisiak, James P.; Goetzman, Eric S.

    2015-01-01

    Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation—the pathway by which fatty acids are catabolized for energy—in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with L-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 hr), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. PMID:26051273

  17. Inhibiting Intuitive Thinking in Mathematics Education

    Science.gov (United States)

    Thomas, Michael O. J.

    2015-01-01

    The papers in this issue describe recent collaborative research into the role of inhibition of intuitive thinking in mathematics education. This commentary reflects on this research from a mathematics education perspective and draws attention to some of the challenges that arise in collaboration between research fields with different cultures,…

  18. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A. [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States); Yap, Sook Fan [Faculty of Medicine and Health Sciences, Department of Pre-Clinical Sciences, University of Tunku Abdul Rahman (Malaysia); Ngeow, Yun Fong [Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603 (Malaysia); Chin, Khew-Voon, E-mail: khew-voon.chin@utoledo.edu [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  19. Undecylenic Acid Inhibits Morphogenesis of Candida albicans

    OpenAIRE

    McLain, Nealoo; Ascanio, Rhoda; Baker, Carol; Strohaver, Robert A.; Dolan, Joseph W.

    2000-01-01

    Resilient liners are frequently used to treat denture stomatitis, a condition often associated with Candida albicans infections. Of 10 liners tested, 2 were found to inhibit the switch from the yeast form to hyphae and a third was found to stimulate this switch. The inhibitor was determined to be undecylenic acid.

  20. Undecylenic acid inhibits morphogenesis of Candida albicans.

    Science.gov (United States)

    McLain, N; Ascanio, R; Baker, C; Strohaver, R A; Dolan, J W

    2000-10-01

    Resilient liners are frequently used to treat denture stomatitis, a condition often associated with Candida albicans infections. Of 10 liners tested, 2 were found to inhibit the switch from the yeast form to hyphae and a third was found to stimulate this switch. The inhibitor was determined to be undecylenic acid.

  1. Cellulase Inhibition by High Concentrations of Monosaccharides

    DEFF Research Database (Denmark)

    Hsieh, Chia-Wen; Cannella, David; Jørgensen, Henning

    2014-01-01

    Biological degradation of biomass on an industrial scale culminates in high concentrations of end products. It is known that the accumulation of glucose and cellobiose, end products of hydrolysis, inhibit cellulases and decrease glucose yields. Aside from these end products, however, other monosa...

  2. Inhibiting Translation One Protein at a Time.

    Science.gov (United States)

    Disney, Matthew D

    2017-06-01

    Historically, translational inhibitors have been confined to anti-bacterials that globally affect translation. Lintner et al. demonstrate that small molecules can specifically inhibit translation of a single disease-associated protein by stalling the ribosome's nascent chain [1], opening up a new therapeutic strategy for 'undruggable' proteins. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Evaluating the Frequency of aac(6')-IIa, ant(2″)-I, intl1, and intl2 Genes in Aminoglycosides Resistant Klebsiella pneumoniae Isolates Obtained from Hospitalized Patients in Yazd, Iran.

    Science.gov (United States)

    Mokhtari, Hesam; Eslami, Gilda; Zandi, Hengameh; Dehghan-Banadkouki, Amin; Vakili, Mahmood

    2018-01-01

    Klebsiella pneumoniae (K. pneumoniae) is an opportunistic pathogen that could be resistant to many antimicrobial agents. Resistance genes can be carried among gram-negative bacteria by integrons. Enzymatic inactivation is the most important mechanism of resistance to aminoglycosides. In this study, the frequencies of two important resistance gene aac(6')-II a and ant(2″)-I, and genes coding integrase I and II, in K. pneumoniae isolates resistant to aminoglycosides were evaluated. In this cross-sectional study, an attempt was made to assess the antibiotic susceptibility of 130 K. pneumoniae isolates obtained from different samples of patients hospitalized in training hospitals of Yazd evaluated by disk diffusion method. The frequencies of aac(6')-II a, ant(2″)-I, intl1 , and intl2 genes were determined by PCR method. Data were analyzed by chi-square method using SPSS software (Ver. 16). our results showed that resistance to gentamicin, tobramycin, kanamycin, and amikacin were 34.6, 33.8, 43.8, and 14.6%, respectively. The frequencies of aac (6')-II a, ant(2″)-I, intl1 , and intl2 genes were 44.6, 27.7, 90, and 0%, respectively. This study showed there are high frequencies of genes coding aminoglycosides resistance in K. pneumoniae isolates. Hence, it is very important to monitor and inhibit the spread of antibiotic resistance genes.

  4. Polysulfonate suramin inhibits Zika virus infection.

    Science.gov (United States)

    Tan, Chee Wah; Sam, I-Ching; Chong, Wei Lim; Lee, Vannajan Sanghiran; Chan, Yoke Fun

    2017-07-01

    Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log 10  PFU viral reduction with IC 50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Neural Synchrony during Response Production and Inhibition

    Science.gov (United States)

    Müller, Viktor; Anokhin, Andrey P.

    2012-01-01

    Inhibition of irrelevant information (conflict monitoring) and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs) elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG) recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300–600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations. PMID:22745691

  6. WEE1 inhibition sensitizes osteosarcoma to radiotherapy

    International Nuclear Information System (INIS)

    PosthumaDeBoer, Jantine; Würdinger, Thomas; Graat, Harm CA; Beusechem, Victor W van; Helder, Marco N; Royen, Barend J van; Kaspers, Gertjan JL

    2011-01-01

    The use of radiotherapy in osteosarcoma (OS) is controversial due to its radioresistance. OS patients currently treated with radiotherapy generally are inoperable, have painful skeletal metastases, refuse surgery or have undergone an intralesional resection of the primary tumor. After irradiation-induced DNA damage, OS cells sustain a prolonged G 2 cell cycle checkpoint arrest allowing DNA repair and evasion of cell death. Inhibition of WEE1 kinase leads to abrogation of the G 2 arrest and could sensitize OS cells to irradiation induced cell death. WEE1 expression in OS was investigated by gene-expression data analysis and immunohistochemistry of tumor samples. WEE1 expression in OS cell lines and human osteoblasts was investigated by Western blot. The effect of WEE1 inhibition on the radiosensitivity of OS cells was assessed by cell viability and caspase activation analyses after combination treatment. The presence of DNA damage was visualized using immunofluorescence microscopy. Cell cycle effects were investigated by flow cytometry and WEE1 kinase regulation was analyzed by Western blot. WEE1 expression is found in the majority of tested OS tissue samples. Small molecule drug PD0166285 inhibits WEE1 kinase activity. In the presence of WEE1-inhibitor, irradiated cells fail to repair their damaged DNA, and show higher levels of caspase activation. The inhibition of WEE1 effectively abrogates the irradiation-induced G 2 arrest in OS cells, forcing the cells into premature, catastrophic mitosis, thus enhancing cell death after irradiation treatment. We show that PD0166285, a small molecule WEE1 kinase inhibitor, can abrogate the G 2 checkpoint in OS cells, pushing them into mitotic catastrophe and thus sensitizing OS cells to irradiation-induced cell death. This suggests that WEE1 inhibition may be a promising strategy to enhance the radiotherapy effect in patients with OS

  7. Neural synchrony during response production and inhibition.

    Directory of Open Access Journals (Sweden)

    Viktor Müller

    Full Text Available Inhibition of irrelevant information (conflict monitoring and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300-600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations.

  8. Contrasting neural effects of aging on proactive and reactive response inhibition

    NARCIS (Netherlands)

    Bloemendaal, Mirjam; Zandbelt, Bram; Wegman, Joost; Rest, van de O.; Cools, Roshan; Aarts, Esther

    2016-01-01

    Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition

  9. Mullerian Inhibiting Substances (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2006-01-01

    MIS is a member of the TGF family. The purpose of this study is to test the hypothesis that MIS and IFN-gamma might be more effective in the inhibition of breast cancer cell growth than either agent alone...

  10. Mullerian Inhibiting Substance (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2004-01-01

    Mullerian Inhibiting Substance (MIS), a member of the TGFB family regulates growth, differentiation, and apoptosis in many cell types In the male embryo, MIS causes regression of the Mullerian duct...

  11. A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients.

    Science.gov (United States)

    Derfuss, Tobias; Curtin, François; Guebelin, Claudia; Bridel, Claire; Rasenack, Maria; Matthey, Alain; Du Pasquier, Renaud; Schluep, Myriam; Desmeules, Jules; Lang, Alois B; Perron, Hervé; Faucard, Raphael; Porchet, Hervé; Hartung, Hans-Peter; Kappos, Ludwig; Lalive, Patrice H

    2015-06-01

    GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period. © The Author(s) 2014.

  12. Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro

    International Nuclear Information System (INIS)

    Mahalingam, Sharada; Gao, Liying; Gonnering, Marni; Helferich, William; Flaws, Jodi A.

    2016-01-01

    Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral follicles isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, and 100 μM) for 48 and 96 h. Every 24 h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. - Highlights: • Equol exposure inhibits antral follicle growth. • Equol exposure increases follicle atresia. • Equol exposure inhibits sex steroid hormone levels. • Equol exposure inhibits mRNA levels of certain steroidogenic enzymes.

  13. Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Mahalingam, Sharada, E-mail: mahalin2@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Gao, Liying, E-mail: lgao@uiuc.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Gonnering, Marni, E-mail: mgonne2@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Helferich, William, E-mail: helferic@illinois.edu [Department of Food Science and Human Nutrition, University of Illinois, 905 S. Goodwin, Urbana, IL 61801 (United States); Flaws, Jodi A., E-mail: jflaws@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States)

    2016-03-15

    Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral follicles isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, and 100 μM) for 48 and 96 h. Every 24 h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. - Highlights: • Equol exposure inhibits antral follicle growth. • Equol exposure increases follicle atresia. • Equol exposure inhibits sex steroid hormone levels. • Equol exposure inhibits mRNA levels of certain steroidogenic enzymes.

  14. Proactive modulation of long-interval intracortical inhibition during response inhibition

    Science.gov (United States)

    Cowie, Matthew J.; MacDonald, Hayley J.; Cirillo, John

    2016-01-01

    Daily activities often require sudden cancellation of preplanned movement, termed response inhibition. When only a subcomponent of a whole response must be suppressed (required here on Partial trials), the ensuing component is markedly delayed. The neural mechanisms underlying partial response inhibition remain unclear. We hypothesized that Partial trials would be associated with nonselective corticomotor suppression and that GABAB receptor-mediated inhibition within primary motor cortex might be responsible for the nonselective corticomotor suppression contributing to Partial trial response delays. Sixteen right-handed participants performed a bimanual anticipatory response inhibition task while single- and paired-pulse transcranial magnetic stimulation was delivered to elicit motor evoked potentials in the left first dorsal interosseous muscle. Lift times, amplitude of motor evoked potentials, and long-interval intracortical inhibition were examined across the different trial types (Go, Stop-Left, Stop-Right, Stop-Both). Go trials produced a tight distribution of lift times around the target, whereas those during Partial trials (Stop-Left and Stop-Right) were substantially delayed. The modulation of motor evoked potential amplitude during Stop-Right trials reflected anticipation, suppression, and subsequent reinitiation of movement. Importantly, suppression was present across all Stop trial types, indicative of a “default” nonselective inhibitory process. Compared with blocks containing only Go trials, inhibition increased when Stop trials were introduced but did not differ between trial types. The amount of inhibition was positively correlated with lift times during Stop-Right trials. Tonic levels of inhibition appear to be proactively modulated by task context and influence the speed at which unimanual responses occur after a nonselective “brake” is applied. PMID:27281744

  15. Cell Cycle Inhibition To Treat Sleeping Sickness

    Directory of Open Access Journals (Sweden)

    Conrad L. Epting

    2017-09-01

    Full Text Available African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR, which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens.

  16. Product inhibition of five Hypocrea jecorina cellulases

    DEFF Research Database (Denmark)

    Murphy, Leigh; Westh, Peter; Bohlin, Christina

    2013-01-01

    Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information...... on individual cellulases hydrolyzing insoluble cellulose remains insufficient. Such knowledge is necessary to pinpoint and quantify inhibitory weak-links in cellulose hydrolysis, but has proven challenging to come by. Here we show that product inhibition of mono-component cellulases hydrolyzing unmodified...... cellulose may be monitored by calorimetry. The key advantage of this approach is that it directly measures the rate of hydrolysis while being essentially blind to the background of added product. We investigated the five major cellulases from Hypocrea jecorina (anamorph: Tricoderma reesei), Cel7A (formerly...

  17. How x rays inhibit amphibian limb regeneration

    International Nuclear Information System (INIS)

    Maden, M.; Wallace, H.

    1976-01-01

    The effects of an inhibiting dose of 2,000 rad of x-rays on the regenerating limbs of axolotl larvae have been examined in a histological and cytological study. Particular attention was paid to the mitotic indices of normal and irradiated epidermal and blastemal cells. Both the characteristic pattern of epidermal mitotic stimulation which normally follows amputation and the later increase in blastemal mitoses are suppressed by irradiation. In most cells the effects are permanent, but in a small proportion a mitotic delay is induced and upon subsequent division chromosome damage in the form of micronuclei is revealed. Thus irradiated cells which do divide almost certainly die. These results are discussed in relation to other theories of x-ray inhibition of regeneration with particular reference to the view that irradiated cells can be reactivated

  18. Myrtenal inhibits acetylcholinesterase, a known Alzheimer target.

    Science.gov (United States)

    Kaufmann, Dorothea; Dogra, Anudeep Kaur; Wink, Michael

    2011-10-01

    Inhibition of acetylcholinesterase (AChE) is a common treatment for early stages of the most general form of dementia, Alzheimer's disease. In this study selected components of essential oils, which carry a variety of important functional groups, were tested for their in-vitro anti-acetylcholinesterase activity. In-vitro anti-acetylcholinesterase activity was measured by an adapted version of Ellman's colorimetric assay. 1,8-cineole, carvacrol, myrtenal and verbenone apparently inhibited AChE; the highest inhibitory activity was observed for myrtenal (IC50 = 0.17 mm). This is the first study showing the AChE inhibitory activity of myrtenal. Our investigations provided evidence for the efficacy of monoterpenes as inhibitors of AChE. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

  19. Theobromine inhibits sensory nerve activation and cough.

    Science.gov (United States)

    Usmani, Omar S; Belvisi, Maria G; Patel, Hema J; Crispino, Natascia; Birrell, Mark A; Korbonits, Márta; Korbonits, Dezso; Barnes, Peter J

    2005-02-01

    Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

  20. Direct renin inhibition in chronic kidney disease

    DEFF Research Database (Denmark)

    Persson, Frederik; Rossing, Peter; Parving, Hans-Henrik

    2013-01-01

    that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need....... In addition, combination treatment seemed safe and effective also in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated...... early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic...

