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Sample records for jwh-015 significantly inhibits

  1. The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons.

    Science.gov (United States)

    Murataeva, N; Mackie, K; Straiker, A

    2012-11-01

    The G protein coupled receptors CB(1) and CB(2) are targets for the psychoactive constituents of cannabis, chief among them Δ(9)-THC. They are also key components of the multifunctional endogenous cannabinoid signaling system. CB(1) and CB(2) receptors modulate a wide variety of physiological systems including analgesia, memory, mood, reward, appetite and immunity. Identification and characterization of selective CB(1) and CB(2) receptor agonists and antagonists will facilitate understanding the precise physiological and pathophysiological roles of cannabinoid receptors in these systems. This is particularly necessary in the case of CB(2) because these receptors are sparsely expressed and problematic to detect using traditional immunocytochemical approaches. 1-Propyl-2-methyl-3-(1-naphthoyl)indole (JWH015) is an aminoalkylindole that has been employed as a "CB(2)-selective" agonist in more than 40 published papers. However, we have found that JWH015 potently and efficaciously activates CB(1) receptors in neurons. Using murine autaptic hippocampal neurons, which express CB(1), but not CB(2) receptors, we find that JWH015 inhibits excitatory postsynaptic currents with an EC50 of 216nM. JWH015 inhibition is absent in neurons from CB(1)(-/-) cultures and is reversed by the CB(1) antagonist, SR141716 [200nM]. Furthermore, JWH015 partially occludes CB(1)-mediated DSE (∼35% remaining), an action reversed by the CB(2) antagonist, AM630 [1 and 3μM], suggesting that high concentrations of AM630 also antagonize CB(1) receptors. We conclude that while JWH015 is a CB(2)-preferring agonist, it also activates CB(1) receptors at experimentally encountered concentrations. Thus, CB(1) agonism of JWH015 needs to be considered in the design and interpretation of experiments that use JWH015 to probe CB(2)-signaling.

  2. The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids.

    Directory of Open Access Journals (Sweden)

    Roger Negrete

    Full Text Available BACKGROUND: Cannabinoid 2 receptor (CB2R agonists attenuate inflammatory pain but the precise mechanism implicated in these effects is not completely elucidated. We investigated if the peripheral nitric oxide-cGMP-protein kinase G (PKG-ATP-sensitive K(+ (KATP channels signaling pathway triggered by the neuronal nitric oxide synthase (NOS1 and modulated by opioids, participates in the local antinociceptive effects produced by a CB2R agonist (JWH-015 during chronic inflammatory pain. METHODOLOGY/PRINCIPAL FINDINGS: In wild type (WT and NOS1 knockout (NOS1-KO mice, at 10 days after the subplantar administration of complete Freund's adjuvant (CFA, we evaluated the antiallodynic (von Frey filaments and antihyperalgesic (plantar test effects produced by the subplantar administration of JWH-015 and the reversion of their effects by the local co-administration with CB2R (AM630, peripheral opioid receptor (naloxone methiodide, NX-ME or CB1R (AM251 antagonists. Expression of CB2R and NOS1 as well as the antinociceptive effects produced by a high dose of JWH-015 combined with different doses of selective L-guanylate cyclase (ODQ or PKG (Rp-8-pCPT-cGMPs inhibitors or a KATP channel blocker (glibenclamide, were also assessed. Results show that the local administration of JWH-015 dose-dependently inhibited the mechanical and thermal hypersensitivity induced by CFA which effects were completely reversed by the local co-administration of AM630 or NX-ME, but not AM251. Inflammatory pain increased the paw expression of CB2R and the dorsal root ganglia transcription of NOS1. Moreover, the antinociceptive effects of JWH-015 were absent in NOS1-KO mice and diminished by their co-administration with ODQ, Rp-8-pCPT-cGMPs or glibenclamide. CONCLUSIONS/SIGNIFICANCE: These data indicate that the peripheral antinociceptive effects of JWH-015 during chronic inflammatory pain are mainly produced by the local activation of the nitric oxide-cGMP-PKG-KATP signaling pathway

  3. 大鼠鞘内注射JWH015对瑞芬太尼诱发痛觉过敏的影响%Effect of intrathecal injection JWH015 on the remifentani-induced hyperalgesia in rats

    Institute of Scientific and Technical Information of China (English)

    张威; 刘晓杰; 蒋明; 刘成龙; 张娟; 马正良; 顾小萍

    2012-01-01

    before plantar incision,while group C,I and R received the equivalent amount of normal saline 20% DMSO 10 μl in the same way.Plantar incision surgery was operated in group I,R,JI,and JR.In group R and JR,remifentanil (0.04 mg/kg,0.4 ml) was infused subcutaneously with a pump for 30 min at the moment of surgical incision.The other groups were received the equivalent amount of normal saline (0.4 ml) instead of remifentanil.The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measurd one day before and at 2,6,24 and 48 h after incision. Results Compared with group C and the baseline,the level of PWMT and PWTL significantly decreased at 2,6,24 and 48 h after incision in group I (P<0.05); Compared with group I,the significant decrease of PWMT (6.3±0.8),(6.4±0.8),(6.3± 1.0),(6.8±0.9) g and PWTL( 12.8± 1.2),(12.2±0.9),( 13.4± 1.1 ),( 13.5± 1.3 ) s were observed after incision in group R (P<0.05).Compared with group R,the significant increase of PWMT (7.9±1.0),(9.9±1.1),(8.4±1.1) g and PWTL (17.3±1.9),(19.9±1.3),(17.7±1.2) s were observed at 6,24 and 48 h after incision in group JR (P<0.05). Conclusions Intrathecal injection of JWH015 can be effectively alleviated remifentanil-induced hyperalgesia in a rat model of incision pain.

  4. 大麻素受体2激动剂JWH015对瑞芬太尼诱发痛觉过敏的影响%The effect of cannabinoid receptor 2 agonist JWH015 on the hyperalgesia induced by remifentanil

    Institute of Scientific and Technical Information of China (English)

    张威; 张伟; 刘晓杰; 张娟; 蒋明; 马正良; 顾小萍

    2012-01-01

    目的 探讨大麻素受体2( cannabinoid receptor 2,CB2R)激动剂JWH015对瑞芬太尼诱发的切口痛模型大鼠痛觉过敏的影响.方法 60只雄性SD大鼠采用随机数字表法随机分成2大组:鞘内给药组和腹腔给药组.每大组又随机分为5小组:鞘内给药组分为对照组1(C1组)、切口痛组1(I1组)、瑞芬太尼组1(R1组)、切口痛+JWH015组(QI组)、切口痛+瑞芬太尼+JWH015组(QR组);腹腔给药组分为对照组2(C2组)、切口痛组2(I2组)、瑞芬太尼组2(R2组)、切口痛+JWH015组(FI组),切口痛+瑞芬太尼+ JWH015组(FR组),每组6只.QI组与QR组在造模前30 min鞘内注射10μg JWH015,C1、I1、R1组均鞘内给予20%的二甲基亚砜(DMSO)溶液,容积均为10μl;而FI组与FR组在造模前30 min腹腔注射100 μg JWH015,C2、I2、R2组均腹腔给予4%的DMSO溶液,容积均为0.5ml.除C1/C2组外,其余各组均制作切口痛模型,R1/R2组、QR组和FR组在造模的同时皮下泵注瑞芬太尼0.04 mg/kg,其余组皮下泵注生理盐水,容积均为0.4ml,30 min泵完.测量术前24h及术后2,6,24,48 h大鼠手术切口同侧后爪的机械缩足反射阈值(PWMT)及热缩足潜伏期(PWTL).结果 与C1/C2组和基础值比较,I1/I2组术后PWMT和PWTL均降低(P<0.01);与I1/I2组比较,R1/R2组术后PWMT和PWTL均明显降低(P<0.05);与R1/R2组相比,QR组从术后6h的PWMT[ (7.78±1.09)g]和PWTL[( 17.28±1.58)s]开始明显升高(P<0.05),与FR组在术后6h、24h和48 h的PWMT[ (7.79 ±0.72)g,(9.50±1.17)g,(7.86±1.16)g]和PWTL[ (16.23±1.50)s,(19.53±1.63)s,(18.10 ±0.93)s]升高的结果一致.结论 鞘内及腹腔注射JW H015均可以有效缓解由瑞芬太尼诱发的切口周围组织痛觉过敏.%Objective To investigate the effects of cannabinoid receptor 2 (cannabinoid receptor 2,CB2R) agonist JWHO15 on the hyperalgesia induced by remifentanil in a rat model of postoperative pain.Methods Sixty SD rats were randomly divided into 10 groups ( n =6 each

  5. 大麻素受体2激动剂JWH-015对骨癌痛大鼠脊髓背角磷酸化环磷酸腺苷反应元件结合蛋白的影响%The effect of intraperitoneal injection cannabinoid 2 receptor agonist JWH-015 on the expression of phosphorylated cyclic AMP response element binding protein in spinal dorsal horn in a rat model of bone cancer pain

    Institute of Scientific and Technical Information of China (English)

    孙蓓; 张羽; 冷鑫; 顾小萍; 马正良

    2014-01-01

    into the intramedullary space of the left tibia of rat to induce ongoing bone cancer pain model,rats of group S were implanted 5 μl NS.On 10 d after implantation,JWH-015 (100 μg/500 μl) was injected into rats of group J,and DMSO was injected into rats of group D and S.The paw withdrawal mechanical threshold(PWMT) and ambulatory pain of each group were detected on 1 d before implantation,and 4,7,10 d after implantation,and 2,6,24,48,72 h after injection.Then,Lumbar intumescentia of rat were taken out to analyze Western-blotting at 4,7 d after implantation of group D and S,10 d after implantation,6,24,72 h after injection of group J,D,S.Results Compared with group S,at day 7 after the implantation,the PWMT of group J and D were significantly decreased (P<0.05),at day 10 after the implantation,the ambulatory pain of group J and D were obviously increased.The expression of pCREB in spinal dorsal horn were up-regulated at day 7 and 10 (P<0.05).Compared with group D,24 h after injection,the rat of group J showed remarkable rising of PWMT (8.7±1.6) g and reducing of ambulatory pain (1.0±0.6) and the expression of pCREB (0.56±0.10) (P<0.05).Conclusions Iintraperitoneal injection JWH-015 attenuated bone cancer pain,which may be acted via down-regulating the expression of pCREB in spinal dorsal horn.

  6. Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis.

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    Preet, Anju; Qamri, Zahida; Nasser, Mohd W; Prasad, Anil; Shilo, Konstantin; Zou, Xianghong; Groopman, Jerome E; Ganju, Ramesh K

    2011-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available. Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC. We observed expression of CB1 (24%) and CB2 (55%) in NSCLC patients. Furthermore, we have shown that the treatment of NSCLC cell lines (A549 and SW-1573) with CB1/CB2- and CB2-specific agonists Win55,212-2 and JWH-015, respectively, significantly attenuated random as well as growth factor-directed in vitro chemotaxis and chemoinvasion in these cells. We also observed significant reduction in focal adhesion complex, which plays an important role in migration, upon treatment with both JWH-015 and Win55,212-2. In addition, pretreatment with CB1/CB2 selective antagonists, AM251 and AM630, prior to JWH-015 and Win55,212-2 treatments, attenuated the agonist-mediated inhibition of in vitro chemotaxis and chemoinvasion. In addition, both CB1 and CB2 agonists Win55,212-2 and JWH-133, respectively, significantly inhibited in vivo tumor growth and lung metastasis (∼50%). These effects were receptor mediated, as pretreatment with CB1/CB2 antagonists abrogated CB1/CB2 agonist-mediated effects on tumor growth and metastasis. Reduced proliferation and vascularization, along with increased apoptosis, were observed in tumors obtained from animals treated with JWH-133 and Win55,212-2. Upon further elucidation into the molecular mechanism, we observed that both CB1 and CB2 agonists inhibited phosphorylation of AKT, a key signaling molecule controlling cell survival, migration, and apoptosis, and reduced matrix metalloproteinase 9 expression and activity. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.

  7. Antiapoptotic mechanism of cannabinoid receptor 2 agonist on cisplatin-induced apoptosis in the HEI-OC1 auditory cell line.

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    Jeong, Hyun-Ja; Kim, Su-Jin; Moon, Phil-Dong; Kim, Na-Hyun; Kim, Jung-Sun; Park, Rae-Kil; Kim, Min-Sun; Park, Byung-Rim; Jeong, Sejin; Um, Jae-Young; Kim, Hyung-Min; Hong, Seung-Heon

    2007-03-01

    Cisplatin is a highly effective chemotherapeutic agent but with significant ototoxic side effects. Apoptosis is an important mechanism of cochlear hair cell loss following exposure to an ototoxic level of cisplatin. The present study investigated the effects of the cannabinoid receptor 2 (CB2) ligand JWH-015 on cisplatin-induced apoptosis. CB2 mRNA was constitutively expressed in the auditory cell line HEI-OC1. By using MTT assay, DNA fragmentation, and FACS analysis, we demonstrated that apoptosis induced by cisplatin was inhibited by treatment with JWH-015 in a dose-dependent manner. Activation of caspase-3, caspase-8, and caspase-9 was detected after treatment with cisplatin, and the cleavage of poly-(ADP)-ribose polymerase (PARP) was observed within cisplatin-treated HEI-OC1 cells. JWH-015 inhibited the activation of caspase-3, caspase-8, and caspase-9; cleavage of PARP; and release of cytochrome c. JWH-015 also inhibited the apoptosis through activation of the extracellular signal-regulated kinase pathway. Finally, JWH-015 inhibited cisplatin-induced reactive oxygen species and tumor necrosis factor-alpha production. Collectively, these findings show that blocking a critical step in apoptosis by using JWH-015 may be a useful strategy to prevent harmful side effects of cisplatin ototoxicity in patients having to undergo chemotherapy.

  8. Role of pre-junctional CB1, but not CB2 , TRPV1 or GPR55 receptors in anandamide-induced inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats.

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    Marichal-Cancino, Bruno A; Altamirano-Espinoza, Alain H; Manrique-Maldonado, Guadalupe; MaassenVanDenBrink, Antoinette; Villalón, Carlos M

    2014-03-01

    Stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. Interestingly, endocannabinoids such as anandamide (which interacts with CB1 , CB2 , TRPV1 and GPR55 receptors) can regulate the activity of perivascular sensory nerves in dural blood vessels by modulating CGRP release. Yet, as no publication has reported whether this mechanism is operative in the healthy systemic vasculature, this study has specifically analysed the receptors mediating the potential inhibitory effects of the cannabinoid (CB) receptor agonists anandamide (non-selective), JWH-015 (CB2 ) and lysophosphatidylinositol (GPR55) on the rat vasodepressor sensory CGRPergic outflow (an index of systemic vasodilatation). Healthy pithed rats were pre-treated with consecutive i.v. continuous infusions of hexamethonium, methoxamine and the above agonists. Electrical spinal (T9 -T12 ) stimulation of the vasodepressor sensory CGRPergic outflow or i.v. injections of α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The infusions of anandamide in a dose-dependent manner inhibited the vasodepressor responses by electrical stimulation (remaining unaffected by JWH-015 or lysophosphatidylinositol), but not those by α-CGRP. After i.v. administration of antagonists, the inhibition by 3.1 μg/kg min anandamide was: (i) potently blocked by 31-100 μg/kg NIDA41020 (CB1 ), (ii) unaffected by 180 μg/kg AM630 (CB2 ), 31 μg/kg cannabidiol (GPR55) or 31-100 μg/kg capsazepine (TRPV1) and (iii) slightly blocked by 310 μg/kg AM630. The above doses of antagonists were enough to block their respective receptors. These results suggest that anandamide-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by pre-junctional activation of CB1 receptors, with no pharmacological evidence for the role of CB2 , TRPV1 or GPR55 receptors.

  9. Coeliac disease autoantibodies mediate significant inhibition of tissue transglutaminase.

    LENUS (Irish Health Repository)

    Byrne, Greg

    2012-02-01

    The detection of antibodies directed against tissue transglutaminase (tTG) in serum is a sensitive and specific test for suspected coeliac disease. tTG is a ubiquitous, multifunctional enzyme that has been implicated in many important physiological processes as well as the site-specific deamidation of glutamine residues in gluten-derived peptides. This modification of gluten peptides facilitates their binding to HLA-DQ2, which results in amplification of the T-cell response to gluten. The purpose of this study was to investigate the possibility that patient IgA autoantibodies directed against tTG interfere with the crosslinking activity of the enzyme. IgA autoantibodies against tTG were isolated\\/depleted from patient serum and tested for their capacity to interfere with tTG activity in vitro using a sensitive fluorescence-based activity assay. We have demonstrated that autoantibodies cause significant inhibition of tTG-mediated crosslinking at equimolar and 2:1 ratios of antibody to enzyme.

  10. Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation

    Directory of Open Access Journals (Sweden)

    Landry Russell P

    2009-05-01

    Full Text Available Abstract Background Cannabinoid receptor type 2 (CBR2 inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK pathway, via mitogen-activated protein kinase-phosphatase (MKP induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood. Results JWH015 (a CBR2 agonist increased MKP-1 and MKP-3 expression, which in turn reduced p-ERK1/2 in LPS-stimulated primary microglia. These effects resulted in a significant reduction of tumor necrosis factor-α (TNF expression and microglial migration. We confirmed the causative link of these findings by using MKP inhibitors. We found that the selective inhibition of MKP-1 by Ro-31-8220 and PSI2106, did not affect p-ERK expression in LPS+JWH015-treated microglia. However, the inhibition of both MKP-1 and MKP-3 by triptolide induced an increase in p-ERK expression and in microglial migration using LPS+JWH015-treated microglia. Conclusion Our results uncover a cellular microglial pathway triggered by CBR2 activation. These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development.

  11. Clinically significant CYP2C inhibition by noscapine but not by glucosamine.

    Science.gov (United States)

    Rosenborg, S; Stenberg, M; Otto, S; Ostervall, J; Masquelier, M; Yue, Q-Y; Bertilsson, L; Eliasson, E

    2010-09-01

    Noscapine and glucosamine reportedly interact with warfarin. We investigated the effects of these drugs on various cytochrome P450 (CYP) activity markers. Twelve healthy subjects were phenotyped at baseline and during separate treatments with noscapine and glucosamine. Whereas glucosamine had no significant effect on CYP activity, noscapine caused marked inhibition of CYP2C9 (4.9-fold increase in urinary losartan/E3174 ratio) and CYP2C19 (3.6-fold increase in the plasma omeprazole/5-hydroxyomeprazole ratio). Noscapine-dependent inhibition of CYP2C9 may explain the interaction with warfarin.

  12. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

    Science.gov (United States)

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2015-12-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

  13. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

    Science.gov (United States)

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2015-12-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

  14. Behaviorally inhibited individuals demonstrate significantly enhanced conditioned response acquisition under non-optimal learning conditions.

    Science.gov (United States)

    Holloway, J L; Allen, M T; Myers, C E; Servatius, R J

    2014-03-15

    Behavioral inhibition (BI) is an anxiety vulnerability factor associated with hypervigilance to novel stimuli, threat, and ambiguous cues. The progression from anxiety risk to a clinical disorder is unknown, although the acquisition of defensive learning and avoidance may be a critical feature. As the expression of avoidance is also central to anxiety development, the present study examined avoidance acquisition as a function of inhibited temperament using classical eyeblink conditioning. Individuals were classified as behaviorally inhibited (BI) or non-inhibited (NI) based on combined scores from the Adult and Retrospective Measures of Behavioural Inhibition (AMBI and RMBI, respectively). Acquisition was assessed using delay, omission, or yoked conditioning schedules of reinforcement. Omission training was identical to delay, except that the emission of an eyeblink conditioned response (CR) resulted in omission of the unconditioned airpuff stimulus (US) on that trial. Each subject in the yoked group was matched on total BI score to a subject in the omission group, and received the same schedule of CS and US delivery, resulting in a partial reinforcement training schedule. Delay conditioning elicited significantly more CRs compared to the omission and yoked contingencies, the latter two of which did not differ from each other. Thus, acquisition of an avoidance response was not apparent. BI individuals demonstrated enhanced acquisition overall, while partial reinforcement training significantly distinguished between BI and NI groups. Enhanced learning in BI may be a function of an increased defensive learning capacity, or sensitivity to uncertainty. Further work examining the influence of BI on learning acquisition is important for understanding individual differences in disorder etiology in anxiety vulnerable cohorts.

  15. Significance of bacterial flora in abdominal irradiation-induced inhibition of lung metastases

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, T.; Ando, K.; Koike, S.

    1988-06-01

    We have previously reported that abdominal irradiation prior to i.v. injection of syngeneic tumor cells reduced metastases in lung. Our report described an investigation of the significance of intestinal organisms in the radiation effect. We found that eliminating intestinal organisms with antibiotics totally abolished the radiation effect. Monoassociation of germ-free mice revealed that the radiation effect was observable only for Enterobacter cloacae, never for Streptococcus faecium, Bifidobacterium adlesentis, or Escherichia coli. After abdominal irradiation of regular mice, E. cloacae multiplied in cecal contents, adhered to mucous membranes, invaded the cecal wall, and translocated to mesenteric lymph nodes. Intravenous administration of E. cloacae in place of abdominal irradiation inhibited metastases. E. cloacae-monoassociated mice developed fewer metastases than germ-free mice, and the reduction was further enhanced by abdominal irradiation. We concluded that abdominal irradiation caused the invasion of E. cloacae from the mucous membrane of the intestine and inhibited formation of lung metastases.

  16. Pinelliae Rhizoma, a Toxic Chinese Herb, Can Significantly Inhibit CYP3A Activity in Rats

    Directory of Open Access Journals (Sweden)

    Jinjun Wu

    2015-01-01

    Full Text Available Raw Pinelliae Rhizoma (RPR is a representative toxic herb that is widely used for eliminating phlegm or treating cough and vomiting. Given its irritant toxicity, its processed products, including Pinelliae Rhizoma Praeparatum (PRP and Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (PRPZA, are more commonly applied and administered concomitantly with other chemical drugs, such as cough medications. This study aimed to investigate the effects of RPR, PRP, and PRPZA on CYP3A activity. Testosterone (Tes and buspirone (BP were used as specific probe substrates ex vivo and in vivo, respectively. CYP3A activity was determined by the metabolite formation ratios from the substrates. Ex vivo results show that the metabolite formation ratios from Tes significantly decreased, indicating that RPR, PRP, and PRPZA could inhibit CYP3A activity in rats. CYP3A protein and mRNA levels were determined to explore the underlying mechanism. These levels showed marked and consistent down-regulation with CYP3A activity. A significant decrease in metabolite formation ratios from BP was also found in PRPZA group in vivo, implying that PRPZA could inhibit CYP3A activity. Conclusively, co-administration of PR with other CYP3A-metabolizing drugs may cause drug–drug interactions. Clinical use of PR-related formulae should be monitored carefully to avoid adverse interactions.

  17. Inhibition of class IIb histone deacetylase significantly improves cloning efficiency in mice.

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    Ono, Tetsuo; Li, Chong; Mizutani, Eiji; Terashita, Yukari; Yamagata, Kazuo; Wakayama, Teruhiko

    2010-12-01

    Since the first mouse clone was produced by somatic cell nuclear transfer, the success rate of cloning in mice has been extremely low. Some histone deacetylase inhibitors, such as trichostatin A and scriptaid, have improved the full-term development of mouse clones significantly, but the mechanisms allowing for this are unclear. Here, we found that two other specific inhibitors, suberoylanilide hydroxamic acid and oxamflatin, could also reduce the rate of apoptosis in blastocysts, improve the full-term development of cloned mice, and increase establishment of nuclear transfer-generated embryonic stem cell lines significantly without leading to obvious abnormalities. However, another inhibitor, valproic acid, could not improve cloning efficiency. Suberoylanilide hydroxamic acid, oxamflatin, trichostatin A, and scriptaid are inhibitors for classes I and IIa/b histone deacetylase, whereas valproic acid is an inhibitor for classes I and IIa, suggesting that inhibiting class IIb histone deacetylase is an important step for reprogramming mouse cloning efficiency.

  18. Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.

    Science.gov (United States)

    Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy.

  19. The CO2 inhibition of terrestrial isoprene emission significantly affects future ozone projections

    Directory of Open Access Journals (Sweden)

    J. A. Pyle

    2008-11-01

    Full Text Available Simulations of future tropospheric composition often include substantial increases in biogenic isoprene emissions arising from the Arrhenius-like leaf emission response and warmer surface temperatures, and from enhanced vegetation productivity in response to temperature and atmospheric CO2 concentration. However, a number of recent laboratory and field data have suggested a direct inhibition of leaf isoprene production by increasing atmospheric CO2 concentration, notwithstanding isoprene being produced from precursor molecules that include some of the primary products of carbon assimilation. The cellular mechanism that underlies the decoupling of leaf photosynthesis and isoprene production still awaits a full explanation but accounting for this observation in a dynamic vegetation model that contains a semi-mechanistic treatment of isoprene emissions has been shown to change future global isoprene emission estimates notably. Here we use these estimates in conjunction with a chemistry-climate model to compare the effects of isoprene simulations without and with a direct CO2-inhibition on late 21st century O3 and OH levels. The impact on surface O3 was significant. Including the CO2-inhibition of isoprene resulted in opposing responses in polluted (O3 decreases of up to 10 ppbv vs. less polluted (O3 increases of up to 10 ppbv source regions, due to isoprene nitrate and peroxy acetyl nitrate (PAN chemistry. OH concentration increased with relatively lower future isoprene emissions, decreasing methane lifetime by ~7 months. Our simulations underline the large uncertainties in future chemistry and climate studies due to biogenic emission patterns and emphasize the problems of using globally averaged climate metrics to quantify the atmospheric impact of reactive, heterogeneously distributed substances.

  20. The CO2 inhibition of terrestrial isoprene emission significantly affects future ozone projections

    Science.gov (United States)

    Young, P. J.; Arneth, A.; Schurgers, G.; Zeng, G.; Pyle, J. A.

    2009-04-01

    Simulations of future tropospheric composition often include substantial increases in biogenic isoprene emissions arising from the Arrhenius-like leaf emission response and warmer surface temperatures, and from enhanced vegetation productivity in response to temperature and atmospheric CO2 concentration. However, a number of recent laboratory and field data have suggested a direct inhibition of leaf isoprene production by increasing atmospheric CO2 concentration, notwithstanding isoprene being produced from precursor molecules that include some of the primary products of carbon assimilation. The cellular mechanism that underlies the decoupling of leaf photosynthesis and isoprene production still awaits a full explanation but accounting for this observation in a dynamic vegetation model that contains a semi-mechanistic treatment of isoprene emissions has been shown to change future global isoprene emission estimates notably. Here we use these estimates in conjunction with a chemistry-climate model to compare the effects of isoprene simulations without and with a direct CO2-inhibition on late 21st century O3 and OH levels. The impact on surface O3 was significant. Including the CO2-inhibition of isoprene resulted in opposing responses in polluted (O3 decreases of up to 10 ppbv) vs. less polluted (O3 increases of up to 10 ppbv) source regions, due to isoprene nitrate and peroxy acetyl nitrate (PAN) chemistry. OH concentration increased with relatively lower future isoprene emissions, decreasing methane lifetime by ~7 months (6.6%). Our simulations underline the large uncertainties in future chemistry and climate studies due to biogenic emission patterns and emphasize the problems of using globally averaged climate metrics (such as global radiative forcing) to quantify the atmospheric impact of reactive, heterogeneously distributed substances.

  1. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro.

    Science.gov (United States)

    Kato, Takahiro; Monji, Akira; Hashioka, Sadayuki; Kanba, Shigenobu

    2007-05-01

    Microglia has recently been regarded to be a mediator of neuroinflammation via the release of proinflammatory cytokines, nitric oxide (NO) and reactive oxygen species (ROS) in the central nervous system (CNS). Microglia has thus been reported to play an important role in the pathology of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The pathological mechanisms of schizophrenia remain unclear while some recent neuroimaging studies suggest even schizophrenia may be a kind of neurodegenerative disease. Risperidone has been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia. Many recent studies have demonstrated that immunological mechanisms via such as interferon (IFN)-gamma and cytokines might be relevant to the pathophysiology of schizophrenia. In the present study, we thus investigated the effects of risperidone on the generation of nitric oxide, inducible NO synthase (iNOS) expression and inflammatory cytokines: interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha by IFN-gamma-activated microglia by using Griess assay, Western blotting and ELISA, respectively. In comparison with haloperidol, risperidone significantly inhibited the production of NO and proinflammatory cytokines by activated microglia. The iNOS levels of risperidone-treated cells were much lower than those of the haloperidol-treated cells. Antipsychotics, especially risperidone may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia.

  2. Cannabinoid receptor type 1- and 2-mediated increase in cyclic AMP inhibits T cell receptor-triggered signaling.

    Science.gov (United States)

    Börner, Christine; Smida, Michal; Höllt, Volker; Schraven, Burkhart; Kraus, Jürgen

    2009-12-18

    The aim of this study was to characterize inhibitory mechanisms on T cell receptor signaling mediated by the cannabinoid receptors CB1 and CB2. Both receptors are coupled to G(i/o) proteins, which are associated with inhibition of cyclic AMP formation. In human primary and Jurkat T lymphocytes, activation of CB1 by R(+)-methanandamide, CB2 by JWH015, and both by Delta9-tetrahydrocannabinol induced a short decrease in cyclic AMP lasting less than 1 h. However, this decrease was followed by a massive (up to 10-fold) and sustained (at least up to 48 h) increase in cyclic AMP. Mediated by the cyclic AMP-activated protein kinase A and C-terminal Src kinase, the cannabinoids induced a stable phosphorylation of the inhibitory Tyr-505 of the leukocyte-specific protein tyrosine kinase (Lck). By thus arresting Lck in its inhibited form, the cannabinoids prevented the dephosphorylation of Lck at Tyr-505 in response to T cell receptor activation, which is necessary for the subsequent initiation of T cell receptor signaling. In this way the cannabinoids inhibited the T cell receptor-triggered signaling, i.e. the activation of the zeta-chain-associated protein kinase of 70 kDa, the linker for activation of T cells, MAPK, the induction of interleukin-2, and T cell proliferation. All of the effects of the cannabinoids were blocked by the CB1 and CB2 antagonists AM281 and AM630. These findings help to better understand the immunosuppressive effects of cannabinoids and explain the beneficial effects of these drugs in the treatment of T cell-mediated autoimmune disorders like multiple sclerosis.

  3. [Diagnostic significance of the spinal-brain stem polysynaptic reflex and the period of inhibition].

    Science.gov (United States)

    Ivanichev, G A

    1985-01-01

    Electrical stimulation of the radial nerve associated with voluntary contraction of the shoulder girdle inhibited bioelectrical activity not only in the muscles of the hypothenar but also in the proximal muscles. In resting muscles, such stimulation elicited a reflex response with a large latent period. With weak voluntary tension stimulation elicited a reflex response while in the presence of considerable contraction the reflex response merged with bioelectrical activity, with a clearly demonstrable subsequent period of inhibition. The current viewpoint about the antidromal blockade of the segmental motoneurons is debated. It is suggested that the polysynaptic reflex and the inhibition period are connected with the same level of realization -- the oral portions of the brain stem.

  4. Nitration of Tyrosine Residue Y10 of Aβ1-42 Significantly Inhibits Its Aggregation and Cytotoxicity.

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    Zhao, Jie; Wu, Jinming; Yang, Zhen; Li, Hailing; Gao, Zhonghong

    2017-04-17

    Amyloid-β plaques and oxidative stress are the major hallmarks of Alzheimer's disease. Our previous study found that the heme-Aβ complex enhanced the catalytic effect of free heme on protein tyrosine nitration in the presence of hydrogen peroxide (H2O2) and nitrite (NO2(-)). Y10 in Aβ could be the first target to be nitrated. We also found that nitration of Aβ1-40 significantly decreased its aggregation. However, a contrary report showed that nitration of Aβ1-42 by peroxynitrite enhanced its aggregation. To rule out the interference of peroxynitrite caused Aβ oxidation, we used synthetic Y10 nitrated Aβ1-42 to study the influence of Y10 nitration on Aβ1-42's aggregation and cytotoxicity in this study. We confirmed that Aβ1-42 could be nitrated in the presence of H2O2, NO2(-), and heme by dot blotting. CD spectroscopy showed an increase of β-sheet structure of Aβ1-42 and its mutants. The thioflavin T (ThT) flourescence assay revealed that both nitration and chlorination significantly inhibited Aβ1-42 fibril formation. TEM and AFM observations of Aβ peptide aggregates further confirmed that Y10 modification inhibited Aβ1-42 fibril formation. The cytotoxicity study of native and modified Aβ peptides on SH-SY5Y cells revealed that nitration of Aβ1-42 remarkably decreased the neurotoxicity of Aβ1-42. On the basis of these results, we hypothesized that nitration of Y10 may block the π-π stacking interactions of Aβ1-42 so that it inhibit its aggregation and neurotoxicity. More importantly, considerable evidence suggested that the levels of nitrite plus nitrate significantly decreased in the brain of AD patients. Thus, we believe that these findings would be helpful for further understanding the function of Aβ in AD.

  5. Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium.

    Science.gov (United States)

    Marques, Joana; Vilanova, Eduardo; Mourão, Paulo A S; Fernàndez-Busquets, Xavier

    2016-04-13

    The antimalarial activity of heparin, against which there are no resistances known, has not been therapeutically exploited due to its potent anticoagulating activity. Here, we have explored the antiplasmodial capacity of heparin-like sulfated polysaccharides from the sea cucumbers Ludwigothurea grisea and Isostichopus badionotus, from the red alga Botryocladia occidentalis, and from the marine sponge Desmapsamma anchorata. In vitro experiments demonstrated for most compounds significant inhibition of Plasmodium falciparum growth at low-anticoagulant concentrations. This activity was found to operate through inhibition of erythrocyte invasion by Plasmodium, likely mediated by a coating of the parasite similar to that observed for heparin. In vivo four-day suppressive tests showed that several of the sulfated polysaccharides improved the survival of Plasmodium yoelii-infected mice. In one animal treated with I. badionotus fucan parasitemia was reduced from 10.4% to undetectable levels, and Western blot analysis revealed the presence of antibodies against P. yoelii antigens in its plasma. The retarded invasion mediated by sulfated polysaccharides, and the ensuing prolonged exposure of Plasmodium to the immune system, can be explored for the design of new therapeutic approaches against malaria where heparin-related polysaccharides of low anticoagulating activity could play a dual role as drugs and as potentiators of immune responses.

  6. Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium

    Science.gov (United States)

    Marques, Joana; Vilanova, Eduardo; Mourão, Paulo A. S.; Fernàndez-Busquets, Xavier

    2016-01-01

    The antimalarial activity of heparin, against which there are no resistances known, has not been therapeutically exploited due to its potent anticoagulating activity. Here, we have explored the antiplasmodial capacity of heparin-like sulfated polysaccharides from the sea cucumbers Ludwigothurea grisea and Isostichopus badionotus, from the red alga Botryocladia occidentalis, and from the marine sponge Desmapsamma anchorata. In vitro experiments demonstrated for most compounds significant inhibition of Plasmodium falciparum growth at low-anticoagulant concentrations. This activity was found to operate through inhibition of erythrocyte invasion by Plasmodium, likely mediated by a coating of the parasite similar to that observed for heparin. In vivo four-day suppressive tests showed that several of the sulfated polysaccharides improved the survival of Plasmodium yoelii-infected mice. In one animal treated with I. badionotus fucan parasitemia was reduced from 10.4% to undetectable levels, and Western blot analysis revealed the presence of antibodies against P. yoelii antigens in its plasma. The retarded invasion mediated by sulfated polysaccharides, and the ensuing prolonged exposure of Plasmodium to the immune system, can be explored for the design of new therapeutic approaches against malaria where heparin-related polysaccharides of low anticoagulating activity could play a dual role as drugs and as potentiators of immune responses. PMID:27071342

  7. Compounds from Terminalia mantaly L. (Combretaceae Stem Bark Exhibit Potent Inhibition against Some Pathogenic Yeasts and Enzymes of Metabolic Significance

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    Marthe Aimée Tchuente Tchuenmogne

    2017-01-01

    Full Text Available Background: Pathogenic yeasts resistance to current drugs emphasizes the need for new, safe, and cost-effective drugs. Also, new inhibitors are needed to control the effects of enzymes that are implicated in metabolic dysfunctions such as cancer, obesity, and epilepsy. Methods: The anti-yeast extract from Terminalia mantaly (Combretaceae was fractionated and the structures of the isolated compounds established by means of spectroscopic analysis and comparison with literature data. Activity was assessed against Candida albicans, C. parapsilosis and C. krusei using the microdilution method, and against four enzymes of metabolic significance: glucose-6-phosphate dehydrogenase, human erythrocyte carbonic anhydrase I and II, and glutathione S-transferase. Results: Seven compounds, 3,3′-di-O-methylellagic acid 4′-O-α-rhamnopyranoside; 3-O-methylellagic acid; arjungenin or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid; arjunglucoside or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid glucopyranoside; 2α,3α,24-trihydroxyolean-11,13(18-dien-28-oïc acid; stigmasterol; and stigmasterol 3-O-β-d-glucopyranoside were isolated from the extract. Among those, 3,3′-di-O-methylellagic acid 4′-O-α-rhamnopyranoside, 3-O-methylellagic acid, and arjunglucoside showed anti-yeast activity comparable to that of reference fluconazole with minimal inhibitory concentrations (MIC below 32 µg/mL. Besides, Arjunglucoside potently inhibited the tested enzymes with 50% inhibitory concentrations (IC50 below 4 µM and inhibitory constant (Ki <3 µM. Conclusions: The results achieved indicate that further SAR studies will likely identify potent hit derivatives that should subsequently enter the drug development pipeline.