  1. Extinction Generates Outcome-Specific Conditioned Inhibition.

    Science.gov (United States)

    Laurent, Vincent; Chieng, Billy; Balleine, Bernard W

    2016-12-05

    Extinction involves altering a previously established predictive relationship between a cue and its outcome by repeatedly presenting that cue alone. Although it is widely accepted that extinction generates some form of inhibitory learning [1-4], direct evidence for this claim has been lacking, and the nature of the associative changes induced by extinction have, therefore, remained a matter of debate [5-8]. In the current experiments, we used a novel behavioral approach that we recently developed and that provides a direct measure of conditioned inhibition [9] to compare the influence of extinguished and non-extinguished cues on choice between goal-directed actions. Using this approach, we provide direct evidence that extinction generates outcome-specific conditioned inhibition. Furthermore, we demonstrate that this inhibitory learning is controlled by the infralimbic cortex (IL); inactivation of the IL using M4 DREADDs abolished outcome-specific inhibition and rendered the cue excitatory. Importantly, we found that context modulated this inhibition. Outside its extinction context, the cue was excitatory and functioned as a specific predictor of its previously associated outcome, biasing choice toward actions earning the same outcome. In its extinction context, however, the cue acted as a specific inhibitor and biased choice toward actions earning different outcomes. Context modulation of these excitatory and inhibitory memories was mediated by the dorsal hippocampus (HPC), suggesting that the HPC and IL act in concert to control the influence of conditioned inhibitors on choice. These findings demonstrate for the first time that extinction turns a cue into a net inhibitor that can influence choice via counterfactual action-outcome associations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Fermentation of lignocellulosic hydrolysates: Inhibition and detoxification

    Energy Technology Data Exchange (ETDEWEB)

    Palmqvist, E.

    1998-02-01

    The ethanol yield and productivity obtained during fermentation of lignocellulosic hydrolysates is decreased due to the presence of inhibiting compounds, such as weak acids, furans and phenolic compounds produced during hydrolysis. Evaluation of the effect of various biological, physical and chemical detoxification treatments by fermentation assays using Saccharomyces cerevisiae was used to characterise inhibitors. Inhibition of fermentation was decreased after removal of the non-volatile compounds, pre-fermentation by the filamentous fungus Trichoderma reesei, treatment with the lignolytic enzyme laccase, extraction with ether, and treatment with alkali. Yeast growth in lignocellulosic hydrolysates was inhibited below a certain fermentation pH, most likely due to high concentrations of undissociated weak acids. The effect of individual compounds were studied in model fermentations. Furfural is reduced to furfuryl alcohol by yeast dehydrogenases, thereby affecting the intracellular redox balance. As a result, acetaldehyde accumulated during furfural reduction, which most likely contributed to inhibition of growth. Acetic acid (10 g 1{sup -1}) and furfural (3 g 1{sup -1}) interacted antagonistically causing decreased specific growth rate, whereas no significant individual or interaction effects were detected by the lignin-derived compound 4-hydroxybenzoic acid (2 g 1{sup -1}). By maintaining a high cell mass density in the fermentor, the process was less sensitive to inhibitors affecting growth and to fluctuations in fermentation pH, and in addition the depletion rate of bioconvertible inhibitors was increased. A theoretical ethanol yield and high productivity was obtained in continuous fermentation of spruce hydrolysate when the cell mass concentration was maintained at a high level by applying cell recirculation 164 refs, 16 figs, 5 tabs

  3. Osthole inhibits bone metastasis of breast cancer

    OpenAIRE

    Wu, Chunyu; Sun, Zhenping; Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

    2017-01-01

    Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potent...

  4. Fermented Broth in Tyrosinase- and Melanogenesis Inhibition

    OpenAIRE

    Chin-Feng Chan; Ching-Cheng Huang; Ming-Yuan Lee; Yung-Sheng Lin

    2014-01-01

    Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed.

  5. Fermented Broth in Tyrosinase- and Melanogenesis Inhibition

    Directory of Open Access Journals (Sweden)

    Chin-Feng Chan

    2014-08-01

    Full Text Available Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed.

  6. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    DEFF Research Database (Denmark)

    Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

    2011-01-01

    Background: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine disrupting compounds (EDCs) share a high...... suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades....

  7. Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase

    Directory of Open Access Journals (Sweden)

    Petr Dobes

    2013-05-01

    Full Text Available Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE and/or, butyrylcholinesterase (BChE, the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon’s plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 µmol/L. The predicted free energy of binding was −6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed.

  8. Inhibition of methane production by Methanobacterium formicicum

    Energy Technology Data Exchange (ETDEWEB)

    Hobson, P N; Shaw, B G

    1976-01-01

    The effects of volatile fatty acids, ammonia and copper on methane production by growing cultures of Methanobacterium formicicum were studied. Acetate and butyrate were not inhibitory, but propionate was inhibitory above certain concentrations, as was ammonia. Copper was inhibitory, but inhibitory concentrations are difficult to define as varying amounts may be precipitated as the sulphide. The results are compared with those from piggery-waste digesters and it is suggested that failure of farm-waste digesters from such inhibitions is unlikely.

  9. Evidence of dopaminergic processing of executive inhibition.

    Directory of Open Access Journals (Sweden)

    Rajendra D Badgaiyan

    Full Text Available Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand ((11C-raclopride after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.

  10. Inhibition of enveloped viruses infectivity by curcumin.

    Directory of Open Access Journals (Sweden)

    Tzu-Yen Chen

    Full Text Available Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter than for the pseudorabies virus (approximately 180 nm and the vaccinia virus (roughly 335 × 200 × 200 nm. These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses.

  11. Imitation inhibition in children with Tourette syndrome.

    Science.gov (United States)

    Brandt, Valerie Cathérine; Moczydlowski, Agnes; Jonas, Melanie; Boelmans, Kai; Bäumer, Tobias; Brass, Marcel; Münchau, Alexander

    2017-08-12

    Echopraxia, that is, the open and automatic imitation of other peoples' actions, is common in patients with Gilles de la Tourette syndrome, autism spectrum disorder, and also those with frontal lobe lesions. While systematic reaction time tasks have confirmed increased automatic imitation in the latter two groups, adult patients with Tourette syndrome appear to compensate for automatic imitation tendencies by an overall slowing in response times. However, whether children with Tourette syndrome are already able to inhibit automatic imitation tendencies has not been investigated. Fifteen children with Tourette syndrome and 15 healthy children (aged 7-12 years) performed an imitation inhibition paradigm. Participants were asked to respond to an auditory cue by lifting their index finger or their little finger. Participants were simultaneously presented with either compatible or incompatible visual stimuli. Overall responses in children with Tourette syndrome were slower than in healthy children. Although responses were faster in compatible than in incompatible trials in both groups, this 'interference effect' was smaller in children with Tourette syndrome. Children with Tourette syndrome have a smaller interference effect than healthy children, indicating an enhanced ability to behaviourally control automatic imitation tendencies at the cost of reacting slower. The results suggest that children with Tourette syndrome already employ different or additional inhibition strategies compared to healthy children. © 2017 The British Psychological Society.

  12. Inhibition of Enveloped Viruses Infectivity by Curcumin

    Science.gov (United States)

    Wen, Hsiao-Wei; Ou, Jun-Lin; Chiou, Shyan-Song; Chen, Jo-Mei; Wong, Min-Liang; Hsu, Wei-Li

    2013-01-01

    Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA) activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB)-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter) than for the pseudorabies virus (approximately 180 nm) and the vaccinia virus (roughly 335 × 200 × 200 nm). These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses. PMID:23658730

  13. Scaling Up Cortical Control Inhibits Pain

    Directory of Open Access Journals (Sweden)

    Jahrane Dale

    2018-05-01

    Full Text Available Summary: Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain. : Dale et al. find that acute pain increases activity levels in the prefrontal cortex. Chronic pain reduces both basal spontaneous and pain-evoked activity in this region, whereas neurostimulation to restore basal activities can in turn enhance nociception-evoked prefrontal activities to inhibit pain. Keywords: chronic pain, neuromodulation, prefrontal cortex, PFC, cortical gain control

  14. Pharmacological inhibition of feline immunodeficiency virus (FIV).

    Science.gov (United States)

    Mohammadi, Hakimeh; Bienzle, Dorothee

    2012-05-01

    Feline immunodeficiency virus (FIV) is a member of the retroviridae family of viruses and causes an acquired immunodeficiency syndrome (AIDS) in domestic and non-domestic cats worldwide. Genome organization of FIV and clinical characteristics of the disease caused by the virus are similar to those of human immunodeficiency virus (HIV). Both viruses infect T lymphocytes, monocytes and macrophages, and their replication cycle in infected cells is analogous. Due to marked similarity in genomic organization, virus structure, virus replication and disease pathogenesis of FIV and HIV, infection of cats with FIV is a useful tool to study and develop novel drugs and vaccines for HIV. Anti-retroviral drugs studied extensively in HIV infection have targeted different steps of the virus replication cycle: (1) inhibition of virus entry into susceptible cells at the level of attachment to host cell surface receptors and co-receptors; (2) inhibition of fusion of the virus membrane with the cell membrane; (3) blockade of reverse transcription of viral genomic RNA; (4) interruption of nuclear translocation and viral DNA integration into host genomes; (5) prevention of viral transcript processing and nuclear export; and (6) inhibition of virion assembly and maturation. Despite much success of anti-retroviral therapy slowing disease progression in people, similar therapy has not been thoroughly investigated in cats. In this article we review current pharmacological approaches and novel targets for anti-lentiviral therapy, and critically assess potentially suitable applications against FIV infection in cats.

  15. Wnt signaling inhibits CTL memory programming.

    Science.gov (United States)

    Xiao, Zhengguo; Sun, Zhifeng; Smyth, Kendra; Li, Lei

    2013-12-01

    Induction of functional CTLs is one of the major goals for vaccine development and cancer therapy. Inflammatory cytokines are critical for memory CTL generation. Wnt signaling is important for CTL priming and memory formation, but its role in cytokine-driven memory CTL programming is unclear. We found that wnt signaling inhibited IL-12-driven CTL activation and memory programming. This impaired memory CTL programming was attributed to up-regulation of eomes and down-regulation of T-bet. Wnt signaling suppressed the mTOR pathway during CTL activation, which was different to its effects on other cell types. Interestingly, the impaired memory CTL programming by wnt was partially rescued by mTOR inhibitor rapamycin. In conclusion, we found that crosstalk between wnt and the IL-12 signaling inhibits T-bet and mTOR pathways and impairs memory programming which can be recovered in part by rapamycin. In addition, direct inhibition of wnt signaling during CTL activation does not affect CTL memory programming. Therefore, wnt signaling may serve as a new tool for CTL manipulation in autoimmune diseases and immune therapy for certain cancers. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Response inhibition in motor conversion disorder.

    Science.gov (United States)

    Voon, Valerie; Ekanayake, Vindhya; Wiggs, Edythe; Kranick, Sarah; Ameli, Rezvan; Harrison, Neil A; Hallett, Mark

    2013-05-01

    Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. © 2013 Movement Disorder Society. Copyright © 2013 Movement Disorder Society.

  17. The Kinetics of Carrier Transport Inhibition

    DEFF Research Database (Denmark)

    Rosenberg, T.; Wilbrandt, Robert Walter

    1962-01-01

    The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing with the subst......The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing...... with the substrate for the enzyme or the carrier or for both, competing with the carrier for the enzyme, or non-competitive) and in the ability of penetrating the membrane. Experiments are reported on the inhibition of glucose and fructose transport across the human red cell membrane by phlorizine, phloretine...... and polyphloretinephosphate. The results of the analysis for these inhibitors indicate a substrate competitive mode of action. The effect of reversing the transport direction by interchanging the substrate concentration has been treated for the case of a non-penetrating substrate competitive inhibitor in the external medium...

  18. Trace element inhibition of phytase activity.

    Science.gov (United States)

    Santos, T; Connolly, C; Murphy, R

    2015-02-01

    Nowadays, 70 % of global monogastric feeds contains an exogenous phytase. Phytase supplementation has enabled a more efficient utilisation of phytate phosphorous (P) and reduction of P pollution. Trace minerals, such as iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn) are essential for maintaining health and immunity as well as being involved in animal growth, production and reproduction. Exogenous sources of phytase and trace elements are regularly supplemented to monogastric diets and usually combined in a premix. However, the possibility for negative interaction between individual components within the premix is high and is often overlooked. Therefore, this initial study focused on assessing the potential in vitro interaction between inorganic and organic chelated sources of Fe, Zn, Cu and Mn with three commercially available phytase preparations. Additionally, this study has investigated if the degree of enzyme inhibition was dependent of the type of chelated sources. A highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration, p phytases for Fe and Zn, as well as for Cu with E. coli and Aspergillus niger phytases. Different chelate trace mineral sources demonstrated diversifying abilities to inhibit exogenous phytase activity.

  19. Bioassays for the determination of nitrification inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Grunditz, Camilla

    1999-07-01

    Requirements for nitrogen reduction in wastewater treatment plants were introduced in Sweden in the early 1990's. This was a governmental move to reduce the nitrogen discharges to the Baltic and Kattegat in order to prevent eutrophication. The nitrification process in wastewater treatment plants is performed by nitrifying bacteria. These are susceptible to inhibition and it is of great importance that the influent water does not contain toxic compounds. Therefore, there is a need for assays for the determination of nitrification inhibition. This thesis describes the development and applications of such bioassays. Pure cultures of Nitrosomonas sp. and Nitrobacter sp. were isolated from activated sludge of a wastewater treatment plant. These cultures were used as test organisms in the development of bioassays for nitrification inhibition measurements. The assays are based on two different principles; cell suspensions of the bacteria, performed in test tubes, and mediated amperometric biosensors with the bacteria immobilised. Ammonia oxidation and nitrite oxidation are studied separately without interference from other organisms, which makes it easier to interpret the results. The cell suspension assays were applied to samples of industrial and municipal wastewater. The Nitrosomonas and Nitrobacter assays showed to have different inhibition patterns. A large percentage of the Swedish municipal wastewater treatment plants were found to receive inhibitory influent water, but the inhibition level was generally low. Compared to an assay based on activated sludge, the screening method, the pure culture assays found more samples of influent water strongly inhibitory or stimulating. The highest correlation was found between the screening method and the Nitrosomonas assay. The Nitrobacter assay was found to be the most sensitive method. Assessment of toxicity of a number of chemical substances was studied using the biosensors, together with the cell suspension assays

  20. Inhibition of Breast Cancer Metastasis by Heregulin-Beta 1

    National Research Council Canada - National Science Library

    Yu, Dihua

    1999-01-01

    The major goal of this Idea proposal is to determine whether and how HRG-Beta1 inhibits breast cancer metastasis and to identify the functional domains that are sufficient for inhibition of breast cancer metastasis...

  1. A specific bioassay for the inhibition of flowering.

    Science.gov (United States)

    Blake, J

    1972-06-01

    A bioassay for the inhibition of flowering involving the in vitro culture of excised, partially-induced, apices of Viscaria candida is described. This bioassay has been used to detect flowering inhibition in extracts from Kalanchoe blossfeldiana.

  2. Differential effects of cognitive inhibition and intelligence on creativity

    OpenAIRE

    Benedek, Mathias; Franz, Fabiola; Heene, Moritz; Neubauer, Aljoscha C.

    2012-01-01

    There are different conceptions about how cognitive inhibition is related to creativity. Creativity has either been associated with effective inhibition, or with disinhibition, or with an adaptive engagement of inhibition. In this study, we examined the relationship of cognitive inhibition, assessed by means of the random motor generation task, with different measures of creativity. We also analyzed whether this relation is mediated by intelligence. We generally found a positive correlation o...

  3. Attention Inhibition Training Can Reduce Betel-Nut Chewing Time

    OpenAIRE

    Ho, Ming-Chou; Li, Ren-Hau; Tang, Tze-Chun

    2011-01-01

    Betel nut (or areca) is the fourth most commonly used drug worldwide after tobacco, alcohol, and caffeine. Many chemical ingredients of betel nut are carcinogenic. We examined whether the manipulation of attentional inhibition toward the areca-related stimuli could affect betel-nut chewing time. Three matched groups of habitual chewers were recruited: inhibit-areca, inhibit-non-areca, and control. This study consisted of a Go/No-Go task for inhibition training, followed by a taste test for ob...

  4. Use of bacillus subtilis strains to inhibit postharvest pathogenic fungi

    International Nuclear Information System (INIS)

    Arras, G.; Gambella, F.; Demontis, S.; Petretto, A.

    1995-01-01

    An isolate (87) of the bacillus subtilis strains isolated from cold stored citrus fruit 13 proved to inhibit the growth in vitro of the penicillium italicum used in the experiment (from 50.6% to 92.2%) and to inhibit botrytis cinerea (from 65.3% to 95.9%). A further test, superimposing on plates containing PDA strains Nos. 13, 173, and 160, totally inhibited the fungi. Tested in vivo on artificially bruised oranges, they significantly inhibited two fungi

  5. The development of children's inhibition: Does parenting matter?

    OpenAIRE

    Roskam, I.; Stievenart, Marie; Meunier, J.-C.; Noël, M.-P.

    2014-01-01

    Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8. years of age. Data were collected from 421 families, with 348 mother-child dyads and 342 father-child dyads participating. Children's inhibition ...

  6. Contour detection based on nonclassical receptive field inhibition

    NARCIS (Netherlands)

    Grigorescu, Cosmin; Petkov, Nicolai; Westenberg, Michel A.

    We propose a biologically motivated computational step, called nonclassical receptive field (non-CRF) inhibition, more generally surround inhibition or suppression, to improve contour detection in machine vision. Non-CRF inhibition is exhibited by 80% of the orientation-selective neurons in the

  7. The Effectiveness of Reward and Punishment Contingencies on Response Inhibition

    Science.gov (United States)

    Costantini, Arthur F.; Hoving, Kenneth L.

    1973-01-01

    The relative effectiveness of reward and punishment on the development of response inhibition was evaluated developmentally with kindergarteners and second graders. Removal of positive reinforcers was apparently more effective than reward in producing inhibiting at both age levels. Transfer of inhibition training was also evaluated. (DP)

  8. Effect of Adenine Concentration on the Corrosion Inhibition of Aisi ...

    African Journals Online (AJOL)

    This gave a surface coverage of 0.8956 and corrosion penetration rate of 0.022132mm/yr. Hence, the best adenine concentration for the corrosion inhibition of alloys 304L in 1.0M sulphuric acid solution to obtain optimum inhibition efficiency is 0.011M. Keywords: Corrosion, AISI 304L Steel, Inhibition efficiency, Degree of ...

  9. Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi.

    Science.gov (United States)

    Miyazawa, M; Tougo, H; Ishihara, M

    2001-01-01

    Inhibition of acetylcholinesterase (AChE) activity by essential oils of Citrus paradisi (grapefruit pink in USA) was studied. Inhibition of AChE was measured by the colorimetric method. Nootkatone and auraptene were isolated from C. paradisi oil and showed 17-24% inhibition of AChE activity at the concentration of 1.62 microg/mL.

  10. Inhibition and Adsorption impact of Leave Extracts of Cnidoscolus ...

    African Journals Online (AJOL)

    Corrosion inhibition in the presence of alokaloid and non alkaloid extracts of Cnidoscolus aconitifolius in 1M HCl was studied using the weight loss and hydrogen evolution techniques at 303, 313 and 333 K. The results obtained revealed that the inhibition efficiency decreased with increase in temperature. Inhibition ...

  11. A fusion-inhibiting peptide against Rift Valley fever virus inhibits multiple, diverse viruses.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Koehler

    Full Text Available For enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. This fusion process is mediated by at least three classes of fusion proteins (Class I, II, and III based on the protein sequence and structure. For Rift Valley fever virus (RVFV, the glycoprotein Gc (Class II fusion protein mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. Here, we show that peptides analogous to the RVFV Gc stem region inhibited RVFV infectivity in cell culture by inhibiting the fusion process. Further, we show that infectivity can be inhibited for diverse, unrelated RNA viruses that have Class I (Ebola virus, Class II (Andes virus, or Class III (vesicular stomatitis virus fusion proteins using this single peptide. Our findings are consistent with an inhibition mechanism similar to that proposed for stem peptide fusion inhibitors of dengue virus in which the RVFV inhibitory peptide first binds to both the virion and cell membranes, allowing it to traffic with the virus into the endocytic pathway. Upon acidification and rearrangement of Gc, the peptide is then able to specifically bind to Gc and prevent fusion of the viral and endocytic membranes, thus inhibiting viral infection. These results could provide novel insights into conserved features among the three classes of viral fusion proteins and offer direction for the future development of broadly active fusion inhibitors.

  12. Curcumin inhibits aggregation of alpha-synuclein.

    Science.gov (United States)

    Pandey, Neeraj; Strider, Jeffrey; Nolan, William C; Yan, Sherry X; Galvin, James E

    2008-04-01

    Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid and prevent further oligomerization of Abeta monomers onto growing amyloid beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation are similar in Parkinson's disease (PD) and AD, we investigated the effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of AS aggregation was developed by treatment of purified AS protein (wild-type) with 1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin inhibited aggregation in a dose-dependent manner and increased AS solubility. The aggregation-inhibiting effect of curcumin was next investigated in cell culture utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and its aggregation examined under different concentrations of curcumin. To estimate aggregation in an unbiased manner, a protocol was developed in which the images were captured automatically through a high-throughput cell-based screening microscope. The obtained images were processed automatically for aggregates within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant alpha-synuclein aggregation was observed within 48 h subsequent to curcumin addition. Our data suggest that curcumin inhibits AS oligomerization into higher molecular weight aggregates and therefore should be further explored as a potential therapeutic compound for PD and related disorders.

  13. Interferon-γ Inhibits Ebola Virus Infection.

    Directory of Open Access Journals (Sweden)

    Bethany A Rhein

    Full Text Available Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  14. Interferon-γ Inhibits Ebola Virus Infection.

    Science.gov (United States)

    Rhein, Bethany A; Powers, Linda S; Rogers, Kai; Anantpadma, Manu; Singh, Brajesh K; Sakurai, Yasuteru; Bair, Thomas; Miller-Hunt, Catherine; Sinn, Patrick; Davey, Robert A; Monick, Martha M; Maury, Wendy

    2015-01-01

    Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  15. Cannabidiol inhibits angiogenesis by multiple mechanisms.

    Science.gov (United States)

    Solinas, M; Massi, P; Cantelmo, A R; Cattaneo, M G; Cammarota, R; Bartolini, D; Cinquina, V; Valenti, M; Vicentini, L M; Noonan, D M; Albini, A; Parolaro, D

    2012-11-01

    Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  16. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

    Energy Technology Data Exchange (ETDEWEB)

    Jan, Yi-Hua [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Richardson, Jason R., E-mail: jricha3@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Baker, Angela A. [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Mishin, Vladimir [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Department of Environmental Health Science, New York Medical College, Valhalla, NY (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States)

    2015-10-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.

  17. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

    International Nuclear Information System (INIS)

    Jan, Yi-Hua; Richardson, Jason R.; Baker, Angela A.; Mishin, Vladimir; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

    2015-01-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.

  18. Saw palmetto ethanol extract inhibits adipocyte differentiation.

    Science.gov (United States)

    Villaverde, Nicole; Galvis, Adriana; Marcano, Adriana; Priestap, Horacio A; Bennett, Bradley C; Barbieri, M Alejandro

    2013-07-01

    The fruits of saw palmetto have been used for the treatment of a variety of urinary and reproductive system problems. In this study we investigated whether the fruit extracts affect in vitro adipogenesis. Saw palmetto ethanol extract inhibited the lipid droplet accumulation by induction media in a dose-dependent manner, and it also attenuated the protein expressions of C-EBPα and PPARγ. Phosphorylation of Erk1/2 and Akt1 were also decreased by saw palmetto ethanol extract. This report suggests that saw palmetto extracts selectively affect the adipocyte differentiation through the modulation of several key factors that play a critical role during adipogenesis.

  19. Irradiation inhibits the regeneration of aneurogenic limbs

    International Nuclear Information System (INIS)

    Wallace, H.; Maden, M.

    1976-01-01

    The developing arms of axolotl larvae from the 2-digit stage onward and the aneurogenic arms of surgically denervated larvae maintained in parabiosis are able to regenerate after amputation. Such regeneration is uniformly inhibited by local irradiation of the arm, whether innervated or not. This demonstration refutes a recent hypothesis that x-rays interfere with a special activity of nerves required for regeneration, and supports the earlier concept that x-rays act directly on those cells which must proliferate to form the regenerated tissues

  20. Inhibition of sulfate reduction in paddy soils

    Energy Technology Data Exchange (ETDEWEB)

    Vamos, R

    1958-12-13

    The hydrogen sulfide formed in waterlogged soils is a serious problem in rice cultivation. It inhibits the uptake of water and nutrients and may even cause root-rot. Results can best be obtained by preventing the formation of hydrogen sulfide. It is formed mainly by reduction of sulfate for which the cellulose-butyric acid fermentation provides the hydrogen source. Addition of ammonium or potassium nitrate prevents the formation of H/sub 2/S. The hydrogen produced by butyric acid fermentation is used to reduce nitrate and consequently cannot be utilized by the sulfate-reducing bacteria as a source of energy. 6 references.

  1. Vaginal Lactobacillus isolates inhibit uropathogenic Escherichia coli.

    OpenAIRE

    Atassi , Fabrice; Brassart , Dominique; Grob , Philipp; Graf , Federico; Servin , Alain ,

    2006-01-01

    The purpose of this study was to investigate the antibacterial activities of Lactobacillus jensenii KS119.1 and KS121.1, and Lactobacillus gasserii KS120.1 and KS124.3 strains isolated from the vaginal microflora of healthy women, against uropathogenic, diffusely adhering Afa/Dr Escherichia coli (Afa/Dr DAEC) strains IH11128 and 7372 involved in recurrent cystitis. We observed that some of the Lactobacillus isolates inhibited the growth and decreased the viability of E. coli IH11128 and 7372....

  2. Research on inhibition of corneal neovascularization

    Directory of Open Access Journals (Sweden)

    Zhang-Hui Yang

    2015-12-01

    Full Text Available Corneal transparency is the basis of the normal physiological functions.However, corneal neovascularization(CNVmay occur in the infection, mechanical and chemical injury or under other pathological conditions,which make the cornea lose original transparency and severe visual impairment. In recent years, along with the development of immunology, molecular biology, biochemistry and other disciplines, there is more in-depth understanding on the CNV, and clinical treatment of CNV has made new breakthroughs. This article provides an overview of the inhibition of CNV.

  3. Na+/K+-ATPase: Activity and inhibition

    Science.gov (United States)

    Čolović, M.; Krstić, D.; Krinulović, K.; Momić, T.; Savić, J.; Vujačić, A.; Vasić, V.

    2009-09-01

    The aim of the study was to give an overview of the mechanism of inhibition of Na+/K+-ATPase activity induced by some specific and non specific inhibitors. For this purpose, the effects of some ouabain like compounds (digoxin, gitoxin), noble metals complexes ([PtCl2DMSO2], [AuCl4]-, [PdCl4]2-, [PdCl(dien)]+, [PdCl(Me4dien)]+), transition metal ions (Cu2+, Zn2+, Fe2+, Co2+), and heavy metal ions (Hg2+, Pb2+, Cd2+) on the activity of Na+/K+-ATPase from rat synaptic plasma membranes (SPM), porcine cerebral cortex and human erythrocytes were discussed.

  4. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  5. Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing

    International Nuclear Information System (INIS)

    Tropea, J.E.; Molyneux, R.J.; Kaushal, G.P.; Pan, Y.T.; Mitchell, M.; Elbein, A.D.

    1989-01-01

    Australine is a polyhydroxylated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis. Since swainsonine and catanospermine are polyhydroxylated indolizidine alkaloids that inhibit specific glycosidases, the authors tested australine against a variety of exoglycosidases to determine whether it would inhibit any of these enzymes. This alkaloid proved to be a good inhibitor of the α-glucosidase amyloglucosidase (50% inhibition at 5.8 μM), but it did not inhibit β-glucosidase, α- or β-mannosidase, or α- or β-galactosidase. The inhibition of amyloglucosidase was of a competitive nature. Australine also inhibited the glycoprotein processing enzyme glucosidase I, but had only slight activity toward glucosidase II. When incubated with cultured cells, this alkaloid inhibited glycoprotein processing at the glucosidase I step and caused the accumulation of glycoproteins with Glc 3 Man 7-9 (GlcNAc) 2 -oligosaccharides

  6. Sprouting inhibition of rhizomes by gamma irradiation

    International Nuclear Information System (INIS)

    Hilmy, Nazly; Chosdu, Rahayu

    1985-01-01

    Sprouting inhibition by gamma irradiation to prolong the storage life of 4 species of rhizomes, namely curcuma domestica, kaemferia galanga, curcuma xanthoriza and curcuma aeruginosa, has been carried out. Two groups of samples were used, freshly harvested rhizomes and fresh rhizomes which have been stored for about two weeks. The samples were packed in a plastic net bag, each contained about 100 grams of rhizomes. Irradiation was carried out at room temperature at the doses of 0, 0.02, 0.04, 0.06, 0.08, 0.10, 0.15, 0.20 and 0.25 kGy. Post irradiation storage was done at room temperature with relative humidity ranging between 85 and 95%. The results showed that irradiation doses of 0.06 to 0.08 kGy was sufficient to inhibit sprouting of freshly harvested rhizomes and prolonged its storage life for 6 weeks, while in the other group sprouting still occured at the dose of 0.25 kGy. Irradiation dose up to 0.25 kGy did not cause significant effect on moisture and volatile oil contents, as well as volatile oil characteristics of the samples. About 50% of weight losses were found either in irradiated or unirradiated samples after being stored for 8 weeks. Odour and texture were evaluated organoleptically while mould growth and insect damage were observed visually. (author)

  7. Inhibition of DNA replication by ultraviolet light

    International Nuclear Information System (INIS)

    Edenberg, H.J.