  8. Interactions outside the proteinase-binding loop contribute significantly to the inhibition of activated coagulation factor XII by its canonical inhibitor from corn.

    Science.gov (United States)

    Korneeva, Vera A; Trubetskov, Mikhail M; Korshunova, Alena V; Lushchekina, Sofya V; Kolyadko, Vladimir N; Sergienko, Olga V; Lunin, Vladimir G; Panteleev, Mikhail A; Ataullakhanov, Fazoil I

    2014-05-16

    Activated factor XII (FXIIa) is selectively inhibited by corn Hageman factor inhibitor (CHFI) among other plasma proteases. CHFI is considered a canonical serine protease inhibitor that interacts with FXIIa through its protease-binding loop. Here we examined whether the protease-binding loop alone is sufficient for the selective inhibition of serine proteases or whether other regions of a canonical inhibitor are involved. Six CHFI mutants lacking different N- and C-terminal portions were generated. CHFI-234, which lacks the first and fifth disulfide bonds and 11 and 19 amino acid residues at the N and C termini, respectively, exhibited no significant changes in FXIIa inhibition (Ki = 3.2 ± 0.4 nm). CHFI-123, which lacks 34 amino acid residues at the C terminus and the fourth and fifth disulfide bridges, inhibited FXIIa with a Ki of 116 ± 16 nm. To exclude interactions outside the FXIIa active site, a synthetic cyclic peptide was tested. The peptide contained residues 20-45 (Protein Data Bank code 1BEA), and a C29D substitution was included to avoid unwanted disulfide bond formation between unpaired cysteines. Surprisingly, the isolated protease-binding loop failed to inhibit FXIIa but retained partial inhibition of trypsin (Ki = 11.7 ± 1.2 μm) and activated factor XI (Ki = 94 ± 11 μm). Full-length CHFI inhibited trypsin with a Ki of 1.3 ± 0.2 nm and activated factor XI with a Ki of 5.4 ± 0.2 μm. Our results suggest that the protease-binding loop is not sufficient for the interaction between FXIIa and CHFI; other regions of the inhibitor also contribute to specific inhibition.

  9. Inhibition of tumor progression during allergic airway inflammation in a murine model: significant role of TGF-β.

    Science.gov (United States)

    Tirado-Rodriguez, Belen; Baay-Guzman, Guillermina; Hernandez-Pando, Rogelio; Antonio-Andres, Gabriela; Vega, Mario I; Rocha-Zavaleta, Leticia; Bonifaz, Laura C; Huerta-Yepez, Sara

    2015-09-01

    TGF-β is an important mediator of pulmonary allergic inflammation, and it has been recently reported to be a potential inhibitor of lung tumor progression. The correlation between cancer and allergic inflammatory diseases remains controversial. Thus, the aim of the present study was to evaluate the effects of pulmonary allergic inflammation and in particular the role of TGF-β on cancer progression. Cancer cells were implanted in a BALB/c mice model of allergic airway inflammation, and tumor growth was measured. Apoptosis was evaluated by TUNEL assay, and TGF-β was measured by ELISA. Expression of proliferating cell nuclear antigen, TGF-β, TGF-β receptors I and II, phospho-Smad2 and phospho-Smad4 was evaluated by immunohistochemistry and quantified using digital pathology. The effect of a TGF-β activity inhibitor and recombinant TGF-β on tumor growth was analyzed. The effect of exogenous TGF-β on cell proliferation and apoptosis was evaluated in vitro. Mice with allergic airway inflammation exhibited decreased tumor volumes due to cell proliferation inhibition and increased apoptosis. TGF-β was increased in the sera and tumor tissues of allergic mice. TGF-β activity inhibition increased tumor progression in allergic mice by enhancing proliferation and decreasing apoptosis of tumor cells. The administration of TGF-β resulted in reduced tumor growth. This study is the first to establish an inverse relationship between allergic airway inflammation and tumor progression. This effect appears to be mediated by TGF-β, which is overexpressed in tumor cells during pulmonary allergic inflammation. This study indicates that TGF-β is a potential target for antitumor therapy.

  10. Fusion of protegrin-1 and plectasin to MAP30 shows significant inhibition activity against dengue virus replication.

    Directory of Open Access Journals (Sweden)

    Hussin A Rothan

    Full Text Available Dengue virus (DENV broadly disseminates in tropical and sub-tropical countries and there are no vaccine or anti-dengue drugs available. DENV outbreaks cause serious economic burden due to infection complications that requires special medical care and hospitalization. This study presents a new strategy for inexpensive production of anti-DENV peptide-fusion protein to prevent and/or treat DENV infection. Antiviral cationic peptides protegrin-1 (PG1 and plectasin (PLSN were fused with MAP30 protein to produce recombinant antiviral peptide-fusion protein (PG1-MAP30-PLSN as inclusion bodies in E. coli. High yield production of PG1-MAP30-PLSN protein was achieved by solubilization of inclusion bodies in alkaline buffer followed by the application of appropriate refolding techniques. Antiviral PG1-MAP30-PLSN protein considerably inhibited DENV protease (NS2B-NS3pro with half-maximal inhibitory concentration (IC50 0.5±0.1 μM. The real-time proliferation assay (RTCA and the end-point proliferation assay (MTT assay showed that the maximal-nontoxic dose of the peptide-fusion protein against Vero cells is approximately 0.67±0.2 μM. The cell-based assays showed considerable inhibition of the peptide-fusion protein against binding and proliferating stages of DENV2 into the target cells. The peptide-fusion protein protected DENV2-challeged mice with 100% of survival at the dose of 50 mg/kg. In conclusion, producing recombinant antiviral peptide-fusion protein by combining short antiviral peptide with a central protein owning similar activity could be useful to minimize the overall cost of short peptide production and take advantage of its synergistic antiviral activities.

  11. Differential CB1 and CB2 cannabinoid receptor-inotropic response of rat isolated atria: endogenous signal transduction pathways.

    Science.gov (United States)

    Sterin-Borda, Leonor; Del Zar, Claudia F; Borda, Enri

    2005-06-15

    In this study, we have determined the contractile effects of CB1 and CB2 cannabinoid receptor activation on rat isolated atria and the different signaling pathways involved. Anandamide did not has significantly effect on atria contractility, however, the treatment with both CB1 (AM251) or CB2 (AM630) receptor antagonists, the endocannabinoids triggered stimulation or inhibition on contractility respectively. The ACEA stimulation of CB1 receptor exerted decrease on contractility, that significantly correlated with the decrement of cAMP and the stimulation of nitric oxide synthase (NOS) and the accumulation of cyclic GMP (cGMP). On the contrary, JWH 015 stimulation of CB2 receptor triggered positive contractile response that significantly correlated with the increase cAMP production. The inhibiton of adenylate cyclase activity impaired the JWH 015 activation of CB1 receptor induced positive contractile effect, while inhibitors of phospholipase C (PLC), NOS and soluble nitric oxide (NO)-sensitive guanylate cyclase blocked the dose-response curves of ACEA on contractility. Those inhibitors also attenuated the CB1 receptor-dependent increase in activation of NOS and cGMP accumulation. These results suggest that CB2 receptor agonist mediated positive contractile effect associated with increased production on cAMP while CB1 receptor agonist mediated decrease on contractility associated with decreased cAMP accumulation and increase production of NO and cGMP; that occur secondarily to stimulation of PLC, NOS and soluble guanylate cyclase. Data give pharmacological evidence for the existence of functional CB1 and CB2 cannabinoid receptors in rat isolated atria and may contribute to a better understanding the effects of cannabinoids in the cardiovascular system.

  12. P-glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes.

    Science.gov (United States)

    Farrell, R J; Menconi, M J; Keates, A C; Kelly, C P

    2002-05-01

    To assess the role of P-glycoprotein-170 (P-gp) in transporting cortisol and ciclosporin from human intestinal epithelium and T lymphocytes. The effect of P-gp inhibitors (verapamil, 0-100 microM; PSC 833, 0-20 microM) on the intracellular accumulation of 3H-cortisol and 3H-ciclosporin was studied in confluent layers of human Caco-2 cells (n=6), a P-gp-dependent absorptive intestinal epithelial cell phenotype, and moderately resistant MDRhigh CEM/VBL 100 T cells (n=6). The transport of 3H-vinblastine, a strong multidrug resistance (MDR) substrate, and 3H-progesterone, a poor MDR substrate, was also studied. Caco-2 cells had a 2.4-, 6.6-, 6.7- and 1.03-fold higher net basal to apical transport (efflux) of 3H-cortisol, 3H-ciclosporin, 3H-vinblastine and 3H-progesterone, respectively. PSC 833 (20 microM) reduced cortisol efflux by 69% (0.23 +/- 0.04 to 0.07 +/- 0.01 pmol/cm2/h, P 0.1 microM) and verapamil (> 1 microM) restored the intracellular level of 3H-cortisol and 3H-ciclosporin in MDRhigh CEM/VBL 100 T cells to that of MDRlow CEM cells with little change in accumulation in the MDRlow parental cell line. P-gp inhibitors significantly increase intracellular cortisol and ciclosporin levels in human intestinal epithelium and T lymphocytes in a dose-dependent manner, demonstrating a potential mechanism for overcoming poor response to immunosuppressant therapy in refractory inflammatory bowel disease.

  13. Arborvitae (Thuja plicata essential oil significantly inhibited critical inflammation- and tissue remodeling-related proteins and genes in human dermal fibroblasts

    Directory of Open Access Journals (Sweden)

    Xuesheng Han

    2017-06-01

    Full Text Available Arborvitae (Thuja plicata essential oil (AEO is becoming increasingly popular in skincare, although its biological activity in human skin cells has not been investigated. Therefore, we sought to study AEO's effect on 17 important protein biomarkers that are closely related to inflammation and tissue remodeling by using a pre-inflamed human dermal fibroblast culture model. AEO significantly inhibited the expression of vascular cell adhesion molecule 1 (VCAM-1, intracellular cell adhesion molecule 1 (ICAM-1, interferon gamma-induced protein 10 (IP-10, interferon-inducible T-cell chemoattractant (I-TAC, monokine induced by interferon gamma (MIG, and macrophage colony-stimulating factor (M-CSF. It also showed significant antiproliferative activity and robustly inhibited collagen-I, collagen-III, plasminogen activator inhibitor-1 (PAI-1, and tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2. The inhibitory effect of AEO on increased production of these protein biomarkers suggests it has anti-inflammatory property. We then studied the effect of AEO on the genome-wide expression of 21,224 genes in the same cell culture. AEO significantly and diversely modulated global gene expression. Ingenuity pathway analysis (IPA showed that AEO robustly affected numerous critical genes and signaling pathways closely involved in inflammatory and tissue remodeling processes. The findings of this study provide the first evidence of the biological activity and beneficial action of AEO in human skin cells.

  14. Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727) causes significant melanoma growth delay and regression in vivo.

    Science.gov (United States)

    Cholewa, Brian D; Ndiaye, Mary A; Huang, Wei; Liu, Xiaoqi; Ahmad, Nihal

    2017-01-28

    The objective of this study was to determine the therapeutic potential of polo-like kinase 1 (Plk1) inhibition in melanoma, in vivo. Employing Vectra technology, we assessed the Plk1 expression profile in benign nevi, malignant (stages I-IV) and metastatic melanomas. We found a significant elevation of Plk1 immunostaining in melanoma tissues. Further, a second generation small molecule Plk1 inhibitor, BI 6727, resulted in reductions in growth, viability and clonogenic survival, as well as an increase in apoptosis of A375 and Hs 294T melanoma cells. BI 6727 treatment also resulted in a G2/M-as well as S-phase cell cycle arrest in melanoma cells. Importantly, BI 6727 (intravenous injection; 10 and 25 mg/kg body weight) treatment resulted in significant tumor growth delay and regression in vivo in A375-and Hs 294T-implanted xenografts in athymic nude mice. These anti-melanoma effects were accompanied with a decreased cellular proliferation (Ki-67 staining) and induction of apoptosis (caspase 3 activation). In addition, BI 6727 treatment caused a marked induction of p53 and p21 in vitro as well as in vivo. Overall, we suggest that Plk1 inhibition may be a useful approach as a monotherapy as well as in combination with other existing therapeutics, for melanoma management. Published by Elsevier Ireland Ltd.

  15. Significant enhancement of (R)-mandelic acid production by relieving substrate inhibition of recombinant nitrilase in toluene-water biphasic system.

    Science.gov (United States)

    Zhang, Zhi-Jun; Pan, Jiang; Liu, Jun-Feng; Xu, Jian-He; He, Yu-Cai; Liu, You-Yan

    2011-03-10

    The enantioselective hydrolysis of mandelonitrile with whole cells of a recombinant Escherichia coli expressing nitrilase activity was severely inhibited by the substrate at high concentrations (>300mM), which resulted in a low yield of the target product (R)-(-)-mandelic acid. To relieve the substrate inhibition and to enhance the (R)-(-)-mandelic acid productivity, eight water-organic solvent biphasic systems were attempted in this work. Toluene was found to be the most suitable solvent as the organic phase among the solvents tested. Various parameters were systematically examined and optimized in shake flasks. The phase volume ratio, buffer pH and reaction temperature were shown to be sensitive parameters affecting both the yield and the enantiopurity of product in the biphasic system. Under the optimized conditions, significant enhancement of substrate tolerance from 200mM to 500mM and average productivity from 179.6gl(-1)d(-1) to 352.6gl(-1)d(-1) were achieved. Subsequently, the biocatalytic hydrolysis of mandelonitrile was successfully carried out in a stirred reactor (2-l scale) by repeated use of the calcium alginate entrapped cells for 5 batches, affording 110.7g (R)-(-)-mandelic acid in 98.0% ee (enantiomeric excess) and a specific production of 13.8g (mandelic acid) g(-1) (cell), respectively. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. In vitro exposure to the herbicide atrazine inhibits T cell activation, proliferation, and cytokine production and significantly increases the frequency of Foxp3+ regulatory T cells.

    Science.gov (United States)

    Thueson, Lindsay E; Emmons, Tiffany R; Browning, Dianna L; Kreitinger, Joanna M; Shepherd, David M; Wetzel, Scott A

    2015-02-01

    The herbicide atrazine (2-chloro-4-[ethylamino]-6-[isopropylamino]-s-triazine) is the most common water contaminant in the United States. Atrazine is a phosphodiesterase inhibitor and is classified as an estrogen disrupting compound because it elevates estrogen levels via induction of the enzyme aromatase. Previous studies have shown that atrazine exposure alters the function of innate immune cells such as NK cells, DC, mast cells, and macrophages. In this study we have examined the impact of in vitro atrazine exposure on the activation, proliferation, and effector cytokine production by primary murine CD4(+) T lymphocytes. We found that atrazine exposure significantly inhibited CD4(+) T cell proliferation and accumulation as well as the expression of the activation markers CD25 and CD69 in a dose-dependent manner. Interestingly, the effects were more pronounced in cells from male animals. These effects were partially mimicked by pharmacological reagents that elevate intracellular cAMP levels and addition of exogenous rmIL-2 further inhibited proliferation and CD25 expression. Consistent with these findings, atrazine exposure during T cell activation resulted in a 2- to 5-fold increase in the frequency of Foxp3(+) CD4(+) T cells. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits.

    Science.gov (United States)

    Holm, P; Korsgaard, N; Shalmi, M; Andersen, H L; Hougaard, P; Skouby, S O; Stender, S

    1997-01-01

    The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis. PMID:9259581

  18. NF-κB inhibition significantly upregulates the norepinephrine transporter system, causes apoptosis in pheochromocytoma cell lines and prevents metastasis in an animal model

    Science.gov (United States)

    Pacak, Karel; Sirova, Marta; Giubellino, Alessio; Lencesova, Lubomira; Csaderova, Lucia; Hudecova, Sona; Krizanova, Olga

    2012-01-01

    Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are specific types of neuroendocrine tumors that originate in the adrenal medulla or sympathetic/parasympathetic paraganglia, respectively. Although these tumors are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in the present study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on the cell membrane norepinephrine transporter system (NET), considered to be the gatekeeper for the radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG). We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was carried out on three different stable pheochromocytoma cell lines. We found that blocking NF-κB with TTL or capsaicin (KPSC) increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, MIBG transport was increased in TTL-treated cells and in vivo treatment with TTL significantly reduced metastatic burden in a metastatic animal model of pheochromocytoma. The present study for the first time shows mechanistically how NF-κB inhibitors can be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis. PMID:22407736

  19. Potential triple helix-mediated inhibition of IGF-I gene expression significantly reduces tumorigenicity of glioblastoma in an animal model.

    Science.gov (United States)

    Shevelev, A; Burfeind, P; Schulze, E; Rininsland, F; Johnson, T R; Trojan, J; Chernicky, C L; Hélène, C; Ilan, J; Ilan, J

    1997-01-01

    Oligonucleotide-directed triple helix formation is a powerful approach to block transcription of specific genes. Although the oligonucleotide triplex approach is efficient for inhibiting gene expression in cultured cells, suppression is transient. We developed an approach which inhibits insulin-like growth factor-I (IGF-I) expression following stable transfection of C6 rat glioblastoma cells with a plasmid from which an RNA is transcribed that codes for the third strand of a potential triple helix. We tested the ability of this expression vector to inhibit IGF-I gene expression in vitro as well as tumorigenesis in an animal. A dramatic reduction of IGF-I RNA and protein levels in cultured cells occurred following transfection of rat C6 cells with a eukaryotic expression plasmid encoding the oligopurine variant of the triple helix but not the oligopyrimidine or a control sequence. The cells transfected with the oligopurine variant displayed morphological changes, upregulation of major histocompatibility complex I, and increased expression of protease nexin I. Dramatic inhibition of tumor growth occurred in nude mice following injection of transfected C6 cells. To our knowledge, this is the first example of tumor growth inhibition in an animal model employing a triple helix approach.

  20. Inhibition of basophil histamine release by gangliosides. Further studies on the significance of cell membrane sialic acid in the histamine release process

    DEFF Research Database (Denmark)

    Jensen, C; Norn, S; Thastrup, Ole

    1987-01-01

    with the glucolipid mixture increased the sialic acid content of the cells, and this increase was attributed to an insertion of gangliosides into the cell membrane. The inhibition of histamine release was abolished by increasing the calcium concentration, which substantiates our previous findings that cell membrane......Histamine release from human basophils was inhibited by preincubation of the cells with a glucolipid mixture containing sialic acid-containing gangliosides. This was true for histamine release induced by anti-IgE, Concanavalin A and the calcium ionophore A23187, whereas the release induced by S....... aureus Wood 46 was not affected. It was demonstrated that the inhibitory capacity of the glucolipid mixture could be attributed to the content of gangliosides, since no inhibition was obtained with cerebrosides or with gangliosides from which sialic acid was removed. Preincubation of the cells...

  1. Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial cystitis.

    Science.gov (United States)

    Tambaro, Simone; Casu, Maria Antonietta; Mastinu, Andrea; Lazzari, Paolo

    2014-04-15

    Interstitial cystitis is a debilitating bladder inflammation disorder. To date, the understanding of the causes of interstitial cystitis remains largely fragmentary and there is no effective treatment available. Recent experimental results have shown a functional role of the endocannabinoid system in urinary bladder. In this study, we evaluated the anti-inflammatory effect of selective cannabinoid CB1 and CB2 receptor agonists in a mouse model of interstitial cystitis. Bladder inflammation was induced in mice by lipopolysaccharide (LPS) and whole bladders were removed 24h later. LPS induced a significant increase of the contractile amplitude in spontaneous activity and a hypersensitivity to exogenous acetylcholine-induced contraction of whole-isolated bladder. Next, we evaluated the anti-inflammatory activity of cannabinoidergic compounds by pretreating mice with CB1 or CB2 selective agonist compounds, respectively ACEA and JWH015. Interestingly, JWH015, but not ACEA, antagonized LPS-induced bladder inflammation. Additionally, anti-inflammatory activity was studied by evaluation, leukocytes mucosa infiltration, myeloperoxidase activity, and mRNA expression of pro-inflammatory interleukin (IL-1α and IL-1β), tumor necrosis factor-alpha (TNF-α) and cannabinoid CB1 and CB2 receptors. JWH015 significantly decreased leukocytes infiltration in both submucosa and mucosa, as well as the myeloperoxydase activity, in LPS treated mice. JWH015 reduced mRNA expression of IL-1α, IL-1β, and TNF-α. LPS treatment increased expression of bladder CB2 but not CB1 mRNA. Taken together, these findings strongly suggest that modulation of the cannabinoid CB2 receptors might be a promising therapeutic strategy for the treatment of bladder diseases and conditions characterized by inflammation, such as interstitial cystitis.

  2. Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-dependent and -independent Mechanisms

    Science.gov (United States)

    Singh, Jagdeep K.; Farnie, Gillian; Bundred, Nigel J.; Simões, Bruno M; Shergill, Amrita; Landberg, Göran; Howell, Sacha; Clarke, Robert B.

    2012-01-01

    Purpose Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are predicted to be responsible for tumour initiation, maintenance and metastases. Interleukin-8 (IL-8) is upregulated in breast cancer and associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy. Experimental design CSC activity of metastatic and invasive human breast cancers (n=19) was assessed ex vivo using the mammosphere colony forming assay. Results Metastatic fluid IL-8 level correlated directly with mammosphere formation (r=0.652; P<0.05; n=10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n=17). IL-8 induced activation of EGFR/HER2 and downstream signalling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, PI3K or MEK. Furthermore, lapatinib inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers. Conclusions These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and demonstrate that IL-8/CXCR1/2 signalling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. PMID:23149820

  3. Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure.

    Science.gov (United States)

    Elsby, Robert; Martin, Paul; Surry, Dominic; Sharma, Pradeep; Fenner, Katherine

    2016-03-01

    The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and Cmax, respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC50) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17β-glucuronide. Calculated parameters of maximum enterocyte concentration [Igut max], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant

  4. Double labelling of tissue combining tritiated thymidine autoradiography with immunodetection of bromodeoxyuridine: the autoradiographic significance of inhibition of thymidine incorporation into DNA by bromodeoxyuridine given simultaneously

    Energy Technology Data Exchange (ETDEWEB)

    Hume, W.J.; Thompson, J. (Leeds Univ. (UK). School of Dentistry)

    1989-09-01

    The authors describe a method for combining tritiated thymidine (({sup 3}H)TdR) autoradiography with immunoperoxidase detection of bromodeoxyuridine (BrdU) in paraffin-embedded tissues, which was used to examine, in mouse tongue epithelium, the inhibition of incorporation into DNA of ({sup 3}H)TdR by simultaneous injection of BrdU in the doses that both compounds are likely to be used in cell proliferation studies. The inhibition of uptake into DNA of ({sup 3}H)TdR from 0.23 to 1.85 MBq (6.25 to 50 {mu}Ci) per animal, produced by a simultaneous injection of 2.5 mg BrdU shows a linear, dose-dependent relationship. Provided the injected dose (in {mu}Ci per animal) multiplied by the autoradiographic exposure time (in days) is greater than a value of 700, then all cells that are labelled after incorporation of ({sup 3}H)TdR alone are also labelled after simultaneous double labelling, despite the latter producing a lower average grain count. (author).

  5. miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations

    DEFF Research Database (Denmark)

    Gravgaard, Karina Hedelund; Terp, Mikkel G; Lund, Rikke R

    2015-01-01

    To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered express...

  6. Sequence-specific cleavage of BM2 gene transcript of influenza B virus by 10-23 catalytic motif containing DNA enzymes significantly inhibits viral RNA translation and replication.

    Science.gov (United States)

    Kumar, Binod; Kumar, Prashant; Rajput, Roopali; Saxena, Latika; Daga, Mradul K; Khanna, Madhu

    2013-10-01

    One of the hallmarks of progression of influenza virus replication is the step involving the virus uncoating that occurs in the host cytoplasm. The BM2 ion channel protein of influenza B virus is highly conserved and is essentially required during the uncoating processes of virus, thus an attractive target for designing antiviral drugs. We screened several DNA enzymes (Dzs) containing the 10-23 catalytic motif against the influenza B virus BM2 RNA. Dzs directed against the predicted single-stranded bulge regions showed sequence-specific cleavage activities. The Dz209 not only showed significant intracellular reduction of BM2 gene expression in transient-expression system but also provided considerable protection against influenza B virus challenge in MDCK cells. Our findings suggest that the Dz molecule can be used as selective and effective inhibitor of viral RNA replication, and can be explored further for development of a potent therapeutic agent against influenza B virus infection.

  7. Factors significantly increasing or inhibiting early stages of malignant melanoma (M.M.) and non-invasive evaluation of new treatment by ingestion and external application of optimal doses of the most effective anti-M.M. substances: haritaki, cilantro, vitamin D3, nori, EPA with DHA, & application of special (+) solar energy stored paper, which reduced the M.M. active area & asbestos rapidly.

    Science.gov (United States)

    Omura, Yoshiaki; Jones, Marilyn; Duvvi, Harsha; Paluch, Kamila; Shimotsuura, Yasuhiro; Ohki, Motomu

    2013-01-01

    Sterilizing the pre-cancer skin of malignant melanoma (M.M.) with 70% Isopropyl alcohol intensified malignancy & the malignant response extended to surrounding normal looking skin, while sterilizing with 80% (vodka) or 12% (plum wine) ethyl alcohol completely inhibited M.M. in the area (both effects lasted for about 90 minutes initially). Burnt food (bread, vegetables, meat, and fish), a variety of smoked & non-smoked fish-skin, many animal's skin, pepper, Vitamin C over 75 mg, mango, pineapple, coconut, almond, sugars, Saccharine & Aspartame, garlic, onion, etc & Electromagnetic field from cellular phones worsened M.M. & induced abnormal M.M. response of surrounding skin. We found the following factors inhibit early stage of M.M. significantly: 1) Increasing normal cell telomere, by taking 500 mg Haritaki, often reached between 400-1150 ng& gradually diminished, but the M.M. response was completely inhibited until normal cell telomeres are reduced to 150 ng, which takes 6-8 hours. More than 70 mg Vitamin C, Orange Juice, & other high Vitamin C containing substances shouldn't be taken because they completely inhibit the effects of Haritaki. 2) We found Chrysotile asbestos & Tremolite asbestos (% of the Chrysotile amount) coexist. A special Cilantro tablet was used to remove asbestos & some toxic metals. 3) Vitamin D3 400 I.U. has a maximum inhibiting effect on M.M. but 800 I.U. or higher promotes malignancy. 4) Noricontaining Iodine, etc., was used. 5) EPA 180 mm with DHA 120 mg was most effectively used after metastasis to the surrounding skin was eliminated. When we combined 1 Cilantro tablet & Vitamin D3 400 I.U. withsmall Nori pieces & EPA with DHA, the effect of complete inhibition of M.M. lasted 9-11 hours. When these anti-M.M.substances (Haritaki, Vitamin D3, Cilantro, Nori, EPA. with DHA) were taken together, the effect lasted 12-14 hoursand M.M. involvement in surrounding normal-looking skin disappeared rapidly & original dark brown or black are as

  8. 大麻素受体在肝星状细胞活化中的作用及姜黄素干预效应%Research on the role of cannabinoid receptors in hepaticstellate cell activation and interfering effects of curcumin

    Institute of Scientific and Technical Information of China (English)

    张自力; 张涉; 郭瑶; 王妤清; 倪雯霞; 张衍; 孔德松; 郑仕中

    2013-01-01

    Aim To explore the role of cannabinoid receptors in the activation of hepatic stellate cells ( HSCs ) and the interfering effects of curcumin in the hope of providing basis for elucidating the mechanism of liver fibrosis and curcumin inhibition of liver fibro-sis. Methods Influence of CBR1 agonist NADA and antagonist AM630, CBR2 agonist JWH015 and antagonist AM251 on the proliferation of HSCs was evaluated by MTT assay. Western blot assays were used to detect the expression of ERK, JNK and p38 and their phos-phorylation levels in HSCs treated with AM251. The effect of curcumin on the expression of two types of cannabinoid receptors CBR1 and CBR2 in HSCs was determined by Western blot and immunofluorescence. The effect of curcumin on extracellular matrix ( ECM ) components α1 ( Ⅰ ) collagen and fibronectin in HSCs stimulating by CBR1 agonist and antagonist was also examined by Western blot. Results Activating CBR1 promoted the proliferation of HSCs; on the contrary, CBR1 antagonism inhibited HSCs proliferation ( P 0. 05 ). CBR1 antagonist AM251 significantly inhibited the phosphorylation of ERK and JNK in a dose-dependent manner ( P 0. 05 ). Curcumin inhibited the expression of CBR1 ( P 0. 05 ). Curcumin inhibited the expression of ECM components upregulated by CBR1 agonist dose-depend-ently in HSCs, and collaboratively inhibited the expression of ECM components in HSCs exposed to CBR1 antagonist ( P 0.05).CBR1拮抗剂AM251能够明显抑制ERK与JNK的磷酸化,并呈剂量依赖性的关系(P0.05).姜黄素可抑制HSCs中CBR1的表达(P0.05).姜黄素可呈剂量依赖性的抑制CBR1激动剂导致的ECM成分表达的上升,并可协同 CBR1拮抗剂抑制HSCs表达ECM成分的作用(P<0.05,P<0.01).结论 大麻素受体在HSCs的增殖活化过程中具有重要作用,姜黄素可能通过干预大麻素受体信号通路这一途径达到治疗肝纤维化的目的.

  9. Stimulation of cannabinoid receptor 2 (CB2 suppresses microglial activation

    Directory of Open Access Journals (Sweden)

    Fernandez Francisco

    2005-12-01

    Full Text Available Abstract Background Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD, multiple sclerosis (MS, and HIV dementia. It is well known that inflammatory mediators such as nitric oxide (NO, cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Our previous studies have shown that CD40 signaling is involved in pathological activation of microglial cells. Many data reveal that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of cannabinoid receptor 2 (CB2. Methods In this study, we investigated the effects of a cannabinoid agonist on CD40 expression and function by cultured microglial cells activated by IFN-γ using RT-PCR, Western immunoblotting, flow cytometry, and anti-CB2 small interfering RNA (siRNA analyses. Furthermore, we examined if the stimulation of CB2 could modulate the capacity of microglial cells to phagocytise Aβ1–42 peptide using a phagocytosis assay. Results We found that the selective stimulation of cannabinoid receptor CB2 by JWH-015 suppressed IFN-γ-induced CD40 expression. In addition, this CB2 agonist markedly inhibited IFN-γ-induced phosphorylation of JAK/STAT1. Further, this stimulation was also able to suppress microglial TNF-α and nitric oxide production induced either by IFN-γ or Aβ peptide challenge in the presence of CD40 ligation. Finally, we showed that CB2 activation by JWH-015 markedly attenuated CD40-mediated inhibition of microglial phagocytosis of Aβ1–42 peptide. Taken together, these results provide mechanistic insight into beneficial effects provided by cannabinoid receptor CB2 modulation in neurodegenerative diseases, particularly AD.

  10. 酶抑制法测定m-AS T试剂性能评价及其在肝病中的意义%Evaluation on the reagent performance for the determination of m-AST by enzyme inhibition method and ;the clinical significance of m-AST in patients with liver disease

    Institute of Scientific and Technical Information of China (English)

    李君; 谢劲松; 臧桂珍

    2013-01-01

    目的:评价酶抑制法测定天门冬氨酸氨基转移酶(AST)线粒体同工酶(m-AST)活性的性能,并探讨m-AST在肝脏疾病中的临床价值。方法采用酶抑制法检测m-AST活性[即采用蛋白酶完全抑制AST细胞质同工酶(c-AST)的活性,然后用速率法进行检测],并与免疫抑制法比较。采用酶抑制法检测259例肝病患者(包括急性肝炎43例、慢性病毒性肝炎95例、肝衰竭20例、重型肝炎11例、肝硬化代偿期40例、肝硬化失代偿期9例、原发性肝癌41例)及220名健康体检者(正常对照组)m-AST活性,并与AST比较。结果酶抑制法批内变异系数(CV)为0.59%~2.23%,批间 CV为5.24%~6.23%;回收率为101.6%~108.0%,平均为104.97%;线性方程Y=0.997X-1.51,r=0.9999,m-AST活性在450 U/L内线性良好;可完全抑制1500 U/L的c-AST活性;与免疫抑制法结果呈高度正相关(r=0.9998);溶血对m-AST检测结果干扰较大;以95%可信区间(x-±1.96s)初步确定m-AST参考区间男性为3.1~9.5 U/L,女性为2.5~8.7 U/L。肝病患者m-AST活性均高于正常对照组(P<0.05),并与AST呈正相关。正常对照组m-AST/AST比值为0.30±0.07,肝病患者m-AST/AST比值均低于正常对照组(P<0.05),但变化不如m-AST活性明显。结论酶抑制法测定m-AST活性自动化程度高,结果准确可靠,重复性好,线性范围宽。m-AST活性能反映肝细胞损伤的严重程度,对肝脏疾病的临床分类和预后具有重要价值。%Objective To evaluate the performance of mitochondrial aspartate aminotransferase (m-AST)by enzyme inhibition method,and to investigate the clinical significance of m-AST in patients with liver disease.Methods The m-AST activity was determined by enzyme inhibition method,and the activity of cytosolic aspartate aminotransferase (c-AST)was inhibited by protease

  11. Significant NRC Enforcement Actions

    Data.gov (United States)

    Nuclear Regulatory Commission — This dataset provides a list of Nuclear Regulartory Commission (NRC) issued significant enforcement actions. These actions, referred to as "escalated", are issued by...

  12. Choosing Outcomes of Significance.

    Science.gov (United States)

    Spady, William G.

    1994-01-01

    Outcomes are high-quality, culminating demonstrations of significant learning in context. The High Success Network uses the "Demonstration Mountain" to differentiate among three major "learning zones" and six different forms of learning demonstrations that increase in complexity, generalizability, and significance, along with…

  13. Significance Testing Without Truth

    Science.gov (United States)

    2012-07-27

    ICES REPORT 12-34 August 2012 Significance testing without truth by William Perkins, Mark Tygert, and Rachel Ward The Institute for Computational...testing without truth , ICES REPORT 12-34, The Institute for Computational Engineering and Sciences, The University of Texas at Austin, August 2012...2. REPORT TYPE 3. DATES COVERED 00-00-2012 to 00-00-2012 4. TITLE AND SUBTITLE Significance testing without truth 5a. CONTRACT NUMBER 5b

  14. A Significant Play

    Institute of Scientific and Technical Information of China (English)

    梁海光; 陈明

    2002-01-01

    Yesterday evening, I went to see a play. It was really significant. It was about Zheng Xiaoyue, a very clever and diligent middle school student. Unfortunately, her mother died when she and her brother were very young. Her father was out of work and,

  15. Significant Tsunami Events

    Science.gov (United States)

    Dunbar, P. K.; Furtney, M.; McLean, S. J.; Sweeney, A. D.

    2014-12-01

    Tsunamis have inflicted death and destruction on the coastlines of the world throughout history. The occurrence of tsunamis and the resulting effects have been collected and studied as far back as the second millennium B.C. The knowledge gained from cataloging and examining these events has led to significant changes in our understanding of tsunamis, tsunami sources, and methods to mitigate the effects of tsunamis. The most significant, not surprisingly, are often the most devastating, such as the 2011 Tohoku, Japan earthquake and tsunami. The goal of this poster is to give a brief overview of the occurrence of tsunamis and then focus specifically on several significant tsunamis. There are various criteria to determine the most significant tsunamis: the number of deaths, amount of damage, maximum runup height, had a major impact on tsunami science or policy, etc. As a result, descriptions will include some of the most costly (2011 Tohoku, Japan), the most deadly (2004 Sumatra, 1883 Krakatau), and the highest runup ever observed (1958 Lituya Bay, Alaska). The discovery of the Cascadia subduction zone as the source of the 1700 Japanese "Orphan" tsunami and a future tsunami threat to the U.S. northwest coast, contributed to the decision to form the U.S. National Tsunami Hazard Mitigation Program. The great Lisbon earthquake of 1755 marked the beginning of the modern era of seismology. Knowledge gained from the 1964 Alaska earthquake and tsunami helped confirm the theory of plate tectonics. The 1946 Alaska, 1952 Kuril Islands, 1960 Chile, 1964 Alaska, and the 2004 Banda Aceh, tsunamis all resulted in warning centers or systems being established.The data descriptions on this poster were extracted from NOAA's National Geophysical Data Center (NGDC) global historical tsunami database. Additional information about these tsunamis, as well as water level data can be found by accessing the NGDC website www.ngdc.noaa.gov/hazard/

  16. A Significant Step Forward

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Australia officially ratified the Kyoto Protocol on December 3,the first act of its new government under Prime Minister Kevin Rudd.Rudd signed the instrument of ratification the very day he was sworn in by Australia’s Governor General Michael Jeffery. This is a significant step in Australia’s efforts to fight climate change domestically and with the international community,Rudd said in a statement.The Australian Government will do everything in its power to help Australia meet its Kyoto obligations,he added.