    1976-01-01

    DNA replication in ultraviolet-irradiated HeLa cells was studied by two different techniques: measurements of the kinetics of semiconservative DNA synthesis, and DNA fiber autoradiography. In examining the kinetics of semiconservative DNA synthesis, density label was used to avoid measuring the incorporation due to repair replication. The extent of inhibition varied with time. After doses of less than 10 J/m 2 the rate was initially depressed but later showed some recovery. After higher doses, a constant, low rate of synthesis was seen for at least the initial 6 h. An analysis of these data indicated that the inhibition of DNA synthesis could be explained by replication forks halting at pyrimidine dimers. DNA fiber autoradiography was used to further characterize replication after ultraviolet irradiation. The average length of labeled segments in irradiated cells increased in the time immediately after irradiation, and then leveled off. This is the predicted pattern if DNA synthesis in each replicon continued at its previous rate until a lesion is reached, and then halted. The frequency of lesions that block synthesis is approximately the same as the frequency of pyrimidine dimers

  8. Soluble Aβ aggregates can inhibit prion propagation.

    Science.gov (United States)

    Sarell, Claire J; Quarterman, Emma; Yip, Daniel C-M; Terry, Cassandra; Nicoll, Andrew J; Wadsworth, Jonathan D F; Farrow, Mark A; Walsh, Dominic M; Collinge, John

    2017-11-01

    Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP C ). Ligands that bind to PrP C can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP C , and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrP C and emphasize the bidirectional nature of the interplay between Aβ and PrP C in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common. © 2017 The Authors.

  9. Ketose induced respiratory inhibition in isolated hepatocytes.

    Science.gov (United States)

    Martínez, P; Carrascosa, J M; Núñez de Castro, I

    1987-06-01

    The addition of 10 mM fructose or 10 mM tagatose to a suspension of hepatocytes caused respiratory inhibition, whereas no change in oxygen uptake was observed following the addition of glucose. However, incubations in the presence of fructose showed a high, aerobic glycolytic activity. Tagatose is phosphorylated to tagatose 1-phosphate but is not further metabolized by cell free liver extract. Moreover, the addition of fructose to glucagon treated cells also caused the Crabtree-like effect. The concentration of adenine nucleotides and inorganic phosphate (Pi) in the mitochondrial and cytosolic compartments during incubation (time 30 min) was determined by the digitonin fractionation procedure. In the presence of 10 mM fructose or tagatose, the total adenine nucleotide pools decreased by 40%; however, glucose produced no change. The addition of ketoses diminished the asymmetric distribution of extramitochondrial (ATP/ADP)e ratio and intramitochondrial (ATP/ADP)i ratio. At the same time the total mitochondrial Pi fell from 17 mM to 6-7 mM. The mitochondrial membrane potential (-161 mV) in the presence of fructose showed no changes during the 30 min experimental period. An increase in the NADH/NAD+ ratio was observed. These results suggest that in hepatocytes the inhibition of respiration is not necessarily linked with the enhanced aerobic glycolysis, by competition for common substrates.

  10. Lactam inhibiting Streptococcus mutans growth on titanium

    Energy Technology Data Exchange (ETDEWEB)

    Xavier, J.G.; Geremias, T.C.; Montero, J.F.D. [Center for Research on Dental Implants (CEPID), School of Dentistry (ODT), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-900 (Brazil); Vahey, B.R. [Herman Ostrow School of Dentistry of USC, 925 W 34 St, Los Angeles, CA 90089 (United States); Benfatti, C.A.M.; Souza, J.C.M.; Magini, R.S. [Center for Research on Dental Implants (CEPID), School of Dentistry (ODT), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-900 (Brazil); Pimenta, A.L., E-mail: andrea@intelab.ufsc.br [Department of Biologia, ERRMECe, Université de Cergy Pontoise, 2, Av. Adolphe Chauvin 95302 Cergy, Pontoise (France); Integrated Laboratories Technologies (InteLab), Dept. Chemical and Food Engineering (EQA), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-970 (Brazil)

    2016-11-01

    The aim of this work was to analyze the activity of novel synthetic lactams on preventing biofilm formation on titanium surfaces. Titanium (Ti6Al4V) samples were exposed to Streptococcus mutans cultures in the presence or absence of a synthetic lactam. After 48 h incubation, planktonic growth was determined by spectrophotometry. Biofilm was evaluated by crystal violet staining and colony forming units (CFU·ml{sup −1}), followed by scanning electron microscopy (SEM). Results showed that the average of adhered viable cells was approximately 1.5 × 10{sup 2} CFU/ml in the presence of lactam and 4 × 10{sup 2} CFU/ml in its absence. This novel compound was considerable active in reducing biofilm formation over titanium surfaces, indicating its potential for the development of antimicrobial drugs targeting the inhibition of the initial stages of bacterial biofilms on dental implants abutments. - Highlights: • A novel synthetic compound is tested on preventing biofilm formation on titanium surfaces • Biofilm inhibition has been achieved on titanium surfaces containing the novel compound. • Planktonic growth of S. mutans was not affected by the presence of lactams on titanium.

  11. Universal water-dilutable inhibited protective lubricants

    International Nuclear Information System (INIS)

    Mamtseva, M.V.; Kardash, N.V.; Latynina, M.B.

    1993-01-01

    In the interest of environmental protection, improvement of working conditions, and reduced fire hazard in production operations, water-based protective lubricants are now available in a wide assortment, and the production volume has increased greatly. The term water-dilutable inhibited protective lubricants (WDIPL) means water-soluble, water-emulsifiable, or water-dispersible products with the dual function of reducing friction and wear and protecting metal surfaces against corrosion for specified periods of time. According to the standard Unified System of Protection Against Corrosion and Aging (COST 9.103-78), WDIPLs are classed as products for the temporary corrosion protection of metals and end-items. In the general class of WDIPLs one can identify water-dilutable combination corrosion inhibitors, film-forming inhibited petroleum compositions (FIPC-d), detergent-preservative fluids, operational-preservative lubricating-cooling process compounds (ICPC), and, finally, universal multifunctional products. Combined corrosion inhibitors may consist of water-soluble organic and inorganic compounds; water/oil and oil-soluble surfactants - corrosion inhibitors of the chemisorption type or donor and/or acceptor types; shielding inhibitors of the adsorption type; and fast-acting water-displacing components. 23 refs

  12. Salinomycin, A Polyether Ionophoric Antibiotic, Inhibits Adipogenesis

    Science.gov (United States)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-01-01

    The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy. PMID:23123626

  13. Structural basis of kynurenine 3-monooxygenase inhibition.

    Science.gov (United States)

    Amaral, Marta; Levy, Colin; Heyes, Derren J; Lafite, Pierre; Outeiro, Tiago F; Giorgini, Flaviano; Leys, David; Scrutton, Nigel S

    2013-04-18

    Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases.

  14. PD-1 checkpoint inhibition: Toxicities and management.

    Science.gov (United States)

    Hahn, Andrew W; Gill, David M; Agarwal, Neeraj; Maughan, Benjamin L

    2017-12-01

    With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others. In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities. Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil. There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Platelets Inhibit Migration of Canine Osteosarcoma Cells.

    Science.gov (United States)

    Bulla, S C; Badial, P R; Silva, R C; Lunsford, K; Bulla, C

    2017-01-01

    The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition. Copyright © 2016. Published by Elsevier Ltd.

  16. Kaempferol inhibits thrombosis and platelet activation.

    Science.gov (United States)

    Choi, Jun-Hui; Park, Se-Eun; Kim, Sung-Jun; Kim, Seung

    2015-08-01

    The objectives of the present study were to investigate whether kaempferol affects pro-coagulant proteinase activity, fibrin clot formation, blood clot and thrombin (or collagen/epinephrine)-stimulated platelet activation, thrombosis, and coagulation in ICR (Imprinting Control Region) mice and SD (Sprague-Dawley) rats. Kaempferol significantly inhibited the enzymatic activities of thrombin and FXa by 68 ± 1.6% and 52 ± 2.4%, respectively. Kaempferol also inhibited fibrin polymer formation in turbidity. Microscopic analysis was performed using a fluorescent conjugate. Kaempferol completely attenuated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and phosphoinositide 3-kinase (PI3K)/PKB (AKT) in thrombin-stimulated platelets and delayed aggregation time (clotting) by 34.6% in an assay of collagen/epinephrine-stimulated platelet activation. Moreover, kaempferol protected against thrombosis development in 3 animal models, including collagen/epinephrine- and thrombin-induced acute thromboembolism models and an FeCl3-induced carotid arterial thrombus model. The ex vivo anticoagulant effect of kaempferol was further confirmed in ICR mice. This study demonstrated that kaempferol may be clinically useful due to its ability to reduce or prevent thrombotic challenge. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  17. Lactam inhibiting Streptococcus mutans growth on titanium

    International Nuclear Information System (INIS)

    Xavier, J.G.; Geremias, T.C.; Montero, J.F.D.; Vahey, B.R.; Benfatti, C.A.M.; Souza, J.C.M.; Magini, R.S.; Pimenta, A.L.

    2016-01-01

    The aim of this work was to analyze the activity of novel synthetic lactams on preventing biofilm formation on titanium surfaces. Titanium (Ti6Al4V) samples were exposed to Streptococcus mutans cultures in the presence or absence of a synthetic lactam. After 48 h incubation, planktonic growth was determined by spectrophotometry. Biofilm was evaluated by crystal violet staining and colony forming units (CFU·ml −1 ), followed by scanning electron microscopy (SEM). Results showed that the average of adhered viable cells was approximately 1.5 × 10 2 CFU/ml in the presence of lactam and 4 × 10 2 CFU/ml in its absence. This novel compound was considerable active in reducing biofilm formation over titanium surfaces, indicating its potential for the development of antimicrobial drugs targeting the inhibition of the initial stages of bacterial biofilms on dental implants abutments. - Highlights: • A novel synthetic compound is tested on preventing biofilm formation on titanium surfaces • Biofilm inhibition has been achieved on titanium surfaces containing the novel compound. • Planktonic growth of S. mutans was not affected by the presence of lactams on titanium.

  18. Periostin Limits Tumor Response to VEGFA Inhibition.

    Science.gov (United States)

    Keklikoglou, Ioanna; Kadioglu, Ece; Bissinger, Stefan; Langlois, Benoît; Bellotti, Axel; Orend, Gertraud; Ries, Carola H; De Palma, Michele

    2018-03-06

    Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA + stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  19. Heat enhances radiation inhibition of wound healing

    International Nuclear Information System (INIS)

    Twomey, P.; Hill, S.; Joiner, M.; Hobson, B.; Denekamp, J.

    1987-01-01

    To study the effect of hyperthermia on the inhibition of healing by radiation, the authors used 2 models of wound tensile strength in mice. In one, tensile strength of 1 cm strips of wounded skin was measured. In the other, strength was measured on 2 by 1 by .3 cm surgical prosthetic sponges of polyvinyl alcohol which has been cut, resutured, and implanted subcutaneously. Granulation tissue grows into the pores of the sponges which gradually fill with collagen. Tensile strength in both models was measured on day 14 using a constant strain extensiometer. The wounds were given graduated doses of ortho-voltage radiation with or without hyperthermia. Maximum radiation sensitivity occurred during the period of rapid neovascularization in the first 5 days after wounding, when a loss of 80% in wound strength occurred with doses less than 20 gray. For single radiation doses given 48 hours after wounding, the authors found a steep dose-response curve with half maximum reduction in strength occurring in both models at approximately 10 gray. Hyperthermia was produced in two ways. Skin wounds were heated in a circulating water bath. In the sponge model, more uniform heating occurs with an RF generator scaled to the mouse. At a dose of 43 C for 30 minutes, no inhibition of healing by heat alone was found. However the combination of heat and radiation produced definite enhancement of radiation damage, with thermal enhancement ratios of up to 1.9 being observed

  20. Periostin Limits Tumor Response to VEGFA Inhibition

    Directory of Open Access Journals (Sweden)

    Ioanna Keklikoglou

    2018-03-01

    Full Text Available Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs under extended vascular-endothelial growth factor A (VEGFA blockade are dependent on periostin (POSTN, a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2, an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs.

  1. Inhibition by acrolein of light-induced stomatal opening through inhibition of inward-rectifying potassium channels in Arabidopsis thaliana.

    Science.gov (United States)

    Islam, Md Moshiul; Ye, Wenxiu; Matsushima, Daiki; Khokon, Md Atiqur Rahman; Munemasa, Shintaro; Nakamura, Yoshimasa; Murata, Yoshiyuki

    2015-01-01

    Acrolein is a reactive α,β-unsaturated aldehyde derived from lipid peroxides, which are produced in plants under a variety of stress. We investigated effects of acrolein on light-induced stomatal opening using Arabidopsis thaliana. Acrolein inhibited light-induced stomatal opening in a dose-dependent manner. Acrolein at 100 μM inhibited plasma membrane inward-rectifying potassium (Kin) channels in guard cells. Acrolein at 100 μM inhibited Kin channel KAT1 expressed in a heterologous system using Xenopus leaves oocytes. These results suggest that acrolein inhibits light-induced stomatal opening through inhibition of Kin channels in guard cells.

  2. 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

    Science.gov (United States)

    Xian, Shu-Lin; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

    2015-02-01

    Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro . However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

  3. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition?

    NARCIS (Netherlands)

    Petrykiv, Sergei; Laverman, Gozewijn D.; de Zeeuw, Dick; Heerspink, Hiddo J. L.

    Individual patients show a large variation in their response to renin-angiotensin-aldosteron system (RAAS) inhibition (RAASi), both in surrogates such as albuminuria and in hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer

  4. Ketoconazole inhibits the cellular uptake of anandamide via inhibition of FAAH at pharmacologically relevant concentrations.

    Directory of Open Access Journals (Sweden)

    Emmelie Björklund

    Full Text Available The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA.The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 µM, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component of 34 µM.The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer.

  5. Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis.

    Science.gov (United States)

    Li, Qingli; Lambrechts, Mark J; Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Yin, Rutie; Xi, Mingrong; You, Zongbing

    2013-01-01

    Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose) polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy.

  6. Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells.

    Science.gov (United States)

    Ge, Peng-Fei; Zhang, Ji-Zhou; Wang, Xiao-Fei; Meng, Fan-Kai; Li, Wen-Chen; Luan, Yong-Xin; Ling, Feng; Luo, Yi-Nan

    2009-07-01

    The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the effect of autophagy on the destiny of glioma cells remains unclear. In this study, we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells. The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells, and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. The expression of autophagy related proteins was determined by Western blot. MG-132 inhibited cell proliferation, induced cell death and cell cycle arrest at G(2)/M phase, and activated autophagy in SHG-44 glioma cells. The expression of autophagy-related Beclin-1 and LC3-I was significantly up-regulated and part of LC3-I was converted into LC3-II. However, when SHG-44 glioma cells were co-treated with MG-132 and 3-MA, the cells became less viable, but cell death and cell numbers at G(2)/M phase increased. Moreover, the accumulation of acidic vesicular organelles was decreased, the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-II from LC3-I was also inhibited. Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells, and inhibition of autophagy increases cell death. This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.Acta Pharmacologica Sinica (2009) 30: 1046-1052; doi: 10.1038/aps.2009.71.

  7. Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.

    Directory of Open Access Journals (Sweden)

    Chaonan Sun

    Full Text Available The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER homeostatic state and result in ER stress (ERS, subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05. Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.

  8. A novel approach to inhibit bone resorption

    DEFF Research Database (Denmark)

    Panwar, Preety; Søe, Kent; Guido, Rafael VC

    2016-01-01

    BACKGROUND AND PURPOSE: Cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Potent active site-directed inhibitors have been developed and showed variable success in clinical trials. These inhibitors block the entire activity of CatK and thus may interfere with other...... pathways. The present study investigates the antiresorptive effect of an exosite inhibitor that selectively inhibits only the therapeutically relevant collagenase activity of CatK. EXPERIMENTAL APPROACH: Human osteoclasts and fibroblasts were used to analyse the effect of the exosite inhibitor, ortho......-dihydrotanshinone (DHT1), and the active site inhibitor, odanacatib (ODN), on bone resorption and TGF-ß1 degradation. Cell cultures, Western blot, light and scanning electron microscopy as well as energy dispersive X-ray spectroscopy, molecular modelling and enzymatic assays were used to evaluate the inhibitors. KEY...

  9. Diclofenac inhibits 27-hydroxycholesterol-induced inflammation.

    Science.gov (United States)

    Kim, Bo-Young; Son, Yonghae; Eo, Seong-Kug; Park, Young Chul; Kim, Koanhoi

    2016-09-23

    27-Hydroxycholesterol (27OHChol) is a cholesterol oxidation product that induces inflammation. In the current study we investigated the effects of diclofenac on inflammatory responses caused by 27OHChol using human monocyte/macrophage (THP-1) cells. Transcription and secretion of CCL2, CCL3, and CCL4 chemokines enhanced by 27OHChol were significantly attenuated by diclofenac in a concentration dependent manner. Migrations of monocytic cells and CCR5-positive Jurkat T cells were reduced proportionally to the concentrations of diclofenac. Superproduction of CCL2 and monocytic cell migration induced by 27OHChol plus LPS were significantly attenuated by diclofenac. Diclofenac also attenuated transcription of MMP-9 and release of its active gene product. These results indicate that diclofenac inhibits 27OHChol-induced inflammatory responses, thereby suppressing inflammation in a milieu rich in cholesterol oxidation products. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Isoform-specific inhibition of cyclophilins.

    Science.gov (United States)

    Daum, Sebastian; Schumann, Michael; Mathea, Sebastian; Aumüller, Tobias; Balsley, Molly A; Constant, Stephanie L; de Lacroix, Boris Féaux; Kruska, Fabian; Braun, Manfred; Schiene-Fischer, Cordelia

    2009-07-07

    Cyclophilins belong to the enzyme class of peptidyl prolyl cis-trans isomerases which catalyze the cis-trans isomerization of prolyl bonds in peptides and proteins in different folding states. Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4(+) T cells by the inhibitor provided biological proof of discrimination in vivo.

  11. Inhibition of cellular oxidation by fluoride

    Energy Technology Data Exchange (ETDEWEB)

    Borei, H

    1945-01-01

    An attempt has been made to investigate the inhibition by fluoride of the oxidative processes which occur in the cell by way of the cytochrome oxidase-cytochrome system. Some chemical and physical properties of the fluoride ion are discussed, together with certain quantitative methods for the determination of fluoride. An exhaustive review of the literature concerning the effect of fluoride on enzymic processes has been compiled. The experiments have shown that the point of the attack by fluoride is to be found among the cytochromes. The inhibitory mechanism appears to be such that the haemoprotein is prevented from taking part in the preceding and succeeding links in the reaction chain. The blocking action leaves the prosthetic group of the haemoprotein completely unchanged. The experimental results indicate the formation of a fluorophosphoprotein complex, analogous to that found in the case of enolase. Magnesium may possibly play a part in this process.

  12. Inhibition of Neurogenesis by Zika virus Infection.

    Science.gov (United States)

    Ahmad, Fahim; Siddiqui, Amna; Kamal, Mohammad A; Sohrab, Sayed S

    2018-02-01

    The association between Zika virus infection and neurological disorder has raised urgent global alarm. The ongoing epidemic has triggered quick responses in the scientific community. The first case of Zika virus was reported in 2015 from Brazil and now has spread over 30 countries. Nearly four hundred cases of travel-associated Zika virus infection have also been reported in the United States. Zika virus is primarily transmitted by mosquito belongs to the genus Aedes that are widely distributed throughout the world including the Southern United States. Additionally, the virus can also be transmitted from males to females by sexual contact. The epidemiological investigations during the current outbreak found a causal link between infection in pregnant women and development of microcephaly in their unborn babies. This finding is a cause for grave concern since microcephaly is a serious neural developmental disorder that can lead to significant post-natal developmental abnormalities and disabilities. Recently, published data indicate that Zika virus infection affects the growth of fetal neural progenitor cells and cerebral neurons that results in malformation of cerebral cortex leading to microcephaly. Recently, it has been reported that Zika virus infection deregulates the signaling pathway of neuronal cell and inhibit the neurogenesis resulting into dementia. In this review we have discussed about the information about cellular and molecular mechanisms in neurodegeneration of human neuronal cells and inhibit the neurogenesis. Additionally, this information will be very helpful further not only in neuro-scientific research but also designing and development of management strategies for microcephaly and other mosquito borne disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Spice phenolics inhibit human PMNL 5-lipoxygenase.

    Science.gov (United States)

    Prasad, N Satya; Raghavendra, R; Lokesh, B R; Naidu, K Akhilender

    2004-06-01

    A wide variety of phenolic compounds and flavonoids present in spices possess potent antioxidant, antimutagenic and anticarcinogenic activities. We examined whether 5-lipoxygenase (5-LO), the key enzyme involved in biosynthesis of leukotrienes is a possible target for the spices. Effect of aqueous extracts of turmeric, cloves, pepper, chili, cinnamon, onion and also their respective active principles viz., curcumin, eugenol, piperine, capsaicin, cinnamaldehyde, quercetin, and allyl sulfide were tested on human PMNL 5-LO activity by spectrophotomeric and HPLC methods. The formation of 5-LO product 5-HETE was significantly inhibited in a concentration-dependent manner with IC(50) values of 0.122-1.44 mg for aqueous extracts of spices and 25-83 microM for active principles, respectively. The order of inhibitory activity was of quercetin>eugenol>curcumin>cinnamaldehyde>piperine>capsaicin>allyl sulfide. Quercetin, eugenol and curcumin with one or more phenolic ring and methoxy groups in their structure showed high inhibitory effect, while the non-phenolic spice principle allyl sulfide showed least inhibitory effect on 5-LO. The inhibitory effect of quercetin, curcumin and eugenol was similar to that of synthetic 5-LO inhibitors-phenidone and NDGA. Moreover, the inhibitory potency of aqueous extracts of spice correlated with the active principles of their respective spices. The synergistic or antagonistic effect of mixtures of spice active principles and spice extracts were investigated and all the combinations of spice active principles/extracts exerted synergistic effect in inhibiting 5-LO activity. These findings clearly suggest that phenolic compounds present in spices might have physiological role in modulating 5-LO pathway.

  14. Inhibition of Zika Virus Replication by Silvestrol

    Directory of Open Access Journals (Sweden)

    Fabian Elgner

    2018-03-01

    Full Text Available The Zika virus (ZIKV outbreak in 2016 in South America with specific pathogenic outcomes highlighted the need for new antiviral substances with broad-spectrum activities to react quickly to unexpected outbreaks of emerging viral pathogens. Very recently, the natural compound silvestrol isolated from the plant Aglaia foveolata was found to have very potent antiviral effects against the (−-strand RNA-virus Ebola virus as well as against Corona- and Picornaviruses with a (+-strand RNA-genome. This antiviral activity is based on the impaired translation of viral RNA by the inhibition of the DEAD-box RNA helicase eukaryotic initiation factor-4A (eIF4A which is required to unwind structured 5´-untranslated regions (5′-UTRs of several proto-oncogenes and thereby facilitate their translation. Zika virus is a flavivirus with a positive-stranded RNA-genome harboring a 5′-capped UTR with distinct secondary structure elements. Therefore, we investigated the effects of silvestrol on ZIKV replication in A549 cells and primary human hepatocytes. Two different ZIKV strains were used. In both infected A549 cells and primary human hepatocytes, silvestrol has the potential to exert a significant inhibition of ZIKV replication for both analyzed strains, even though the ancestor strain from Uganda is less sensitive to silvestrol. Our data might contribute to identify host factors involved in the control of ZIKV infection and help to develop antiviral concepts that can be used to treat a variety of viral infections without the risk of resistances because a host protein is targeted.

  15. Notch Inhibits Osteoblast Differentiation and Causes Osteopenia

    Science.gov (United States)

    Zanotti, Stefano; Smerdel-Ramoya, Anna; Stadmeyer, Lisa; Durant, Deena; Radtke, Freddy; Canalis, Ernesto

    2008-01-01

    Notch receptors are determinants of cell fate decisions. To define the role of Notch in the adult skeleton, we created transgenic mice overexpressing the Notch intracellular domain (NICD) under the control of the type I collagen promoter. First-generation transgenics were small and osteopenic. Bone histomorphometry revealed that NICD caused a decrease in bone volume, secondary to a reduction in trabecular number; osteoblast and osteoclast number were decreased. Low fertility of founder mice and lethality of young pups did not allow the complete establishment of transgenic lines. To characterize the effect of Notch overexpression in vitro, NICD was induced in osteoblasts and stromal cells from Rosanotch mice, in which a STOP cassette flanked by loxP sites is upstream of NICD, by transduction with an adenoviral vector expressing Cre recombinase (Cre) under the control of the cytomegalovirus (CMV) promoter (Ad-CMV-Cre). NICD impaired osteoblastogenesis and inhibited Wnt/β-catenin signaling. To determine the effects of notch1 deletion in vivo, mice in which notch1 was flanked by loxP sequences (notch1loxP/loxP) were mated with mice expressing Cre recombinase under the control of the osteocalcin promoter. Conditional null notch1 mice had no obvious skeletal phenotype, possibly because of rescue by notch2; however, 1-month-old females exhibited a modest increase in osteoclast surface and eroded surface. Osteoblasts from notch1loxP/loxP mice, transduced with Ad-CMV-Cre and transfected with Notch2 small interfering RNA, displayed increased alkaline phosphatase activity. In conclusion, Notch signaling in osteoblasts causes osteopenia and impairs osteo-blastogenesis by inhibiting the Wnt/β-catenin pathway. PMID:18420737

  16. Cartilage proteoglycans inhibit fibronectin-mediated adhesion

    Science.gov (United States)

    Rich, A. M.; Pearlstein, E.; Weissmann, G.; Hoffstein, S. T.

    1981-09-01

    Normal tissues and organs show, on histological examination, a pattern of cellular and acellular zones that is characteristic and unique for each organ or tissue. This pattern is maintained in health but is sometimes destroyed by disease. For example, in mobile joints, the articular surfaces consist of relatively acellular hyaline cartilage, and the joint space is enclosed by a capsule of loose connective tissue with a lining of fibroblasts and macrophages. In the normal joint these cells are confined to the synovial lining and the articular surface remains acellular. In in vitro culture, macrophages and their precursor monocytes are very adhesive, and fibroblasts can migrate and overgrow surfaces such as collagen or plastic used for tissue culture. The fibroblasts adhere to collagen by means of fibronectin, which they synthesize and secrete1. Because the collagen of cartilage is capable of binding serum fibronectin2 and fibronectin is present in cartilage during its development3, these cells should, in theory, slowly migrate from the synovial lining to the articular surface. It is their absence from the articular cartilage in normal circumstances, and then presence in such pathological states as rheumatoid arthritis, that is striking. We therefore set out to determine whether a component of cartilage could prevent fibroblast adherence in a defined adhesion assay. As normal cartilage is composed of 50% proteoglycans and 50% collagen by dry weight4, we tested the possibility that the proteoglycans in cartilage inhibit fibroblast adhesion to collagen. We present here evidence that fibroblast spreading and adhesion to collagenous substrates is inhibited by cartilage proteoglycans.

  17. Inhibition of MAO by fractions and constituents of hypericum extract.

    Science.gov (United States)

    Bladt, S; Wagner, H

    1994-10-01

    The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition.

  18. Gliclazide directly inhibits arginine-induced glucagon release

    DEFF Research Database (Denmark)

    Cejvan, Kenan; Coy, David H; Holst, Jens Juul

    2002-01-01

    Arginine-stimulated insulin and somatostatin release is enhanced by the sulfonylurea gliclazide. In contrast, gliclazide inhibits the glucagon response. The aim of the present study was to investigate whether this inhibition of glucagon release was mediated by a direct suppressive effect of glicl......Arginine-stimulated insulin and somatostatin release is enhanced by the sulfonylurea gliclazide. In contrast, gliclazide inhibits the glucagon response. The aim of the present study was to investigate whether this inhibition of glucagon release was mediated by a direct suppressive effect....... In islet perifusions with DC-41-33, arginine-induced glucagon release was inhibited by 66%. We therefore concluded that gliclazide inhibits glucagon release by a direct action on the pancreatic A cell....

  19. Molecular mechanisms of DNA repair inhibition by caffeine

    Energy Technology Data Exchange (ETDEWEB)

    Selby, C.P.; Sancar, A. (Univ. of North Carolina School of Medicine, Chapel Hill (USA))

    1990-05-01

    Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, including acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA.

  20. Inhibition of Action, Thought, and Emotion: A Selective Neurobiological Review

    OpenAIRE

    Dillon, Daniel; Pizzagalli, Diego

    2007-01-01

    The neural bases of inhibitory function are reviewed, covering data from paradigms assessing inhibition of motor responses (antisaccade, go/nogo, stop-signal), cognitive sets (e.g., Wisconsin Card Sort Test), and emotion (fear extinction). The frontal cortex supports performance on these paradigms, but the specific neural circuitry varies: response inhibition depends upon fronto-basal ganglia networks, inhibition of cognitive sets is supported by orbitofrontal cortex, and retention of fear ex...