  17. Predicting significant torso trauma.

    Science.gov (United States)

    Nirula, Ram; Talmor, Daniel; Brasel, Karen

    2005-07-01

    Identification of motor vehicle crash (MVC) characteristics associated with thoracoabdominal injury would advance the development of automatic crash notification systems (ACNS) by improving triage and response times. Our objective was to determine the relationships between MVC characteristics and thoracoabdominal trauma to develop a torso injury probability model. Drivers involved in crashes from 1993 to 2001 within the National Automotive Sampling System were reviewed. Relationships between torso injury and MVC characteristics were assessed using multivariate logistic regression. Receiver operating characteristic curves were used to compare the model to current ACNS models. There were a total of 56,466 drivers. Age, ejection, braking, avoidance, velocity, restraints, passenger-side impact, rollover, and vehicle weight and type were associated with injury (p < 0.05). The area under the receiver operating characteristic curve (83.9) was significantly greater than current ACNS models. We have developed a thoracoabdominal injury probability model that may improve patient triage when used with ACNS.

  18. Anthropological significance of phenylketonuria.

    Science.gov (United States)

    Saugstad, L F

    1975-01-01

    The highest incidence rates of phenylketonuria (PKU) have been observed in Ireland and Scotlant. Parents heterozygous for PKU in Norway differ significantly from the general population in the Rhesus, Kell and PGM systems. The parents investigated showed an excess of Rh negative, Kell plus and PGM type 1 individuals, which makes them similar to the present populations in Ireland and Scotlant. It is postulated that the heterozygotes for PKU in Norway are descended from a completely assimilated sub-population of Celtic origin, who came or were brought here, 1ooo years ago. Bronze objects of Western European (Scottish, Irish) origin, found in Viking graves widely distributed in Norway, have been taken as evidence of Vikings returning with loot (including a number of Celts) from Western Viking settlements. The continuity of residence since the Viking age in most habitable parts of Norway, and what seems to be a nearly complete regional relationship between the sites where Viking graves contain western imported objects and the birthplaces of grandparents of PKUs identified in Norway, lend further support to the hypothesis that the heterozygotes for PKU in Norway are descended from a completely assimilated subpopulation. The remarkable resemblance between Iceland and Ireland, in respect of several genetic markers (including the Rhesus, PGM and Kell systems), is considered to be an expression of a similar proportion of people of Celtic origin in each of the two countries. Their identical, high incidence rates of PKU are regarded as further evidence of this. The significant decline in the incidence of PKU when one passes from Ireland, Scotland and Iceland, to Denmark and on to Norway and Sweden, is therefore explained as being related to a reduction in the proportion of inhabitants of Celtic extraction in the respective populations.

  19. Meaning and significance of

    Directory of Open Access Journals (Sweden)

    Ph D Student Roman Mihaela

    2011-05-01

    Full Text Available The concept of "public accountability" is a challenge for political science as a new concept in this area in full debate and developement ,both in theory and practice. This paper is a theoretical approach of displaying some definitions, relevant meanings and significance odf the concept in political science. The importance of this concept is that although originally it was used as a tool to improve effectiveness and eficiency of public governance, it has gradually become a purpose it itself. "Accountability" has become an image of good governance first in the United States of America then in the European Union.Nevertheless,the concept is vaguely defined and provides ambiguous images of good governance.This paper begins with the presentation of some general meanings of the concept as they emerge from specialized dictionaries and ancyclopaedies and continues with the meanings developed in political science. The concept of "public accontability" is rooted in economics and management literature,becoming increasingly relevant in today's political science both in theory and discourse as well as in practice in formulating and evaluating public policies. A first conclusin that emerges from, the analysis of the evolution of this term is that it requires a conceptual clarification in political science. A clear definition will then enable an appropriate model of proving the system of public accountability in formulating and assessing public policies, in order to implement a system of assessment and monitoring thereof.

  20. Latent inhibition in schizophrenia.

    Science.gov (United States)

    Swerdlow, N R; Braff, D L; Hartston, H; Perry, W; Geyer, M A

    1996-05-01

    Latent inhibition (LI) refers to the retarded acquisition of a conditioned response that occurs if the subject being tested is first preexposed to the to-be-conditioned stimulus (CS) without the paired unconditioned stimulus (UCS). Because the 'irrelevance' of the to-be-conditioned stimulus is established during non-contingent preexposure, the slowed acquisition of the CS-UCS association is thought to reflect the process of overcoming this learned irrelevance. Latent inhibition has been reported to be diminished in acutely hospitalized schizophrenia patients. If acutely hospitalized schizophrenia patients are preexposed to the CS, they learn the association as fast as, and perhaps faster than, patients who are not preexposed to the CS. This finding has been interpreted as reflecting the inability of acute schizophrenia patients to ignore irrelevant stimuli. In this study, the LI paradigm was identical to the one used in previous reports of LI deficits in schizophrenia patients (Baruch et al., 1988). Latent inhibition was observed in normal control subjects (n = 73), including individuals identified as 'psychosis-prone' based on established screening criteria, and in anxiety (n = 19) and mood disorder (n = 13) patients. Learning scores (trials to criterion) in "acutely' hospitalized as well as "chronic' hospitalized schizophrenia patients (n = 45) were significantly elevated in both preexposed and non-preexposed subjects, compared to controls. Acute schizophrenia patients exhibited intact LI. Separate cohorts of acute and chronic schizophrenia patients (n = 23) and normal controls (n = 34) exhibited intact LI when tested in a new, easier-to-acquire computerized LI paradigm. These results fail to identify specific LI deficits in schizophrenia patients, and raise the possibility that previously observed LI deficits in schizophrenia patients may reflect, at least in part, performance deficits related to learning acquisition.

  1. Lateral inhibition during nociceptive processing.

    Science.gov (United States)

    Quevedo, Alexandre S; Mørch, Carsten Dahl; Andersen, Ole K; Coghill, Robert C

    2017-06-01

    Spatial summation of pain (SSP) is the increase of perceived intensity that occurs as the stimulated area increases. Spatial summation of pain is subadditive in that increasing the stimulus area produces a disproportionately small increase in the perceived intensity of pain. A possible explanation for subadditive summation may be that convergent excitatory information is modulated by lateral inhibition. To test the hypothesis that lateral inhibition may limit SSP, we delivered different patterns of noxious thermal stimuli to the abdomens of 15 subjects using a computer-controlled CO2 laser. Lines (5 mm wide) of variable lengths (4, 8 cm) were compared with 2-point stimuli delivered at the same position/separation as the length of lines. When compared with one-point control stimuli, 2-point stimulus patterns produced statistically significant SSP, while no such summation was detected during line stimulus patterns. Direct comparison of pain intensity evoked by 2-point pattern stimuli with line pattern stimuli revealed that 2-point patterns were perceived as significantly more painful, despite the fact that the 2-point pattern stimulated far smaller areas of skin. Thus, the stimulation of the skin region between the endpoints of the lines appears to produce inhibition. These findings indicate that lateral inhibition limits SSP and is an intrinsic component of nociceptive information processing. Disruption of such lateral inhibition may contribute substantially to the radiation of some types of chronic pain.

  2. Inhibited and Uninhibited Types of Children.

    Science.gov (United States)

    Kagan, Jerome; And Others

    1989-01-01

    Investigates the preservation of inhibited and uninhibited behaviors in 100 children of 14, 20, 32, and 48 months. Children who had been extremely inhibited or uninhibited at 14 and 20 months differed significantly at 4 years of age in behavior and cardiac acceleration. (RJC)

  3. Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability.

    Directory of Open Access Journals (Sweden)

    Bo Ram Seo

    Full Text Available The PI3K/Akt and mTOR signaling pathways are important for cell survival and growth, and they are highly activated in cancer cells compared with normal cells. Therefore, these signaling pathways are targets for inducing cancer cell death. The dual PI3K/Akt and mTOR inhibitor NVP-BEZ235 completely inhibited both signaling pathways. However, NVP-BEZ235 had no effect on cell death in human renal carcinoma Caki cells. We tested whether combined treatment with natural compounds and NVP-BEZ235 could induce cell death. Among several chemopreventive agents, curcumin, a natural biologically active compound that is extracted from the rhizomes of Curcuma species, markedly induced apoptosis in NVP-BEZ235-treated cells. Co-treatment with curcumin and NVP-BEZ235 led to the down-regulation of Mcl-1 protein expression but not mRNA expression. Ectopic expression of Mcl-1 completely inhibited curcumin plus NVP-NEZ235-induced apoptosis. Furthermore, the down-regulation of Bcl-2 was involved in curcumin plus NVP-BEZ235-induced apoptosis. Curcumin or NVP-BEZ235 alone did not change Bcl-2 mRNA or protein expression, but co-treatment reduced Bcl-2 mRNA and protein expression. Combined treatment with NVP-BEZ235 and curcumin reduced Bcl-2 expression in wild-type p53 HCT116 human colon carcinoma cells but not p53-null HCT116 cells. Moreover, Bcl-2 expression was completely reversed by treatment with pifithrin-α, a p53-specific inhibitor. Ectopic expression of Bcl-2 also inhibited apoptosis in NVP-BE235 plus curcumin-treated cells. In contrast, NVP-BEZ235 combined with curcumin did not have a synergistic effect on normal human skin fibroblasts and normal human mesangial cells. Taken together, combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level.

  4. Monoclonal gammopathy of undetermined significance

    National Research Council Canada - National Science Library

    Kyle, Robert A; Vincent Rajkumar, S

    2006-01-01

    Summary Significant advances have been made in our understanding of the natural history, pathogenesis, mechanisms of progression and prognosis of monoclonal gammopathy of undetermined significance (MGUS...

  5. Reciprocal inhibition in man.

    Science.gov (United States)

    Crone, C

    1993-11-01

    Reciprocal inhibition is the automatic antagonist alpha motor neurone inhibition which is evoked by contraction of the agonist muscle. This so-called natural reciprocal inhibition is a ubiquitous and pronounced phenomenon in man and must be suspected of playing a major role in the control of voluntary movements. The spinal pathways underlying this inhibitory phenomenon were studied. The disynaptic reciprocal Ia inhibitory pathway between the tibial anterior muscle and the soleus alpha motor neurones was identified and described in man. It was shown that the inhibition can be evoked in most healthy subjects at rest, but the degree of inhibition varies considerably from one subject to another. It was concluded that it corresponds to the disynaptic reciprocal Ia inhibitory pathway which has been extensively described in animal experiments. The disynaptic reciprocal inhibition was shown to increase during the dynamic phase of a dorsiflexion movement of the foot, but not during the tonic phase. However, when the peripheral afferent feedback from the contracting muscle was blocked by ischaemia, an increase of the inhibition was revealed also during the tonic phase of the dorsiflexion. The concealment of this increase during unrestrained peripheral feedback from the muscle was thought to be due to the post-activation depression mechanism; a mechanism which was described further and which probably involves reduced transmitter release at Ia afferent terminals as a result of previous activation of these afferent fibers. Hence the hypothesis was supported that alpha motor neurones and the corresponding inhibitory interneurones, which project reciprocal inhibition to the antagonist motor neurones, are activated in parallel during voluntary contraction of agonist muscles. An additional reciprocal inhibitory mechanism, the long latency reciprocal inhibition, was described between the tibial anterior muscle and the soleus alpha motor neurones. It was shown to be evoked by group I

  6. Quassinoids and Their Chemotaxonomic Significance

    Directory of Open Access Journals (Sweden)

    Anakshi Khare

    2013-06-01

    Full Text Available The quassinoids are a group of complex, highly oxygenated, degraded triterpene mostly found in Simaroubaceae family. Two quassinoids (degraded triterpenes, 1 and 2 were isolated first time from the stem bark of Ailanthus excelsa. Compound 1 is C19 quassinoid. C19 quassinoid derived biogenetically from a C20 quassinoid, via a 1,2 –dioxo derivative. The structural elucidation is based on the analysis of spectroscopic data. Interest in these quassinoids has increased enormously in recent years due in part to the finding of the American National Cancer Institute that these compounds display marked antileukamic activity. The ways in which plants interact with other organisms in an environment are complex. Ailanthus also produces toxins in its root, bark and leaves. These toxins inhibit the growth of other plants. The isolated quassinoids are currently being studied as a possible source of a natural herbicide. Extracts of this plant have anti-insect activity and anti-tuberculosis activity.

  7. Significance Tests for Periodogram Peaks

    CERN Document Server

    Frescura, F A M; Frank, B S

    2007-01-01

    We discuss methods currently in use for determining the significance of peaks in the periodograms of time series. We discuss some general methods for constructing significance tests, false alarm probability functions, and the role played in these by independent random variables and by empirical and theoretical cumulative distribution functions. We also discuss the concept of "independent frequencies" in periodogram analysis. We propose a practical method for estimating the significance of periodogram peaks, applicable to all time series irrespective of the spacing of the data. This method, based on Monte Carlo simulations, produces significance tests that are tailor-made for any given astronomical time series.

  8. Significant Scales in Community Structure

    CERN Document Server

    Traag, V A; Van Dooren, P

    2013-01-01

    Many complex networks show signs of modular structure, uncovered by community detection. Although many methods succeed in revealing various partitions, it remains difficult to detect at what scale some partition is significant. This problem shows foremost in multi-resolution methods. We here introduce an efficient method for scanning for resolutions in one such method. Additionally, we introduce the notion of "significance" of a partition, based on subgraph probabilities. Significance is independent of the exact method used, so could also be applied in other methods, and can be interpreted as the gain in encoding a graph by making use of a partition. Using significance, we can determine "good" resolution parameters, which we demonstrate on benchmark networks. Moreover, optimizing significance itself also shows excellent performance. We demonstrate our method on voting data from the European Parliament. Our analysis suggests the European Parliament has become increasingly ideologically divided and that nationa...

  9. Astronomical Significance of Ancient Monuments

    Science.gov (United States)

    Simonia, I.

    2011-06-01

    Astronomical significance of Gokhnari megalithic monument (eastern Georgia) is considered. Possible connection of Amirani ancient legend with Gokhnari monument is discussed. Concepts of starry practicality and solar stations are proposed.

  10. Historical Significant Volcanic Eruption Locations

    Data.gov (United States)

    Department of Homeland Security — A significant eruption is classified as one that meets at least one of the following criteriacaused fatalities, caused moderate damage (approximately $1 million or...

  11. Significance analysis of prognostic signatures.

    Directory of Open Access Journals (Sweden)

    Andrew H Beck

    Full Text Available A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that "random" gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically

  12. Potentiation of latent inhibition.

    Science.gov (United States)

    Rodriguez, Gabriel; Hall, Geoffrey

    2008-07-01

    Rats were given exposure either to an odor (almond) or a compound of odor plus taste (almond plus saline), prior to training in which the odor served as the conditioned stimulus. It was found, for both appetitive and aversive procedures, that conditioning was retarded by preexposure (a latent inhibition effect), and the extent of the retardation was greater in rats preexposed to the compound (i.e., latent inhibition to the odor was potentiated by the presence of the taste). In contrast, the presence of the taste during conditioning itself overshadowed learning about the odor. We argue that the presence of the salient taste in compound with the odor enhances the rate of associative learning, producing a rapid loss in the associability of the odor. This loss of associability will generate both overshadowing and the potentiation of latent inhibition that is observed after preexposure to the compound.

  13. Significant advancement in algebraic geometry

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Supported by a grant for Distinguished Young Scholars of the National Natural Science Foundation of China,Prof.SUN Xiaotao with the CAS Academy of Mathematics and Systems Science has recently achieved a research breakthrough in revealing the deep relationship between stability of vector bundles and Frobenius morphism.It is considered as significant work with important theoretical value.

  14. 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...

  15. 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...

  16. 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.

  17. Significance and Progress of Bionics

    Institute of Scientific and Technical Information of China (English)

    Yongxiang Lu

    2004-01-01

    The four topics are described including the driving force and source of the scientific and technological creation, the definition and history of the bionics, the important significance of bionics in the development of the human beings, and the leading edge and progress of bionics. The appetency of human for the creation is the essential motivity of the innovation in science and technology. Nature and society are the objects for us to cognize and serve, meanwhile, the best teachers for us to learn from them. It is only 5 million years for human's development, but evolution of life has over 3.5 billion years history. Although, copying the creation from the human being is important, however, it has much more potential and opportunity in imitating the nature, and more possibility to promote the ability of original innovation. The significance and progress of bionics are summarized, in this paper, and the leading edges of bionics, in the near future, are forecasted.

  18. Significance evaluation in factor graphs

    DEFF Research Database (Denmark)

    Madsen, Tobias; Hobolth, Asger; Jensen, Jens Ledet

    2017-01-01

    Background Factor graphs provide a flexible and general framework for specifying probability distributions. They can capture a range of popular and recent models for analysis of both genomics data as well as data from other scientific fields. Owing to the ever larger data sets encountered...... in genomics and the multiple-testing issues accompanying them, accurate significance evaluation is of great importance. We here address the problem of evaluating statistical significance of observations from factor graph models. Results Two novel numerical approximations for evaluation of statistical....... Conclusions The applicability of saddlepoint approximation and importance sampling is demonstrated on known models in the factor graph framework. Using the two methods we can substantially improve computational cost without compromising accuracy. This contribution allows analyses of large datasets...

  19. Which Reconstruction Results are Significant?

    Science.gov (United States)

    1980-05-01

    other significant result is due to Tutte [17]. Tutte’s Theorem: The characteristic polynomial of a graph can be reconstructed. Equivalently, two...hypomorphic graphs must have the same characteristic polynomial . Several points should be noted concerning this theorem: 1. The derivative of the...characteristic polynomial is the sum of the char- acteristic polynomials of the vertex-deleted subgraphs. Thus the characteristic polynomials of hypomorphic

  20. Robust Simulations and Significant Separations

    CERN Document Server

    Fortnow, Lance

    2010-01-01

    We define and study a new notion of "robust simulations" between complexity classes which is intermediate between the traditional notions of infinitely-often and almost-everywhere, as well as a corresponding notion of "significant separations". A language L has a robust simulation in a complexity class C if there is a language in C which agrees with L on arbitrarily large polynomial stretches of input lengths. There is a significant separation of L from C if there is no robust simulation of L in C. The new notion of simulation is a cleaner and more natural notion of simulation than the infinitely-often notion. We show that various implications in complexity theory such as the collapse of PH if NP = P and the Karp-Lipton theorem have analogues for robust simulations. We then use these results to prove that most known separations in complexity theory, such as hierarchy theorems, fixed polynomial circuit lower bounds, time-space tradeoffs, and the theorems of Allender and Williams, can be strengthened to signifi...

  1. Significance of biofilms in dentistry.

    Science.gov (United States)

    Wróblewska, Marta; Strużycka, Izabela; Mierzwińska-Nastalska, Elżbieta

    2015-01-01

    In the past decades significant scientific progress has taken place in the knowledge about biofilms. They constitute multilayer conglomerates of bacteria and fungi, surrounded by carbohydrates which they produce, as well as substances derived from saliva and gingival fluid. Modern techniques showed significant diversity of the biofilm environment and a system of microbial communication (quorum sensing), enhancing their survival. At present it is believed that the majority of infections, particularly chronic with exacerbations, are a result of biofilm formation, particularly in the presence of biomaterials. It should be emphasised that penetration of antibiotics and other antimicrobial agents into deeper layers of a biofilm is poor, causing therapeutic problems and necessitating sometimes removal of the implant or prosthesis. Biofilms play an increasing role in dentistry as a result of more and more broad use in dental practice of plastic and implantable materials. Biofilms are produced on the surfaces of teeth as dental plaque, in the para-nasal sinuses, on prostheses, dental implants, as well as in waterlines of a dental unit, constituting a particular risk for severely immunocompromised patients. New methods of therapy and prevention of infections linked to biofilms are under development.

  2. Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition.

    Science.gov (United States)

    Mukherjee, Pinku; Basu, Gargi D; Tinder, Teresa L; Subramani, Durai B; Bradley, Judy M; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

    2009-01-01

    With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRAS(G12D) mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E(2) and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

  3. Genetic or chemical protease inhibition causes significant changes in the Bacillus subtilis exoproteome

    NARCIS (Netherlands)

    Westers, Lidia; Westers, Helga; Zanen, Geeske; Antelmann, Haike; Hecker, Michael; Noone, David; Devine, Kevin M.; van Dijl, Jan Maarten; Quax, Wim J.

    2008-01-01

    Bacillus subtilis is a prolific producer of enzymes and biopharmaceuticals. However, the susceptibility of heterologous proteins to degradation by (extracellular) proteases is a major limitation for use of B. subtilis as a protein cell factory. An increase in protein production levels has previously

  4. The history of Z-VAD-FMK, a tool for understanding the significance of caspase inhibition.

    Science.gov (United States)

    Van Noorden, C J

    2001-07-01

    Dr. Robert Smith is one of the pioneers in histochemistry. One of his most important achievements is the recognition of proteolysis as a major physiological and pathophysiological process. As a consequence, he developed selective fluorogenic and chromogenic substrates and specific inhibitors of proteases that allow the (histochemical) analysis of protease activity. One of the latest successes is the design of Z-VAD-fluoromethylketone (FMK), the specific caspase inhibitor, that is a key compound for studies on apoptosis. Its development was originally meant for therapeutic use but unforeseen cytotoxicity of a metabolic derivative of the FMK compound disabled its potential as a drug. However, as a tool for fundamental research it is a great success. The history of Z-VAD-FMK is an example of the creative brain and the tireless perseverance of Robert Smith for which histochemistry and cytochemistry owes him so much. This history of Z-VAD-FMK is a well-deserved tribute at the occasion of his 70th birthday.

  5. Biochemical Effects of Cadmium Exposure and the Potential Pharmacologic Significance of Cadmium Mediated Hydrolase Inhibition

    Science.gov (United States)

    1997-04-18

    increase Cd absorption from the intestines (Larson and Piscator 1971; Itokawa, Abe et al. 197 4; Pond and Walker 1975). Pyridoxine, vitamin B 6 , is...considerations on uptake and retention of cadmium in human kidney cortex. Cadmium in the Environment. L. Friberg, M. Piscator and G. F. Nordberg. Cleveland...Columbia, Missouri, University of Missouri. Larson, S.-E. and M. Piscator (1971). "Effect of cadmium on skeletal tissue in normal and calcium

  6. The significance of constitutional values

    Directory of Open Access Journals (Sweden)

    HN Nisihara

    2001-12-01

    Full Text Available This article addresses the question of the meaning and legal significance of constitutional values in contemporary times. The article attends also to related questions namely, what constitute “constitutional values” and what are the limitations of the meaning afforded to this notion. Attention is paid in the particular, to freedom, equality and democracy as value-neutral criteria of fairness and government neutrality with reference to the South African and German contexts as well as to value-neutrality as a culturally conditioned value. The author concludes with a cosmopolitan view of freedom and the right to peace with reference to the constitutional texts of Japan and the United States.

  7. The significance of small streams

    Science.gov (United States)

    Wohl, Ellen

    2017-09-01

    Headwaters, defined here as first- and secondorder streams, make up 70%‒80% of the total channel length of river networks. These small streams exert a critical influence on downstream portions of the river network by: retaining or transmitting sediment and nutrients; providing habitat and refuge for diverse aquatic and riparian organisms; creating migration corridors; and governing connectivity at the watershed-scale. The upstream-most extent of the channel network and the longitudinal continuity and lateral extent of headwaters can be difficult to delineate, however, and people are less likely to recognize the importance of headwaters relative to other portions of a river network. Consequently, headwaters commonly lack the legal protections accorded to other portions of a river network and are more likely to be significantly altered or completely obliterated by land use.

  8. [Hypertriglyceridemia: concept and clinical significance].

    Science.gov (United States)

    Hirano, Tsutomu

    2013-09-01

    Hypertriglyceridemia is a common lipid disorder as well as hypercholesterolemia. However clinical significance of hypertriglyceridemia is not fully understood because of its heterogeneous lipoprotein phenotypes and complex etiology. Severe hypertriglyceridemia increases the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Patients with hypertriglyceridemia are usually accompanied by other cardiovascular related disorders, such as central obesity, type 2 diabetes, and liver steatosis. Ectopic fat accumulation is often seen in hypertriglyceridemic subjects and various organ injuries are developed by the lipotoxicity. Hypertriglyceridemia is strongly associated with remnant lipoprotein accumulation, increased small dense LDL, and low HDL-cholesterol. All these lipid abnormalities are recognized as cardiovascular risk factors. The pathophysiology of lipoprotein metabolism related to the hypertriglyceridemia is summarized in this brief review.

  9. 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.

  10. Inhibition and Brain Work

    OpenAIRE

    Buzsáki, György; Kaila, Kai; Raichle, Marcus

    2007-01-01

    The major part of the brain’s energy budget (~60%–80%) is devoted to its communication activities. While inhibition is critical to brain function, relatively little attention has been paid to its metabolic costs. Understanding how inhibitory interneurons contribute to brain energy consumption (brain work) is not only of interest in understanding a fundamental aspect of brain function but also in understanding functional brain imaging techniques which rely on measurements related to blood flow...

  11. Clinical significance of MET in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Mikito; Inokuchi; Sho; Otsuki; Yoshitaka; Fujimori; Yuya; Sato; Masatoshi; Nakagawa; Kazuyuki; Kojima

    2015-01-01

    Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer(GC),although outcomes remain unfavorable.Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed,and monoclonal antibodies targeting human epidermal growth factor receptor 2 or vascular endothelial growth factor receptor 2 have become standard therapy for GC.Hepatocyte growth factor and its receptor,c-MET(MET),play key roles in tumor growth through activated signaling pathways from receptor in GC cells.Genomic amplification of MET leads to the aberrant activation found in GC tumors and is related to survival in patients with GC.This review discusses the clinical significance of MET in GC and examines MET as a potential therapeutic target in patients with GC.Preclinical studies in animal models have shown that MET antibodies or smallmolecule MET inhibitors suppress tumor-cell proliferation and tumor progression in MET-amplified GC cells.These drugs are now being evaluated in clinical trials as treatments for metastatic or unresectable GC.

  12. Reflex excitability regulates prepulse inhibition.

    Science.gov (United States)

    Schicatano, E J; Peshori, K R; Gopalaswamy, R; Sahay, E; Evinger, C

    2000-06-01

    Presentation of a weak stimulus, a prepulse, before a reflex-evoking stimulus decreases the amplitude of the reflex response relative to reflex amplitude evoked without a preceding prepulse. For example, presenting a brief tone before a trigeminal blink-eliciting stimulus significantly reduces reflex blink amplitude. A common explanation of such data are that sensory processing of the prepulse modifies reflex circuit behavior. The current study investigates the converse hypothesis that the intrinsic characteristics of the reflex circuit rather than prepulse processing determine prepulse modification of trigeminal and acoustic reflex blinks. Unilateral lesions of substantia nigra pars compacta neurons created rats with hyperexcitable trigeminal reflex blinks but normally excitable acoustic reflex blinks. In control rats, presentation of a prepulse reduced the amplitude of both trigeminal and acoustic reflex blinks. In 6-OHDA-lesioned rats, however, the same acoustic prepulse facilitated trigeminal reflex blinks but inhibited acoustic reflex blinks. The magnitude of prepulse modification correlated with reflex excitability. Humans exhibited the same pattern of prepulse modification. An acoustic prepulse facilitated the trigeminal reflex blinks of subjects with hyperexcitable trigeminal reflex blinks caused by Parkinson's disease. The same prepulse inhibited trigeminal reflex blinks of age-matched control subjects. Prepulse modification also correlated with trigeminal reflex blink excitability. These data show that reflex modification by a prepulse reflects the intrinsic characteristics of the reflex circuit rather than an external adjustment of the reflex circuit by the prepulse.

  13. Statistically significant relational data mining :

    Energy Technology Data Exchange (ETDEWEB)

    Berry, Jonathan W.; Leung, Vitus Joseph; Phillips, Cynthia Ann; Pinar, Ali; Robinson, David Gerald; Berger-Wolf, Tanya; Bhowmick, Sanjukta; Casleton, Emily; Kaiser, Mark; Nordman, Daniel J.; Wilson, Alyson G.

    2014-02-01

    This report summarizes the work performed under the project (3z(BStatitically significant relational data mining.(3y (BThe goal of the project was to add more statistical rigor to the fairly ad hoc area of data mining on graphs. Our goal was to develop better algorithms and better ways to evaluate algorithm quality. We concetrated on algorithms for community detection, approximate pattern matching, and graph similarity measures. Approximate pattern matching involves finding an instance of a relatively small pattern, expressed with tolerance, in a large graph of data observed with uncertainty. This report gathers the abstracts and references for the eight refereed publications that have appeared as part of this work. We then archive three pieces of research that have not yet been published. The first is theoretical and experimental evidence that a popular statistical measure for comparison of community assignments favors over-resolved communities over approximations to a ground truth. The second are statistically motivated methods for measuring the quality of an approximate match of a small pattern in a large graph. The third is a new probabilistic random graph model. Statisticians favor these models for graph analysis. The new local structure graph model overcomes some of the issues with popular models such as exponential random graph models and latent variable models.

  14. Determining Semantically Related Significant Genes.

    Science.gov (United States)

    Taha, Kamal

    2014-01-01

    GO relation embodies some aspects of existence dependency. If GO term xis existence-dependent on GO term y, the presence of y implies the presence of x. Therefore, the genes annotated with the function of the GO term y are usually functionally and semantically related to the genes annotated with the function of the GO term x. A large number of gene set enrichment analysis methods have been developed in recent years for analyzing gene sets enrichment. However, most of these methods overlook the structural dependencies between GO terms in GO graph by not considering the concept of existence dependency. We propose in this paper a biological search engine called RSGSearch that identifies enriched sets of genes annotated with different functions using the concept of existence dependency. We observe that GO term xcannot be existence-dependent on GO term y, if x- and y- have the same specificity (biological characteristics). After encoding into a numeric format the contributions of GO terms annotating target genes to the semantics of their lowest common ancestors (LCAs), RSGSearch uses microarray experiment to identify the most significant LCA that annotates the result genes. We evaluated RSGSearch experimentally and compared it with five gene set enrichment systems. Results showed marked improvement.

  15. Astrobiological Significance of Microbial Extremophiles

    Science.gov (United States)

    Pikuta, Elena V.; Hoover, Richard B.

    2007-01-01

    The microflora of the cryosphere of planet Earth provides the best analogs for life forms that might be found in the permafrost or polar ice caps of Mars, near the surface of the cometary nuclei, or in the liquid water beneath and the ice crusts of icy moons of Jupiter and Saturn. The importance of study alkaliphilic microorganisms for astrobiology was enhanced by the findings of abundant carbonates and carbonate globules rimmed with possibly biogenic magnetites in association with the putative microfossils in the ALH84001 meteorite. Although the ALH84001 "nanofossils" were to small and simple to be unambiguously recognized as biogenic, they stimulated Astrobiology research and studies of microbial extremophiles and biomarkers in ancient rocks and meteorites. Recent studies of CI and CM carbonaceous meteorites have resulted in the detection of the well-preserved mineralized remains of coccoidal and filamentous microorganisms in cyanobacterial mats. Energy Dispersive X-ray Analysis has shown anomalous biogenic element ratios clearly indicating they are not recent biological contaminants. This paper reviews microbial extremophiles in context of their significance to Astrobiology. The study of halophilic microorganisms was started from work with saline soils and lakes, and one of the record of good growth for Haloferax mediterranei was shown at 30 percent NaC1. Although alkali-tolerant nitrifying bacteria had previously been reported, the first described alkaliphilic microorganism was the bacterium Streptococcus faecalis. Halophilic and alkaliphilic forms are relevant to conditions that might be found in closed impact basins and craters on Mars filled with evaporite deposits. The first obligately acidophilic bacterium described was Acidithiobacillus ferrooxydans (formally Thiobacillus ferrooxidans). Later thermophilic lithotrophic acidophiles were found, and the hyperacidophilic moderately thermophilic species of the genus Picrophilus were found to grow at negative p

  16. Gastric siderosis: patterns and significance.

    Science.gov (United States)

    Marginean, Esmeralda C; Bennick, Michael; Cyczk, Jan; Robert, Marie E; Jain, Dhanpat

    2006-04-01

    Recently, we encountered 2 cases of diffuse iron deposition in gastric antral and fundic glandular epithelium, which in 1 patient eventually led to the diagnosis of hemochromatosis. Gastric mucosal siderosis (GS) has previously been described in hemochromatosis patients, alcoholics, and in association with iron medications. However, the prevalence of various patterns of iron deposition in the gastric mucosa and their clinical significance have not been studied in detail. The 2 index cases mentioned above and 500 additional consecutive gastric biopsies examined over a period of 8 months at our institution were stained for iron by the Prussian blue method. In addition, all patients with genetic hemochromatosis diagnosed by liver biopsy in our department between 1998 and 2003 who also had gastric biopsies were identified from the surgical pathology files and included in the study (n = 3). The location of iron deposition [stromal cells (endothelium, fibroblasts, macrophages), glandular epithelium, or extracellular] was recorded and subjectively graded as 1+ to 3+ according to the severity of deposition within the mucosa. Relevant histologic changes (inflammation, presence of H. pylori, ulceration) and clinical features were reviewed. Three patterns of GS were identified: A) "nonspecific GS" with predominant iron deposition in the stromal cells including macrophages, and focally in epithelium; B) "iron-pill gastritis" with often mild gastritis and reactive gastropathy type changes, and mostly extracellular deposition with focal stromal cells and epithelial deposition; and C) predominant deposition in antral and fundic glandular epithelium. Of the 500 cases studied, a total of 18 (3.6%) cases were found to have GS. Of these 18 cases, 11 (2.2%) showed pattern A, 4 (0.8%) showed pattern B, and 3 (0.6%) showed pattern C. The GS in patterns A and B was always focal or patchy (1+ to 2+), whereas in pattern C it was generally diffuse and strong (2+ to 3+). A history of oral

  17. Involvement of CB1 and CB2 receptors in the modulation of cholinergic neurotransmission in mouse gastric preparations.

    Science.gov (United States)

    Mulè, Flavia; Amato, Antonella; Baldassano, Sara; Serio, Rosa

    2007-09-01

    While most of the studies concerning the role of cannabinoids on gastric motility have focused the attention on the gastric emptying in in vivo animal models, there is little information about the cannabinoid peripheral influence in the stomach. In addition, the functional features of CB2 receptors in the gastrointestinal tract have been poorly characterized. The purpose of the present study was to investigate the effects of cannabinoid drugs on the excitatory cholinergic and inhibitory non-adrenergic non-cholinergic (NANC) neurotransmission in mouse isolated gastric preparations. Intraluminal pressure from isolated whole stomach was recorded and mechanical responses induced by electrical field stimulation (EFS) were analyzed in different experimental conditions. EFS (0.5ms duration, supramaximal voltage, in trains of 5s, 2-16Hz) caused a cholinergic contraction, which was abolished by atropine or tetrodotoxin (TTX). The cannabinoid receptor agonist, WIN 55,212-2, the endogenous ligand, anandamide, the selective CB1 receptor agonist ACEA, and the selective CB2 receptor agonists, JWH015 and JWH133, produced a concentration-dependent reduction of the EFS-evoked cholinergic contractions. SR141716A, CB1 receptor antagonist, significantly attenuated the inhibitory effects induced by WIN 55,212-2, anandamide or ACEA, without affecting those caused by JWH133. AM630, CB2 receptor antagonist, reduced the inhibitory effects induced by WIN 55,212-2, anandamide, JWH015 or JWH133, without affecting those caused by ACEA. The joint application of SR141716A and AM630 was able of fully preventing the WIN 55,212-2 and anandamide actions. The cannabinoid antagonists failed per se to affect the neurally evoked responses. Cannabinoids did not modify the contractions produced by exogenous carbachol. In the presence of atropine and guanethidine (NANC conditions) EFS-induced TTX-sensitive relaxation consisting in an early and rapid component followed by a second slow phase, which were

  18. Beneficial bacteria inhibit cachexia.

    Science.gov (United States)

    Varian, Bernard J; Goureshetti, Sravya; Poutahidis, Theofilos; Lakritz, Jessica R; Levkovich, Tatiana; Kwok, Caitlin; Teliousis, Konstantinos; Ibrahim, Yassin M; Mirabal, Sheyla; Erdman, Susan E

    2016-03-15

    Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny.

  19. Btk inhibition treats TLR7/IFN driven murine lupus.

    Science.gov (United States)

    Bender, Andrew T; Pereira, Albertina; Fu, Kai; Samy, Eileen; Wu, Yin; Liu-Bujalski, Lesley; Caldwell, Richard; Chen, Yi-Ying; Tian, Hui; Morandi, Federica; Head, Jared; Koehler, Ursula; Genest, Melinda; Okitsu, Shinji L; Xu, Daigen; Grenningloh, Roland

    2016-03-01

    Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling.

  20. Habituation, latent inhibition, and extinction.

    Science.gov (United States)

    Jordan, Wesley P; Todd, Travis P; Bucci, David J; Leaton, Robert N

    2015-06-01

    In two conditioned suppression experiments with a latent inhibition (LI) design, we measured the habituation of rats in preexposure, their LI during conditioning, and then extinction over days. In the first experiment, lick suppression, the preexposed group (PE) showed a significant initial unconditioned response (UR) to the target stimulus and significant long-term habituation (LTH) of that response over days. The significant difference between the PE and nonpreexposed (NPE) groups on the first conditioning trial was due solely to the difference in their URs to the conditioned stimulus (CS)-a habituated response (PE) and an unhabituated response (NPE). In the second experiment, bar-press suppression, little UR to the target stimulus was apparent during preexposure, and no detectable LTH. Thus, there was no difference between the PE and NPE groups on the first conditioning trial. Whether the UR to the CS confounds the interpretation of LI (Exp. 1) or not (Exp. 2) can only be known if the UR is measured. In both experiments, LI was observed in acquisition. Also in both experiments, rats that were preexposed and then conditioned to asymptote were significantly more resistant to extinction than were the rats not preexposed. This result contrasts with the consistently reported finding that preexposure either produces less resistance to extinction or has no effect on extinction. The effect of stimulus preexposure survived conditioning to asymptote and was reflected directly in extinction. These two experiments provide a cautionary procedural note for LI experiments and have shown an unexpected extinction effect that may provide new insights into the interpretation of LI.

  1. Pyrilamine inhibits nicotine-induced catecholamine secretion.

    Science.gov (United States)

    Kim, Dong-Chan; Yun, So Jeong; Park, Yong-Soo; Jun, Dong-Jae; Kim, Dongjin; Jiten Singh, N; Kim, Sanguk; Kim, Kyong-Tai

    2014-07-01

    Function of nicotine, which induces activation of all parts of the body including our brain, has been receiving much attention for a long period of time and also been actively studied by researchers for its pharmacological actions in the central nervous system. The modulation of nicotine concentration and the inhibition of nicotine binding on target receptors in the brain are the key factors for smoking addiction therapy. In previous studies showed that influx of nicotine at the blood-brain barrier was through the pyrilamine-sensitive organic cation transporters. But the direct interacting mechanism of pyrilamine on the nicotine binding target receptors has not yet been clarified. The aim of the present study is to investigate the direct binding mechanisms of a pyrilamine on the nicotinic acetylcholine receptors (nAChRs). We found that pyrilamine shares the same ligand binding pocket of nicotine (NCT) on nAChRs but interacts with more amino acid residues than NCT does. The extended part of pyrilamine interacts with additional residues in the ligand binding pocket of nAChRs which are located nearby the entrance of the binding pocket. The catecholamine (CA) secretion induced by nAChR agonist (NCT') was significantly inhibited by the pyrilamine pretreatment. Real time carbon-fiber amperometry confirmed the inhibition of the NCT'-induced exocytosis by pyrilamine in a single cell level. We also found that pyrilamine inhibited the NCT'-induced [Ca(2+)]i. In contrast, pyrilamine did not affect the increase in calcium induced by high K(+). Overall, these data suggest that pyrilamine directly docks into the ligand binding site of nAChRs and specifically inhibits the nAChR-mediated effects thereby causing inhibition of CA secretion. Therefore, pyrilamine may play an important role to explore new treatments to aid smoking cessation.

  2. 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

  3. 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…

  4. Lateral inhibition during nociceptive processing

    DEFF Research Database (Denmark)

    Quevedo, Alexandre S.; Mørch, Carsten Dahl; Andersen, Ole Kæseler

    2017-01-01

    of skin. Thus, the stimulation of the skin region between the endpoints of the lines appears to produce inhibition. These findings indicate that lateral inhibition limits spatial summation of pain and is an intrinsic component of nociceptive information processing. Disruption of such lateral inhibition......Spatial summation of pain is the increase of perceived intensity that occurs as the stimulated area increases. Spatial summation of pain is sub-additive in that increasing the stimulus area produces a disproportionately small increase in the perceived intensity of pain. A possible explanation...... for sub-additive summation may be that convergent excitatory information is modulated by lateral inhibition. To test the hypothesis that lateral inhibition may limit spatial summation of pain, we delivered different patterns of noxious thermal stimuli to the abdomens of 15 subjects using a computer...

  5. Molecular signals controlling the inhibition of nodulation by nitrate in Medicago truncatula

    NARCIS (Netherlands)

    Noorden, Van Giel E.; Verbeek, Rob; Dinh, Peter; Jin, Jian; Green, Alexandra; Ng, Jason Liang Pin; Mathesius, Ulrike

    2016-01-01

    The presence of nitrogen inhibits legume nodule formation, but the mechanism of this inhibition is poorly understood. We found that 2.5 mM nitrate and above significantly inhibited nodule initiation but not root hair curling in Medicago trunatula. We analyzed protein abundance in M. truncatula ro

  6. Reduced surround inhibition in musicians.

    Science.gov (United States)

    Shin, Hae-Won; Kang, Suk Y; Hallett, Mark; Sohn, Young H

    2012-06-01

    To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia.

  7. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists.

    Science.gov (United States)

    Altun, Ahmet; Yildirim, Kemal; Ozdemir, Ercan; Bagcivan, Ihsan; Gursoy, Sinan; Durmus, Nedim

    2015-09-01

    Cannabinoid CB1 and CB2 receptor antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance. The aim of this study was to investigate the effects of AM251 (a selective CB1 antagonist) and JTE907 (a selective CB2 antagonist) on morphine analgesia and tolerance in rats. Adult male Wistar albino rats weighing 205-225 g were used in these experiments. To constitute morphine tolerance, we used a 3 day cumulative dosing regimen. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated by analgesia tests. The analgesic effects of morphine (5 mg/kg), ACEA (a CB1 receptor agonist, 5 mg/kg), JWH-015 (a CB2 receptor agonist, 5 mg/kg), AM251 (1 mg/kg) and JTE907 (5 mg/kg) were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Our findings indicate that ACEA and JWH907 significantly increased morphine analgesia and morphine antinociceptive tolerance in the analgesia tests. In contrast, the data suggested that AM251 and JTE907 significantly attenuated the expression of morphine tolerance. In conclusion, we observed that co-injection of AM251 and JTE907 with morphine attenuated expression of tolerance to morphine analgesic effects and decreased the morphine analgesia.

  8. Cytochrome P450 structure, function and clinical significance: A review.

    Science.gov (United States)

    Palrasu, Manikandan; Nagini, Siddavaram

    2017-01-25

    The cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins that play a pivotal role in the detoxification of xenobiotics, cellular metabolism and homeostasis. Induction or inhibition of CYP enzymes is a major mechanism that underlies drug-drug interactions. CYP enzymes can be transcriptionally activated by various xenobiotics and endogenous substrates through receptor-dependent mechanisms. CYP enzyme inhibition is a principal mechanism for metabolism-based drug-drug interactions. Many chemotherapeutic drugs can cause drug interactions due to their ability to either inhibit or induce the CYP enzyme system. Predictions based on in silico analyses followed by validation have identified several microRNAs that regulate CYPs. Genetic polymorphisms and epigenetic changes in CYP genes may be responsible for inter-individual and inter-ethnic variations in disease susceptibility and the therapeutic efficacy of drugs. Knowledge about the substrates, inducers, inhibitors of CYP isoforms, and the polymorphisms of CYP enzymes may be used as an aid by clinicians to determine therapeutic strategy, and treatment doses for drugs that are metabolized by CYP gene products. The present review is a comprehensive compilation of cytochrome P450 structure, function, pharmacogenetics, and pharmacoepigenetics and clinical significance.

  9. Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin

    Science.gov (United States)

    Verespy III, Stephen; Mehta, Akul Y.; Afosah, Daniel; Al-Horani, Rami A.; Desai, Umesh R.

    2016-01-01

    Allosteric partial inhibition of soluble, monomeric proteases can offer major regulatory advantages, but remains a concept on paper to date; although it has been routinely documented for receptors and oligomeric proteins. Thrombin, a key protease of the coagulation cascade, displays significant conformational plasticity, which presents an attractive opportunity to discover small molecule probes that induce sub-maximal allosteric inhibition. We synthesized a focused library of some 36 sulfated coumarins to discover two agents that display sub-maximal efficacy (~50%), high potency (150-fold). Michaelis-Menten, competitive inhibition, and site-directed mutagenesis studies identified exosite 2 as the site of binding for the most potent sulfated coumarin. Stern-Volmer quenching of active site-labeled fluorophore suggested that the allosteric regulators induce intermediate structural changes in the active site as compared to those that display ~80–100% efficacy. Antithrombin inactivation of thrombin was impaired in the presence of the sulfated coumarins suggesting that allosteric partial inhibition arises from catalytic dysfunction of the active site. Overall, sulfated coumarins represent first-in-class, sub-maximal inhibitors of thrombin. The probes establish the concept of allosteric partial inhibition of soluble, monomeric proteins. This concept may lead to a new class of anticoagulants that are completely devoid of bleeding. PMID:27053426

  10. Gold Nanoparticles Inhibit Matrix Metalloproteases without Cytotoxicity.

    Science.gov (United States)

    Hashimoto, M; Sasaki, J I; Yamaguchi, S; Kawai, K; Kawakami, H; Iwasaki, Y; Imazato, S

    2015-08-01

    Nanoparticles (NPs) are currently the focus of considerable attention for dental applications; however, their biological effects have not been fully elucidated. The long-term, slow release of matrix metalloproteases (MMPs) digests collagen fibrils within resin-dentin bonds. Therefore, MMP inhibitors can prolong the durability of resin-dentin bonds. However, there have been few reports evaluating the combined effect of MMP inhibition and the cytotoxic effects of NPs for dentin bonding. The aim of this study was to evaluate MMP inhibition and cytotoxic responses to gold (AuNPs) and platinum nanoparticles (PtNPs) stabilized by polyvinylpyrrolidone (PVP) in cultured murine macrophages (RAW264) by using MMP inhibition assays, measuring cell viability and inflammatory responses (quantitative reverse transcription polymerase chain reaction [RT-qPCR]), and conducting a micromorphological analysis by fluorescence and transmission electron microscopy. Cultured RAW264 cells were exposed to metal NPs at various concentrations (1, 10, 100, and 400 µg/mL). AuNPs and PtNPs markedly inhibited MMP-8 and MMP-9 activity. Although PtNPs were cytotoxic at high concentrations (100 and 400 µg/mL), no cytotoxic effects were observed for AuNPs at any concentration. Transmission electron microscopy images showed a significant nonrandom intercellular distribution for AuNPs and PtNPs, which were mostly observed to be localized in lysosomes but not in the nucleus. RT-qPCR analysis demonstrated inflammatory responses were not induced in RAW264 cells by AuNPs or PtNPs. The cytotoxicity of nanoparticles might depend on the core metal composition and arise from a "Trojan horse" effect; thus, MMP inhibition could be attributed to the surface charge of PVP, which forms the outer coating of NPs. The negative charge of the surface coating of PVP binds to Zn(2+) from the active center of MMPs by chelate binding and results in MMP inhibition. In summary, AuNPs are attractive NPs that effectively

  11. Phytic Acid Inhibits Lipid Peroxidation In Vitro

    Directory of Open Access Journals (Sweden)

    Alicja Zajdel

    2013-01-01

    Full Text Available Phytic acid (PA has been recognized as a potent antioxidant and inhibitor of iron-catalyzed hydroxyl radical formation under in vitro and in vivo conditions. Therefore, the aim of the present study was to investigate, with the use of HPLC/MS/MS, whether PA is capable of inhibiting linoleic acid autoxidation and Fe(II/ascorbate-induced peroxidation, as well as Fe(II/ascorbate-induced lipid peroxidation in human colonic epithelial cells. PA at 100 μM and 500 μM effectively inhibited the decay of linoleic acid, both in the absence and presence of Fe(II/ascorbate. The observed inhibitory effect of PA on Fe(II/ascorbate-induced lipid peroxidation was lower (10–20% compared to that of autoxidation. PA did not change linoleic acid hydroperoxides concentration levels after 24 hours of Fe(II/ascorbate-induced peroxidation. In the absence of Fe(II/ascorbate, PA at 100 μM and 500 μM significantly suppressed decomposition of linoleic acid hydroperoxides. Moreover, PA at the tested nontoxic concentrations (100 μM and 500 μM significantly decreased 4-hydroxyalkenal levels in Caco-2 cells which structurally and functionally resemble the small intestinal epithelium. It is concluded that PA inhibits linoleic acid oxidation and reduces the formation of 4-hydroxyalkenals. Acting as an antioxidant it may help to prevent intestinal diseases induced by oxygen radicals and lipid peroxidation products.

  12. Phytic acid inhibits lipid peroxidation in vitro.

    Science.gov (United States)

    Zajdel, Alicja; Wilczok, Adam; Węglarz, Ludmiła; Dzierżewicz, Zofia

    2013-01-01

    Phytic acid (PA) has been recognized as a potent antioxidant and inhibitor of iron-catalyzed hydroxyl radical formation under in vitro and in vivo conditions. Therefore, the aim of the present study was to investigate, with the use of HPLC/MS/MS, whether PA is capable of inhibiting linoleic acid autoxidation and Fe(II)/ascorbate-induced peroxidation, as well as Fe(II)/ascorbate-induced lipid peroxidation in human colonic epithelial cells. PA at 100 μM and 500 μM effectively inhibited the decay of linoleic acid, both in the absence and presence of Fe(II)/ascorbate. The observed inhibitory effect of PA on Fe(II)/ascorbate-induced lipid peroxidation was lower (10-20%) compared to that of autoxidation. PA did not change linoleic acid hydroperoxides concentration levels after 24 hours of Fe(II)/ascorbate-induced peroxidation. In the absence of Fe(II)/ascorbate, PA at 100 μM and 500 μM significantly suppressed decomposition of linoleic acid hydroperoxides. Moreover, PA at the tested nontoxic concentrations (100 μM and 500 μM) significantly decreased 4-hydroxyalkenal levels in Caco-2 cells which structurally and functionally resemble the small intestinal epithelium. It is concluded that PA inhibits linoleic acid oxidation and reduces the formation of 4-hydroxyalkenals. Acting as an antioxidant it may help to prevent intestinal diseases induced by oxygen radicals and lipid peroxidation products.

  13. 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.

  14. Cross-domain inhibition of TACE ectodomain

    DEFF Research Database (Denmark)

    Tape, Christopher J; Willems, Sofie H; Dombernowsky, Sarah L;

    2011-01-01

    Proteolytic release from the cell surface is an essential activation event for many growth factors and cytokines. TNF-a converting enzyme (TACE) is a membrane-bound metalloprotease responsible for solubilizing many pathologically significant membrane substrates and is an attractive therapeutic...... target for the treatment of cancer and arthritis. Prior attempts to antagonize cell-surface TACE activity have focused on small-molecule inhibition of the metalloprotease active site. Given the highly conserved nature of metalloprotease active sites, this paradigm has failed to produce a truly specific...... individual antibody variable domains to desired epitopes. The resulting "cross-domain" human antibody is a previously undescribed selective TACE antagonist and provides a unique alternative to small-molecule metalloprotease inhibition....

  15. Non-Classical Inhibition of Carbonic Anhydrase

    Science.gov (United States)

    Lomelino, Carrie L.; Supuran, Claudiu T.; McKenna, Robert

    2016-01-01

    Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, are examined as antiglaucoma, antiepileptic, antiobesity, antineuropathic pain and anticancer compounds. However, many sulfonamide compounds inhibit all CA isoforms nonspecifically, diluting drug effectiveness and causing undesired side effects due to off-target inhibition. In addition, a small but significant percentage of the general population cannot be treated with sulfonamide-based compounds due to a sulfa allergy. Therefore, CAIs must be developed that are not only isoform specific, but also non-classical, i.e. not based on sulfonamides, sulfamates, or sulfamides. This review covers the classes of non-classical CAIs and the recent advances in the development of isoform-specific inhibitors based on phenols, polyamines, coumarins and their derivatives. PMID:27438828

  16. Novel Bioactivity of Ellagic Acid in Inhibiting Human Platelet Activation

    Directory of Open Access Journals (Sweden)

    Yi Chang

    2013-01-01

    Full Text Available Pomegranates are widely consumed either as fresh fruit or in beverage form as juice and wine. Ellagic acid possesses potent antioxidative properties; it is known to be an effective phytotherapeutic agent with antimutagenic and anticarcinogenic qualities. Ellagic acid (20 to 80 μM exhibited a potent activity in inhibiting platelet aggregation stimulated by collagen; however, it did not inhibit platelet aggregation stimulated by thrombin, arachidonic acid, or U46619. Treatment with ellagic acid (50 and 80 μM significantly inhibited platelet activation stimulated by collagen; this alteration was accompanied by the inhibition of relative [Ca2+]i mobilization, and the phosphorylation of phospholipase C (PLCγ2, protein kinase C (PKC, mitogen-activated protein kinases (MAPKs, and Akt, as well as hydroxyl radical (OH● formation. In addition, ellagic acid also inhibited p38 MAPK and Akt phosphorylation stimulated by hydrogen peroxide. By contrast, ellagic acid did not significantly affect PKC activation and platelet aggregation stimulated by PDBu. This study is the first to show that, in addition to being considered a possible agent for preventing tumor growth, ellagic acid possesses potent antiplatelet properties. It appears to initially inhibit the PLCγ2-PKC cascade and/or hydroxyl radical formation, followed by decreased phosphorylation of MAPKs and Akt, ultimately inhibiting platelet aggregation.

  17. Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans.

    Science.gov (United States)

    Di Lazzaro, V; Oliviero, A; Saturno, E; Dileone, M; Pilato, F; Nardone, R; Ranieri, F; Musumeci, G; Fiorilla, T; Tonali, P

    2005-04-15

    Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABA(A) receptors, tonically inhibits cholinergic activity. Little is known about the effects of GABA on the cholinergic activity in the human central nervous system. In vivo evaluation of some cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with TMS of the motor cortex. Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short latency afferent inhibition, SAI). We investigated whether GABA(A) activity enhancement by lorazepam modifies SAI. We also evaluated the effects produced by lorazepam on a different TMS protocol of cortical inhibition, the short interval intracortical inhibition (SICI), which is believed to be directly related to GABA(A) activity. In 10 healthy volunteers, the effects of lorazepam were compared with those produced by quetiapine, a psychotropic drug with sedative effects with no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors, and with those of a placebo using a randomized double-blind study design. Administration of lorazepam produced a significant increase in SICI (F(3,9) = 3.19, P = 0.039). In contrast to SICI, SAI was significantly reduced by lorazepam (F(3,9) = 9.39, P = 0.0002). Our findings demonstrate that GABA(A) activity enhancement determines a suppression of SAI and an increase of SICI.

  18. Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome

    Science.gov (United States)

    2016-08-01

    model of the human syndrome. In addition, we propose an innovative way of reversing the reduced tonic inhibition by boosting GABAAR trafficking to...showed that phosphorylation of these residues changes the trafficking of the subunits so the changes observed in Fmr1 KO mice would predictably have...consequences for trafficking of these essential inhibitory subunits. We noted that there was a significant decrease in tonic inhibition in dentate

  19. Inhibition of cellular respiration by endogenously produced carbon monoxide.

    Science.gov (United States)

    D'Amico, Gabriela; Lam, Francis; Hagen, Thilo; Moncada, Salvador

    2006-06-01

    Endogenously produced nitric oxide (NO) interacts with mitochondrial cytochrome c oxidase, leading to inhibition of cellular respiration. This interaction has been shown to have important physiological and pathophysiological consequences. Exogenous carbon monoxide (CO) is also known to inhibit cytochrome c oxidase in vitro; however, it is not clear whether endogenously produced CO can inhibit cellular respiration and, if so, what the significance of this might be. In this study, we show that exogenous CO inhibits respiration in a moderate but persistent manner in HEK293 cells under ambient (21%) oxygen concentrations (K(i) = 1.44 microM). This effect of CO was increased (K(i) = 0.35 microM) by incubation in hypoxic conditions (1% oxygen). Endogenous CO, generated by HEK293 cells transfected with the inducible isoform of haem oxygenase (haem oxygenase-1; HO-1), also inhibited cellular respiration moderately (by 12%) and this was accompanied by inhibition (23%) of cytochrome c oxidase activity. When the cells were incubated in hypoxic conditions during HO-1 induction, the inhibitory effect of CO on cell respiration was markedly increased to 70%. Furthermore, endogenously produced CO was found to be responsible for the respiratory inhibition that occurs in RAW264.7 cells activated in hypoxic conditions with lipopolysaccharide and interferon-gamma, in the presence of N-(iminoethyl)-L-ornithine to prevent the synthesis of NO. Our results indicate that CO contributes significantly to the respiratory inhibition in activated cells, particularly under hypoxic conditions. Inhibition of cell respiration by endogenous CO through its interaction with cytochrome c oxidase might have an important role in inflammatory and hypoxic conditions.

  20. Inhibition of Rac and ROCK Signalling Influence Osteoblast Adhesion, Differentiation and Mineralization on Titanium Topographies

    Science.gov (United States)

    Prowse, Paul D. H.; Elliott, Christopher G.; Hutter, Jeff; Hamilton, Douglas W.

    2013-01-01

    Reducing the time required for initial integration of bone-contacting implants with host tissues would be of great clinical significance. Changes in osteoblast adhesion formation and reorganization of the F-actin cytoskeleton in response to altered topography are known to be upstream of osteoblast differentiation, and these processes are regulated by the Rho GTPases. Rac and RhoA (through Rho Kinase (ROCK)). Using pharmacological inhibitors, we tested how inhibition of Rac and ROCK influenced osteoblast adhesion, differentiation and mineralization on PT (Pre-treated) and SLA (sandblasted large grit, acid etched) topographies. Inhibition of ROCK, but not Rac, significantly reduced adhesion number and size on PT, with adhesion size consistent with focal complexes. After 1 day, ROCK, but not Rac inhibition increased osteocalcin mRNA levels on SLA and PT, with levels further increasing at 7 days post seeding. ROCK inhibition also significantly increased bone sialoprotein expression at 7 days, but not BMP-2 levels. Rac inhibition significantly reduced BMP-2 mRNA levels. ROCK inhibition increased nuclear translocation of Runx2 independent of surface roughness. Mineralization of osteoblast cultures was greater on SLA than on PT, but was increased by ROCK inhibition and attenuated by Rac inhibition on both topographies. In conclusion, inhibition of ROCK signalling significantly increases osteoblast differentiation and biomineralization in a topographic dependent manner, and its pharmacological inhibition could represent a new therapeutic to speed bone formation around implanted metals and in regenerative medicine applications. PMID:23505566

  1. Inhibition of Rac and ROCK signalling influence osteoblast adhesion, differentiation and mineralization on titanium topographies.

    Directory of Open Access Journals (Sweden)

    Paul D H Prowse

    Full Text Available Reducing the time required for initial integration of bone-contacting implants with host tissues would be of great clinical significance. Changes in osteoblast adhesion formation and reorganization of the F-actin cytoskeleton in response to altered topography are known to be upstream of osteoblast differentiation, and these processes are regulated by the Rho GTPases. Rac and RhoA (through Rho Kinase (ROCK. Using pharmacological inhibitors, we tested how inhibition of Rac and ROCK influenced osteoblast adhesion, differentiation and mineralization on PT (Pre-treated and SLA (sandblasted large grit, acid etched topographies. Inhibition of ROCK, but not Rac, significantly reduced adhesion number and size on PT, with adhesion size consistent with focal complexes. After 1 day, ROCK, but not Rac inhibition increased osteocalcin mRNA levels on SLA and PT, with levels further increasing at 7 days post seeding. ROCK inhibition also significantly increased bone sialoprotein expression at 7 days, but not BMP-2 levels. Rac inhibition significantly reduced BMP-2 mRNA levels. ROCK inhibition increased nuclear translocation of Runx2 independent of surface roughness. Mineralization of osteoblast cultures was greater on SLA than on PT, but was increased by ROCK inhibition and attenuated by Rac inhibition on both topographies. In conclusion, inhibition of ROCK signalling significantly increases osteoblast differentiation and biomineralization in a topographic dependent manner, and its pharmacological inhibition could represent a new therapeutic to speed bone formation around implanted metals and in regenerative medicine applications.

  2. Inhibition of SIRT2 suppresses hepatic fibrosis.

    Science.gov (United States)

    Arteaga, Maribel; Shang, Na; Ding, Xianzhong; Yong, Sherri; Cotler, Scott J; Denning, Mitchell F; Shimamura, Takashi; Breslin, Peter; Lüscher, Bernhard; Qiu, Wei

    2016-06-01

    Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.

  3. ROCK inhibition prevents early mouse embryo development.

    Science.gov (United States)

    Duan, Xing; Chen, Kun-Lin; Zhang, Yu; Cui, Xiang-Shun; Kim, Nam-Hyung; Sun, Shao-Chen

    2014-08-01

    ROCK is a Rho-GTPase effector that is important for actin assembly and is involved in various cellular functions, including cell contraction, migration, motility, and tumor cell invasion. In this study, we investigated ROCK expression and function during early mouse embryo development. Inhibiting ROCK by Y-27632 treatment at the zygote stage resulted in first cleavage failure, and most embryos failed to develop to the 8-cell stage. When adding Y-27632 at the 8-cell stage, embryos failed to undergo compaction and could not develop into blastocysts. In addition, fluorescence staining intensity analysis indicated that actin expression at blastomere membranes was significantly reduced. After ROCK inhibition, two or more nuclei were observed in a cell, which indicated possible cytokinesis failure. Moreover, after ROCK inhibition with Y-27632, the phosphorylation levels of LIMK1/2, a downstream molecule of ROCK, were decreased at blastomere membranes. Thus, our results showed conserved roles for ROCK in this mammalian embryo model and indicated that a ROCK-LIMK1/2-actin pathway might regulate cleavage and blastocyst formation during early mouse embryo development.

  4. Gas hydrate inhibition of drilling fluid additives

    Energy Technology Data Exchange (ETDEWEB)

    Xiaolan, L.; Baojiang, S.; Shaoran, R. [China Univ. of Petroleum, Dongying (China). Inst. of Petroleum Engineering

    2008-07-01

    Gas hydrates that form during offshore well drilling can have adverse impacts on well operational safety. The hydrates typically form in the risers and the annulus between the casing and the drillstring, and can stop the circulation of drilling fluids. In this study, experiments were conducted to measure the effect of drilling fluid additives on hydrate inhibition. Polyalcohols, well-stability control agents, lubricating agents, and polymeric materials were investigated in a stirred tank reactor at temperatures ranging from -10 degree C to 60 degrees C. Pressure, temperature, and torque were used to detect onset points of hydrate formation and dissociation. The inhibitive effect of the additives on hydrate formation was quantified. Phase boundary shifts were measured in terms of temperature difference or sub-cooling gained when chemicals were added to pure water. Results showed that the multiple hydroxyl groups in polyalcohol chemicals significantly inhibited hydrate formation. Polymeric and polyacrylamide materials had only a small impact on hydrate formation, while sulfonated methyl tannins were found to increase hydrate formation. 6 refs., 1 tab., 4 figs.

  5. 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.

  6. Inhibition of nitric oxide synthesis for four days induces vascular abnormalities and myocardial infarct areas but not significant arterial hypertension Inibição da síntese do óxido nítrico durante quatro dias induz anormalidades vasculares e áreas de infarto miocárdico, porém, não induz hipertensão arterial significativa

    Directory of Open Access Journals (Sweden)

    Ricardo Xavier-Vidal

    2012-06-01

    Full Text Available BACKGROUND: Nitric oxide is an endothelium vasorelaxing factor and at least in some cases is the main cause of arterial hypertension, which is one of the most important risk factors of cardiovascular diseases. In Brazil, cardiovascular diseases are the first cause of mortality, representing about 30% of the total deaths. The L-NAME (Nω-nitro-arginine-methyl-ester blocks the nitric oxide synthesis necessary to maintain the normal arterial pressure. OBJECTIVE: To study lesions in myocardium due to the inhibition of nitric oxide synthesis during four days (via L-NAME oral administration, concentration: 75 mgs versus 100 mL-1. METHODS: Fourteen normotensive young adults Wistar rats were submitted, during four days, to L-NAME. Six rats were utilized as the Control Group. At day 4 of the experiment, the animals were anesthetized, weighed, and their thoraxes were opened, and the cardiotomy was performed. The hearts were weighed, fixed, and processed using routine methods, and they were sectioned in 3 µm and stained. RESULTS: Abnormalities were observed in the wall of arterial vessels of any dimension, as vascular damage with increasing wall thickness related mainly to proliferation of arterial smooth muscle cell in submitted animals. Proliferation of cells in the intimal layer and its thickening were also observed in small arterial vessels (arteriole. Infarct areas were present. CONCLUSIONS: The present data suggested that inhibition of nitric oxide synthesis for four days induces vascular abnormalities and myocardial infarct areas, but not arterial hypertension.CONTEXTO: O óxido nítrico é um fator de relaxamento vascular e, pelo menos em certos casos, é a principal causa de hipertensão arterial no ser humano. A hipertensão arterial é um importante fator de risco de doenças cardiovasculares. No Brasil, as doenças cardiovasculares são a primeira causa de mortalidade, representando cerca de 30% do total de óbitos. O L-NAME (N

  7. Biological significance of glucocorticoid receptor beta

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Alternative splicing of the human glucocorticoid receptor (hGR) primary transcript produces two receptor isoforms, termed hGRα and hGRβ. hGRα is a ligand-activated transcription factor which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes by binding to specific glucocorticoid response element (GRE) DNA sequences. In contrast, hGRβ dose not bind glucocorticoids and is transcriptionally inactive. We demonstrate here that hGRβ inhibits the hormone-induced, hGRα-mediated stimulations of gene expression, including glucocorticoid-responsive reporter gene (cat) and endogenous p21 gene. We also demonstrate that hGRβ can inhibit hGRα-mediated regulation of proliferation and differentiation of a human osteosarcoma cell line (HOS-8603). Our studies on the expression of hGR mRNA in nephrotic syndrome patients indicate that the hGRα/hGRβ mRNA ratio in peripheral white blood cell of hormone-resistant patients is lower than that of hormone-sensitive patients and health volunteers. These results indicate that hGRβ may be a physiologically and pathophysiologically relevant endogenous inhibitor of hGRα

  8. Interactions of trace elements: clinical significance.

    Science.gov (United States)

    Brewer, G J; Hill, G M; Dick, R D; Prasad, A S; Cossack, Z T

    1985-01-01

    We examined interaction of the trace element zinc with copper and lead. In sickle cell anemia, the usual situation is one of mild to moderate zinc deficiency owing to renal loss of zinc. Zinc deficiency seems to produce a mild overburden of copper and an increased ceruloplasmin level, probably by enhancing copper absorption. With zinc therapy, this process is reversed. Pharmacological doses of zinc, when administered in a way to ensure effectiveness (without food) will usually lead to copper deficiency. We have taken advantage of the copper-depleting effect of zinc to design a new therapy for Wilson's disease. Zinc, by inducing intestinal metallothionein, inhibits absorption of copper from food, and inhibits reabsorption of endogenously secreted copper, thereby producing a negative copper balance in Wilson's disease. Once we are certain that zinc blocks accumulation of copper in the liver of Wilson's disease patients, zinc therapy will be available as one approach for treating this fatal disease. The animal literature indicates that zinc protects against lead toxicity when both elements are given orally, no doubt through the intestinal metallothionein mechanism. In preliminary experiments in rats, we have not been able to show that toxicity from lead that arrives into the body through a nonoral route is affected by oral zinc supplements.

  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. 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

  11. Neural correlates of central inhibition during physical fatigue.

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    Masaaki Tanaka

    Full Text Available Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG. Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs in the posterior cingulated cortex (PCC, with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.

  12. Lactobacillus acidophilus Probiotic Inhibits the Growth of Candida albicans

    Directory of Open Access Journals (Sweden)

    Sawitri D. Pertami

    2014-04-01

    Full Text Available Normal 0 false false false IN X-NONE X-NONE MicrosoftInternetExplorer4 Candida albicans is the most common organism causing oral candidiasis. Drug resistance to synthetic antifungal medication is becoming a problem in the treatment of oral candidiasis, especially in immunocompromised patients.Probiotic has been known for its health benefits. It produces lactic acid and bacteriocin that has antibacterial effect. Research focuses on antifungal effect of probiotic, escpecially for C. albicans is still needed. Objective: To determinethe inhibition effect of probiotic in the growth of C. albicans. Methods: Three concentrations of Lactobacillus acidophilus-containing probiotic (McFarland 6, 8, 10 were used to determine their inhibition effect on C. albicans (McFarland 0.5 growing in trypticase yeast-extract cystine (TYC agar. The inhibition effect of probiotic was determined by measuring the inhibition zone produced after 48 hours of culture. Difference in inhibition zone among experimental groups was analyzed using one-way ANOVA and LSD post-test. Results: Probiotic with McFarland 10 had the highest inhibition effect against C. albicans and the difference to other experimental groups was statistically significant (p<0.05. Conclusion: L. acidophilus probiotic has inhibition effect in the growth of C. albicans.DOI: 10.14693/jdi.v20i3.196

  13. Inhibition of Human Neutrophil Elastase by Pentacyclic Triterpenes

    Science.gov (United States)

    Feng, Li; Liu, Xiaoyu; Zhu, Weiliang; Guo, Fujiang; YingchunWu; Wang, Rui; Chen, Kaixian; Huang, Cheng; Li, Yiming

    2013-01-01

    Scope Inhibiting human neutrophil elastase (HNE) is a promising strategy for treating inflammatory lung diseases, such as H1N1 and SARS virus infections. The use of sivelestat, the only clinically registered synthesized HNE inhibitor, is largely limited by its risk of organ toxicity because it irreversibly inhibits HNE. Therefore, potent reversible HNE inhibitors are promising alternatives to sivelestat. Methods and Results An in vitro HNE inhibition assay was employed to screen a series of triterpenes. Six pentacyclic triterpenes, but not tetracyclic triterpenes, significantly inhibited HNE. Of these pentacyclic triterpenes, ursolic acid exhibited the highest inhibitory potency (IC50 = 5.51 µM). The HNE inhibitory activity of ursolic acid was further verified using a mouse model of acute smoke-induced lung inflammation. The results of nuclear magnetic resonance and HNE inhibition kinetic analysis showed that the pentacyclic triterpenes competitively and reversibly inhibited HNE. Molecular docking experiments indicated that the molecular scaffold, 28-COOH, and a double bond at an appropriate location in the pentacyclic triterpenes are important for their inhibitory activity. Conclusion Our results provide insights into the effects of pentacyclic triterpenes on lung inflammatory actions through reversible inhibition of HNE activity. PMID:24376583

  14. Effects of renin inhibition in systemic hypertension.

    Science.gov (United States)

    Anderson, P W; Do, Y S; Schambelan, M; Horton, R; Boger, R S; Luther, R R; Hsueh, W A

    1990-12-01

    The effect of the direct renin inhibitor enalkiren (Abbott Laboratories) was examined in 8 healthy patients with essential hypertension. With an unrestricted sodium diet, plasma renin concentration was inhibited within 10 minutes by intravenous enalkiren and remained essentially undetectable for greater than or equal to 6 hours (11.9 +/- 4 to 1.0 +/- 0.6 ng angiotensin I/ml/hour, p less than 0.05). Mean arterial blood pressure declined gradually (108 +/- 5 to 84 +/- 4 mm Hg, p = 0.02), as did plasma aldosterone concentration (14.4 +/- 3.8 to 4.4 +/- 0.8 ng/dl, p = 0.03), whereas plasma immunoreactive active renin concentration increased progressively (35 +/- 14 to 160 +/- 60 pg/ml, p greater than 0.05). Urinary excretion of the stable metabolite of prostacyclin (6-keto-prostaglandin F1 alpha) decreased slightly, but not significantly (42 +/- 10 to 33 +/- 11 ng/g creatinine, p = 0.13). The addition of a diuretic decreased baseline blood pressure and increased baseline plasma renin and aldosterone values. Blood pressure responses to enalkiren were slightly (though not significantly) greater than those observed before diuretic administration. We conclude that enalkiren is effective in decreasing blood pressure and in inhibiting the renin system, without significantly altering urinary prostacyclin excretion, in patients with essential hypertension. These results suggest that the renin system contributes to the maintenance of elevated blood pressure in some patients with essential hypertension.