  1. High molecular weight polysaccharide that binds and inhibits virus

    Science.gov (United States)

    Konowalchuk, Thomas W

    2014-01-14

    This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods on inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

  2. Inhibition of poliovirus RNA synthesis by brefeldin A.

    OpenAIRE

    Maynell, L A; Kirkegaard, K; Klymkowsky, M W

    1992-01-01

    Brefeldin A (BFA), a fungal metabolite that blocks transport of newly synthesized proteins from the endoplasmic reticulum, was found to inhibit poliovirus replication 10(5)- to 10(6)-fold. BFA does not inhibit entry of poliovirus into the cell or translation of viral RNA. Poliovirus RNA synthesis, however, is completely inhibited by BFA. A specific class of membranous vesicles, with which the poliovirus replication complex is physically associated, is known to proliferate in poliovirus-infect...

  3. Chemical mechanism of the fluoride-inhibition of fermentation

    Energy Technology Data Exchange (ETDEWEB)

    Warburg, O; Christian, W

    1941-08-01

    Among the fluoride-sensitive fermentation elements, enolase is the most sensitive. An investigation was made, quantitatively, of fluoride inhibition for chemically pure magnesium-enolase using an optical enolase test. Data show that the effective compound for fluoride inhibition is a complex magnesium-fluoro-phosphate and that the magnesium-fluoro-phosphate inhibits fermentation by combining proportionally to its concentration with the ferment-protein in a dissociating manner.

  4. High molecular weight polysaccharide that binds and inhibits virus

    Energy Technology Data Exchange (ETDEWEB)

    Konowalchuk, Thomas W.; Konowalchuk, Jack

    2017-07-18

    This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods of inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further includes methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

  5. A speculated cause of respiratory inhibition in infants.

    Science.gov (United States)

    Minowa, Hideki; Arai, Ikuyo; Yasuhara, Hajime; Ebisu, Reiko; Ohgitani, Ayako

    2018-10-01

    In our previous studies, we documented that threatened premature labor and asymmetrical intrauterine growth restriction were risk factors for respiratory inhibition. The goal of this study was to determine the cause of respiratory inhibition by considering perinatal risk factors. We examined 1497 infants with a gestational age of 36 weeks or greater. All infants were monitored using pulse oximetry and examined via cranial sonography. Respiratory inhibition was defined as severe hypoxemia caused by respiratory inhibition immediately after crying or gastroesophageal reflux or as a respiratory pause during feeding. We examined the relationships between respiratory inhibition and perinatal factors and speculated on the cause of respiratory inhibition. The median gestational age, birth weight, Apgar score at 1 min, and Apgar score at 5 min of the subjects were 38.9 weeks, 2930 g, 8.0 points, and 9.0 points, respectively. Respiratory inhibition was observed in 422 infants. Lateral ventricle enlargement and increased echogenicity in the ganglionic eminence were observed in 417 and 516 infants, respectively. Respiratory inhibition was significantly correlated with shorter gestational periods, twin pregnancies, lateral ventricle enlargement, and increased echogenicity in the ganglionic eminence. We speculate that umbilical cord compression is a major cause of respiratory inhibition.

  6. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying-Nan P.; LaMarche, Matthew J.; Chan, Ho Man; Fekkes, Peter; Garcia-Fortanet, Jorge; Acker, Michael G.; Antonakos, Brandon; Chen, Christine Hiu-Tung; Chen, Zhouliang; Cooke, Vesselina G.; Dobson, Jason R.; Deng, Zhan; Fei, Feng; Firestone, Brant; Fodor, Michelle; Fridrich, Cary; Gao, Hui; Grunenfelder, Denise; Hao, Huai-Xiang; Jacob, Jaison; Ho, Samuel; Hsiao, Kathy; Kang, Zhao B.; Karki, Rajesh; Kato, Mitsunori; Larrow, Jay; La Bonte, Laura R.; Lenoir, Francois; Liu, Gang; Liu, Shumei; Majumdar, Dyuti; Meyer, Matthew J.; Palermo, Mark; Perez, Lawrence; Pu, Minying; Price, Edmund; Quinn, Christopher; Shakya, Subarna; Shultz, Michael D.; Slisz, Joanna; Venkatesan, Kavitha; Wang, Ping; Warmuth, Markus; Williams, Sarah; Yang, Guizhi; Yuan, Jing; Zhang, Ji-Hu; Zhu, Ping; Ramsey, Timothy; Keen, Nicholas J.; Sellers, William R.; Stams, Travis; Fortin , Pascal D. (Novartis)

    2016-06-29

    The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase1. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma1, 2, 3, 4, 5. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2, 3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways6, 7. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy8, 9. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

  7. Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα

    OpenAIRE

    Ying Sun; Ying Sun; Yu-jun Tan; Yu-jun Tan; Zhan-zhao Lu; Zhan-zhao Lu; Bing-bing Li; Bing-bing Li; Cheng-hong Sun; Cheng-hong Sun; Tao Li; Tao Li; Li-li Zhao; Li-li Zhao; Zhong Liu

    2018-01-01

    Burdock (Arctium lappa) is a popular vegetable in China and Japan that is consumed for its general health benefits. The principal active component of burdock is arctigenin, which shows a range of bioactivities in vivo and in vitro. Here, we investigated the potential anti-tumor effects of arctigenin using two human hepatocellular carcinoma (HCC) cell lines, HepG2 and Hep3B, and sought to elucidate its potential mechanisms of action. Our results showed that arctigenin treatment inhibited cell ...

  8. Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis

    Directory of Open Access Journals (Sweden)

    Li Q

    2013-07-01

    Full Text Available Qingli Li,1,2 Mark J Lambrechts,1 Qiuyang Zhang,1 Sen Liu,1 Dongxia Ge,1 Rutie Yin,2 Mingrong Xi,2 Zongbing You1 1Departments of Structural and Cellular Biology and Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, and Tulane Center for Aging, Tulane University Health Sciences Center, New Orleans, LA, USA; 2Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA, are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy. Keywords: serine hydroxymethyltransferase, prostate cancer, apoptosis

  9. Ketamine inhibits 45Ca influx and catecholamine secretion by inhibiting 22Na influx in cultured bovine adrenal medullary cells

    International Nuclear Information System (INIS)

    Takara, Hiroshi; Wada, Akihiko; Arita, Masahide; Izumi, Futoshi; Sumikawa, Koji

    1986-01-01

    The effects of ketamine, an intravenous anesthetic, on 22 Na influx, 45 Ca influx and catecholamine secretion were investigated in cultured bovine adrenal medullary cells. Ketamine inhibited carbachol-induced 45 Ca influx and catecholamine secretion in a concentration-dependent manner with a similar potency. Ketamine also reduced veratridine-induced 45 Ca influx and catecholamine secretion. The influx of 22 Na caused by carbachol or by veratridine was suppressed by ketamine with a concentration-inhibition curve similar to that of 45 Ca influx and catecholamine secretion. Inhibition by ketamine of the carbachol-induced influx of 22 Na, 45 Ca and secretion of catecholamines was not reversed by the increased concentrations of carbachol. These observations indicate that ketamine, at clinical concentrations, can inhibit nicotinic receptor-associated ionic channels and that the inhibition of Na influx via the receptor-associated ionic channels is responsible for the inhibition of carbachol-induced Ca influx and catecholamine secretion. (Auth.)

  10. Fluoxetine-induced inhibition of synaptosomal [3H]5-HT release: Possible Ca2+-channel inhibition

    International Nuclear Information System (INIS)

    Stauderman, K.A.; Gandhi, V.C.; Jones, D.J.

    1992-01-01

    Fluoxetine, a selective 5-Ht uptake inhibitor, inhibited 15 mM K + -induced [ 3 H]5-HT release from rat spinal cord and cortical synaptosomes at concentrations > 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K + used to depolarize the synaptosomes and the concentration of external Ca 2+ . Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [ 3 H]5-HT release induced by the Ca 2+ -ionophore A 23187 or Ca 2+ -independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K + -induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca 2+ channels and Ca 2+ entry

  11. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication.

    Science.gov (United States)

    Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A; Mishin, Vladimir; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

    2015-10-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Inhibition of chrysin on xanthine oxidase activity and its inhibition mechanism.

    Science.gov (United States)

    Lin, Suyun; Zhang, Guowen; Liao, Yijing; Pan, Junhui

    2015-11-01

    Chrysin, a bioactive flavonoid, was investigated for its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme catalyzing xanthine to uric acid and finally causing gout. The kinetic analysis showed that chrysin possessed a strong inhibition on XO ability in a reversible competitive manner with IC50 value of (1.26±0.04)×10(-6)molL(-1). The results of fluorescence titrations indicated that chrysin bound to XO with high affinity, and the interaction was predominately driven by hydrogen bonds and van der Waals forces. Analysis of circular dichroism demonstrated that chrysin induced the conformational change of XO with increases in α-helix and β-sheet and reductions in β-turn and random coil structures. Molecular simulation revealed that chrysin interacted with the amino acid residues Leu648, Phe649, Glu802, Leu873, Ser876, Glu879, Arg880, Phe1009, Thr1010, Val1011 and Phe1013 located within the active cavity of XO. The mechanism of chrysin on XO activity may be the insertion of chrysin into the active site occupying the catalytic center of XO to avoid the entrance of xanthine and causing conformational changes in XO. Furthermore, the interaction assays indicated that chrysin and its structural analog apigenin exhibited an additive effect on inhibition of XO. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Inhibition of lignin-derived phenolic compounds to cellulase.

    Science.gov (United States)

    Qin, Lei; Li, Wen-Chao; Liu, Li; Zhu, Jia-Qing; Li, Xia; Li, Bing-Zhi; Yuan, Ying-Jin

    2016-01-01

    Lignin-derived phenolic compounds are universal in the hydrolysate of pretreated lignocellulosic biomass. The phenolics reduce the efficiency of enzymatic hydrolysis and increase the cost of ethanol production. We investigated inhibition of phenolics on cellulase during enzymatic hydrolysis using vanillin as one of the typical lignin-derived phenolics and Avicel as cellulose substrate. As vanillin concentration increased from 0 to 10 mg/mL, cellulose conversion after 72-h enzymatic hydrolysis decreased from 53 to 26 %. Enzyme deactivation and precipitation were detected with the vanillin addition. The enzyme concentration and activity consecutively decreased during hydrolysis, but the inhibition degree, expressed as the ratio of the cellulose conversion without vanillin to the conversion with vanillin (A 0 /A), was almost independent on hydrolysis time. Inhibition can be mitigated by increasing cellulose loading or cellulase concentration. The inhibition degree showed linear relationship with the vanillin concentration and exponential relationship with the cellulose loading and the cellulase concentration. The addition of calcium chloride, BSA, and Tween 80 did not release the inhibition of vanillin significantly. pH and temperature for hydrolysis also showed no significant impact on inhibition degree. The presence of hydroxyl group, carbonyl group, and methoxy group in phenolics affected the inhibition degree. Besides phenolics concentration, other factors such as cellulose loading, enzyme concentration, and phenolic structure also affect the inhibition of cellulose conversion. Lignin-blocking agents have little effect on the inhibition effect of soluble phenolics, indicating that the inhibition mechanism of phenolics to enzyme is likely different from insoluble lignin. The inhibition of soluble phenolics can hardly be entirely removed by increasing enzyme concentration or adding blocking proteins due to the dispersity and multiple binding sites of phenolics

  14. Altered cortical processing of motor inhibition in schizophrenia.

    Science.gov (United States)

    Lindberg, Påvel G; Térémetz, Maxime; Charron, Sylvain; Kebir, Oussama; Saby, Agathe; Bendjemaa, Narjes; Lion, Stéphanie; Crépon, Benoît; Gaillard, Raphaël; Oppenheim, Catherine; Krebs, Marie-Odile; Amado, Isabelle

    2016-12-01

    Inhibition is considered a key mechanism in schizophrenia. Short-latency intracortical inhibition (SICI) in the motor cortex is reduced in schizophrenia and is considered to reflect locally deficient γ-aminobutyric acid (GABA)-ergic modulation. However, it remains unclear how SICI is modulated during motor inhibition and how it relates to neural processing in other cortical areas. Here we studied motor inhibition Stop signal task (SST) in stabilized patients with schizophrenia (N = 28), healthy siblings (N = 21) and healthy controls (n = 31) matched in general cognitive status and educational level. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were used to investigate neural correlates of motor inhibition. SST performance was similar in patients and controls. SICI was modulated by the task as expected in healthy controls and siblings but was reduced in patients with schizophrenia during inhibition despite equivalent motor inhibition performance. fMRI showed greater prefrontal and premotor activation during motor inhibition in schizophrenia. Task-related modulation of SICI was higher in subjects who showed less inhibition-related activity in pre-supplementary motor area (SMA) and cingulate motor area. An exploratory genetic analysis of selected markers of inhibition (GABRB2, GAD1, GRM1, and GRM3) did not explain task-related differences in SICI or cortical activation. In conclusion, this multimodal study provides direct evidence of a task-related deficiency in SICI modulation in schizophrenia likely reflecting deficient GABA-A related processing in motor cortex. Compensatory activation of premotor areas may explain similar motor inhibition in patients despite local deficits in intracortical processing. Task-related modulation of SICI may serve as a useful non-invasive GABAergic marker in development of therapeutic strategies in schizophrenia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

    Science.gov (United States)

    Kottmann, Robert Matthew; Trawick, Emma; Judge, Jennifer L; Wahl, Lindsay A; Epa, Amali P; Owens, Kristina M; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

    2015-12-01

    Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-β (TGF-β) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-β. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-β-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-β and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-β-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-β bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-β-induced myofibroblast differentiation. Gossypol inhibits TGF-β-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-β bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis. Copyright © 2015 the American Physiological Society.

  16. High outgroup entitativity can inhibit intergroup retribution.

    Science.gov (United States)

    Newheiser, Anna-Kaisa; Dovidio, John F

    2015-06-01

    Understanding the psychological processes that are involved in the perpetuation and escalation of intergroup conflict remains an important goal for intergroup relations research. In the present research, we examined perceived outgroup entitativity as a potential determinant of intergroup hostility. In intergroup conflict situations, high-entitative outgroups are perceived as particularly deserving of retribution; however, high-entitative outgroups are also perceived as efficacious and capable of retaliating successfully, suggesting that people may inhibit hostility against high-entitative (vs. low-entitative) outgroups that are in a position to retaliate. We tested this prediction in two studies. In Study 1, we manipulated intergroup provocation and outgroup entitativity, and found that higher negative mood predicted greater aggression against a low-entitative provoker outgroup, but failed to predict aggression against a high-entitative provoker outgroup that was plausibly in a position to retaliate. In Study 2, we held provocation constant while manipulating outgroup entitativity and the possibility of retaliation by the outgroup, and found that people acted in a retributive manner against a high-entitative provoker outgroup only when the outgroup was not in a position to retaliate. Implications for intergroup conflict are discussed. © 2014 The British Psychological Society.