  15. 联合检测糖化血红蛋白、尿微量白蛋白、胱抑素C和同型半胱氨酸在糖尿病早期肾损害诊断中的临床意义%Clinical Significance of Joint Detection, Glycosylated Hemoglobin, Urine Trace Albumin Urinary Inhibition, Cystatin-C and Homocysteine with Early Renal Damage in Diabetes

    Institute of Scientific and Technical Information of China (English)

    林华峰; 兰忠诚; 李丽

    2015-01-01

    目的:探讨联合检测糖化血红蛋白(HbA1c)、尿微量白蛋白(UmA1c)、胱抑素C(CysC)和同型半胱氨酸(Hcy)在预测、诊断和治疗糖尿病早期肾病的关系。方法检测108例单纯糖尿病组和52例糖尿病早期肾病的HbA1c、CysC、Hcy、UmA1c水平变化;以100例健康体检者为对照组。结果糖尿病早期肾病组的几项检测水平均高于单纯糖尿病组和健康对照组,差异有统计学意义(P<0.05);在单纯糖尿病和健康对照组比较中CysC、HbA1c水平差异有统计学意义(P<0.05);而Hcy和UmA1c差异无统计学意义(P>0.05)。结论联合检测HbA1c、CysC、Hcy、UmA1c可提高糖尿病肾病的早期诊断效率,并在控制血糖和病程进展中有监测作用,对于延缓甚至逆转糖尿病早期肾病具有积极意义。%Objective To explore the combined detection of glycosylated hemoglobin (HbA1c), urine trace albumin urinary inhibition (UmA1c), Cystatin-C (CysC) and homocysteine (Hcy) in the prediction, diagnosis and treatment of early diabetic nephropathy.Methods 108 cases of simple diabetes group and 52 cases of early diabetic nephropathy HbA1c, CysC, Hcy, UmA1c level changes; in 100 cases of healthy physical examination for the control group.Results Several levels of early diabetic nephropathy group were higher than simple diabetes group and healthy controls, the difference was statistically signiifcant (P0.05).Conclusion The combined detection of HbA1c, CysC, Hcy, UmA1c can improve the efifciency of the early diagnosis of diabetic nephropathy, and in the control of blood sugar and progression monitoring function, to slow or reverse diabetes early kidney disease has positive signiifcance.

  16. 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 BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  17. Proteasome inhibition as a novel therapeutic target in human cancer.

    Science.gov (United States)

    Rajkumar, S Vincent; Richardson, Paul G; Hideshima, Teru; Anderson, Kenneth C

    2005-01-20

    The 26S proteasome is a large intracellular adenosine 5'-triphosphate-dependent protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib.

  18. The Inhibition of Lipase and Glucosidase Activities by Acacia Polyphenol

    Directory of Open Access Journals (Sweden)

    Nobutomo Ikarashi

    2011-01-01

    Full Text Available Acacia polyphenol (AP extracted from the bark of the black wattle tree (Acacia mearnsii is rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. In an in vitro study, we measured the inhibitory activity of AP on lipase and glucosidase. In addition, we evaluated the effects of AP on absorption of orally administered olive oil, glucose, maltose, sucrose and starch solution in mice. We found that AP concentration-dependently inhibited the activity of lipase, maltase and sucrase with an IC50 of 0.95, 0.22 and 0.60 mg ml−1, respectively. In ICR mice, olive oil was administered orally immediately after oral administration of AP solution, and plasma triglyceride concentration was measured. We found that AP significantly inhibited the rise in plasma triglyceride concentration after olive oil loading. AP also significantly inhibited the rise in plasma glucose concentration after maltose and sucrose loading, and this effect was more potent against maltose. AP also inhibited the rise in plasma glucose concentration after glucose loading and slightly inhibited it after starch loading. Our results suggest that AP inhibits lipase and glucosidase activities, which leads to a reduction in the intestinal absorption of lipids and carbohydrates.

  19. Activated sludge inhibition capacity index

    Directory of Open Access Journals (Sweden)

    V. Surerus

    2014-06-01

    Full Text Available Toxic compounds in sewage or industrial wastewater may inhibit the biological activity of activated sludge impairing the treatment process. This paper evaluates the Inhibition Capacity Index (ICI for the assessment of activated sludge in the presence of toxicants. In this study, activated sludge was obtained from industrial treatment plants and was also synthetically produced. Continuous respirometric measurements were carried out in a reactor, and the oxygen uptake rate profile obtained was used to evaluate the impact of inhibiting toxicants, such as dissolved copper, phenol, sodium alkylbenzene sulfonate and amoxicillin, on activated sludge. The results indicate that ICI is an efficient tool to quantify the intoxication capacity. The activated sludge from the pharmaceutical industry showed higher resistance than the sludge from other sources, since toxicants are widely discharged in the biological treatment system. The ICI range was from 58 to 81% when compared to the synthetic effluent with no toxic substances.

  20. Kinetics of Inhibition of Polyphenol Oxidase Obtained from Tobacco Nicotiana Tobacum

    Institute of Scientific and Technical Information of China (English)

    刘卫群; 饶学明; 潘继承; 周海梦

    2004-01-01

    In this study, the kinetics of inhibition of polyphenol oxidase by L-cysteine has been investigated.The inhibition of tobacco polyphenol oxidase was studied using the progress-of-substrate-reaction method proposed by Tsou, following the substrate reaction during irreversible inhibition of the enzyme activity. Analysis of the inhibition kinetics shows that inhibition occurs by an irreversible and non-complexation reaction. The microscopic rate constants were determined for reaction of the inhibitor both with the free enzyme and with the enzyme-substrate complex. The results show that the presence of the substrate has a significant protective effect of the enzyme against inactivation by L-cysteine.

  1. 48 CFR 2110.7003 - Significant events.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Significant events. 2110..., AND OTHER PURCHASE DESCRIPTIONS Contract Specifications 2110.7003 Significant events. The contractor is required to inform the contracting officer of all significant events....

  2. Creating Significant Learning Experiences across Disciplines

    Science.gov (United States)

    Levine, Laura E.; Fallahi, Carolyn R.; Nicoll-Senft, Joan M.; Tessier, Jack T.; Watson, Cheryl L.; Wood, Rebecca M.

    2008-01-01

    The purpose of this study was to use Fink's (2003) taxonomy of significant learning to redesign courses and assess student learning. Significant improvements were found across the semester for students in the six courses, but there were differences in which taxa showed improvement in each course. The meta-analysis showed significant, positive…

  3. 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.

  4. 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.

  5. On combining significances. Some trivial examples

    CERN Document Server

    Krasnikov, N V

    2010-01-01

    For Poisson distribution $Pois(n, \\lambda)$ with $\\lambda \\gg 1$, $n \\gg 1$ we propose to determine significance as $S = \\frac{n_{obs}-\\lambda}{\\sqrt{\\lambda}}$. The significance $S$ coincides up to sign with often used significance. For experiments which measure the same quantities the natural but not unique rule for significance combining is $S_{comb}(S_1, S_2) = \\frac{S_1\\sigma_1+S_2\\sigma_2}{\\sqrt{\\sigma^2_1+\\sigma^2_2}}$, where $\\sigma_1$ and $\\sigma_2$ are variations. We also propose the rule for significances combining for the case with systematic errors.

  6. Reactor design for minimizing product inhibition during enzymatic lignocellulose hydrolysis II. Quantification of inhibition and suitability of membrane reactors

    DEFF Research Database (Denmark)

    Andric, Pavle; Meyer, Anne S.; Jensen, Peter Arendt;

    2010-01-01

    hydrolysis rates and higher enzyme usage efficiency (kg(product/)kg(enzyme)). Current membrane reactor designs are however not feasible for large scale operations. The report emphasizes that the industrial realization of cellulosic ethanol requires more focus on the operational feasibility within......Product inhibition of cellulolytic enzymes affects the efficiency of the biocatalytic conversion of lignocellulosic biomass to ethanol and other valuable products. New strategies that focus on reactor designs encompassing product removal, notably glucose removal, during enzymatic cellulose...... conversion are required for alleviation of glucose product inhibition. Supported by numerous calculations this review assesses the quantitative aspects of glucose product inhibition on enzyme-catalyzed cellulose degradation rates. The significance of glucose product inhibition on dimensioning of different...

  7. Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase.

    Science.gov (United States)

    Wang, Chunhuai; Xiang, Ru; Zhang, Xiangzhong; Chen, Yunxian

    2015-09-01

    Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix‑coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti‑β1‑integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)‑2 and MMP‑9 expression. Furthermore, incubation with blocking anti‑β1‑integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia.

  8. How do we make sense of significance?

    DEFF Research Database (Denmark)

    Lyhne, Ivar; Kørnøv, Lone

    2013-01-01

    Determination of significance is widely recognised as an important step in environmental assessment (EA) processes. The prescriptive literature and guidance on significance determination is comprehensive within the field of EA, whereas descriptive and explorative studies of how we go about making...... sense, or construct meaning, of actions to determine significance are few. This article makes use of sense-making theory to explore how sense-making among EA researchers and practitioners influence significance determination. Focus is on the situation when persons have their first look at information...... about a strategic choice and as part of this make their initial judgement of significance. An experiment is designed and conducted to investigate how persons make sense of a specific case and determine significance in a screening and scoping context. The experiment indicates patterns in the test persons...

  9. Strigolactone inhibition of shoot branching

    NARCIS (Netherlands)

    Gomez-Roldan, M.V.; Fermas, S.; Brewer, P.B.; Puech-Pages, V.; Dun, E.A.; Pillot, J.P.; Letisse, F.; Matusova, R.; Danoun, S.; Portais, J.C.; Bouwmeester, H.J.; Becard, G.; Beveridge, C.A.; Rameau, C.; Rochange, S.F.

    2008-01-01

    A carotenoid-derived hormonal signal that inhibits shoot branching in plants has long escaped identification. Strigolactones are compounds thought to be derived from carotenoids and are known to trigger the germination of parasitic plant seeds and stimulate symbiotic fungi. Here we present evidence

  10. Strigolactone inhibition of shoot branching

    NARCIS (Netherlands)

    Gomez-Roldan, M.V.; Fermas, S.; Brewer, P.B.; Puech-Pages, V.; Dun, E.A.; Pillot, J.P.; Letisse, F.; Matusova, R.; Danoun, S.; Portais, J.C.; Bouwmeester, H.J.; Becard, G.; Beveridge, C.A.; Rameau, C.; Rochange, S.F.

    2008-01-01

    A carotenoid-derived hormonal signal that inhibits shoot branching in plants has long escaped identification. Strigolactones are compounds thought to be derived from carotenoids and are known to trigger the germination of parasitic plant seeds and stimulate symbiotic fungi. Here we present evidence

  11. Methanogenic inhibition by arsenic compounds.

    Science.gov (United States)

    Sierra-Alvarez, Reyes; Cortinas, Irail; Yenal, Umur; Field, Jim A

    2004-09-01

    The acute acetoclastic methanogenic inhibition of several inorganic and organic arsenicals was assayed. Trivalent species, i.e., methylarsonous acid and arsenite, were highly inhibitory, with 50% inhibitory concentrations of 9.1 and 15.0 microM, respectively, whereas pentavalent species were generally nontoxic. The nitrophenylarsonate derivate, roxarsone, displayed moderate toxicity.

  12. Inhibition of carcinogenesis by tea.

    Science.gov (United States)

    Yang, Chung S; Maliakal, Pius; Meng, Xiaofeng

    2002-01-01

    Tea has received a great deal of attention because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. The bioavailability and biotransformation of tea polyphenols, however, are key factors limiting these activities in vivo. The inhibition of tumorigenesis by green or black tea preparations has been demonstrated in animal models on different organ sites such as skin, lung, oral cavity, esophagus, forestomach, stomach, small intestine, colon, pancreas, and mammary gland. Epidemiological studies, however, have not yielded clear conclusions concerning the protective effects of tea consumption against cancer formation in humans. The discrepancy between the results from humans and animal models could be due to 1) the much higher doses of tea used in animals in comparison to human consumption, 2) the differences in causative factors between the cancers in humans and animals, and 3) confounding factors limiting the power of epidemiological studies to detect an effect. It is possible that tea may be only effective against specific types of cancer caused by certain etiological factors. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways that leads to the inhibition of cell proliferation and transformation, induction of apoptosis of preneoplastic and neoplastic cells, as well as inhibition of tumor invasion and angiogenesis. These mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer.

  13. 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...

  14. Islam Does Not Inhibit Science.

    Science.gov (United States)

    Shanavas, T. O.

    1999-01-01

    Compares the science/religion relationship in both Christian and Islamic countries. Presents Muslim scholars' ideas about the presence of humans on earth. Presents ideas on active nature, Noah's curse, and the age of the universe. Refutes the notion that Islam inhibited science and advocates the belief that Islam promoted science. (YDS)

  15. Epigallocatechin gallate inhibits endothelial exocytosis.

    Science.gov (United States)

    Yamakuchi, Munekazu; Bao, Clare; Ferlito, Marcella; Lowenstein, Charles J

    2008-07-01

    Consumption of green tea is associated with a decrease in cardiovascular mortality. The beneficial health effects of green tea are attributed in part to polyphenols, organic compounds found in tea that lower blood pressure, reduce body fat, decrease LDL cholesterol, and inhibit inflammation. We hypothesized that epigallocatechin gallate (EGCG), the most abundant polyphenol in tea, inhibits endothelial exocytosis, the initial step in leukocyte trafficking and vascular inflammation. To test this hypothesis, we treated human umbilical-vein endothelial cells with EGCG and other polyphenols, and then measured endothelial exocytosis. We found that EGCG decreases endothelial exocytosis in a concentration-dependent manner, with the effects most prominent after 4 h of treatment. Other catechin polyphenols had no effect on endothelial cells. By inhibiting endothelial exocytosis, EGCG decreases leukocyte adherence to endothelial cells. In searching for the mechanism by which EGCG affects endothelial cells, we found that EGCG increases Akt phosphorylation, eNOS phosphorylation, and nitric oxide (NO) production. NOS inhibition revealed that NO mediates the anti-inflammatory effects of EGCG. Our data suggest that polyphenols can decrease vascular inflammation by increasing the synthesis of NO, which blocks endothelial exocytosis.

  16. Infant Predictors of Behavioural Inhibition

    Science.gov (United States)

    Moehler, Eva; Kagan, Jerome; Oelkers-Ax, Rieke; Brunner, Romuald; Poustka, Luise; Haffner, Johann; Resch, Franz

    2008-01-01

    Behavioural inhibition in the second year of life is a hypothesized predictor for shyness, social anxiety and depression in later childhood, adolescence and even adulthood. To search for the earliest indicators of this fundamental temperamental trait, this study examined whether behavioural characteristics in early infancy can predict behavioural…

  17. Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition.

    Science.gov (United States)

    Abusnina, Abdurazzag; Keravis, Thérèse; Zhou, Qingwei; Justiniano, Hélène; Lobstein, Annelise; Lugnier, Claire

    2015-02-01

    Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis by stimulating endothelial cells. Increase in cyclic AMP (cAMP) level inhibits VEGF-induced endothelial cell proliferation and migration. Cyclic nucleotide phosphodiesterases (PDEs), which specifically hydrolyse cyclic nucleotides, are critical in the regulation of this signal transduction. We have previously reported that PDE2 and PDE4 up-regulations in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 activities prevents the development of the in vitro angiogenesis by increasing cAMP level, as well as the in vivo chicken embryo angiogenesis. We have also shown that polyphenols are able to inhibit PDEs. The curcumin having anti-cancer properties, the present study investigated whether PDE2 and PDE4 inhibitors and curcumin could have similar in vivo anti-tumour properties and whether the anti-angiogenic effects of curcumin are mediated by PDEs. Both PDE2/PDE4 inhibitor association and curcumin significantly inhibited in vivo tumour growth in C57BL/6N mice. In vitro, curcumin inhibited basal and VEGF-stimulated HUVEC proliferation and migration and delayed cell cycle progression at G0/G1, similarly to the combination of selective PDE2 and PDE4 inhibitors. cAMP levels in HUVECs were significantly increased by curcumin, similarly to rolipram (PDE4 inhibitor) and BAY-60-550 (PDE2 inhibitor) association, indicating cAMP-PDE inhibitions. Moreover, curcumin was able to inhibit VEGF-induced cAMP-PDE activity without acting on cGMP-PDE activity and to modulate PDE2 and PDE4 expressions in HUVECs. The present results suggest that curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition.

  18. Safrole oxide inhibits angiogenesis by inducing apoptosis.

    Science.gov (United States)

    Zhao, Jing; Miao, Junying; Zhao, Baoxiang; Zhang, Shangli; Yin, Deling

    2005-06-01

    Our previous studies indicate that 3, 4-(methylenedioxy)-1-(2', 3'-epoxypropyl)-benzene (safrole oxide), a newly synthesized compound, induces apoptosis in vascular endothelial cells (VECs) and A549 lung cancer cells. To our knowledge, the inhibition of angiogenesis by safrole oxide has not been reported yet. We report here that cultured rat aorta treated with safrole oxide exhibited a significant microvessel reduction as determined by counting the number of microvessels in a phase contrast microscope. There were more microvessels formed in the presence of A549 lung cancer cells in rat aorta model, while a dramatic inhibition of angiogenesis was obtained by adding 220-450 micromol l(-1) of safrole oxide to the growth medium (Psafrole oxide produced only some abortive endothelial cells but not microvessels. Furthermore, safrole oxide induced antiangiogenic effect in the chorioallantoic membranes (CAM) as a dose dependent manner. Eggs treated with 2-11 micromol 100 microl(-1) per egg of the safrole oxide for 48 h exhibited a significant reduction in blood vessel area of the CAM, a process likely mediated by apoptosis as demonstrated by DNA fragmentation. Our results suggest that safrole oxide has antiangiogenic activity and this effect might occur by induction of cellular apoptosis.

  19. Central Region Regionally Ecological Significant Areas

    Data.gov (United States)

    Minnesota Department of Natural Resources — This is an analysis of regionally significant Terrestrial and Wetland Ecological Areas in the seven county metropolitan area. Individual forest, grassland and...

  20. Regionally Significant Ecological Areas - MLCCS derived 2008

    Data.gov (United States)

    Minnesota Department of Natural Resources — This is an analysis of regionally significant Terrestrial and Wetland Ecological Areas in the seven county metropolitan area. Individual forest, grassland and...

  1. A small yeast RNA inhibits HCV IRES mediated translation and inhibits replication of poliovirus in vivo

    Institute of Scientific and Technical Information of China (English)

    Xue-Song Liang; Jian-Qi Lian; Yong-Xing Zhou; Qing-He Nie; Chun-Qiu Hao

    2003-01-01

    AIM: To investigate the anti-virus infection activity of internal ribosome entry site (IRES) specific inhibitor RNA (IRNA).METHODS: IRNA eukaryotic vector pcRz-IRNA or mIRNA eukaryotic vector pcRz-mIRNA was tansfected into human hepatocarcinoma cells (HHCC), then selected with neomycin G418 for 4 to 8 weeks, and then infected with polio virus vaccinas line. The cytopethogenesis effect was investigated and the cell extract was collected. At last the polio virus titer of different cells was determined by plaque assay.RESULTS: Constitutive expression of IRNA was not detrimental to cell growth. HCV IRES-mediated capindependent translation was markedly inhibited in cells constitutively expressing IRNA compared to control hepatoma cells. However, cap-dependent translation was not significantly affected in these cell line. Additionally, HHCC cells constitutively expressing IRNA became refractory to infection of polio virus.CONCLUSION: IRES specific IRNA can inhibit HCV IRES mediated translation and poliovirus replication.

  2. Asymptotic Distributions for Tests of Combined Significance.

    Science.gov (United States)

    Becker, Betsy Jane

    This paper discusses distribution theory and power computations for four common "tests of combined significance." These tests are calculated using one-sided sample probabilities or p values from independent studies (or hypothesis tests), and provide an overall significance level for the series of results. Noncentral asymptotic sampling…

  3. A Differentiated Program: Significant Curriculum Adaptations.

    Science.gov (United States)

    Alonso, Juan A.

    1999-01-01

    This article describes a model for curricular adaptations for gifted students. A distinction is made between non-significant curriculum adaptations that can be easily made by the regular teacher and significant curriculum adaptations that involve deep changes in aims, content, and evaluation criteria. (Contains references.) (DB)

  4. The Vernier Caliper and Significant Figures.

    Science.gov (United States)

    Oberhofer, E. S.

    1985-01-01

    Misconceptions occur because the caliper is often read with the same significant figures as a meter stick; however, the precision of the vernier caliper is greater than the precision of a meter stick. Clarification of scale reading, precision of both tools, and significant figures are discussed. (JN)

  5. Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression

    Directory of Open Access Journals (Sweden)

    Richard Ventura

    2015-08-01

    Research in context: Fatty acid synthase (FASN is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.

  6. The thresholds for statistical and clinical significance

    DEFF Research Database (Denmark)

    Jakobsen, Janus Christian; Gluud, Christian; Winkel, Per

    2014-01-01

    threshold if the trial is stopped early or if interim analyses have been conducted; (4) adjust the confidence intervals and the P-values for multiplicity due to number of outcome comparisons; and (5) assess clinical significance of the trial results. CONCLUSIONS: If the proposed five-step procedure...... not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true. Second, a confidence interval or a P-value showing significance may be caused by multiplicity. Third, statistical significance does not necessarily result in clinical significance. Therefore......, assessment of intervention effects in randomised clinical trials deserves more rigour in order to become more valid. METHODS: Several methodologies for assessing the statistical and clinical significance of intervention effects in randomised clinical trials were considered. Balancing simplicity...

  7. Clinical significance of metallothioneins in cell therapy and nanomedicine

    Directory of Open Access Journals (Sweden)

    Sharma S

    2013-04-01

    Full Text Available Sushil Sharma,1 Afsha Rais,1 Ranbir Sandhu,1 Wynand Nel,1 Manuchair Ebadi21Saint James School of Medicine, Bonaire, The Netherlands; 2Department of Pharmacology, Physiology, and Therapeutics, Center of Excellence in Neuroscience, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USAAbstract: Mammalian metallothioneins (MTs are low molecular weight (6–7 kDa cysteine-rich proteins that are specifically induced by metal nanoparticles (NPs. MT induction in cell therapy may provide better protection by serving as antioxidant, anti-inflammatory, antiapoptotic agents, and by augmenting zinc-mediated transcriptional regulation of genes involved in cell proliferation and differentiation. Liposome-encapsulated MT-1 promoter has been used extensively to induce growth hormone or other genes in culture and gene-manipulated animals. MTs are induced as a defensive mechanism in chronic inflammatory conditions including neurodegenerative diseases, cardiovascular diseases, cancer, and infections, hence can serve as early and sensitive biomarkers of environmental safety and effectiveness of newly developed NPs for clinical applications. Microarray analysis has indicated that MTs are significantly induced in drug resistant cancers and during radiation treatment. Nutritional stress and environmental toxins (eg, kainic acid and domoic acid induce MTs and aggregation of multilamellar electron-dense membrane stacks (Charnoly body due to mitochondrial degeneration. MTs enhance mitochondrial bioenergetics of reduced nicotinamide adenine dinucleotide–ubiquinone oxidoreductase (complex-1, a rate-limiting enzyme complex involved in the oxidative phosphorylation. Monoamine oxidase-B inhibitors (eg, selegiline inhibit α-synuclein nitration, implicated in Lewy body formation, and inhibit 1-methyl 4-phenylpyridinium and 3-morpholinosydnonimine-induced apoptosis in cultured human dopaminergic neurons and mesencephalic fetal stem cells. MTs

  8. Common neural substrates for inhibition of spoken and manual responses.

    Science.gov (United States)

    Xue, Gui; Aron, Adam R; Poldrack, Russell A

    2008-08-01

    The inhibition of speech acts is a critical aspect of human executive control over thought and action, but its neural underpinnings are poorly understood. Using functional magnetic resonance imaging and the stop-signal paradigm, we examined the neural correlates of speech control in comparison to manual motor control. Initiation of a verbal response activated left inferior frontal cortex (IFC: Broca's area). Successful inhibition of speech (naming of letters or pseudowords) engaged a region of right IFC (including pars opercularis and anterior insular cortex) as well as presupplementary motor area (pre-SMA); these regions were also activated by successful inhibition of a hand response (i.e., a button press). Moreover, the speed with which subjects inhibited their responses, stop-signal reaction time, was significantly correlated between speech and manual inhibition tasks. These findings suggest a functional dissociation of left and right IFC in initiating versus inhibiting vocal responses, and that manual responses and speech acts share a common inhibitory mechanism localized in the right IFC and pre-SMA.

  9. Alpha oscillatory correlates of motor inhibition in the aged brain

    Directory of Open Access Journals (Sweden)

    Marlene eBoenstrup

    2015-10-01

    Full Text Available Exerting inhibitory control is a cognitive ability mediated by functions known to decline with age. The goal of this study is to add to the mechanistic understanding of cortical inhibition during motor control in aged brains. Based on behavioral findings of impaired inhibitory control with age we hypothesized that elderly will show a reduced or a lack of EEG alpha-power increase during tasks that require motor inhibition. Since inhibitory control over movements has been shown to rely on prior motor memory formation, we investigated cortical inhibitory processes at two points in time - early after learning and after an overnight consolidation phase and hypothesized an overnight increase of inhibitory capacities. Young and elderly participants acquired a complex finger movement sequence and in each experimental session brain activity during execution and inhibition of the sequence was recorded with multi-channel EEG. We assessed cortical processes of sustained inhibition by means of task-induced changes of alpha oscillatory power. During inhibition of the learned movement, young participants showed a significant alpha power increase at the sensorimotor cortices whereas elderly did not. Interestingly, for both groups, the overnight consolidation phase improved up-regulation of alpha power during sustained inhibition. This points to deficits in the generation and enhancement of local inhibitory mechanisms at the sensorimotor cortices in aged brains. However, the alpha power increase in both groups implies neuroplastic changes that strengthen the network of alpha power generation over time in young as well as elderly brains.

  10. Significance of input correlations in striatal function.

    Directory of Open Access Journals (Sweden)

    Man Yi Yim

    2011-11-01

    Full Text Available The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background activity. We suggest that for the network architecture of the striatum, there is a preferred cortico-striatal input configuration for optimal signal representation. It is further enhanced by the low-rate asynchronous background activity in striatum, supported by the balance between feedforward and feedback inhibitions in the striatal network. Thus, an appropriate combination of rates and correlations in the striatal input sets the stage for action selection presumably implemented in the basal ganglia.

  11. Dietary Polyphenols and Their Biological Significance

    Directory of Open Access Journals (Sweden)

    Hongxiang Lou

    2007-09-01

    Full Text Available Dietary polyphenols represent a wide variety of compounds that occur in fruits,vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products. They aremostly derivatives and/or isomers of flavones, isoflavones, flavonols, catechins andphenolic acids, and possess diverse biological properties such as antioxidant, antiapoptosis,anti-aging, anticarcinogen, anti-inflammation, anti-atherosclerosis, cardiovascularprotection, improvement of the endothelial function, as well as inhibition of angiogenesisand cell proliferation activity. Most of these biological actions have been attributed to theirintrinsic reducing capabilities. They may also offer indirect protection by activatingendogenous defense systems and by modulating cellular signaling processes such asnuclear factor-kappa B (NF-кB activation, activator protein-1(AP-1 DNA binding,glutathione biosynthesis, phosphoinositide 3 (PI3-kinase/protein kinase B (Akt pathway,mitogen-activated protein kinase (MAPK proteins [extracellular signal-regulated proteinkinase (ERK, c-jun N-terminal kinase (JNK and P38 ] activation, and the translocationinto the nucleus of nuclear factor erythroid 2 related factor 2 (Nrf2. This paper covers themost recent literature on the subject, and describes the biological mechanisms of action andprotective effects of dietary polyphenols.

  12. Reactor design for minimizing product inhibition during enzymatic lignocellulose hydrolysis: I. Significance and mechanism of cellobiose and glucose inhibition on cellulolytic enzymes

    DEFF Research Database (Denmark)

    Andric, Pavle; Meyer, Anne S.; Jensen, Peter Arendt;

    2010-01-01

    Achievement of efficient enzymatic degradation of cellulose to glucose is one of the main prerequisites and one of the main challenges in the biological conversion of lignocellulosic biomass to liquid fuels and other valuable products. The specific inhibitory interferences by cellobiose and gluco...

  13. Mining significant semantic locations from GPS data

    DEFF Research Database (Denmark)

    Cao, Xin; Cong, Gao; Jensen, Christian S.

    2010-01-01

    With the increasing deployment and use of GPS-enabled devices, massive amounts of GPS data are becoming available. We propose a general framework for the mining of semantically meaningful, significant locations, e.g., shopping malls and restaurants, from such data. We present techniques capable...... of extracting semantic locations from GPS data. We capture the relationships between locations and between locations and users with a graph. Significance is then assigned to locations using random walks over the graph that propagates significance among the locations. In doing so, mutual reinforcement between...

  14. Mining significant semantic locations from GPS data

    DEFF Research Database (Denmark)

    Cao, Xin; Cong, Gao; Jensen, Christian S.

    2010-01-01

    With the increasing deployment and use of GPS-enabled devices, massive amounts of GPS data are becoming available. We propose a general framework for the mining of semantically meaningful, significant locations, e.g., shopping malls and restaurants, from such data. We present techniques capable...... of extracting semantic locations from GPS data. We capture the relationships between locations and between locations and users with a graph. Significance is then assigned to locations using random walks over the graph that propagates significance among the locations. In doing so, mutual reinforcement between...

  15. Discovering the Significance of Scientific Design Practice

    DEFF Research Database (Denmark)

    Pries-Heje, Jan; Baskerville, Richard

    2016-01-01

    This paper discusses and defines the achievement of significance in design science research. We review the values and processes of old-science and how this mode of science attacks the complexity of scientific knowledge production through analysis. We then explain how new-science attacks...... the complexity of scientific knowledge production through synthesis. The work argues that significance of the new-science contribution in design science can be obfuscated when wrapped in old-science. This understanding helps reveal how new-science, such as design science research, constitutes its significance...

  16. Inhibition by somatostatin interneurons in olfactory cortex

    Directory of Open Access Journals (Sweden)

    Adam M Large

    2016-08-01

    Full Text Available Inhibitory circuitry plays an integral cortical network activity. The development of transgenic mouse lines targeting unique interneuron classes has significantly advanced our understanding of the functional roles of specific inhibitory circuits in neocortical sensory processing. In contrast, considerably less is known about the circuitry and function of interneuron classes in piriform cortex, a paleocortex responsible for olfactory processing. In this study, we sought to utilize transgenic technology to investigate inhibition mediated by somatostatin (SST interneurons onto pyramidal cells, parvalbumin (PV interneurons and other interneuron classes. As a first step, we characterized the anatomical distributions and intrinsic properties of SST and PV interneurons in four transgenic lines (SST-cre, GIN, PV-cre and G42 that are commonly interbred to investigate inhibitory connectivity. Surprisingly, the distributions SST and PV cell subtypes targeted in the GIN and G42 lines were sparse in piriform cortex compared to neocortex. Moreover, two-thirds of interneurons recorded in the SST-cre line had electrophysiological properties similar to fast spiking (FS interneurons rather than regular (RS or low threshold spiking (LTS phenotypes. Nonetheless, like neocortex, we find that SST-cells broadly inhibit a number of unidentified interneuron classes including putatively identified PV cells and surprisingly, other SST cells. We also confirm that SST-cells inhibit pyramidal cell dendrites and thus, influence dendritic integration of afferent and recurrent inputs to the piriform cortex. Altogether, our findings suggest that somatostatin interneurons play an important role in regulating both excitation and the global inhibitory network during olfactory processing.

  17. How do we make sense of significance?

    DEFF Research Database (Denmark)

    Lyhne, Ivar; Kørnøv, Lone

    2013-01-01

    sense, or construct meaning, of actions to determine significance are few. This article makes use of sense-making theory to explore how sense-making among EA researchers and practitioners influence significance determination. Focus is on the situation when persons have their first look at information...... about a strategic choice and as part of this make their initial judgement of significance. An experiment is designed and conducted to investigate how persons make sense of a specific case and determine significance in a screening and scoping context. The experiment indicates patterns in the test persons......' sense-making, including important differences in the way individuals screen and scope. These patterns concern what we notice, how fast we frame the choice, and when we are critical about the provided information. The indications provide a basis for reflections on practice and on how to organise EA...

  18. SIGWX Charts - High Level Significant Weather

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — High level significant weather (SIGWX) forecasts are provided for the en-route portion of international flights. NOAA's National Weather Service Aviation Center...

  19. Significant communities in large sparse networks

    CERN Document Server

    Mirshahvalad, Atieh; Derlen, Mattias; Rosvall, Martin

    2011-01-01

    Researchers use community-detection algorithms to reveal large-scale organization in biological and social networks, but community detection is useful only if the communities are significant and not a result of noisy data. To assess the statistical significance of the network communities, or the robustness of the detected structure, one approach is to perturb the network structure by removing links and measure how much the communities change. However, perturbing sparse networks is challenging because they are inherently sensitive; they shatter easily if links are removed. Here we propose a simple method to perturb sparse networks and assess the significance of their communities. We generate resampled networks by adding extra links based on local information, then we aggregate the information from multiple resampled networks to find a coarse-grained description of significant clusters. In addition to testing our method on benchmark networks, we use our method on the sparse network of the European Court of Just...

  20. SRS Process Facility Significance Fire Frequency

    Energy Technology Data Exchange (ETDEWEB)

    Sarrack, A.G. [Westinghouse Savannah River Company, AIKEN, SC (United States)

    1995-10-01

    This report documents the method and assumptions of a study performed to determine a site generic process facility significant fire initiator frequency and explains the proper way this value should be used.

  1. Fostering significant learning in graduate nursing education.

    Science.gov (United States)

    Marrocco, Geraldine F

    2014-03-01

    Faculty who want to energize graduate students with creative classes that lead to long-lasting learning will benefit by designing course objectives, learning activities, and assessment tools using Fink's taxonomy of significant learning and Wiggins's insights on performance-based or educative assessments. Research shows that course designs relying on content-driven lectures and written examinations do not promote significant learning among adult learners. This article reviews six types of significant learning using Fink's taxonomy and examines Wiggins's "backward" approach to designing courses using performance-based assessments that gauge true learning and learning that promotes a lasting change. When designing courses, educators should ask: "What do I really want students to get out of this course?" The answers will direct the design of objectives, learning activities, and assessment tools. Designing graduate courses using Fink's taxonomy and Wiggins's backward approach can lead to significant learning to better prepare nurse practitioners for the future of health care. Copyright 2014, SLACK Incorporated.

  2. Bryostatin I inhibits growth of breast cancer cells through the inhibition of synuclein-A expression

    Directory of Open Access Journals (Sweden)

    Jun-Xia Sun

    2016-09-01

    Full Text Available The present study was aimed to investigate the effect of bryostatin I on the expression of synuclein-A in breast cancer cells. Western blot analysis showed a significant (p<0.005 reduction in the expression of synuclein-A from a concentration of 20 µM in H3922 cells. The inhibitory effect of bryostatin I on synuclein-A expression was further confirmed by the treatment of H3922 cells with known synuclein-A inhibitor, cytokine oncostatin M. Bryostatin I treatment of H3922 cells also significantly increased their sensitivity to the taxol. Incubation of the cells with 25 µM concentration of bryostatin I followed by treatment with 0.5 μM concentration of taxol induced apoptosis in 89% cells compared to 9% cells in the taxol alone treated cultures. Treatment of the H3922 cells with bryostatin I at 25 µM concentration led to a significant increase in the activation of histone H1 protein. The results from MTT assay showed a significant decrease in the cell viability from 10 µM concentration of bryostatin I. Thus, bryostatin I inhibits the growth of breast cancer cells through inhibition of synuclein-A expression and can be used for breast cancer treatment.

  3. Significance of Studies of Stylistics and Rhetoric

    Institute of Scientific and Technical Information of China (English)

    孙越

    2015-01-01

    Stylistics is a scientific study of style. It is a mode of encoding and decoding language and can be associated with various fields. In this paper,we talk about the great significances of stylistic and rhetoric studies. It refers to great help in expressing and understanding languages;in combining the linguistics and literary criticism and linguistics;great help in promoting and developing computer science and information technology;great significance in sharing heritage of human civilizations.

  4. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    Directory of Open Access Journals (Sweden)

    Maharjan Anu S

    2010-11-01

    Full Text Available Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN-α, IFN-γ, interleukin (IL-12, aggregated immunoglobulin G (IgG or serum amyloid P (SAP, factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.

  5. Activation of GABA B receptors in the anterior pituitary inhibits prolactin and luteinizing hormone secretion.

    Science.gov (United States)

    Lux-Lantos, V; Rey, E; Libertun, C

    1992-11-01

    Previous work from our laboratory showed that baclofen could lower serum prolactin (PRL) levels acting at the central nervous system. The present experiments were designed to evaluate whether the gamma-aminobutyric acid B agonist was also effective in inhibiting hormone release at the pituitary level. In monolayer cultures of adenohypophyseal dispersed cells, baclofen inhibited basal PRL secretion after 1 or 2 h of incubation. This inhibition was significantly abolished by three antagonists: phaclofen, 3-aminopropyl-phosphonic acid and 4-aminobutylphosphonic acid. Furthermore, baclofen inhibited the thyrotropin-releasing hormone-induced PRL release in a concentration-dependent manner. With regard to gonadotropin secretion, baclofen was unable to modify basal luteinizing hormone (LH) secretion, but significantly inhibited the LH-releasing hormone-induced LH release. These results show that baclofen, in addition to its central neuroendocrine effects, inhibits pituitary hormone secretion, under basal and/or stimulated conditions, by direct action at the pituitary level.

  6. Corrosion Chemistry in Inhibited HDA.

    Science.gov (United States)

    1980-11-30

    Titanium and chromium have sufficiently low Flade potentials to pass- ivate in non-oxidising acids, but Iron will only exhibit self-passivity if the...inhibition e.g. involving organic and pickling inhibitors* the rest potential can actually 4.5,4.6become more negative " This is due to cathodic rather...media. 321 stainless steel, titanium stabilised, was the particular steel studied, being very similar in composition to the 347also stainless steel

  7. Notch Signaling Inhibits Axon Regeneration

    OpenAIRE

    Bejjani, Rachid El; Hammarlund, Marc

    2012-01-01

    Many neurons have limited capacity to regenerate their axons after injury. Neurons in the mammalian CNS do not regenerate, and even neurons in the PNS often fail to regenerate to their former targets. This failure is likely due in part to pathways that actively restrict regeneration; however, only a few factors that limit regeneration are known. Here, using single-neuron analysis of regeneration in vivo, we show that Notch/lin-12 signaling inhibits the regeneration of mature C. elegans neuron...

  8. The significance of the washout period in Preconditioning.

    Science.gov (United States)

    Salie, Ruduwaan; Lochner, Amanda; Loubser, Dirk J

    2017-01-24

    Exposure of the heart to 5 min global ischaemia (I) followed by 5 min reperfusion (R) (ischaemic preconditioning, IPC) or transient Beta 2-adrenergic receptor (B2-AR) stimulation with formoterol (B2PC), followed by 5 min washout before index ischaemia, elicits cardioprotection against subsequent sustained ischaemia. Since the washout period during preconditioning is essential for subsequent cardioprotection, the aim of this study was to investigate the involvement of protein kinase A (PKA), reactive oxygen species (ROS), extracellular signal-regulated kinase (ERK), PKB/Akt, p38 MAPK and c-jun N-terminal kinase (JNK) during this period. Isolated perfused rat hearts were exposed to IPC (1x5min I / 5min R) or B2PC (1x5min Formoterol / 5min R) followed by 35 min regional ischaemia and reperfusion. Inhibitors for PKA (Rp-8CPT-cAMP)(16μM), ROS (NAC)(300μM), PKB (A-6730)(2.5μM), ERKp44/p42 (PD98,059)(10μM), p38MAPK (SB239063)(1μM) or JNK (SP600125)(10μM) were administered for 5 minutes before 5 minutes global ischaemia / 5 min reperfusion (IPC) or for 5 minutes before and during administration of formoterol ( B2PC) prior to regional ischaemia, reperfusion and infarct size (IS) determination. Hearts exposed to B2PC or IPC were freeze-clamped during the washout period for Western blots analysis of PKB, ERKp44/p42, p38MAPK and JNK. The PKA blocker abolished both B2PC and IPC, while NAC significantly increased IS of IPC but not of B2PC. Western blot analysis showed that ERKp44/p42 and PKB activation during washout after B2PC compared to IPC was significantly increased. IPC compared to B2PC showed significant p38MAPK and JNKp54/p46 activation. PKB and ERK inhibition or p38MAPK and JNK inhibition during the washout period of B2PC and IPC respectively, significantly increased IS. PKA activation before regional ischaemia is a prerequisite for cardioprotection in both B2PC and IPC. However, ROS was crucial only in IPC. Kinase activation during the washout phase of IPC and B2

  9. Interneuron-mediated inhibition synchronizes neuronal activity during slow oscillation

    Science.gov (United States)

    Chen, Jen-Yung; Chauvette, Sylvain; Skorheim, Steven; Timofeev, Igor; Bazhenov, Maxim

    2012-01-01

    The signature of slow-wave sleep in the electroencephalogram (EEG) is large-amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron-mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure-like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms. PMID:22641778

  10. AI-2 of Aggregatibacter actinomycetemcomitans Inhibits Candida albicans Biofilm Formation

    Directory of Open Access Journals (Sweden)

    Endang W. Bachtiar

    2014-07-01

    Full Text Available Aggregatibacter actinomycetemcomitans, a Gram-negative bacterium, and Candida albicans, a polymorphic fungus, are both commensals of the oral cavity but both are opportunistic pathogens that can cause oral diseases. A. actinomycetemcomitans produces a quorum-sensing molecule called autoinducer-2 (AI-2, synthesized by LuxS, that plays an important role in expression of virulence factors, in intra- but also in interspecies communication. The aim of this study was to investigate the role of AI-2 based signaling in the interactions between C. albicans and A. actinomycetemcomitans. A. actinomycetemcomitans adhered to C. albicans and inhibited biofilm formation by means of a molecule that was secreted during growth. C. albicans biofilm formation increased significantly when co-cultured with A. actinomycetemcomitans luxS, lacking AI-2 production. Addition of wild-type-derived spent medium or synthetic AI-2 to spent medium of the luxS strain, restored inhibition of C. albicans biofilm formation to wild-type levels. Addition of synthetic AI-2 significantly inhibited hypha formation of C. albicans possibly explaining the inhibition of biofilm formation. AI-2 of A. actinomycetemcomitans is synthesized by LuxS, accumulates during growth and inhibits C. albicans hypha- and biofilm formation. Identifying the molecular mechanisms underlying the interaction between bacteria and fungi may provide important insight into the balance within complex oral microbial communities.

  11. Th2 cytokines inhibit lymphangiogenesis.

    Directory of Open Access Journals (Sweden)

    Ira L Savetsky

    Full Text Available Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2 cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4 and interleukin-13 (IL-13 have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis.

  12. Conditioned inhibition and reinforcement rate.

    Science.gov (United States)

    Harris, Justin A; Kwok, Dorothy W S; Andrew, Benjamin J

    2014-07-01

    We investigated conditioned inhibition in a magazine approach paradigm. Rats were trained on a feature negative discrimination between an auditory conditioned stimulus (CS) reinforced at one rate versus a compound of that CS and a visual stimulus (L) reinforced at a lower rate. This training established L as a conditioned inhibitor. We then tested the inhibitory strength of L by presenting it in compound with other auditory CSs. L reduced responding when tested with a CS that had been reinforced at a high rate, but had less or even no inhibitory effect when tested with a CS that had been reinforced at a low rate. The inhibitory strength of L was greater if it signaled a decrease in reinforcement from an already low rate than if it signaled an equivalent decrease in reinforcement from a high rate. We conclude that the strength of inhibition is not a linear function of the change in reinforcement that it signals. We discuss the implications of this finding for models of learning (e.g., Rescorla & Wagner, 1972) that identify inhibition with a difference (subtraction) rule.

  13. Glycation inhibits trichloroacetic acid (TCA)-induced whey protein precipitation

    Science.gov (United States)

    Four different WPI saccharide conjugates were successfully prepared to test whether glycation could inhibit WPI precipitation induced by trichloroacetic acid (TCA). Conjugates molecular weights after glycation were analyzed with SDS-PAGE. No significant secondary structure change due to glycation wa...

  14. Effects of swim stress on latent inhibition using a conditioned taste aversion procedure.

    Science.gov (United States)

    Smith, Shawn; Fieser, Sarah; Jones, Jennifer; Schachtman, Todd R

    2008-10-20

    Rats were used to examine the effects of inescapable swim stress on latent inhibition using a conditioned taste aversion procedure. Subjects were subjected to inescapable swim after each of three saccharin taste preexposures and saccharin was later paired with LiCl. The ability of swim to influence latent inhibition was assessed on subsequent saccharin test trials. Swim stress significantly attenuated latent inhibition. The implications of these results regarding the effects of swim stress on conditioned taste aversion are discussed.

  15. Innovative trend significance test and applications

    Science.gov (United States)

    Şen, Zekai

    2017-02-01

    Hydro-climatological time series might embed characteristics of past changes concerning climate variability in terms of shifts, cyclic fluctuations, and more significantly in the form of trends. Identification of such features from the available records is one of the prime tasks of hydrologists, climatologists, applied statisticians, or experts in related topics. Although there are different trend identification and significance tests in the literature, they require restrictive assumptions, which may not be existent in the structure of hydro-climatological time series. In this paper, a method is suggested with statistical significance test for trend identification in an innovative manner. This method has non-parametric basis without any restrictive assumption, and its application is rather simple with the concept of sub-series comparisons that are extracted from the main time series. The method provides privilege for selection of sub-temporal half periods for the comparison and, finally, generates trend on objective and quantitative manners. The necessary statistical equations are derived for innovative trend identification and statistical significance test application. The application of the proposed methodology is suggested for three time series from different parts of the world including Southern New Jersey annual temperature, Danube River annual discharge, and Tigris River Diyarbakir meteorology station annual total rainfall records. Each record has significant trend with increasing type in the New Jersey case, whereas in other two cases, decreasing trends exist.

  16. Meaning reconstruction in bereavement: sense and significance.

    Science.gov (United States)

    Hibberd, Rachel

    2013-08-01

    Recently there has been growing empirical and theoretical attention to the role of meaning in grief along with increased recognition of the need for more sophisticated definitions of meaning. The present article highlights philosophical issues inherent in the study of meaning and grief reviews the place of meaning in current theories of grief and provides a brief overview of the ways that meaning has been operationalized by grief researchers, including sense-making, benefit finding, identity change, and purpose in life. It is argued that, in our focus on the ways mourners make sense of loss, we have neglected an important aspect of meaning: life significance. Life significance is the felt perception that some aspect of one's life experience "matters." The construct is explored as a potentially important outcome of bereavement; mourners may lose life significance along with their lost loved one, or they may develop new avenues to life significance as they confront mortality and rebuild shattered worldviews. Related literature, such as appreciation of life as a facet of posttraumatic growth, is surveyed for clues as to the role of life significance in grief. Suggestions for future study are offered.

  17. Endogenous Inhibition of Somatic Pain is Impaired in Girls with Irritable Bowel Syndrome Compared with Healthy Girls

    OpenAIRE

    Williams, Amy E; Heitkemper, Margaret; Self, Mariella M.; Czyzewski, Danita I.; Shulman, Robert J.

    2013-01-01

    Endogenous pain-inhibition is often deficient in adults with chronic pain conditions including irritable bowel syndrome (IBS). It is unclear whether deficiencies in pain-inhibition are present in young children with IBS. The present study compared endogenous pain-inhibition, somatic pain threshold, and psychosocial distress in young girls with IBS versus controls. Girls with IBS did not show significant endogenous pain-inhibition of heat pain-threshold during a cold-pressor task in contrast t...

  18. 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.

  19. Tigecycline inhibits proliferation of Acanthamoeba castellanii.

    Science.gov (United States)

    Jha, Bijay Kumar; Seo, Incheol; Kong, Hyun-Hee; Suh, Seong-Il; Suh, Min-Ho; Baek, Won-Ki

    2015-03-01

    Acanthamoeba is an opportunistic protozoan parasite responsible for different diseases in humans, such as granulomatous amoebic encephalitis and amoebic keratitis. Tigecycline, a third-generation tetracycline antibiotic, has potential activity to treat most of the antibiotic resistant bacterial infections. The effects of tigecycline in eukaryotic cells as well as parasites are less well studied. In the present study, we tested the effects of tigecycline on trophozoites of Acanthamoeba castellanii. The inhibitory effect of tigecycline on Acanthamoeba was determined by resazurin reduction and trypan blue exclusion assays. We found that tigecycline significantly inhibited the growth of Acanthamoeba (46.4 % inhibition at the concentration of 100 μM) without affecting cell viability and induction of encystation, whereas other tetracycline groups of antibiotics such as tetracycline and doxycycline showed no inhibitory effects. Furthermore, tigecycline decreased cellular adenosine triphosphate (ATP) level by 26 % than the control and increased mitochondrial mass, suggesting mitochondrial dysfunction in tigecycline-treated cells. These findings suggest that mitochondrial dysfunction with decreased ATP production might play an important mechanism of tigecycline in suppression of Acanthamoeba proliferation.

  20. 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.

  1. Statistical significance of cis-regulatory modules

    Directory of Open Access Journals (Sweden)

    Smith Andrew D

    2007-01-01

    Full Text Available Abstract Background It is becoming increasingly important for researchers to be able to scan through large genomic regions for transcription factor binding sites or clusters of binding sites forming cis-regulatory modules. Correspondingly, there has been a push to develop algorithms for the rapid detection and assessment of cis-regulatory modules. While various algorithms for this purpose have been introduced, most are not well suited for rapid, genome scale scanning. Results We introduce methods designed for the detection and statistical evaluation of cis-regulatory modules, modeled as either clusters of individual binding sites or as combinations of sites with constrained organization. In order to determine the statistical significance of module sites, we first need a method to determine the statistical significance of single transcription factor binding site matches. We introduce a straightforward method of estimating the statistical significance of single site matches using a database of known promoters to produce data structures that can be used to estimate p-values for binding site matches. We next introduce a technique to calculate the statistical significance of the arrangement of binding sites within a module using a max-gap model. If the module scanned for has defined organizational parameters, the probability of the module is corrected to account for organizational constraints. The statistical significance of single site matches and the architecture of sites within the module can be combined to provide an overall estimation of statistical significance of cis-regulatory module sites. Conclusion The methods introduced in this paper allow for the detection and statistical evaluation of single transcription factor binding sites and cis-regulatory modules. The features described are implemented in the Search Tool for Occurrences of Regulatory Motifs (STORM and MODSTORM software.

  2. Impact of Sodium Tungstate and Tungsten Alloys on the Growth of Selected Microorganisms with Environmental Significance

    Science.gov (United States)

    2010-07-30

    TUNGSTEN ALLOYS ON THE GROWTH OF SELECTED MICROORGANISMS WITH ENVIROMENTAL SIGNIFICANCE 5a. Contract Number: 5b. Grant Number: 5c. Program Element...either of these effects would be an issue in environmental settings is unclear. The water-soluble components of both alloys inhibited bacterial

  3. Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

    Institute of Scientific and Technical Information of China (English)

    Peng-fei GE; Ji-zhou ZHANG; Xiao-fei WANG; Fan-kai MENG; Wen-chen LI; Yong-xin LUAN; Feng LING; Yi-nan LUO

    2009-01-01

    Aim: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.Methods: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.Results:MG-132 inhibited cell proliferation,induced cell death and cell cycle arrest at G~JM phase,and activated autophagy in SHG-44 glioma cells.The expression of autophagy-related Beclin-1 and LC3-1 was significantly up-regulated and part of LC3-1 was converted into LC3-11.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 G2/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 LC3-11 from LC3-1 was also inhibited.Conclusion: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.

  4. Significance of oxygen transport through aquaporins

    Science.gov (United States)

    Zwiazek, Janusz J.; Xu, Hao; Tan, Xiangfeng; Navarro-Ródenas, Alfonso; Morte, Asunción

    2017-01-01

    Aquaporins are membrane integral proteins responsible for the transmembrane transport of water and other small neutral molecules. Despite their well-acknowledged importance in water transport, their significance in gas transport processes remains unclear. Growing evidence points to the involvement of plant aquaporins in CO2 delivery for photosynthesis. The role of these channel proteins in the transport of O2 and other gases may also be more important than previously envisioned. In this study, we examined O2 permeability of various human, plant, and fungal aquaporins by co-expressing heterologous aquaporin and myoglobin in yeast. Two of the most promising O2-transporters (Homo sapiens AQP1 and Nicotiana tabacum PIP1;3) were confirmed to facilitate O2 transport in the spectrophotometric assay using yeast protoplasts. The over-expression of NtPIP1;3 in yeasts significantly increased their O2 uptake rates in suspension culture. In N. tabacum roots subjected to hypoxic hydroponic conditions, the transcript levels of the O2-transporting aquaporin NtPIP1;3 significantly increased after the seven-day hypoxia treatment, which was accompanied by the increase of ATP levels in the apical root segments. Our results suggest that the functional significance of aquaporin-mediated O2 transport and the possibility of controlling the rate of transmembrane O2 transport should be further explored. PMID:28079178

  5. Mycotoxins: significance to global economics and health

    Science.gov (United States)

    Mycotoxins are fungal metabolites produced my micro-fungi (molds and mildews) that have significant impacts on global economics and health. Some of these metabolites are beneficial, but most are harmful and have been associated with well-known epidemics dating back to medieval times. The terms ‘myco...

  6. Social significance of community structure: statistical view.

    Science.gov (United States)

    Li, Hui-Jia; Daniels, Jasmine J

    2015-01-01

    Community structure analysis is a powerful tool for social networks that can simplify their topological and functional analysis considerably. However, since community detection methods have random factors and real social networks obtained from complex systems always contain error edges, evaluating the significance of a partitioned community structure is an urgent and important question. In this paper, integrating the specific characteristics of real society, we present a framework to analyze the significance of a social community. The dynamics of social interactions are modeled by identifying social leaders and corresponding hierarchical structures. Instead of a direct comparison with the average outcome of a random model, we compute the similarity of a given node with the leader by the number of common neighbors. To determine the membership vector, an efficient community detection algorithm is proposed based on the position of the nodes and their corresponding leaders. Then, using a log-likelihood score, the tightness of the community can be derived. Based on the distribution of community tightness, we establish a connection between p-value theory and network analysis, and then we obtain a significance measure of statistical form . Finally, the framework is applied to both benchmark networks and real social networks. Experimental results show that our work can be used in many fields, such as determining the optimal number of communities, analyzing the social significance of a given community, comparing the performance among various algorithms, etc.

  7. The Philosophical Significance of Universal Grammar

    Science.gov (United States)

    Hinzen, Wolfram

    2012-01-01

    Throughout its long history, the project of a science of grammar has always been an inherently philosophical one, in which the study of grammar was taken to have special epistemological significance. I ask why 20th and 21st century inquiry into Universal Grammar (UG) has largely lost this dimension, a fact that I argue is partially responsible for…

  8. Significance tests and sample homogeneity loophole

    CERN Document Server

    Kupczynski, Marian

    2015-01-01

    In their recent comment, published in Nature, Jeffrey T.Leek and Roger D.Peng discuss how P-values are widely abused in null hypothesis significance testing . We agree completely with them and in this short comment we discuss the importance of sample homogeneity tests. No matter with how much scrutiny data are gathered if homogeneity tests are not performed the significance tests suffer from sample homogeneity loophole and the results may not be trusted. For example sample homogeneity loophole was not closed in the experiment testing local realism in which a significant violation of Eberhard inequality was found. We are not surprised that Bell type inequalities are violated since if the contextual character of quantum observables is properly taken into account these inequalities cannot be proven. However in order to trust the significance of the violation sample homogeneity loophole must be closed. Therefore we repeat after Jeffrey T.Leek and Roger D.Peng that sample homogeneity loophole is probably just the ...

  9. Significant Workplace Change: Perspectives of Survivors

    Science.gov (United States)

    Kohut, Ann Marie

    2010-01-01

    The ever-increasing pace of workplace change is well documented in the literature, yet little is known about how an individual adapts to significant change in the workplace. Continuous learning is key to successful adaptation; however, are employees' adaptation to change influenced by their approaches to learning? The purpose of this study was to…

  10. Scope and Significance of Eating Disorders.

    Science.gov (United States)

    Mitchell, James E.; Eckert, Elke D.

    1987-01-01

    Describes the increasing prevalence of anorexia nervosa and bulimia in many industrialized societies, and their association with significant morbidity and mortality. Discusses the genetic risks for the development of anorexia nervosa, and treatment strategies. Of these, pharmacotherapy and psychotherapy, particularly those incorporating…

  11. Can Educationally Significant Learning Be Assessed?

    Science.gov (United States)

    Stolz, Steven A.

    2017-01-01

    This article argues that assessment is a central feature of teaching, particularly as a means to determine whether what has been taught has been learnt. However, I take issue with the current trend in education which places a significant amount of emphasis upon large-scale public testing, which in turn has exacerbated the…

  12. Social significance of community structure: Statistical view

    Science.gov (United States)

    Li, Hui-Jia; Daniels, Jasmine J.

    2015-01-01

    Community structure analysis is a powerful tool for social networks that can simplify their topological and functional analysis considerably. However, since community detection methods have random factors and real social networks obtained from complex systems always contain error edges, evaluating the significance of a partitioned community structure is an urgent and important question. In this paper, integrating the specific characteristics of real society, we present a framework to analyze the significance of a social community. The dynamics of social interactions are modeled by identifying social leaders and corresponding hierarchical structures. Instead of a direct comparison with the average outcome of a random model, we compute the similarity of a given node with the leader by the number of common neighbors. To determine the membership vector, an efficient community detection algorithm is proposed based on the position of the nodes and their corresponding leaders. Then, using a log-likelihood score, the tightness of the community can be derived. Based on the distribution of community tightness, we establish a connection between p -value theory and network analysis, and then we obtain a significance measure of statistical form . Finally, the framework is applied to both benchmark networks and real social networks. Experimental results show that our work can be used in many fields, such as determining the optimal number of communities, analyzing the social significance of a given community, comparing the performance among various algorithms, etc.

  13. Bullying in Academe: Prevalent, Significant, and Incessant

    Science.gov (United States)

    Cassell, Macgorine A.

    2011-01-01

    This paper examines the top-down perspective of bullying and mobbing of professors by analyzing why it is prevalent, significant, and incessant and then proposes a framework to produce a caring, respectful, and safe environment for professors to engage in their teaching, scholarship, and service. The author suggests that the failure of…

  14. Encounter Probability of Significant Wave Height

    DEFF Research Database (Denmark)

    Liu, Z.; Burcharth, H. F.

    The determination of the design wave height (often given as the significant wave height) is usually based on statistical analysis of long-term extreme wave height measurement or hindcast. The result of such extreme wave height analysis is often given as the design wave height corresponding to a c...

  15. Surface characterization based upon significant topographic features

    Energy Technology Data Exchange (ETDEWEB)

    Blanc, J; Grime, D; Blateyron, F, E-mail: fblateyron@digitalsurf.fr [Digital Surf, 16 rue Lavoisier, F-25000 Besancon (France)

    2011-08-19

    Watershed segmentation and Wolf pruning, as defined in ISO 25178-2, allow the detection of significant features on surfaces and their characterization in terms of dimension, area, volume, curvature, shape or morphology. These new tools provide a robust way to specify functional surfaces.

  16. Discovering the Significance of Scientific Design Practice

    DEFF Research Database (Denmark)

    Pries-Heje, Jan; Baskerville, Richard

    This paper aims at discussing and defining what it is that makes design science research significant. First it reviews the values and processes of old science and how this attacks complexity through analysis. It then shows how new science attacks complexity through synthesis. Then the paper argues...

  17. Significance of Literature in Foreign Language Teaching

    Science.gov (United States)

    Babaee, Ruzbeh; Yahya, Wan Roselezam Bt Wan

    2014-01-01

    This research aims to consider literature as a significant tool for teaching fundamental language skills including speaking, listening, reading and writing. Reasons for the use of literature in language classrooms and major factors for choosing appropriate kinds of literary texts in such classes should be highlighted in order to make readers aware…

  18. Formal conditions for the significance-effect

    DEFF Research Database (Denmark)

    Thellefsen, Torkild Leo; Sørensen, Bent; Thellefsen, Martin

    2006-01-01

    The significance-effect is the right effect of meaning caused upon an interpreting mind. The right effect is understood as the right interpretation of an intended meaning caused by a sign communicated by an utterer. In the article, which is inspired by Charles S. Peirce's doctrine of signs, his...

  19. Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition1

    Science.gov (United States)

    Mukherjee, Pinku; Basu, Gargi D.; Tinder, Teresa L.; Subramani, Durai B.; Bradley, Judy M.; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

    2013-01-01

    With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRASG12D mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E2 and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer. PMID:19109152

  20. Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease

    Science.gov (United States)

    Beghdadi, Walid; Porcherie, Adeline; Schneider, Bradley S.; Dubayle, David; Peronet, Roger; Huerre, Michel; Watanabe, Takeshi; Ohtsu, Hiroshi; Louis, Jacques; Mécheri, Salaheddine

    2008-01-01

    From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase–deficient (HDC−/−) mice, which are free of histamine. HDC−/− mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC−/− mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC−/− mice to CM was associated with preserved blood–brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria. PMID:18227221

  1. Inhibition of brain tumor cell proliferation by alternating electric fields

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Hyesun; Oh, Seung-ick; Hong, Sunghoi, E-mail: shong21@korea.ac.kr, E-mail: radioyoon@korea.ac.kr [School of Biosystem and Biomedical Science, Korea University, Seoul 136-703 (Korea, Republic of); Sung, Jiwon; Jeong, Seonghoon; Yoon, Myonggeun, E-mail: shong21@korea.ac.kr, E-mail: radioyoon@korea.ac.kr [Department of Bio-convergence Engineering, Korea University, Seoul 136-703 (Korea, Republic of); Koh, Eui Kwan [Seoul Center, Korea Basic Science Institute, Seoul 136-713 (Korea, Republic of)

    2014-11-17

    This study was designed to investigate the mechanism by which electric fields affect cell function, and to determine the optimal conditions for electric field inhibition of cancer cell proliferation. Low-intensity (<2 V/cm) and intermediate-frequency (100–300 kHz) alternating electric fields were applied to glioblastoma cell lines. These electric fields inhibited cell proliferation by inducing cell cycle arrest and abnormal mitosis due to the malformation of microtubules. These effects were significantly dependent on the intensity and frequency of applied electric fields.

  2. Influence of bacteria on film formation inhibiting corrosion

    Energy Technology Data Exchange (ETDEWEB)

    Gunasekaran, G.; Chongdar, Shobhana; Gaonkar, S.N.; Kumar, Pradeep

    2004-08-01

    Mild steel coupons were incubated separately in two bacterial cultures namely Pseudomonas flava and Pseudomonas stutzeri. A significant reduction in the corrosion rate was observed in presence of P. flava. With a view to understand the mechanisms of microbially influenced corrosion/corrosion inhibition, various electrochemical and biological experiments such as weight change measurements and electrochemical impedance spectroscopy (EIS) measurements were made. The exposed surfaces were examined using scanning electron microscope (SEM) and energy dispersive X-ray analysis (EDAX). The scraped surface film was also examined using FT-IR (Fourier transform infra red) spectroscopy. The results suggest that P. flava have enhancing effect on corrosion inhibitive properties of phosphate film.

  3. Significance of DNMT3b in oral cancer.

    Directory of Open Access Journals (Sweden)

    Wen-Cheng Chen

    Full Text Available The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 -DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy.

  4. Significance of DNMT3b in oral cancer.

    Science.gov (United States)

    Chen, Wen-Cheng; Chen, Miao-Fen; Lin, Paul-Yang

    2014-01-01

    The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 -DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy.

  5. Inhibition of existing denitrification enzyme activity by chloramphenicol

    Science.gov (United States)

    Brooks, M.H.; Smith, R.L.; Macalady, D.L.

    1992-01-01

    Chloramphenicol completely inhibited the activity of existing denitrification enzymes in acetylene-block incubations with (i) sediments from a nitrate-contaminated aquifer and (ii) a continuous culture of denitrifying groundwater bacteria. Control flasks with no antibiotic produced significant amounts of nitrous oxide in the same time period. Amendment with chloramphenicol after nitrous oxide production had begun resulted in a significant decrease in the rate of nitrous oxide production. Chloramphenicol also decreased (>50%) the activity of existing denitrification enzymes in pure cultures of Pseudomonas denitrificans that were harvested during log- phase growth and maintained for 2 weeks in a starvation medium lacking electron donor. Short-term time courses of nitrate consumption and nitrous oxide production in the presence of acetylene with P. denitrificans undergoing carbon starvation were performed under optimal conditions designed to mimic denitrification enzyme activity assays used with soils. Time courses were linear for both chloramphenicol and control flasks, and rate estimates for the two treatments were significantly different at the 95% confidence level. Complete or partial inhibition of existing enzyme activity is not consistent with the current understanding of the mode of action of chloramphenicol or current practice, in which the compound is frequently employed to inhibit de novo protein synthesis during the course of microbial activity assays. The results of this study demonstrate that chloramphenicol amendment can inhibit the activity of existing denitrification enzymes and suggest that caution is needed in the design and interpretation of denitrification activity assays in which chloramphenicol is used to prevent new protein synthesis.

  6. On significance of VLBI/Gaia offsets

    CERN Document Server

    Petrov, L

    2016-01-01

    We have cross matched the Gaia Data Release 1 secondary dataset that contains positions of 1.14 billion objects against the most complete to date catalogue of VLBI positions of 11.4 thousand sources, almost exclusively active galactic nuclei. We found 6,064 matches, i.e. 53% radio objects. The median uncertainty of VLBI positions is a factor of 4 smaller than the median uncertainties of their optical counterparts. Our analysis shows that the distribution of normalized arc lengths significantly deviates from Rayleighian shape with an excess of objects with small normalized arc lengths and with a number of outliers. We found that 8% matches have radio optical offsets significant at 99% confidence level. Therefore, we conclude there exists a population of objects with genuine offsets between centroids of radio and optical emission.

  7. EXPLORE SIGNIFICANT FACTORS TO AFFECT CUSTOMER INVOLVEMENT

    Directory of Open Access Journals (Sweden)

    Yu-Jia Hu

    2012-01-01

    Full Text Available Although literature review supported the concept that customer loyalty, brand equity and perceived risk are significant factors to affect customer involvement, very limited studies have extensively examined the relationship among those variables. This research applied quantitative study to comprehensively explore the relationship between customer loyalty, brand equity, perceived risk and customer involvement for consumers. The population for this research was identified as consumers having the shopping experience for digital camera. The findings supported the hypothesis that customer loyalty, brand equity and perceived risk have significant and positive relationship to customer involvement. The findings identified the predictors of customer loyalty, brand equity and perceived risk on the customer involvement and generated the recommendations for corporate operations and future scholar studies.

  8. Social significance of community structure: Statistical view

    CERN Document Server

    Li, Hui-Jia

    2015-01-01

    Community structure analysis is a powerful tool for social networks, which can simplify their topological and functional analysis considerably. However, since community detection methods have random factors and real social networks obtained from complex systems always contain error edges, evaluating the significance of community structure partitioned is an urgent and important question. In this paper, integrating the specific characteristics of real society, we present a novel framework analyzing the significance of social community specially. The dynamics of social interactions are modeled by identifying social leaders and corresponding hierarchical structures. Instead of a direct comparison with the average outcome of a random model, we compute the similarity of a given node with the leader by the number of common neighbors. To determine the membership vector, an efficient community detection algorithm is proposed based on the position of nodes and their corresponding leaders. Then, using log-likelihood sco...

  9. Significance of primary irradiation creep in graphite

    Energy Technology Data Exchange (ETDEWEB)

    Erasmus, Christiaan, E-mail: christiaan.erasmus@gmail.com [Pebble Bed Modular Reactor (Proprietary) Limited, PO Box 9396, Centurion 0046 (South Africa); Kok, Schalk [Advanced Mathematical Modelling, CSIR Modelling and Digital Science, Pretoria 0001 (South Africa); Hindley, Michael P. [Pebble Bed Modular Reactor (Proprietary) Limited, PO Box 9396, Centurion 0046 (South Africa)

    2013-05-15

    Traditionally primary irradiation creep is introduced into graphite analysis by applying the appropriate amount of creep strain to the model at the initial time-step. This is valid for graphite components that are subjected to high fast neutron flux fields and constant stress fields, but it does not allow for the effect of movement of stress locations around a graphite component during life, nor does it allow primary creep to be applied rate-dependently to graphite components subject to lower fast neutron flux. This paper shows that a differential form of primary irradiation creep in graphite combined with the secondary creep formulation proposed by Kennedy et al. performs well when predicting creep behaviour in experimental samples. The significance of primary irradiation creep in particular in regions with lower flux is investigated. It is shown that in low flux regions with a realistic operating lifetime primary irradiation creep is significant and is larger than secondary irradiation creep.

  10. Cross wavelet analysis: significance testing and pitfalls

    Directory of Open Access Journals (Sweden)

    D. Maraun

    2004-01-01

    Full Text Available In this paper, we present a detailed evaluation of cross wavelet analysis of bivariate time series. We develop a statistical test for zero wavelet coherency based on Monte Carlo simulations. If at least one of the two processes considered is Gaussian white noise, an approximative formula for the critical value can be utilized. In a second part, typical pitfalls of wavelet cross spectra and wavelet coherency are discussed. The wavelet cross spectrum appears to be not suitable for significance testing the interrelation between two processes. Instead, one should rather apply wavelet coherency. Furthermore we investigate problems due to multiple testing. Based on these results, we show that coherency between ENSO and NAO is an artefact for most of the time from 1900 to 1995. However, during a distinct period from around 1920 to 1940, significant coherency between the two phenomena occurs.

  11. Representativeness and significance factors in ESP texts

    Directory of Open Access Journals (Sweden)

    Alejandro Curado Fuentes

    2000-04-01

    Full Text Available The development of communicative approaches and strategies in specialized discourse has led to revising notions of representative and significant language . Particularly in the work with academic genres, in science and technology (EST settings such as our own institution, the need for determining these factors is ever growing. The application of empirical resources such as specific language corpora, in fact, becomes convenient. In this paper, the aim is to specify the type of corpus linguistic representativeness and significance sought in the case of teaching English to our groups of Computer Science students. In that scope, we present data and samples on which to base our suggestions and claims regarding the exploitation of textual material.

  12. Respiratory neuroplasticity - Overview, significance and future directions.

    Science.gov (United States)

    Fuller, David D; Mitchell, Gordon S

    2017-01-01

    Neuroplasticity is an important property of the neural system controlling breathing. However, our appreciation for its importance is still relatively new, and we have much to learn concerning different forms of plasticity, their underlying mechanisms, and their biological and clinical significance. In this brief review, we discuss several well-studied models of respiratory plasticity, including plasticity initiated by inactivity in the respiratory system, intermittent and sustained hypoxia, and traumatic injury to the spinal cord. Other aspects of respiratory plasticity are considered in other contributions to this special edition of Experimental Neurology on respiratory plasticity. Finally, we conclude with discussions concerning the biological and clinical significance of respiratory motor plasticity, and areas in need of future research effort.

  13. Significance testing as perverse probabilistic reasoning

    Directory of Open Access Journals (Sweden)

    Westover Kenneth D

    2011-02-01

    Full Text Available Abstract Truth claims in the medical literature rely heavily on statistical significance testing. Unfortunately, most physicians misunderstand the underlying probabilistic logic of significance tests and consequently often misinterpret their results. This near-universal misunderstanding is highlighted by means of a simple quiz which we administered to 246 physicians at two major academic hospitals, on which the proportion of incorrect responses exceeded 90%. A solid understanding of the fundamental concepts of probability theory is becoming essential to the rational interpretation of medical information. This essay provides a technically sound review of these concepts that is accessible to a medical audience. We also briefly review the debate in the cognitive sciences regarding physicians' aptitude for probabilistic inference.

  14. Evaluative meaning and its cultural significance

    OpenAIRE

    Drazdauskiene, Maria Liudvika

    2008-01-01

    In the framework of traditional descriptive semantics, evaluative meaning is defined as an aspect of affective meaning. By virtue of its general positive and negative evaluation, evaluative meaning finds its place in the compartment of interpersonal meaning in functional linguistics. The concept of evaluative meaning is also in agreement with the categorisation of meaning in contemporary stylistics. Having stated its spread and disagreement with logic, the cultural significance of...

  15. Small colony variants and their clinical significance

    Directory of Open Access Journals (Sweden)

    Venkataramana Venkataramana

    2016-01-01

    Full Text Available Among the many factors that contribute to bacterial colonization, persistence and development of infection, the ability of microorganisms to form small colony variants (SCVs assumes great significance. Although bacteria require intrinsic virulence factors to cause pathogenesis, some of them regularly evolve mechanisms to evade immune mechanisms, become resistant to antibiotics, and sustain in the human/animal cells to cause chronic infections. This mini review highlights the recent advances in the study of SCVs.