  17. Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

    Science.gov (United States)

    Nichols, Daniel Brian; De Martini, William; Cottrell, Jessica

    2017-01-01

    Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence. PMID:28786952

  18. Inhibition of oxidation in nuclear graphite

    International Nuclear Information System (INIS)

    Winston, Philip L.; Sterbentz, James W.; Windes, William E.

    2015-01-01

    Graphite is a fundamental material of high-temperature gas-cooled nuclear reactors, providing both structure and neutron moderation. Its high thermal conductivity, chemical inertness, thermal heat capacity, and high thermal structural stability under normal and off-normal conditions contribute to the inherent safety of these reactor designs. One of the primary safety issues for a high-temperature graphite reactor core is the possibility of rapid oxidation of the carbon structure during an off-normal design basis event where an oxidising atmosphere (air ingress) can be introduced to the hot core. Although the current Generation IV high-temperature reactor designs attempt to mitigate any damage caused by a postulated air ingress event, the use of graphite components that inhibit oxidation is a logical step to increase the safety of these reactors. Recent experimental studies of graphite containing between 5.5 and 7 wt% boron carbide (B 4 C) indicate that oxidation is dramatically reduced even at prolonged exposures at temperatures up to 900 deg. C. The proposed addition of B 4 C to graphite components in the nuclear core would necessarily be enriched in B-11 isotope in order to minimise B-10 neutron absorption and graphite swelling. The enriched boron can be added to the graphite during billet fabrication. Experimental oxidation rate results and potential applications for borated graphite in nuclear reactor components will be discussed. (authors)

  19. Conditioned inhibition in the spatial domain.

    Science.gov (United States)

    Sansa, J; Rodrigo, T; Santamaría, J J; Manteiga, R D; Chamizo, V D

    2009-10-01

    Using a variation on the standard procedure of conditioned inhibition (Trials A+ and AX-), rats (Rattus norvegicus) in a circular pool were trained to find a hidden platform that was located in a specific spatial position in relation to 2 individual landmarks (Trials A --> platform and B --> platform; Experiments 1a and 1b) and to 2 configurations of landmarks (Trials ABC --> platform and FGH --> platform; Experiment 2a). The rats also underwent inhibitory trials (Experiment 1: Trials AZ --> no platform; Experiment 2a: Trials CDE --> no platform) interspersed with these excitatory trials. In both experiments, subsequent test trials without the platform showed both a summation effect and retardation of excitatory conditioning, and in Experiment 2a rats learned to avoid the CDE quadrant over the course of the experiment. Two further experiments established that these results could not be attributed to any difference in salience between the conditioned inhibitors and the control stimuli. All these results contribute to the growing body of evidence consistent with the idea that there is a general mechanism of learning that is associative in nature. PsycINFO Database Record (c) 2009 APA, all rights reserved.

  20. Inhibition of RAS in diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Yacoub R

    2015-04-01

    Full Text Available Rabi Yacoub, Kirk N Campbell Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Abstract: Diabetic kidney disease (DKD is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin–angiotensin system (RAS is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII, the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population. Keywords: renin–angiotensin system, diabetic kidney disease, angiotensin II, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers

  1. Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis.

    Science.gov (United States)

    Lee, Ji-Min; Seo, Woo-Young; Han, Hye-Sook; Oh, Kyoung-Jin; Lee, Yong-Soo; Kim, Don-Kyu; Choi, Seri; Choi, Byeong Hun; Harris, Robert A; Lee, Chul-Ho; Koo, Seung-Hoi; Choi, Hueng-Sik

    2016-01-01

    The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  2. Efficacy of ALK5 inhibition in myelofibrosis

    Science.gov (United States)

    Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.

    2017-01-01

    Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF. PMID:28405618

  3. Inhibition of lignifying processes by sulfur dioxide

    International Nuclear Information System (INIS)

    Pfanz, H.; Oppmann, B.

    1991-01-01

    Intercellular washing fluids (IWF) from spruce needles (Picea abies L. Karst.) contain peroxidases 1-2% of total IWF protein. These apoplastic enzymes show the ability to polymerize monophenols or phenylpropanes to form lignin precursors in vitro. In the presence of potentially acidic air pollutants like NO 2 , HF(20 mM of salts in solution), and in the presence of Pb-, Cd- (0.5 mM) or Al-salts (8 mM) no inhibitory effect on the polymerization reactions examined was detectable. In contrast, the anions of SO 2 (sulfite and bisulfite) revealed a strong inhibition on the dimerization of ferulic and caffeic acid (Ki ca. 1 mM), and on the dehydration of syringaldazine (Ki ca. 8 μM). Polymerization of coniferyl alcohol, on the other hand, seemed to be enhanced. Maier-Maercker and Koch (1986) demonstrated that the cell walls of guard cells from undamaged spruce needles are properly lignified, whereas those of damaged needles seem to be affected. It is therefore assumed that cell wall lignification, and concomitantly stomatal regulation of coniferous needles are disturbed in regions with high atmospheric SO 2 pollution (e.g. Ore Mountains in CSFR)

  4. Bioelectronic sniffer for nicotine using enzyme inhibition.

    Science.gov (United States)

    Mitsubayashi, Kohji; Nakayama, Kazumi; Taniguchi, Midori; Saito, Hirokazu; Otsuka, Kimio; Kudo, Hiroyuki

    2006-07-28

    A novel bioelectronic sniffer for nicotine in the gas phase was developed with enzyme inhibition principle to butyrylcholinesterase activity. The bioelectronic devices for nicotine in the gas and liquid phases were constructed using a Clark-type dissolved oxygen electrode and a membrane immobilized butyrylcholinesterase and choline oxidase. After the assessment of the sensor performances to choline and butyrylcholine as pre-examinations, the characteristics of the biosensor and bio-sniffer for nicotine were evaluated in the liquid and gas phases, respectively. The sensor signal of the bio-devices with 300 micromol l(-1) of butyrylcholine decreased quickly following application of nicotine and reached to the steady-state current, thus relating the concentration of nicotine in the liquid and gas phases. The biosensor was used to measure nicotine solution from 10 to 300 micromol l(-1). In the gas-phase experiment, the current signal of the bio-sniffer was also found to be linearly to the nicotine concentration over the range of 10.0-1000 ppb including 75.0 ppb as threshold limit value (TLV) by American Conference of Governmental Industrial Hygienists (ACGIH).

  5. Radiation metagenesis and inhibition of DNA synthesis

    International Nuclear Information System (INIS)

    Dubinina, L.G.; Sergievskaya, S.P.; Kurashova, Z.I.; Dubinin, N.P.

    1983-01-01

    The study of modification of radiation mutagenesis and inhibition of the DNA synthesis by means of 1-β-D arabinofuranosylcytosine (ara-C) is carried out. It is shown that ara-C-acting on chromosomes in the G 1 phase and G 2 phase does not cause mutations in the C capillaris cells. The modification by means of ara-C radiation effect in the G 1 phase and G 2 phase correlates with duration and time of administering ara-C before and after irradiation. A new form of ara-C DNA synthesis inhibitor interaction with mutation processes has been found out. Protective effect of the DNA synthesis inhibitor (ara-C) from mutageneous radiation effect is stressed. Sensibilization of the radiation mutagenesis during cell treafment by the DNA synthesis inhibitor (ara-C) is shown. It is pointed out that emergence of sensibilization or protective effect, i. e. antimutagenesis phenomenon depends on conditions under which the synthesis inhibitor acted in G 1 and G 2 phases

  6. Lycopene Inhibits Propagation of Chlamydia Infection

    Directory of Open Access Journals (Sweden)

    Naylia A. Zigangirova

    2017-01-01

    Full Text Available Chlamydiaceae is a family of obligate intracellular pathogenic bacteria with similar developmental cycles and cell biology responsible for a wide range of diseases in different hosts including genital and eye inflammatory diseases, arthritis, and inflammatory diseases of the respiratory and cardiovascular systems. In the present paper, we report that lycopene, one of the main dietary carotenoids, which is present in tomato and some other fruits, has a strong inhibitory effect on C. trachomatis and C. pneumoniae infections in alveolar macrophages. This finding was documented by both immunofluorescence analysis and electron microscopy. It was noted that lycopene treatment inhibited intracellular phase of the chlamydial developmental cycle and resulted in a significant loss of infectious progeny. The antichlamydial effect of lycopene was also confirmed in a clinical setting. There was a significant reduction of IgG antibodies against C. pneumoniae in the serum of volunteers treated for a month with oral ingestion of 7 mg of lycopene. Additional studies are needed to further explore the antichlamydial activity of lycopene and its possible effect on C. pneumoniae in relation to antichlamydial activity of lycopene to mechanisms of atherosclerosis.

  7. Clofilium inhibits Slick and Slack potassium channels.

    Science.gov (United States)

    de Los Angeles Tejada, Maria; Stolpe, Kathleen; Meinild, Anne-Kristine; Klaerke, Dan A

    2012-01-01

    Slick and Slack high-conductance potassium channels have been recently discovered, and are found in the central nervous system and in the heart. Both channels are activated by Na(+) and Cl(-), and Slick channels are also inhibited by adenosine triphospate (ATP). An important role of setting the resting membrane potential and controlling the basal excitability of neurons has been suggested for these channels. In addition, no specific blockers for these channels are known up to the present. With the purpose of studying the pharmacological characteristics of Slick and Slack channels, the effects of exposure to the antiarrhythmic compound clofilium were evaluated. Clofilium was able to modulate the activity of Slick and Slack channels effectively, with a stronger effect on Slack than Slick channels. In order to evaluate the pharmacological behavior of Slick and Slack channels further, 38 commonly used potassium channel blockers were tested. Screening of these compounds did not reveal any modulators of Slick and Slack channels, except for clofilium. The present study provides a first approach towards elucidating the pharmacological characteristics of Slick and Slack channels and could be the basis for future studies aimed at developing potent and specific blockers and activators for these channels.

  8. Linking algal growth inhibition to chemical activity

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Mayer, Philipp

    Unitless chemical activity, expressing the energetic level of a compound relative to its energetic level in pure liquid [0-1], has proven useful to quantify the effective exposure to hydrophobic organic compounds through both aerial and aqueous media. Several studies have linked toxicity to chemi......Unitless chemical activity, expressing the energetic level of a compound relative to its energetic level in pure liquid [0-1], has proven useful to quantify the effective exposure to hydrophobic organic compounds through both aerial and aqueous media. Several studies have linked toxicity...... to chemical activity, as opposed to e.g. the total concentration. Baseline toxicity (narcosis) for neutral hydrophobic organic compounds has been shown to initiate in the narrow chemical activity range of 0.01 to 0.1. This presentation focuses on linking algal growth inhibition to chemical activity......-polar liquids were applied to challenge the chemical activity range for baseline toxicity. For each compound, the effective activity (Ea50) was estimated as the ratio of the effective concentration (EC50) and water solubility. Of these ratios, 90% were within the expected chemical activity range of 0.01 to 0...

  9. Type IIA2 urethral duplication: report of an unusual case

    African Journals Online (AJOL)

    obstruction and recurrent urinary tract infection due to a stenosed dorsal urethra .... the child complained of nocturnal incontinence, but this diminished gradually .... urethra because it is hypoplastic and the risk for inadequate urine flow is high.

  10. Prehospital Use of Plasma for Traumatic Hemorrhage - PUPTH-IIA

    Science.gov (United States)

    2016-08-01

    Distribution Unlimited 1 Jun 2012 - 31 May 2016 W81XWH-12-2-0022 13. SUPPLEMENTARY NOTES Dr. Bruce Spiess , MD, Penny S. Reynolds, PhD, (Study PIs) and...decision for termination of the PUPTH trial before the end of the award period was made by Dr. Bruce Spiess (Principal Investigator) and the PUPTH...results and recommendations for future trial management have been submitted for publication in Trials and are currently under review.  Dr Spiess and

  11. Type IIA2 urethral duplication: report of an unusual case

    African Journals Online (AJOL)

    ultrasonography (US) showed left-sided hydroureterone- phrosis with a distended thick-walled bladder. US showed the right testis to be enlarged with increased vascularity suggestive of epididymo-orchitis. A retrograde urethro- gram showed a sagittal duplication of urethra, with the narrow dorsal urethra originating from the ...

  12. LP II--A GOAL PROGRAMMING MODEL FOR MEDIA.

    Science.gov (United States)

    CHARNES, A.; AND OTHERS

    A GOAL PROGRAMING MODEL FOR SELECTING MEDIA IS PRESENTED WHICH ALTERS THE OBJECTIVE AND EXTENDS PREVIOUS MEDIA MODELS BY ACCOUNTING FOR CUMULATIVE DUPLICATING AUDIENCES OVER A VARIETY OF TIME PERIODS. THIS PERMITS DETAILED CONTROL OF THE DISTRIBUTION OF MESSAGE FREQUENCIES DIRECTED AT EACH OF NUMEROUS MARKETING TARGETS OVER A SEQUENCE OF…

  13. Super Natural II--a database of natural products.

    Science.gov (United States)

    Banerjee, Priyanka; Erehman, Jevgeni; Gohlke, Björn-Oliver; Wilhelm, Thomas; Preissner, Robert; Dunkel, Mathias

    2015-01-01

    Natural products play a significant role in drug discovery and development. Many topological pharmacophore patterns are common between natural products and commercial drugs. A better understanding of the specific physicochemical and structural features of natural products is important for corresponding drug development. Several encyclopedias of natural compounds have been composed, but the information remains scattered or not freely available. The first version of the Supernatural database containing ∼ 50,000 compounds was published in 2006 to face these challenges. Here we present a new, updated and expanded version of natural product database, Super Natural II (http://bioinformatics.charite.de/supernatural), comprising ∼ 326,000 molecules. It provides all corresponding 2D structures, the most important structural and physicochemical properties, the predicted toxicity class for ∼ 170,000 compounds and the vendor information for the vast majority of compounds. The new version allows a template-based search for similar compounds as well as a search for compound names, vendors, specific physical properties or any substructures. Super Natural II also provides information about the pathways associated with synthesis and degradation of the natural products, as well as their mechanism of action with respect to structurally similar drugs and their target proteins. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Japanese contributions to IAEA INTOR workshop, phase IIA

    International Nuclear Information System (INIS)

    Hiraoka, Toru; Fujisawa, Noboru; Nishio, Satoshi

    1982-11-01

    This report is one of the chapters of Japanese National Report of INTOR Workshop, Phase 2A. At this Phase 2A, the pumped limiter has been investigated as impurity control concept. The curved-surface double-edged pumped limiter was employed as results of various features. Surface materials are assessed from various aspects such as sputtering, behavior at plasma disruption, thermal characteristics, electro-magnetics, attachment method to substrate materials. Application of newly developed SiC with high thermal conductivity is also investigated. (author)

  15. Luminescence of natural IIa diamond implanted with nitrogen ions

    International Nuclear Information System (INIS)

    Varichenko, V.S.; Zaitsev, A.M.; Stelmakh, V.F.