  16. Significance testing testate amoeba water table reconstructions

    Science.gov (United States)

    Payne, Richard J.; Babeshko, Kirill V.; van Bellen, Simon; Blackford, Jeffrey J.; Booth, Robert K.; Charman, Dan J.; Ellershaw, Megan R.; Gilbert, Daniel; Hughes, Paul D. M.; Jassey, Vincent E. J.; Lamentowicz, Łukasz; Lamentowicz, Mariusz; Malysheva, Elena A.; Mauquoy, Dmitri; Mazei, Yuri; Mitchell, Edward A. D.; Swindles, Graeme T.; Tsyganov, Andrey N.; Turner, T. Edward; Telford, Richard J.

    2016-04-01

    Transfer functions are valuable tools in palaeoecology, but their output may not always be meaningful. A recently-developed statistical test ('randomTF') offers the potential to distinguish among reconstructions which are more likely to be useful, and those less so. We applied this test to a large number of reconstructions of peatland water table depth based on testate amoebae. Contrary to our expectations, a substantial majority (25 of 30) of these reconstructions gave non-significant results (P > 0.05). The underlying reasons for this outcome are unclear. We found no significant correlation between randomTF P-value and transfer function performance, the properties of the training set and reconstruction, or measures of transfer function fit. These results give cause for concern but we believe it would be extremely premature to discount the results of non-significant reconstructions. We stress the need for more critical assessment of transfer function output, replication of results and ecologically-informed interpretation of palaeoecological data.

  17. Characteristics, dynamics and significance of marine snow

    Science.gov (United States)

    Alldredge, Alice L.; Silver, Mary W.

    Macroscopic aggregates of detritus, living organisms and inorganic matter known as marine snow, have significance in the ocean both as unique, partially isolated microenvironments and as transport agents: much of surface-derived matter in the ocean fluxes to the ocean interior and the sea floor as marine snow. As microhabitats, marine snow aggregates contain enriched microbial communities and chemical gradients within which processes of photosynthesis, decomposition, and nutrient regeneration occur at highly elevated levels. Microbial communities associated with marine snow undergo complex successional changes on time scales of hours to days which significantly alter the chemical and biological properties of the particles. Marine snow can be produced either de novo by living plants and animals especially as mucus feeding webs of zooplankton, or by the biologically-enhanced physical aggregation of smaller particles. By the latter pathway, microaggregates, phytoplankton, fecal pellets, organic debris and clay-mineral particles collide by differential settlement or physical shear and adhere by the action of various, biologically-generated, organic compounds. Diatom flocculation is a poorly understood source of marine snow of potential global significance. Rates of snow production and breakdown are not known but are critical to predicting flux and to understanding biological community structure and transformations of matter and energy in the water column. The greatest challenge to the study of marine snow at present is the development of appropriate technology to measure abundances and characteristics of aggregates in situ.

  18. Least significant qubit algorithm for quantum images

    Science.gov (United States)

    Sang, Jianzhi; Wang, Shen; Li, Qiong

    2016-11-01

    To study the feasibility of the classical image least significant bit (LSB) information hiding algorithm on quantum computer, a least significant qubit (LSQb) information hiding algorithm of quantum image is proposed. In this paper, we focus on a novel quantum representation for color digital images (NCQI). Firstly, by designing the three qubits comparator and unitary operators, the reasonability and feasibility of LSQb based on NCQI are presented. Then, the concrete LSQb information hiding algorithm is proposed, which can realize the aim of embedding the secret qubits into the least significant qubits of RGB channels of quantum cover image. Quantum circuit of the LSQb information hiding algorithm is also illustrated. Furthermore, the secrets extracting algorithm and circuit are illustrated through utilizing control-swap gates. The two merits of our algorithm are: (1) it is absolutely blind and (2) when extracting secret binary qubits, it does not need any quantum measurement operation or any other help from classical computer. Finally, simulation and comparative analysis show the performance of our algorithm.

  19. Inhibition of mouse liver respiration by Chelidonium majus isoquinoline alkaloids.

    Science.gov (United States)

    Barreto, M Carmo; Pinto, Ruy E; Arrabaça, João D; Pavão, M Leonor

    2003-12-15

    The alkaloids from Chelidonium majus L. which had a significant inhibitory effect in mitochondrial respiration were those which contain a positive charge due to a quaternary nitrogen atom, i.e., chelerythrine, sanguinarine, berberine and coptisine, both with malate+glutamate or with succinate as substrates. When malate+glutamate was used as substrate, chelerythrine and berberine, which contain methoxy groups, were particularly more active, since they had a strong effect even at low concentrations. In submitochondrial particles, berberine and coptisine had a marked inhibitory effect on NADH dehydrogenase activity but practically no effect on succinate dehydrogenase activity, whereas chelerythrine and sanguinarine inhibited more strongly succinate dehydrogenase than NADH dehydrogenase, which is in agreement with the results found for mitochondrial respiration. Protopine and allocryptopine, which did not inhibit mitochondrial respiration, strongly inhibited NADH dehydrogenase in submitochondrial particles, but had no effect on succinate dehydrogenase activity.

  20. The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication

    Science.gov (United States)

    Sacramento, Carolina Q.; de Melo, Gabrielle R.; de Freitas, Caroline S.; Rocha, Natasha; Hoelz, Lucas Villas Bôas; Miranda, Milene; Fintelman-Rodrigues, Natalia; Marttorelli, Andressa; Ferreira, André C.; Barbosa-Lima, Giselle; Abrantes, Juliana L.; Vieira, Yasmine Rangel; Bastos, Mônica M.; de Mello Volotão, Eduardo; Nunes, Estevão Portela; Tschoeke, Diogo A.; Leomil, Luciana; Loiola, Erick Correia; Trindade, Pablo; Rehen, Stevens K.; Bozza, Fernando A.; Bozza, Patrícia T.; Boechat, Nubia; Thompson, Fabiano L.; de Filippis, Ana M. B.; Brüning, Karin; Souza, Thiago Moreno L.

    2017-01-01

    Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clinical significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurological disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clinically approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addition to the direct inhibition of the viral RNA polymerase, we observed that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV. PMID:28098253

  1. Ketamine protects acetylcholinesterase against inhibition by propoxur and phoxim.

    Science.gov (United States)

    Koutsoviti-Papadopoulou, M; Kounenis, G; Elezoglou, V

    1994-01-01

    In the present study the effect of ketamine on the contractions caused by propoxur and phoxim on the isolated guinea pig ileum was investigated. Ketamine was found able to inhibit in a concentration-dependent manner the contractile responses of the ileum to propoxur and phoxim, while it did not significantly modify the contractions induced by acetylcholine. Propoxur and phoxim augmented the contractile responses induced by acetylcholine in the presence of acetylcholinesterase. This augmentation was prevented by ketamine, in a concentration-dependent manner. These findings suggest that ketamine inhibits the contractile effect of propoxur and phoxim on the guinea pig ileum and this inhibition seems to be associated with the protection of acetylcholinesterase against the action of these two compounds.

  2. Repellents Inhibit P450 Enzymes in Stegomyia (Aedes) aegypti

    Science.gov (United States)

    Jaramillo Ramirez, Gloria Isabel; Logan, James G.; Loza-Reyes, Elisa; Stashenko, Elena; Moores, Graham D.

    2012-01-01

    The primary defence against mosquitoes and other disease vectors is often the application of a repellent. Despite their common use, the mechanism(s) underlying the activity of repellents is not fully understood, with even the mode of action of DEET having been reported to be via different mechanisms; e.g. interference with olfactory receptor neurones or actively detected by olfactory receptor neurones on the antennae or maxillary palps. In this study, we discuss a novel mechanism for repellence, one of P450 inhibition. Thirteen essential oil extracts from Colombian plants were assayed for potency as P450 inhibitors, using a kinetic fluorometric assay, and for repellency using a modified World Health Organisation Pesticide Evaluations Scheme (WHOPES) arm-in cage assay with Stegomyia (Aedes) aegypti mosquitoes. Bootstrap analysis on the inhibition analysis revealed a significant correlation between P450-inhibition and repellent activity of the oils. PMID:23152795

  3. Repellents inhibit P450 enzymes in Stegomyia (Aedes aegypti.

    Directory of Open Access Journals (Sweden)

    Gloria Isabel Jaramillo Ramirez

    Full Text Available The primary defence against mosquitoes and other disease vectors is often the application of a repellent. Despite their common use, the mechanism(s underlying the activity of repellents is not fully understood, with even the mode of action of DEET having been reported to be via different mechanisms; e.g. interference with olfactory receptor neurones or actively detected by olfactory receptor neurones on the antennae or maxillary palps. In this study, we discuss a novel mechanism for repellence, one of P450 inhibition. Thirteen essential oil extracts from Colombian plants were assayed for potency as P450 inhibitors, using a kinetic fluorometric assay, and for repellency using a modified World Health Organisation Pesticide Evaluations Scheme (WHOPES arm-in cage assay with Stegomyia (Aedes aegypti mosquitoes. Bootstrap analysis on the inhibition analysis revealed a significant correlation between P450-inhibition and repellent activity of the oils.

  4. Learning-Inhibiting Problems Experienced by Middle School Teachers: Implications for Staff Development

    OpenAIRE

    Dillard, Patricia Hutcherson

    2000-01-01

    Learning-Inhibiting Problems Experienced by Middle School Teachers: Implications for Staff Development Patricia H. Dillard (ABSTRACT) This study sought to determine if there were statistically significant differences between years of teaching experience and education relative to learning-inhibiting problems in the classroom. These differences were measured by responses on surveys, classroom observations, review of summative teacher appraisal instruments and focus group...

  5. Cholinesterase inhibition of birds inhabiting wheat fields treated with methyl parathion and toxaphene

    Science.gov (United States)

    Niethammer, K.R.; Baskett, T.S.

    1983-01-01

    Red-winged blackbirds (Agelaius phoeniceus) and dickcissels (Spiza americana) inhabiting wheat fields treated with 0.67 kg AI/ha methyl parathion and 1.35 kg AI/ha toxaphene showed brain cholinesterase (ChE) inhibition compared with birds inhabiting untreated fields. Maximum inhibition occurred about five days after insecticide application. ChE activities again approached normal 10 days after treatment. ChE inhibition for dickcissels and red-winged blackbirds differed significantly (p<0.05); maximum inhibition for the former species was 74%, and for the latter, 40%. These differences could not be explained by the diets of the two species, as they were similar.

  6. Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity In Vitro.

    Directory of Open Access Journals (Sweden)

    Anna Beyeler

    Full Text Available It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs. Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons recruit each other through recurrent collaterals and trigger powerful feedback inhibition. Such quantified parameters of neuronal interactions in the hippocampal network may serve as a basis for future characterisation of pathological conditions potentially affecting the interactions between excitation and inhibition in this circuit.

  7. Mechanism of Arsenic Trioxide Inhibiting Angiogenesis in Multiple Myeloma

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In order to explore the molecular mechanism of arsenic trioxide treating multiple myeloma (MM) via inhibition of angiogenesis, the expression of brain derived neurotrophic factor (BD-NF) and its specific receptor TrkB in human MM cell line KM3 and endothelial cell line ECV304 was detected by Western blotting. The angiogenic activity was evaluated by wound migration assay and tubule formation assay in vitro. The results showed that BDNF was detected in the MM cells and TrkB in the endothelial cells. Furthermore, 100 ng/mL BDNF could significantly induced endo thelial cell tubule formation and wound migration. As2 O3 depressed the expression of BDNF and TrkB in the dose- and time-dependent manner. As2O3 inhibited BDNF-induced wound migration and capillary tube formation. It was concluded that BDNF is a novel angiogenic protein as well as VEGF and has a relation with the pathogenesis of MM. As2O3 interrupts a paracrine loop between MM cells and endothelial cells by down-regulating the TrkB expression in endothelial cells and inhibiting BDNF production in MM cells, finally resulting in inhibition of MM angiogenesis. This is probably one part of the mechanisms of the As2O3 treating MM via the inhibition of angiogenesis.

  8. Thyroid peroxidase activity is inhibited by amino acids

    Directory of Open Access Journals (Sweden)

    D.P. Carvalho

    2000-03-01

    Full Text Available Normal in vitro thyroid peroxidase (TPO iodide oxidation activity was completely inhibited by a hydrolyzed TPO preparation (0.15 mg/ml or hydrolyzed bovine serum albumin (BSA, 0.2 mg/ml. A pancreatic hydrolysate of casein (trypticase peptone, 0.1 mg/ml and some amino acids (cysteine, tryptophan and methionine, 50 µM each also inhibited the TPO iodide oxidation reaction completely, whereas casamino acids (0.1 mg/ml, and tyrosine, phenylalanine and histidine (50 µM each inhibited the TPO reaction by 54% or less. A pancreatic digest of gelatin (0.1 mg/ml or any other amino acid (50 µM tested did not significantly decrease TPO activity. The amino acids that impair iodide oxidation also inhibit the TPO albumin iodination activity. The inhibitory amino acids contain side chains with either sulfur atoms (cysteine and methionine or aromatic rings (tyrosine, tryptophan, histidine and phenylalanine. Among the amino acids tested, only cysteine affected the TPO guaiacol oxidation reaction, producing a transient inhibition at 25 or 50 µM. The iodide oxidation inhibitory activity of cysteine, methionine and tryptophan was reversed by increasing iodide concentrations from 12 to 18 mM, while no such effect was observed when the cofactor (H2O2 concentration was increased. The inhibitory substances might interfere with the enzyme activity by competing with its normal substrates for their binding sites, binding to the free substrates or reducing their oxidized form.

  9. Os odontoideum: a significant radiographic finding

    Energy Technology Data Exchange (ETDEWEB)

    Choit, Rachel L.; Reilly, Christopher W. [BC Children' s Hospital, Department of Orthopaedics, Vancouver, BC (Canada); Jamieson, Douglas H. [BC Children' s Hospital, Department of Radiology, Vancouver (Canada)

    2005-08-01

    Os odontoideum can lead to instability of the atlantoaxial joint and places the spinal cord at significant risk for acute catastrophic events after minor trauma or chronic neurological change. We present two cases of os odontoideum in pediatric patients that were not appreciated at earlier remote imaging but were, in retrospect, detectable. One patient presented with an acute spinal cord injury. Incorporating assessment of dens integrity into the evaluation algorithm for all pediatric cervical spine studies should lead to early detection of os odontoideum lesions and allow referral to appropriate clinical spinal services for evaluation, surveillance and possible surgery to prevent future complications. (orig.)

  10. Detecting significant changes in protein abundance

    Directory of Open Access Journals (Sweden)

    Kai Kammers

    2015-06-01

    Full Text Available We review and demonstrate how an empirical Bayes method, shrinking a protein's sample variance towards a pooled estimate, leads to far more powerful and stable inference to detect significant changes in protein abundance compared to ordinary t-tests. Using examples from isobaric mass labelled proteomic experiments we show how to analyze data from multiple experiments simultaneously, and discuss the effects of missing data on the inference. We also present easy to use open source software for normalization of mass spectrometry data and inference based on moderated test statistics.

  11. Clinical significance of HIV-1 coreceptor usage

    Directory of Open Access Journals (Sweden)

    Lusso Paolo

    2010-01-01

    Full Text Available Abstract The identification of phenotypically distinct HIV-1 variants with different prevalence during the progression of the disease has been one of the earliest discoveries in HIV-1 biology, but its relevance to AIDS pathogenesis remains only partially understood. The physiological basis for the phenotypic variability of HIV-1 was elucidated with the discovery of distinct coreceptors employed by the virus to infect susceptible cells. The role of the viral phenotype in the variable clinical course and treatment outcome of HIV-1 infection has been extensively investigated over the past two decades. In this review, we summarize the major findings on the clinical significance of the HIV-1 coreceptor usage.

  12. Significance of Jane Eyre' s Independence

    Institute of Scientific and Technical Information of China (English)

    潘文涛

    2008-01-01

    Jane Eyre, by far the best known of Charlotte Bronte' s literary production, published 1847. Jane, the heroine, a governess's rebelliousness, her hate ot servility, her insistence on equality with her master, and her declaration that she has a right to feelings and passions that impresses me most. This paper, from what Jane Eyre experiences and what she thinks about the happenings, analyses Jane Eyreg independent characters and spirits in five segments each with its own setting: Gateshead, Lowood, Thnmfield, Moor House, Femdean, points out the significance of Jane Eyre's independence in her ages.

  13. Significant exposures to isoeugenol derivaties in perfumes

    DEFF Research Database (Denmark)

    Rastogi, Suresh Chandra; Johansen, Jeanne Duus

    2008-01-01

    in perfumes/aftershaves. MATERIALS AND METHODS: 29 international brand perfumes/aftershaves were analysed for the target fragrance ingredient by gas chromatography-mass spectrometry. All samples were analysed in duplicate at detection levels of 1-5 p.p.m. RESULTS: 16 products (55%) contained isoeugenol...... was not detected in any of the investigated products. CONCLUSIONS: Isoeugenyl acetate is present in perfumes/aftershaves, in some products in significant amounts. This may lead to elicitation of contact allergy in isoeugenol-sensitized individuals and may contribute to unchanged levels of isoeugenol sensitization....

  14. Significance of Conflict Talk in interpersonal Relationships

    Institute of Scientific and Technical Information of China (English)

    柯建华; 罗丹

    2016-01-01

    Conflict talks occur in almost every field of human life such as medicine, school, court, and some other social organizations where the interaction results are of much significance to the conversationalists, or in others words, to their status in the organization and honor in the society. A lot of conflicts go unresolved. Oppositional exchanges in a conflict may be used by participants to achieve certain goals, for instance, exploring and developing verbal skills as candidates in a debate competition do, and maintaining social hierarchies within groups or organizations such as leaders giving orders in an institution. Dealing with conflict helps to promote interpersonal relationships.

  15. Thermodynamic Significance of Human Basal Metabolism

    Institute of Scientific and Technical Information of China (English)

    WangCuncheng

    1993-01-01

    The human basal state,a non-equilibrium steady state,is analysed in this paper in the light of the First and Second Laws of Thermodynamics whereby the thermodynamic significance of the basal metabolic rate and its distinction to the dissipation function and exergy loss are identified.The analysis demonstrates the correct expression of the effects of the blood flow on the heat balance in a human-body bio-heat model and the relationship between the basal metabolic rate and the blood perfusion.

  16. 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.

  17. 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.

  18. 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.

  19. Salicylic acid inhibits enzymatic browning of fresh-cut Chinese chestnut (Castanea mollissima) by competitively inhibiting polyphenol oxidase.

    Science.gov (United States)

    Zhou, Dan; Li, Lin; Wu, Yanwen; Fan, Junfeng; Ouyang, Jie

    2015-03-15

    The inhibitory effect and associated mechanisms of salicylic acid (SA) on the browning of fresh-cut Chinese chestnut were investigated. Shelled and sliced chestnuts were immersed in different concentrations of an SA solution, and the browning of the chestnut surface and interior were inhibited. The activities of polyphenol oxidase (PPO) and peroxidase (POD) extracted from chestnuts were measured in the presence and absence of SA. SA at concentrations higher than 0.3g/L delayed chestnut browning by significantly inhibiting the PPO activity (P0.05). The binding and inhibition modes of SA with PPO and POD, determined by AUTODOCK 4.2 and Lineweaver-Burk plots, respectively, established SA as a competitive inhibitor of PPO.

  20. Significance and popularity in music production

    Science.gov (United States)

    Monechi, Bernardo; Gravino, Pietro; Servedio, Vito D. P.; Tria, Francesca; Loreto, Vittorio

    2017-07-01

    Creative industries constantly strive for fame and popularity. Though highly desirable, popularity is not the only achievement artistic creations might ever acquire. Leaving a longstanding mark in the global production and influencing future works is an even more important achievement, usually acknowledged by experts and scholars. `Significant' or `influential' works are not always well known to the public or have sometimes been long forgotten by the vast majority. In this paper, we focus on the duality between what is successful and what is significant in the musical context. To this end, we consider a user-generated set of tags collected through an online music platform, whose evolving co-occurrence network mirrors the growing conceptual space underlying music production. We define a set of general metrics aiming at characterizing music albums throughout history, and their relationships with the overall musical production. We show how these metrics allow to classify albums according to their current popularity or their belonging to expert-made lists of important albums. In this way, we provide the scientific community and the public at large with quantitative tools to tell apart popular albums from culturally or aesthetically relevant artworks. The generality of the methodology presented here lends itself to be used in all those fields where innovation and creativity are in play.

  1. Significance and popularity in music production.

    Science.gov (United States)

    Monechi, Bernardo; Gravino, Pietro; Servedio, Vito D P; Tria, Francesca; Loreto, Vittorio

    2017-07-01

    Creative industries constantly strive for fame and popularity. Though highly desirable, popularity is not the only achievement artistic creations might ever acquire. Leaving a longstanding mark in the global production and influencing future works is an even more important achievement, usually acknowledged by experts and scholars. 'Significant' or 'influential' works are not always well known to the public or have sometimes been long forgotten by the vast majority. In this paper, we focus on the duality between what is successful and what is significant in the musical context. To this end, we consider a user-generated set of tags collected through an online music platform, whose evolving co-occurrence network mirrors the growing conceptual space underlying music production. We define a set of general metrics aiming at characterizing music albums throughout history, and their relationships with the overall musical production. We show how these metrics allow to classify albums according to their current popularity or their belonging to expert-made lists of important albums. In this way, we provide the scientific community and the public at large with quantitative tools to tell apart popular albums from culturally or aesthetically relevant artworks. The generality of the methodology presented here lends itself to be used in all those fields where innovation and creativity are in play.

  2. Significance of salmonella in pork production chain

    Directory of Open Access Journals (Sweden)

    Karabasil Neđeljko

    2008-01-01

    Full Text Available Animals, feed, meat and meat products are often transported across long distances, being an important part of international trade, which enables a dissemination of salmonella, including even of some resistant strains. Pigs are animals which are difficult to manipulate because of their temperament, build, sharp teeth, irritability, good sense of smell, bad sight and their sensitivity to stress. Animals coming from different farms should be separated in stock yards to prevent both contamination with pathogens such as salmonella and their irritation and aggressiveness caused by contacts with other pigs. These animals are usually a significant reservoir of salmonella which are 'inside' the gastrointestinal tract and gut associated lymph tissue. In contrast to our country, in the EU, even countries which have always had low salmonella prevalence, e.g. Finland, have a control program. The program has to be based on a guarantee that all relevant factors will participate in the prevention of salmonella contamination.

  3. Urban building recognition during significant temporal variations

    DEFF Research Database (Denmark)

    Nguyen, Phuong Giang; Andersen, Hans Jørgen

    2008-01-01

    In literature, existing researches on building recognition mainly concentrate on scales, rotations, and viewpoints variance. In urban environment, large temporal variations of weather and lighting conditions should also be considered as major challenges for robust recognition. For instances......, there are differences between images captured during daytime and nighttime, especially significant changes in building appearances between seasons because of the differences in light setting. To date, these large temporal variation issues have not been fully investigated. In this paper, we therefore focus...... on constructing a system that deals with the temporal difference factors in recognizing urban buildings. In order to build such a system, two main criteria are raised, namely the efficiency of the recognition algorithm and the speed for interactive search purpose. For recognition purpose, we exploit the MOPS...

  4. The origins and significance of contemporary terrorism

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, B. [Calgary Univ., AB (Canada)

    2002-07-01

    Terrorism has been the subject of many presidential and prime ministerial statements over the years. Sixteen weeks before the attacks on the World Trade Centre and the Pentagon, the American Secretary of State, referred to a report that indicated an 8 per cent increase in international terrorist attacks during year 2000 and stated that terrorism shows the dark side of globalization. Of the 423 recorded attacks, 200 were directed against the United States. This paper emphasizes three points to understand the significance of terrorism. First, it is necessary to understand the context within which terrorist acts are carried out, namely the modern world in its spiritual and its material dimensions. It is also necessary to understand the direction and trajectory of recent trends in terrorism and what can be done to stop it. 97 refs.

  5. Human error: A significant information security issue

    Energy Technology Data Exchange (ETDEWEB)

    Banks, W.W.

    1994-12-31

    One of the major threats to information security human error is often ignored or dismissed with statements such as {open_quotes}There is not much we can do about it.{close_quotes} This type of thinking runs counter to reality because studies have shown that, of all systems threats, human error has the highest probability of occurring and that, with professional assistance, human errors can be prevented or significantly reduced Security analysts often overlook human error as a major threat; however, other professionals such as human factors engineers are trained to deal with these probabilistic occurrences and mitigate them. In a recent study 55% of the respondents surveyed considered human error as the most important security threat. Documentation exists to show that human error was a major cause of the consequences suffered at Three Mile Island, Chernobyl, Bhopal, and the Exxon tanker, Valdez. Ironically, causes of human error can usually be quickly and easily eliminated.

  6. THRESHOLD OF SIGNIFICANCE IN STRESS MANAGEMENT

    Directory of Open Access Journals (Sweden)

    Elena RUSE

    2015-12-01

    Full Text Available Stress management is the individual's ability to handle any situation, external conditions, to match the demands of the external environment. The researchers revealed several stages in the stress response. A first phase was called ‘‘alert reaction'' or ‘‘immediate reaction to stress‘‘, phase in which there are physiological modifications and manifestations that occur under psychological aspect. Adaptation phase is the phase in which the reactions from the first phase diminishes or disappears. Exhaustion phase is related to the diversity of stress factors and time and may exceed the resources of the human body to adapt. Influencing factors may be: limited, cognitive, perceptual, and a priori. But there is a threshold of significance in stress management. Once the reaction to external stimuli occurs, awareness is needed. The capability effect occurs, any side effect goes away and comes out the ''I AM'' effect.

  7. Boiling significantly promotes photodegradation of perfluorooctane sulfonate.

    Science.gov (United States)

    Lyu, Xian-Jin; Li, Wen-Wei; Lam, Paul K S; Yu, Han-Qing

    2015-11-01

    The application of photochemical processes for perfluorooctane sulfonate (PFOS) degradation has been limited by a low treatment efficiency. This study reports a significant acceleration of PFOS photodegradation under boiling condition compared with the non-boiling control. The PFOS decomposition rate increased with the increasing boiling intensity, but declined at a higher hydronium level or under oxygenation. These results suggest that the boiling state of solution resulted in higher effective concentrations of reactants at the gas-liquid interface and enhanced the interfacial mass transfer, thereby accelerating the PFOS decomposition. This study broadens our knowledge of PFOS photodegradation process and may have implications for development of efficient photodegradation technologies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. CNOOC Sales Revenues Rise Significantly in 2008

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    @@ China National Offshore Oil Corporation (CNOOC),the country's third largest oil and gas producer,saw its full year sales revenues of 2008 rose 22.4 percent from a year ago to 98.3 billion yuan (US$14.37 billion).By the end of 2008,the total assets of the company were 428.5 billion yuan,up 267 percent from five years earlier.The company's listed ann CNOOC Ltd.said in mid-January it planed to lift its 2009 crude and gas production by 16 percent to 18 percent,as some significant projects are expected to come online this year.Total production will be 225 million to 231 million barrels of oil equivalent (BOE),compared with the estimated production of 194 million to 196 million BOE for 2008.

  9. On Imaginative Criminology and Its Significance

    Directory of Open Access Journals (Sweden)

    Jon Frauley

    2015-08-01

    Full Text Available In growing numbers criminologists are discovering the value of imaginative and creative approaches for enquiry. There is now a critical mass of criminological work that engages substantively and theoretically with cultural artefacts such as film, fiction, music, dance, art, photography and cultural institutions. In doing so these works highlight criminology’s persistent epistemological and methodological weaknesses. The broad and fragmented “imaginative criminology” movement offers a challenge to an orthodox criminology that is guided by the coercive and constraining bureaucratic categories of criminal justice administration and the criminal law. Imaginative criminology displaces these as the governing categories of criminological thought and practice. Drawing on the work of Pierre Bourdieu, Louis Althusser, and C. Wright Mills this paper considers the movement’s epistemological significance and the challenge posed to criminological orthodoxy.

  10. [Pathogenesis and significance of diabetic dyslipidemia].

    Science.gov (United States)

    Zeman, M; Zák, A

    2004-01-01

    Patients with type 2 diabetes mellitus are at the higher risk of development of on arteriosclerosis based cardiovascular diseases. Epidemiological studies have shown that diabetic dislipidemia with hypertriglyceridemia, presence of small dense LDL subfraction, low concentration of HDL-cholesterol and increased postprandial lipemia can represent a serious threat. Several studies have found significant decrease of cardiovascular morbidity and mortality after a treatment of diabetic dislipidemia, namely by statins and fibrates. Contemporary therapeutic algorhithms of European and American professional societies for the hyperlipidemia treatment classify diabetes mellitus as an equivalent of already developed complication of atherosclerosis. Our article presents pathophysiology of the diabetic dislipidemia, recommended target values of pasma lipids in diabetic patients and an overview of present possibilities of pharmacotherapy of the diabetic dislipidemia.

  11. The Symbolic Significance of The Scarlet Letter

    Institute of Scientific and Technical Information of China (English)

    张力

    2007-01-01

    As a great romantic novelist in America in 19th century, Hawthorne was outstanding in handling the application of symbolism. The Scarlet Letter is Hawthorne's most important symbolic novel, which stands as the best work of Hawthorne and one of the indubitable masterpieces of American literature. This thesis aims at the exploration of the usage of the symbolism in the novel. It mainly discusses the deep symbolic significance of the scarlet letter "A" and the little pearl. The scarlet letter is the central symbol of the novel. Its symbolic meaning changes from 'adultery' to 'able', even 'angelic' in the novel. It also examines the symbolic meanings of little Pearl and some typical natural surroundings such as the jail, the forest, the rosebush and so on.

  12. Biotechnological significance of toxic marine dinoflagellates.

    Science.gov (United States)

    Camacho, F Garcia; Rodríguez, J Gallardo; Mirón, A Sánchez; García, M C Cerón; Belarbi, E H; Chisti, Y; Grima, E Molina

    2007-01-01

    Dinoflagellates are microalgae that are associated with the production of many marine toxins. These toxins poison fish, other wildlife and humans. Dinoflagellate-associated human poisonings include paralytic shellfish poisoning, diarrhetic shellfish poisoning, neurotoxic shellfish poisoning, and ciguatera fish poisoning. Dinoflagellate toxins and bioactives are of increasing interest because of their commercial impact, influence on safety of seafood, and potential medical and other applications. This review discusses biotechnological methods of identifying toxic dinoflagellates and detecting their toxins. Potential applications of the toxins are discussed. A lack of sufficient quantities of toxins for investigational purposes remains a significant limitation. Producing quantities of dinoflagellate bioactives requires an ability to mass culture them. Considerations relating to bioreactor culture of generally fragile and slow-growing dinoflagellates are discussed. Production and processing of dinoflagellates to extract bioactives, require attention to biosafety considerations as outlined in this review.

  13. Significant new quantitative EGG patterns in fibromyalgia

    Directory of Open Access Journals (Sweden)

    Jorge Navarro López

    2015-12-01

    Full Text Available Background and Objectives: We analyzed the EEG recordings of a sample of fibromyalgia patients, with the goal of looking for new, more objective indicators on the diagnosis and severity assessment of this pathology, and looking also to establish the relationship of these new indicators with different psychological and neuropsychiatric tests. Methods: We compared the EEG recordings of a group of 13 fibromyalgia patients with a normalized database built into the software of the equipment used (Neuronic, and also with a control group of 13 individuals; both groups were selected under the same criteria of inclusion-exclusion. Patients and controls underwent quantitative EEG (eyes closed, according to international 10-20 EEG system and were specifically evaluated throughout various neuropsychiatric and psychological questionnaires. Results: We obtained the absolute powers of QEEG (quantitative for the different electrode sites and frequency bands, we determined the corresponding values of the deviation from normal (Z-scores, and estimated various indicators and ratios, as well as correlations with the results of psychological tests. Interestingly, the ratios of theta and beta frequencies in relation with alpha appear as one of the most relevant indicators of the severity of the pathology; significant differences were also found in the peak frequency (maximum power per Hz of the alpha band, and in the frequency peak of the total spectrum. Conclusions: The consistency of the abnormal EEG patterns of fibromyalgia patients revealed the presence of systemic dysfunction at the central nervous system level, beyond possible peripheral anomalies and specific tissue pathologies. Among the indicators and benchmarks achieved, the most important changes concern the frequencies theta, alpha and beta, and still more significant were the values of their ratios in the comparison between patients and controls. The relative values of peak frequencies are also of

  14. Vitronectin significantly influences prognosis in osteosarcoma.

    Science.gov (United States)

    Shi, Kai; Lan, Rui-Long; Tao, Xuan; Wu, Chao-Yang; Hong, Hai-Feng; Lin, Jian-Hua

    2015-01-01

    Vitronectin (Vn), a multifunctional adhesive protein, is found in association with tumor progression, angiogenesis and metastasis in a variety of (human) tumors. But no studies concerning its correlation to osteosarcoma prognosis were found. Hence, we aimed to investigate the prognostic value of Vitronectin (Vn) in osteosarcoma. Here, we studied the expression of VN in the tumor tissues from 67 patients with osteosarcoma and 20 patients with osteochondroma using immunohistochemistry and estimated the effects of VN expression in osteosarcoma on progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier curve and COX proportional hazards regression model. Increased expression of VN in osteosarcoma tissue compared to no VN expression in osteochondroma tissue was shown in immunohistochemical assay. No associations were observed between VN expression and osteosarcoma patients' gender (P = 0.675), age (P = 0.813), tumor size (P = 0.436), histologic subtype (P = 0.0.543) or tumor location (P = 0.456). Univariate survival analysis demonstrated significant correlations of high VN expression with shorter PFS (P = 0.002) and OS (P = 0.001); multivariate survival analysis revealed high VN expression as a significant independent prognostic indicator for shorter PFS (HR 2.788, P = 0.003) and OS (HR2.817, P = 0.003). In conclusion, the high expression of VN in tumor cells independently indicated poor clinical prognosis in patients with osteosarcoma, other than large tumor size and non-neoadjuvant chemoradiotherapy, suggesting that VN may serve as a potential therapeutic target in osteosarcoma.

  15. Immunophenotyping in leukemia and its diagnostic significance

    Directory of Open Access Journals (Sweden)

    S. B. Kresno

    2004-09-01

    Full Text Available The identification of cell surface markers, defined as clusters of differentiation antigens (CD’s could be used to classify and sub-classify leukemia. Although the same antigens are expressed on normal cells, the phenotype on malignant cells are aberrantly and frequently asynchronously expressed and may be present in combinations not observed in normal blood or bone marrow. Aberrant expression of surface antigens corresponds with poor therapeutic response and short survival. Additional surface marker analysis complementary to morphologic evaluation and cytochemical staining has greatly improved our ability to characterize hematologic malignancies. A review and illustration on the diagnostic significance of immunophenotyping in leukemia will be presented. Data from 225 patients having complete assessments including morphology, cytochemistry and immunophenotyping in the period of 1994-2001 were collected and analyzed. Based on morphologic evaluation and cytochemistry, the diagnosis of acute myeloid leukemia and acute lymphoblastic leukemia were established in 51.1% and 48.9% of cases, respectively. Based on immunophenotyping AML was found in 49.0% of the cases. ALL could be classified into 4.9% pre-B-ALL, 18.7% B-ALL, and 14.7% T-ALL. Cases expressing cross-lineage antigens were found in 12.7%. The prognostic significance of these aberrant expression of antigens for those cases has yet to be established but some of the cases responded poorly to therapy. Immunophenotyping provides the tool to: 1 distinguish normal from clonal populations of leukemic cells; 2 define lineage and reveal the stage of maturation; 3 identify inappropriate expression of lineage associated antigens; 4 provides more informations to establish diagnosis and prognosis compared to standard methods. (Med J Indones 2004; 13: 195-202 Keywords: Immunophenotyping, clusters of differentiation antigens, lineage associated antigens

  16. The significance of the integumentary profile.

    Science.gov (United States)

    Satravaha, S; Schlegel, K D

    1987-11-01

    Profile analysis was performed on 180 Thai female subjects with ages ranging from 16 to 21 years. Seventy were of Chinese origin. The determination of the profile analysis mean values was based on the methods of Schwarz, Subtelny, Ricketts, Burstone, and Schwartz. The results were compared to Caucasian standards and to the findings of our previous study on a Javanese population. For the profile forms, our investigated groups showed mainly prognathic faces (75% to 84%). A "shift backward" profile flow dominated. We found a "prognathic face" combined with a "shift backward" in 50% to 60% of the Asian subjects analyzed. Our soft-tissue profile results (approximately 165 +/- 6 degrees) showed less convexity than that of the Caucasians and there was no significant difference in overall profile between the 2 Thai groups (approximately 134 +/- 5 degrees); this is in the range given by Subtelny (141 degrees to 131 degrees) except for that of the Javanese subjects. For the lip analysis, we listed a posterior position or a lip position upon the esthetic line between 60% to 70% of both Thai groups with respect to the upper lip and only 28% to 33% for the lower lip. The Javanese group, however, showed 90% anterior position of the upper lip and 93% of the lower lip to this line. It is significant that proper blending of the integumentary profile produces an esthetically pleasing face and this varies in different ethnic groups. A good combination could even make a "prognathic face shift backward" very acceptable as illustrated by a profile analysis of Miss Thailand, 1984.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Quantifying the Clinical Significance of Cannabis Withdrawal

    Science.gov (United States)

    Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molnar, Anna; Lewis, John; Budney, Alan J.