    1986-01-01

    Investigations on the influence of defect environment in the irradiated diamond lattice are presented. The N + implantation with energies from 60 keV up to 60 MeV was used both as method of introducing nitrogen containing defects into the diamond and as a good tool to create different environment of these defects. Photoluminescence, cathodoluminescence, and annealing measurements show that the action of defect environment is revealed through the effective pressure affecting the thermal stability of defects and their inhomogeneous distortion

  16. Japanese contributions to IAEA INTOR Workshop, phase IIA

    International Nuclear Information System (INIS)

    Tomabechi, Ken; Hiraoka, Tohru; Fujisawa, Noboru; Nishio, Satoshi; Sawada, Yoshio; Kobayashi, Takeshi.

    1982-11-01

    Japanese contributions at INTOR Phase 2A are summarized as a first three chapters of the report, Japanese Contributions to INTOR Workshop, Phase 2A. This report contains Introduction, Summary of the total report and INTOR Concepts. (author)

  17. Peliminary examination of herbal extracts on the inhibition of ...

    African Journals Online (AJOL)

    Methods: The activity was quantitatively assessed on the basis of the inhibition zone, and their activity index was also calculated along with the MIC method. Results: All the plants demonstrated antimicrobial activity against H. pylori with zone of inhibition diameters ranging from 0 - 30 mm and minimum inhibitory ...

  18. Attention Inhibition Training Can Reduce Betel-Nut Chewing Time

    Directory of Open Access Journals (Sweden)

    Ming-Chou Ho

    2011-05-01

    Full Text Available Betel nut (or areca is the fourth most commonly used drug worldwide after tobacco, alcohol, and caffeine. Many chemical ingredients of betel nut are carcinogenic. We examined whether the manipulation of attentional inhibition toward the areca-related stimuli could affect betel-nut chewing time. Three matched groups of habitual chewers were recruited: inhibit-areca, inhibit-non-areca, and control. This study consisted of a Go/No-Go task for inhibition training, followed by a taste test for observing chewing behavior. The Go/No-Go task constituted three phases (pretest, training and posttest. In the taste test, the habitual chewers were asked to rate the flavors of one betel nut and one gum. The purpose (blind to the chewers of this taste test was to observe whether their picking order and chewing time were affected by experimental manipulation. Results from the Go/No-Go task showed successful training. Further, the training groups (the inhibit-areca and inhibit-non-areca groups showed a significant reduction in betel nut chewing time, in comparison to the control group. Since both training groups showed reduced chewing time, the inhibition training may affect general control ability, in regardless of the stimulus (areca or not to be inhibited. Reduced chewing time is important for reducing areca-related diseases.

  19. Cohort-Sequential Study of Conflict Inhibition during Middle Childhood

    Science.gov (United States)

    Rollins, Leslie; Riggins, Tracy

    2017-01-01

    This longitudinal study examined developmental changes in conflict inhibition and error correction in three cohorts of children (5, 7, and 9 years of age). At each point of assessment, children completed three levels of Luria's tapping task (1980), which requires the inhibition of a dominant response and maintenance of task rules in working…

  20. Optogenetic inhibition of chemically induced hypersynchronized bursting in mice

    DEFF Research Database (Denmark)

    Berglind, Fredrik; Ledri, Marco; Sørensen, Andreas Toft

    2014-01-01

    hyperpolarization and thereby inactivation of a principal neuronal population in the hippocampus is effectively attenuating seizure activity caused by disconnected network inhibition both in vitro and in vivo. Our data suggest that epileptiform activity in the hippocampus caused by impaired inhibition may...

  1. The role of non-CRF inhibition in contour detection

    NARCIS (Netherlands)

    Grigorescu, C.; Petkov, N.; Westenberg, M.A.

    2003-01-01

    We propose a biologically motivated computational step, called non-classical receptive field (non-CRF) inhibition, to improve the performance of contour detectors. Non-CRF inhibition is exhibited by 80% of the orientation selective neurons in the primary visual cortex of macaque monkeys and has been

  2. Pseudomonas aeruginosa inhibits the growth of Cryptococcus species.

    Science.gov (United States)

    Rella, Antonella; Yang, Mo Wei; Gruber, Jordon; Montagna, Maria Teresa; Luberto, Chiara; Zhang, Yong-Mei; Del Poeta, Maurizio

    2012-06-01

    Pseudomonas aeruginosa is a ubiquitous and opportunistic bacterium that inhibits the growth of different microorganisms, including Gram-positive bacteria and fungi such as Candida spp. and Aspergillus fumigatus. In this study, we investigated the interaction between P. aeruginosa and Cryptococcus spp. We found that P. aeruginosa PA14 and, to a lesser extent, PAO1 significantly inhibited the growth of Cryptococcus spp. The inhibition of growth was observed on solid medium by the visualization of a zone of inhibition of yeast growth and in liquid culture by viable cell counting. Interestingly, such inhibition was only observed when P. aeruginosa and Cryptococcus were co-cultured. Minimal inhibition was observed when cell-cell contact was prevented using a separation membrane, suggesting that cell contact is required for inhibition. Using mutant strains of Pseudomonas quinoline signaling, we showed that P. aeruginosa inhibited the growth of Cryptococcus spp. by producing antifungal molecules pyocyanin, a redox-active phenazine, and 2-heptyl-3,4-dihydroxyquinoline (PQS), an extracellular quorum-sensing signal. Because both P. aeruginosa and Cryptococcus neoformans are commonly found in lung infections of immunocompromised patients, this study may have important implication for the interaction of these microbes in both an ecological and a clinical point of view.

  3. Stuttering Inhibition via Altered Auditory Feedback during Scripted Telephone Conversations

    Science.gov (United States)

    Hudock, Daniel; Kalinowski, Joseph

    2014-01-01

    Background: Overt stuttering is inhibited by approximately 80% when people who stutter read aloud as they hear an altered form of their speech feedback to them. However, levels of stuttering inhibition vary from 60% to 100% depending on speaking situation and signal presentation. For example, binaural presentations of delayed auditory feedback…

  4. Menadione inhibits MIBG uptake in two neuroendocrine cell lines

    NARCIS (Netherlands)

    Cornelissen, J.; Tytgat, G. A.; van den Brug, M.; van Kuilenburg, A. B.; Voûte, P. A.; van Gennip, A. H.

    1997-01-01

    In this paper we report on our studies of the effect of menadione on the uptake of MIBG in the neuroendocrine cell lines PC12 and SK-N-SH. Menadione inhibits the uptake of MIBG in both cell lines in a dose-dependent manner. Inhibition of MIBG uptake is most pronounced in the PC12 cell line.

  5. Methanol Extract of Hydroclathrus clathratus Inhibits Production of ...

    African Journals Online (AJOL)

    Methanol Extract of Hydroclathrus clathratus Inhibits Production of Nitric Oxide, Prostaglandin E2 and Tumor Necrosis Factor-α in Lipopolysaccharidestimulated BV2 Microglial Cells via Inhibition of NF-κB Activity. RGPT Jayasooriya, D-O Moon, YH Chol, C-H Yoon, G-Y Kim ...

  6. Trichilia monadelpha Bark Extracts Inhibit Carrageenan-Induced ...

    African Journals Online (AJOL)

    The present study was undertaken to evaluate the anti-inflammatory properties of aqueous (TWE), alcoholic (TAE) and petroleum ether extract (TPEE) of T. ... The reference anti-inflammatory drugs (diclofenac and dexamethasone) inhibited the chick-carrageenan-induced footpad oedema, with maximal inhibitions of ...

  7. Social inhibition sense of belonging and vulnerability to internalizing problems

    NARCIS (Netherlands)

    de Moor, E.L.; Denollet, J.; Laceulle, O.M.

    2018-01-01

    Background The aim of this study was to provide a conceptual test of how social inhibition, sense of belonging and internalizing problems are related, and whether sense of belonging moderates or mediates the relation between social inhibition and internalizing problems. Methods Data were used from

  8. The Affective Consequences of Cognitive Inhibition: Devaluation or Neutralization?

    Science.gov (United States)

    Frischen, Alexandra; Ferrey, Anne E.; Burt, Dustin H. R.; Pistchik, Meghan; Fenske, Mark J.

    2012-01-01

    Affective evaluations of previously ignored visual stimuli are more negative than those of novel items or prior targets of attention or response. This has been taken as evidence that inhibition has negative affective consequences. But inhibition could act instead to attenuate or "neutralize" preexisting affective salience, predicting opposite…

  9. Distractor Inhibition: Principles of Operation during Selective Attention

    Science.gov (United States)

    Wyatt, Natalie; Machado, Liana

    2013-01-01

    Research suggests that although target amplification acts as the main determinant of the efficacy of selective attention, distractor inhibition contributes under some circumstances. Here we aimed to gain insight into the operating principles that regulate the use of distractor inhibition during selective attention. The results suggest that, in…

  10. Study of electroplated silver-palladium biofouling inhibiting coating

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Hilbert, Lisbeth Rischel; Schroll, Casper

    2008-01-01

    Biofouling can cause many undesirable effects in industrial and medical settings. In this study, a new biofouling inhibiting Ag-Pd surface was designed to form an inhibiting effect by itself. This design was based on silver combined with nobler palladium, both with catalytic properties. Owing to ...

  11. Corrosion Inhibition of Aluminium by Capparis deciduas in Acidic Media

    Directory of Open Access Journals (Sweden)

    P. Arora

    2007-01-01

    Full Text Available The inhibition efficiency of ethanolic extract of different parts of Capparis deciduas (Ker in acidic medium has been evaluated by mass loss and thermometric methods. Values of inhibition efficiency obtained from the two methods are in good agreement and are dependent upon the concentration of inhibitor and acid.

  12. Corrosion Inhibition of Aluminium by Capparis deciduas in Acidic Media

    OpenAIRE

    P. Arora; S. Kumar; M. K. Sharma; S. P. Mathur

    2007-01-01

    The inhibition efficiency of ethanolic extract of different parts of Capparis deciduas (Ker) in acidic medium has been evaluated by mass loss and thermometric methods. Values of inhibition efficiency obtained from the two methods are in good agreement and are dependent upon the concentration of inhibitor and acid.

  13. Experimental and quantum chemical studies on corrosion inhibition ...

    Indian Academy of Sciences (India)

    Abstract. The corrosion inhibition effect of fluconazole (FLU) was investigated on steel in 1 M hydrochloric acid solution. Weight loss measurements and atomic force microscope analysis were utilized to investigate the corrosion inhibition properties and film formation behaviour of FLU. Quantum chemical approach was also ...

  14. Belief Inhibition in Children's Reasoning: Memory-Based Evidence

    Science.gov (United States)

    Steegen, Sara; Neys, Wim De

    2012-01-01

    Adult reasoning has been shown as mediated by the inhibition of intuitive beliefs that are in conflict with logic. The current study introduces a classic procedure from the memory field to investigate belief inhibition in 12- to 17-year-old reasoners. A lexical decision task was used to probe the memory accessibility of beliefs that were cued…

  15. Inhibition of Snl6 expression for biofuel production

    Science.gov (United States)

    Bart, Rebecca; Chern, Mawsheng; Ronald, Pamela; Vega-Sanchez, Miguel

    2018-04-03

    The invention provides compositions and methods for inhibiting the expression of the gene Snl6 in plants. Plants with inhibited expression of Snl6 have use in biofuel production, e.g., by increasing the amount of soluble sugar that can be extracted from the plant.

  16. Apigenin inhibits proliferation and migratory properties of Barrett's ...

    African Journals Online (AJOL)

    dependent fashion, with an IC50 of 75 µM, after 72 h of incubation, and also induced apoptosis, with modulation of pro- and anti-apoptotic genes. Furthermore, apigenin inhibited the motility of OE33 by targeting PI3K/Akt/mTOR signaling. Conclusion: Apigenin effectively inhibits the oncogenicity of OE33 cells by targeting ...

  17. Cognitive Inhibition in Students with and without Dyslexia and Dyscalculia

    Science.gov (United States)

    Wang, Li-Chih; Tasi, Hung-Ju; Yang, Hsien-Ming

    2012-01-01

    The present study presents a comparison of the cognitive inhibition abilities of dyslexic, dyscalculic, and control students. The participants were 45 dyslexic students, 45 dyscalculic students, and 45 age-, gender-, and IQ-matched control students. The major evaluation tools included six cognitive inhibition tasks which were restructured during…

  18. Inhibition of autophagy initiation potentiates chemosensitivity in mesothelioma.

    Science.gov (United States)

    Follo, Carlo; Cheng, Yao; Richards, William G; Bueno, Raphael; Broaddus, Virginia Courtney

    2018-03-01

    The benefits of inhibiting autophagy in cancer are still controversial, with differences in outcome based on the type of tumor, the context and the particular stage of inhibition. Here, we investigated the impact of inhibiting autophagy at different stages on chemosensitivity using 3-dimensional (3D) models of mesothelioma, including ex vivo human tumor fragment spheroids. As shown by LC3B accumulation, we successfully inhibited autophagy using either an early stage ULK1/2 inhibitor (MRT 68921) or a late stage inhibitor (hydroxychloroquine). We found that inhibition of autophagy at the early stage, but not at late stage, potentiated chemosensitivity. This effect was seen only in those spheroids with high autophagy and active initiation at steady state. Inhibition of autophagy alone, at either early or late stage, did not cause cell death, showing that the inhibitors were non-toxic and that mesothelioma did not depend on autophagy at baseline, at least over 24 h. Using ATG13 puncta analysis, we found that autophagy initiation identified tumors that are more chemosensitive at baseline and after autophagy inhibition. Our results highlight a potential role of autophagy initiation in supporting mesothelioma cells during chemotherapy. Our work also highlights the importance of testing the inhibition of different stages in order to uncover the role of autophagy and the potential of its modulation in the treatment of cancer. © 2017 Wiley Periodicals, Inc.

  19. Experimental and quantum chemical studies on corrosion inhibition

    Indian Academy of Sciences (India)

    The corrosion inhibition effect of fluconazole (FLU) was investigated on steel in 1 M hydrochloric acid solution. Weight loss measurements and atomic force microscope analysis were utilized to investigate the corrosion inhibition properties and film formation behaviour of FLU. Quantum chemical approach was also used to ...

  20. Probe substrate and enzyme source-dependent inhibition of UDP ...

    African Journals Online (AJOL)

    Background: Drug-metabolizing enzymes (DMEs) inhibition based drug-drug interaction and herb-drug interaction severely challenge the R&D process of drugs or herbal ingredients. Objective: To evaluate the inhibition potential of wogonin (an important flavonoid isolated from the root of Scutellaria baicalensis) towards ...