    2012-01-01

    Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt. Methods and Results A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001). Conclusions Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes. PMID:23049760

  18. The significance of task significance: Job performance effects, relational mechanisms, and boundary conditions.

    Science.gov (United States)

    Grant, Adam M

    2008-01-01

    Does task significance increase job performance? Correlational designs and confounded manipulations have prevented researchers from assessing the causal impact of task significance on job performance. To address this gap, 3 field experiments examined the performance effects, relational mechanisms, and boundary conditions of task significance. In Experiment 1, fundraising callers who received a task significance intervention increased their levels of job performance relative to callers in 2 other conditions and to their own prior performance. In Experiment 2, task significance increased the job dedication and helping behavior of lifeguards, and these effects were mediated by increases in perceptions of social impact and social worth. In Experiment 3, conscientiousness and prosocial values moderated the effects of task significance on the performance of new fundraising callers. The results provide fresh insights into the effects, relational mechanisms, and boundary conditions of task significance, offering noteworthy implications for theory, research, and practice on job design, social information processing, and work motivation and performance.

  19. Amlodipine inhibits matrix metalloproteinases expression and secretion in mouse macrophage

    Institute of Scientific and Technical Information of China (English)

    Yamin CAO; Shiwen WANG; Haiyun WU

    2005-01-01

    To investigate whether the calcium channel blocker amlodipine could inhibit macrophage matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expression and secretion. Methods Peritoneal macrophages were isolated from BALB/C mice and incubated with low (5μg/L), middle (15μg/L) and high (305μg/L) concentrations of amlodipine, or in the medium alone (controls) for 24 hours, and the expression and secretion of MMP-2 and MM-9 of the cells were analyzed by RT-PCR and gelatin zymography. Results Compared with controls, amlodipine at low concentration had no significant effects on the expression and secretion of either MMP-2 and MMP-9 (P>0.05);at middle concentrationit it could inhibited MMP-2 and MMP-9 expressions completely and significantly reduced the secretion of MMP-9 (P<0.05); but it had no effect on the secretion of MMP-2. At high concentration it also inhibited MMP-2 and MMP-9 expression completely. Conclusion Amlodipine at 15 ìg/L inhibited the expression of MMP-2 and MMP-9 and reduced the secretion of MMP-9, suggesting that amlodipine may stabilize atherosclerotic plaque.

  20. Overcoming PCR Inhibition During DNA-Based Gut Content Analysis of Ants.

    Science.gov (United States)

    Penn, Hannah J; Chapman, Eric G; Harwood, James D

    2016-10-01

    Generalist predators play an important role in many terrestrial systems, especially within agricultural settings, and ants (Hymenoptera: Formicidae) often constitute important linkages of these food webs, as they are abundant and influential in these ecosystems. Molecular gut content analysis provides a means of delineating food web linkages of ants based on the presence of prey DNA within their guts. Although this method can provide insight, its use on ants has been limited, potentially due to inhibition when amplifying gut content DNA. We designed a series of experiments to determine those ant organs responsible for inhibition and identified variation in inhibition among three species (Tetramorium caespitum (L.), Solenopsis invicta Buren, and Camponotus floridanus (Buckley)). No body segment, other than the gaster, caused significant inhibition. Following dissection, we determined that within the gaster, the digestive tract and crop cause significant levels of inhibition. We found significant differences in the frequency of inhibition between the three species tested, with inhibition most evident in T. caespitum The most effective method to prevent inhibition before DNA extraction was to exude crop contents and crop structures onto UV-sterilized tissue. However, if extracted samples exhibit inhibition, addition of bovine serum albumin to PCR reagents will overcome this problem. These methods will circumvent gut content inhibition within selected species of ants, thereby allowing more detailed and reliable studies of ant food webs. As little is known about the prevalence of this inhibition in other species, it is recommended that the protocols in this study are used until otherwise shown to be unnecessary. © The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Functional significance of the emotion-related late positive potential

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    Stephen B.R.E. Brown

    2012-02-01

    Full Text Available The late positive potential (LPP is an event-related potential component over visual cortical areas that is modulated by the emotional intensity of a stimulus. However, the functional significance of this neural modulation remains elusive. We conducted two experiments in which we studied the relation between LPP amplitude, subsequent perceptual sensitivity to a non-emotional stimulus (Experiment 1 and visual cortical excitability, as reflected by P1/N1 components evoked by this stimulus (Experiment 2. During the LPP modulation elicited by unpleasant stimuli, perceptual sensitivity and the P1 component were not affected. In contrast, we found some evidence for a decreased N1 amplitude during the LPP modulation, and consistent negative (but nonsignificant across-subject correlations between the magnitudes of the LPP modulation and corresponding changes in d-prime or P1/N1 amplitude. The results provide preliminary evidence that the LPP reflects a global inhibition of ongoing activity in visual cortex, resulting in the selective survival of activity associated with the processing of the emotional stimulus.

  2. PROGNOSTIC SIGNIFICANCE OF EXPRESSION OF SURVIVIN IN ACUTE LEUKEMIA

    Institute of Scientific and Technical Information of China (English)

    王晓娟; 戴国仪; 曹利民; 王国华; 朱慧芬; 张悦; 沈关心

    2002-01-01

    Objective: To investigate the expression of survivin gene and its significance in acute leukemia. Methods: The expression of surviving in 134 acute leukemia patients and 4 leukemia cell lines was detected by RT-PCR and immunofluorescence analysis. Results: We detected survivin expression in 78 of 134 acute leukemia patients and all the cell lines but not in normal controls and anemia patients. Survivin gene expression correlated with a lower white blood cell count, which was 11×109/L and 48×109/L in the positive and negative group respectively (P<0.01 by the Mann-Whitney test). In 55 cases of FAB M1/M2/M3, it was associated with leukemic cell maturation(P<0.01 by the Fisher test). Survivin expression was strongly related to survival time of acute leukemia patients (P<0.05). Conclusion: These data suggest that survivin expression may be considered as a new unfavorable prognostic factor for acute leukemia due to its important role in apoptosis inhibition that influences disease outcome.

  3. Significances and importance of phytochemical present in Terminalia chebula

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    TARIQ A.L

    2013-09-01

    Full Text Available Phytochemical are naturally present in the plants and shows biologically significance by playing an essential role in the plants to defend themselves against various pathogenic microbes by showing the antimicrobial activity by inhibition or killing mechanisms. The secretion of these compounds is varying from plant to plant some produce more and some produce in minimal quantity. Sometimes they can be harmful and sometimes they can be very helpful. There is evidence from laboratory studies that phytochemicals in fruits and vegetables may reduce the risk of cancer, possibly due to dietary fibers, polyphenol antioxidants and anti-inflammatory effects. Specific phytochemicals, such as fermentable dietary fibers, are allowed limited health claims by the US Food and Drug Administration The present study was focused to find out the photochemical analysis of Terminalia chebula plant extracts of leaves, fruits, seed, stem and roots. The formation of yellow colour indicated the presence of flavonoids while the brown colour formation indicated the presence alkaloids and terpenoids. The phenol content was maximum in roots (82.13 mg/gdw followed by seed leave, stem and fruit. The sugar content was highest in leaves (8.27 mg/gdw followed by fruits, stem, root and seed. The protein content was maximum in fruits (55.59 mg/dgw followed by seeds leaves, stem and root.

  4. Greener Approach towards Corrosion Inhibition

    Directory of Open Access Journals (Sweden)

    Neha Patni

    2013-01-01

    Full Text Available Corrosion control of metals is technically, economically, environmentally, and aesthetically important. The best option is to use inhibitors for protecting metals and alloys against corrosion. As organic corrosion inhibitors are toxic in nature, so green inhibitors which are biodegradable, without any heavy metals and other toxic compounds, are promoted. Also plant products are inexpensive, renewable, and readily available. Tannins, organic amino acids, alkaloids, and organic dyes of plant origin have good corrosion-inhibiting abilities. Plant extracts contain many organic compounds, having polar atoms such as O, P, S, and N. These are adsorbed on the metal surface by these polar atoms, and protective films are formed, and various adsorption isotherms are obeyed. Various types of green inhibitors and their effect on different metals are mentioned in the paper.

  5. Inhibiting scale in oil wells

    Energy Technology Data Exchange (ETDEWEB)

    D' Errico, M.J.; Adler, S.F.

    1972-09-27

    An oil well treatment is described to inhibit the formation of hard scale by precipitation from the oil well brine of scale-forming water insoluble sulfate, carbonate, and other salts. The process consists of incorporating into the oil well during a fracturing treatment, a fluid containing a solid polymeric material characterized by molecular weight in the range of 1,000 to 15,000 and a substantially linear structure, derived by the linear polymerization of at least one monoolefinically unsaturated compound through the olefinically unsaturated group. The linear structure has pendent groups, 50% of which are carboxy groups, the carboxy groups being neutralized with a sufficient proportion of at least one compound having a cation of a metal selected from alkaline earth metals, chromium, aluminum, iron, cobalt, zinc, nickel or copper to render the polymer soluble in water at 25$C to a concentration of not more than 50 ppm. (8 claims)

  6. Assessing statistical significance in causal graphs

    Directory of Open Access Journals (Sweden)

    Chindelevitch Leonid

    2012-02-01

    Full Text Available Abstract Background Causal graphs are an increasingly popular tool for the analysis of biological datasets. In particular, signed causal graphs--directed graphs whose edges additionally have a sign denoting upregulation or downregulation--can be used to model regulatory networks within a cell. Such models allow prediction of downstream effects of regulation of biological entities; conversely, they also enable inference of causative agents behind observed expression changes. However, due to their complex nature, signed causal graph models present special challenges with respect to assessing statistical significance. In this paper we frame and solve two fundamental computational problems that arise in practice when computing appropriate null distributions for hypothesis testing. Results First, we show how to compute a p-value for agreement between observed and model-predicted classifications of gene transcripts as upregulated, downregulated, or neither. Specifically, how likely are the classifications to agree to the same extent under the null distribution of the observed classification being randomized? This problem, which we call "Ternary Dot Product Distribution" owing to its mathematical form, can be viewed as a generalization of Fisher's exact test to ternary variables. We present two computationally efficient algorithms for computing the Ternary Dot Product Distribution and investigate its combinatorial structure analytically and numerically to establish computational complexity bounds. Second, we develop an algorithm for efficiently performing random sampling of causal graphs. This enables p-value computation under a different, equally important null distribution obtained by randomizing the graph topology but keeping fixed its basic structure: connectedness and the positive and negative in- and out-degrees of each vertex. We provide an algorithm for sampling a graph from this distribution uniformly at random. We also highlight theoretical

  7. The public health significance of Trichuris trichiura.

    Science.gov (United States)

    Stephenson, L S; Holland, C V; Cooper, E S

    2000-01-01

    An estimated 1049 million persons harbour T. trichiura, including 114 million preschool-age children and 233 million school-age children. The prevalence of T. trichiura is high and may reach 95% in children in many parts of the world where protein energy malnutrition and anaemias are also prevalent and access to medical care and educational opportunities is often limited. The Trichuris dysentery syndrome (TDS) associated with heavy T. trichiura, which includes chronic dysentery, rectal prolapse, anaemia, poor growth, and clubbing of the fingers constitutes an important public health problem, as do lighter but still heavy infections, even if not strictly TDS, especially in children. The profound growth stunting in TDS can be reversed by repeated treatment for the infection and, initially, oral iron. However findings from Jamaica strongly suggest that the significant developmental and cognitive deficits seen are unlikely to disappear without increasing the positive psychological stimulation in the child's environment. The severe stunting in TDS now appears likely to be a reaction at least in part to a chronic inflammatory response and concomitant decreases in plasma insulin-like growth factor-1 (IGF-1), increases in tumor necrosis factor-alpha (TNF-alpha) in the lamina propria of the colonic mucosa and peripheral blood (which likely decrease appetite and intake of all nutrients) and a decrease in collagen synthesis. Improvements in cognitive performance have been found after treatment for relatively heavy infections (without chronic dysentery) in school-going children; it is unclear precisely how much T. trichiura interferes with children's ability to access educational opportunities, but treatment of infections whenever possible is obviously sensible. The blood loss that can occur in T. trichiura infection is likely to contribute to anaemia, particularly if the child also harbours hookworm, malaria and/or has a low intake of dietary iron. Community control is

  8. Prognostic significance of erythropoietin in pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Thilo Welsch

    Full Text Available BACKGROUND: Erythropoietin (Epo administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC. METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150, serum Epo (sEpo, n = 87 and tissue expression of Epo/Epo receptor (EpoR, n = 104 was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05 and PDAC (p<0.001, reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46, 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99 but not in PDAC (O/P = 0.85. Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml were not significantly different in M0 (20% and M1 (30% groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05. The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold

  9. Relations between episodic memory, suggestibility, theory of mind, and cognitive inhibition in the preschool child.

    Science.gov (United States)

    Melinder, Annika; Endestad, Tor; Magnussen, Svein

    2006-12-01

    The development of episodic memory, its relation to theory of mind (ToM), executive functions (e.g., cognitive inhibition), and to suggestibility was studied. Children (n= 115) between 3 and 6 years of age saw two versions of a video film and were tested for their memory of critical elements of the videos. Results indicated similar developmental trends for all memory measures, ToM, and inhibition, but ToM and inhibition were not associated with any memory measures. Correlations involving source memory was found in relation to specific questions, whereas inhibition and ToM were significantly correlated to resistance to suggestions. A regression analysis showed that age was the main contributor to resistance to suggestions, to correct source monitoring, and to correct responses to specific questions. Inhibition was also a significant main predictor of resistance to suggestive questions, whereas the relative contribution of ToM was wiped out when an extended model was tested.

  10. IL-1β Inhibits Human Osteoblast Migration

    Science.gov (United States)

    Hengartner, Nina-Emily; Fiedler, Jörg; Ignatius, Anita; Brenner, Rolf E

    2013-01-01

    Bone has a high capacity for self-renewal and repair. Prolonged local secretion of interleukin 1β (IL-1β), however, is known to be associated with severe bone loss and delayed fracture healing. Since induction of bone resorption by IL-1β may not sufficiently explain these pathologic processes, we investigated, in vitro, if and how IL-1β affects migration of multipotent mesenchymal stromal cells (MSC) or osteoblasts. We found that homogenous exposure to IL-1β significantly diminished both nondirectional migration and site-directed migration toward the chemotactic factors platelet-derived growth factor (PDGF)-BB and insulinlike growth factor 1 (IGF-1) in osteoblasts. Exposure to a concentration gradient of IL-1β induced an even stronger inhibition of migration and completely abolished the migratory response of osteoblasts toward PDGF-BB, IGF-1, vascular endothelial growth factor A (VEGF-A) and the complement factor C5a. IL-1β induced extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases (JNK) activation and inhibition of these signaling pathways suggested an involvement in the IL-1β effects on osteoblast migration. In contrast, basal migration of MSC and their migratory activity toward PDGF-BB was found to be unaffected by IL-1β. These results indicate that the presence of IL-1β leads to impaired recruitment of osteoblasts which might influence early stages of fracture healing and could have pathological relevance for bone remodeling in inflammatory bone disease. PMID:23508571

  11. Inhibition of morphine metabolism by ketamine.

    Science.gov (United States)

    Qi, Xiaoxin; Evans, Allan M; Wang, Jiping; Miners, John O; Upton, Richard N; Milne, Robert W

    2010-05-01

    Clinical observation of a synergistic effect of ketamine on morphine analgesia remains controversial. Although a pharmacodynamic basis for an interaction has been explored in animal and clinical studies, the possibility of a pharmacokinetic mechanism has not been investigated. Whereas both morphine and morphine-6-glucuronide are effective analgesics, morphine-3-glucuronide (M3G) lacks activity. Thus, changes in the metabolism and disposition of morphine may result in an altered response. First, we investigated the interaction between morphine and ketamine in the isolated perfused rat liver preparation. The clearance of morphine was decreased from 16.8 +/- 4.6 ml/min in the control period to 7.7 +/- 2.8 ml/min in the ketamine-treatment period, with the formation clearance of M3G decreasing from 8.0 +/- 4.1 ml/min to 2.1 +/- 1.1 ml/min. Fractional conversion of morphine to M3G was significantly decreased from 0.46 +/- 0.17 in the control period to 0.28 +/- 0.14 upon the addition of ketamine. The possible mechanism of the interaction was further investigated in vitro with rat liver microsomes as the enzyme source. The formation of M3G followed single-enzyme Michaelis-Menten kinetics, with a mean apparent K(m) of 2.18 +/- 0.45 mM and V(max) of 8.67 +/- 0.59 nmol/min/mg. Ketamine inhibited morphine 3-glucuronidation noncompetitively, with a mean K(i) value of 33.3 +/- 7.9 microM. The results demonstrate that ketamine inhibits the glucuronidation of morphine in a rat model.

  12. Enoxacin Directly Inhibits Osteoclastogenesis without Inducing Apoptosis*

    Science.gov (United States)

    Toro, Edgardo J.; Zuo, Jian; Ostrov, David A.; Catalfamo, Dana; Bradaschia-Correa, Vivian; Arana-Chavez, Victor; Caridad, Aliana R.; Neubert, John K.; Wronski, Thomas J.; Wallet, Shannon M.; Holliday, L. Shannon

    2012-01-01

    Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 μm) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the “housekeeping” a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein l-plastin was altered in cells treated with 50 μm enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in posttranslational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments. PMID:22474295

  13. Enoxacin directly inhibits osteoclastogenesis without inducing apoptosis.

    Science.gov (United States)

    Toro, Edgardo J; Zuo, Jian; Ostrov, David A; Catalfamo, Dana; Bradaschia-Correa, Vivian; Arana-Chavez, Victor; Caridad, Aliana R; Neubert, John K; Wronski, Thomas J; Wallet, Shannon M; Holliday, L Shannon

    2012-05-18

    Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 μM) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the "housekeeping" a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein L-plastin was altered in cells treated with 50 μM enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in posttranslational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments.

  14. CLINICAL SIGNIFICANCE AND PROGNOSIS OF FETAL ARRHYTHMIAS

    Institute of Scientific and Technical Information of China (English)

    Qing-bo Fan; Ming-ying Gai; Jian-qiu Yang; Fei-fei Xing

    2004-01-01

    Objective To explore fetal arrhythmia clinical significance and its correlation with fetal prognosis.Methods Twenty-six cases of fetal arrhythmia detected among 12 799 pregnant women recorded over a ten-year period in Peking Uinon Medical College (PUMC) Hospital were reviewed retrospectively. Fetal arrhythmia was diagnosed by fetal auscultation, ultrasonography, electric fetal heart monitoring, and fetal echocardiography.Results Twenty-six fetuses were documented with fetal arrhythmia (3 tachycardia, 4 bradycardia, 19 normal heart rate with irregular fetal cardiac rhythm). The incidence of fetal arrhythmia in our hospital was 0.2%. They were diagnosed at the average of 35 weeks' gestation (15 to 41 weeks). Twenty-two cases were diagnosed by antenatal fetal auscultation, 1 case was diagnosed by ultrasonography, and 3 cases were diagnosed by electric fetal heart monitoring. Fetal echocardiograms were performed on 17 fetuses, 6 cases (35.3%) of which showed that ventricular premature beats with normal structure of fetal heart.All neonates survived postnatally and 24 of them (92.3%) were followed up. Echocardiograms were performed for 16 neonates and 2 of them were identified as atrial septal defects with normal heart rhythms. The results of follow-up showed that the two patients had no apparent clinical manifestation. The echocardiogram showed that atrial septal defect obliterated already.Conclusion The prognosis is well for most of the fetuses with arrhythmias, with low incidence of heart deformation.

  15. [The significance of meat quality in marketing].

    Science.gov (United States)

    Kallweit, E

    1994-07-01

    Food quality in general and meat quality in particular are not only evaluated by means of objective quality traits but the entire production process is gaining more attention by the modern consumer. Due to this development quality programs were developed to define the majority of the processes in all production and marketing steps which are again linked by contracts. Not all of these items are quality relevant, but are concessions to ethic principles (animal welfare etc.). This is demonstrated by the example of Scharrel-pork production. The price differentiation at the pork market is still influenced predominantly by quantitative carcass traits. On the European market quality programs still are of minor significance. Premiums which are paid for high quality standards are more or less compensated by higher production costs and lower lean meat percentages, which must be expected in stress susceptible strains. The high efforts to establish quality programs, however, help to improve the quality level in general, and secure the market shares for local producers.

  16. Novalike Cataclysmic Variables are Significant Radio Emitters

    CERN Document Server

    Coppejans, Deanne L; Miller-Jones, James C A; Rupen, Michael P; Knigge, Christian; Sivakoff, Gregory R; Groot, Paul J

    2015-01-01

    Radio emission from non-magnetic cataclysmic variables (CVs, accreting white dwarfs) could allow detailed studies of outflows and possibly accretion flows in these nearby, numerous and non-relativistic compact accretors. Up to now, however, very few CVs have been detected in the radio. We have conducted a VLA pilot survey of four close and optically-bright novalike CVs at 6 GHz, detecting three, and thereby doubling the number of radio detections of these systems. RW Sex, V603 Aql and the old nova TT Ari were detected in both of the epochs, while V1084 Her was not detected (to a $3\\sigma$ upper-limit of 7.8 $\\mu\\rm{Jy}\\,\\rm{beam}^{-1}$). These observations clearly show that the sensitivity of previous surveys was typically too low to detect these objects and that non-magnetic CVs can indeed be significant radio emitters. The three detected sources show a range of properties, including flaring and variability on both short ($\\sim$200 s) and longer-term (days) time-scales, as well as circular polarization level...

  17. The diagnosis and clinical significance of polyautoimmunity.

    Science.gov (United States)

    Anaya, Juan-Manuel

    2014-01-01

    Autoimmune diseases (ADs) are chronic and heterogeneous conditions that affect specific target organs or multiple organ systems. The chronic nature of these diseases places a significant burden on the utilization of medical care, direct and indirect economic costs, and quality of life. ADs are observed in genetically susceptible individuals in whom their clinical expression is modified by permissive and protective environments occurring over time. These are complex traits, meaning that their inheritance does not follow a single-gene dominant or single-gene recessive Mendelian law, and thus that they are polygenic. ADs are often diagnosed according to classification criteria, however they share similar subphenotypes including signs and symptoms, non-specific autoantibodies and other immune changes, which are prone to taxonomic problems. Polyautoimmunity is defined as the presence of more than one AD in a single patient. When three or more ADs coexist, this condition is called multiple autoimmune syndrome (MAS), which represents the best example of polyautoimmunity as well as the effect of a single genotype on diverse autoimmune phenotypes. Its study will provide important clues to elucidate the common mechanisms of ADs (i.e., the autoimmune tautology).

  18. THE SIGNIFICANCE OF STRESS HORMONES IN PSORIASIS

    Directory of Open Access Journals (Sweden)

    F Z Zangeneh

    2008-12-01

    Full Text Available "nPsoriasis is a chronic, non-contagious skin condition characterized by inflamed and scaly lesions of skin. Whilst the pathogenesis of psoriasis is not known, psychological stress has been implicated as a potential trigger in the onset and exacerbation of the condition. Psychiatric and psychological factors play an important role in at least 30% of dermatologic disorder and pathophysiologic link between psychological stress (PS and disease expression remains unclear. Recent studies demonstrated PS-induced alterations in permeability barrier homeostasis, mediated by increased endogenous glucocorticoids. As activation of the hypothalamic pituitary adrenal axis (HPA is critical to a successful stress response, we investigated this in patients with psoriasis. This study was performed on 55 patients (40 females and 15 males visited our clinic for treatment of psoriasis in pharmacology department. We measured the rate of activation of HPA by hormonal changes. These patients displayed higher fasting blood sugar (FBS, epinephrine (Ep, adrenocorticotropin hormone (ACTH, aldosterone, prolactin, growth hormone and estradiol hormones value but diminished cortisol and corticotropin releasing factor (CRF. These results show that HPA and psychoneuroendocrine hormones have a significant role in psoriasis.

  19. Significance of FISH in clinical cytogenetics

    Energy Technology Data Exchange (ETDEWEB)

    Gopal Rao, V.V.N.; Harris, S.; Roop, H. [H.A. Chapman Institute of Medical Genetics, Tulsa, OK (United States)] [and others

    1994-09-01

    Ever since its discovery, FISH technology has become an invaluable adjunct to conventional cytogenetics. FISH has been instrumental in resolving previously unresolved cytogenetic dilemmas. FISH has been used to elucidate complex as well as subtle chromosomal translocations, in detection of microdeletions, to confirm duplications and inversions and to identify marker chromosomes. We report a few selected cases where FISH proved to be invaluable in not only confirming the anomaly, but also in arriving at an accurate diagnosis and appropriate counseling of the patients. These include 3 cases of prenatal and 3 cases of postnatal diagnosis. The results clearly demonstrate the significance of FISH in identifying and interpreting the difficult karyotype in clinical cytogenetics. In addition, FISH has been used to rule out microdeletions in Prader-Willi (16), Angelman (3), Miller-Dieker (7), DiGeorge (4) and Smith-Magenis (1) syndrome patients. Without FISH in the majority of these cases, it would not have been possible to accurately identify the karyotype and interpret the results. Hence, we recommend that FISH be used as a powerful adjunct to conventional cytogenetics in order to arrive at an accurate interpretation of the results but not to replace routine cytogenetic studies.

  20. Object caching in corvids: incidence and significance.

    Science.gov (United States)

    Jacobs, Ivo F; Osvath, Mathias; Osvath, Helena; Mioduszewska, Berenika; von Bayern, Auguste M P; Kacelnik, Alex

    2014-02-01

    Food caching is a paramount model for studying relations between cognition, brain organisation and ecology in corvids. In contrast, behaviour towards inedible objects is poorly examined and understood. We review the literature on object caching in corvids and other birds, and describe an exploratory study on object caching in ravens, New Caledonian crows and jackdaws. The captive adult birds were presented with an identical set of novel objects adjacent to food. All three species cached objects, which shows the behaviour not to be restricted to juveniles, food cachers, tool-users or individuals deprived of cacheable food. The pattern of object interaction and caching did not mirror the incidence of food caching: the intensely food caching ravens indeed showed highest object caching incidence, but the rarely food caching jackdaws cached objects to similar extent as the moderate food caching New Caledonian crows. Ravens and jackdaws preferred objects with greater sphericity, but New Caledonian crows preferred stick-like objects (similar to tools). We suggest that the observed object caching might have been expressions of exploration or play, and deserves being studied in its own right because of its potential significance for tool-related behaviour and learning, rather than as an over-spill from food-caching research. This article is part of a Special Issue entitled: CO3 2013. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. The measure and significance of Bateman's principles.

    Science.gov (United States)

    Collet, Julie M; Dean, Rebecca F; Worley, Kirsty; Richardson, David S; Pizzari, Tommaso

    2014-05-07

    Bateman's principles explain sex roles and sexual dimorphism through sex-specific variance in mating success, reproductive success and their relationships within sexes (Bateman gradients). Empirical tests of these principles, however, have come under intense scrutiny. Here, we experimentally show that in replicate groups of red junglefowl, Gallus gallus, mating and reproductive successes were more variable in males than in females, resulting in a steeper male Bateman gradient, consistent with Bateman's principles. However, we use novel quantitative techniques to reveal that current methods typically overestimate Bateman's principles because they (i) infer mating success indirectly from offspring parentage, and thus miss matings that fail to result in fertilization, and (ii) measure Bateman gradients through the univariate regression of reproductive over mating success, without considering the substantial influence of other components of male reproductive success, namely female fecundity and paternity share. We also find a significant female Bateman gradient but show that this likely emerges as spurious consequences of male preference for fecund females, emphasizing the need for experimental approaches to establish the causal relationship between reproductive and mating success. While providing qualitative support for Bateman's principles, our study demonstrates how current approaches can generate a misleading view of sex differences and roles.

  2. Traditional Indian spices and their health significance.

    Science.gov (United States)

    Krishnaswamy, Kamala

    2008-01-01

    India has been recognized all over the world for spices and medicinal plants. Both exhibit a wide range of physiological and pharmacological properties. Current biomedical efforts are focused on their scientific merits, to provide science-based evidence for the traditional uses and to develop either functional foods or nutraceuticals. The Indian traditional medical systems use turmeric for wound healing, rheumatic disorders, gastrointestinal symptoms, deworming, rhinitis and as a cosmetic. Studies in India have explored its anti-inflammatory, cholekinetic and anti-oxidant potentials with the recent investigations focusing on its preventive effect on precarcinogenic, anti-inflammatory and anti atherosclerotic effects in biological systems both under in vitro and in vivo conditions in animals and humans. Both turmeric and curcumin were found to increase detoxifying enzymes, prevent DNA damage, improve DNA repair, decrease mutations and tumour formation and exhibit antioxidative potential in animals. Limited clinical studies suggest that turmeric can significantly impact excretion of mutagens in urine in smokers and regress precancerous palatal lesions. It reduces DNA adducts and micronuclei in oral epithelial cells. It prevents formation of nitroso compounds both in vivo and in vitro. It delays induced cataract in diabetes and reduces hyperlipidemia in obese rats. Recently several molecular targets have been identified for therapeutic / preventive effects of turmeric. Fenugreek seeds, a rich source of soluble fiber used in Indian cuisine reduces blood glucose and lipids and can be used as a food adjuvant in diabetes. Similarly garlic, onions, and ginger have been found to modulate favourably the process of carcinogenesis.

  3. Significance of duon mutations in cancer genomes

    Science.gov (United States)

    Yadav, Vinod Kumar; Smith, Kyle S.; Flinders, Colin; Mumenthaler, Shannon M.; de, Subhajyoti

    2016-06-01

    Functional mutations in coding regions not only affect the structure and function of the protein products, but may also modulate their expression in some cases. This class of mutations, recently dubbed “duon mutations” due to their dual roles, can potentially have major impacts on downstream pathways. However their significance in diseases such as cancer remain unclear. In a survey covering 4606 samples from 19 cancer types, and integrating allelic expression, overall mRNA expression, regulatory motif perturbation, and chromatin signatures in one composite index called REDACT score, we identified potential duon mutations. Several such mutations are detected in known cancer genes in multiple cancer types. For instance a potential duon mutation in TP53 is associated with increased expression of the mutant allelic gene copy, thereby possibly amplifying the functional effects on the downstream pathways. Another potential duon mutation in SF3B1 is associated with abnormal splicing and changes in angiogenesis and matrix degradation related pathways. Our findings emphasize the need to interrogate the mutations in coding regions beyond their obvious effects on protein structures.

  4. The clinical significance of subclinical thyroid dysfunction.

    Science.gov (United States)

    Biondi, Bernadette; Cooper, David S

    2008-02-01

    Subclinical thyroid disease (SCTD) is defined as serum free T(4) and free T(3) levels within their respective reference ranges in the presence of abnormal serum TSH levels. SCTD is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms, signs, and cardiovascular risk. Here, we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine the mechanisms underlying tissue alterations in SCTD and the effects of replacement therapy on progression and tissue parameters. Lastly, we address the issue of the need to treat slight thyroid hormone deficiency or excess in relation to the patient's age.

  5. Death, Catastrophe, and the Significance of Tragedy

    Directory of Open Access Journals (Sweden)

    Jennifer Ballengee

    2014-05-01

    Full Text Available This NANO note will examine the tension between representation, memorial, and the catastrophe of death that emerges in the space of tragedy, as the problem arises in two quite different works: Oedipus at Colonus, a fairly typical fifth-century Greek tragedy, and Falling Man, Don DeLillo’s novel that, in its attempt to address the events of 9/11, reflects in form and subject matter many of Aristotle’s terms of tragic representation. It is not the intent of this note to engage with the recent proliferation of work in “performance theory.” Rather than being concerned with an imagined exchange between audience and actor, this study examines how the supplementary relationship of gesture and speech in tragedy disrupts the public/private distinction, and how this articulation effects and enables the public memorialization of death. Thus, this paper will consider the representation of death as an event whose catastrophic, and somewhat mysterious, collision of the public and the private lends it its tragic significance.

  6. Evolutionary significance of ageing in the wild.

    Science.gov (United States)

    Kowald, Axel; Kirkwood, Thomas B L

    2015-11-01

    Human lifespan has risen dramatically over the last 150 years, leading to a significant increase in the fraction of aged people in the population. Until recently it was believed that this contrasted strongly with the situation in wild populations of animals, where the likelihood of encountering demonstrably senescent individuals was believed to be negligible. Over the recent years, however, a series of field studies has appeared that shows ageing can also be observed for many species in the wild. We discuss here the relevance of this finding for the different evolutionary theories of ageing, since it has been claimed that ageing in the wild is incompatible with the so-called non-adaptive (non-programmed) theories, i.e. those in which ageing is presumed not to offer a direct selection benefit. We show that a certain proportion of aged individuals in the population is fully compatible with the antagonistic pleiotropy and the disposable soma theories, while it is difficult to reconcile with the mutation accumulation theory. We also quantify the costs of ageing using life history data from recent field studies and a range of possible metrics. We discuss the merits and problems of the different metrics and also introduce a new metric, yearly death toll, that aims directly at quantifying the deaths caused by the ageing process. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Taxonomic significance of trichomes micromorphology in cucurbits

    Science.gov (United States)

    Ali, Mohammad Ajmal; Al-Hemaid, Fahad M.A.

    2010-01-01

    Studies on trichomes micromorphology using Scanning Electron Microscope (SEM) were undertaken in 23 species with one variety under 13 genera of the family Cucurbitaceae (viz., Benincasa hispida (Thunb.) Cogn., Citrullus lanatus (Thunb.) Matsum. & Nakai, Cucumis melo var. agrestis Naudin, Cucumis sativus L., Diplocyclos palmatus (L.) C. Jeffrey, Edgaria dargeelingensis C.B. Clarke, Gynostemma burmanicum King ex Chakr., Gynostemma pentaphyllum (Thunb.) Makino, Gynostemma pubescens (Gagnep.) C.Y. Wu, Hemsleya dipterygia Kuang & A.M. Lu, Lagenaria siceraria (Molina) Standl., Luffa acutangula (L.) Roxb., Luffa cylindrica M. Roem., Luffa echinata Roxb., Melothria heterophylla (Lour.) Cogn., Melothria leucocarpa (Blume) Cogn., Melothria maderspatana (L.) Cogn., Sechium edule (Jacq.) Sw., Thladiantha cordifolia (Blume) Cogn., Trichosanthes cucumerina L., T. cucumerina var. anguina (L.) Haines, Trichosanthes dioica Roxb., Trichosanthes lepiniana (Naudin) Cogn. and T. tricuspidata Lour.). The trichomes in the family Cucurbitaceae vary from unicellular to multicellular, conical to elongated, smooth to ridges, with or without flattened disk at base and cyctolithic appendages, thin to thick walled, curved at apices to blunt. Trichomes micromorphology in the family Cucurbitaceae was found significant taxonomically. PMID:23961108

  8. Pseudogene redux with new biological significance.

    Science.gov (United States)

    Salmena, Leonardo

    2014-01-01

    The study of pseudogenes, originally dismissed as genomic relics of evolutionary selection, has seen a resurgence in scientific literature, in addition to being a peculiar topic of discussion in theological debates. For a long time, pseudogenes have been touted as a beacon of natural selection and a definitive proof of evolution due to the slow mutation rate that differentiated them from their parental genes and ultimately caused their genetic demise as functional genes. It now seems that "creationists" have co-opted some recent reports identifying unheralded biological functions to pseudogens and other noncoding RNAs as evidence to undermine the existence of evolution and supporting intelligent design. This issue of Methods in Molecular Biology focused on pseudogenes will certainly not end, nor enter this debate; however, scientists who are also genomics and pseudogene enthusiasts will certainly appreciate that many scientists are thinking about these particular genetic elements in new and interesting ways. With this new interest in a biological significance and "non-junk" role for pseudogenes and other noncoding RNAs, new methods and approaches are being developed to unlock the mystery of these ancient artifacts we know as pseudogenes. In this brief introductory chapter we highlight the renewed interest in pseudogenes and review a rationale for intensification of pseudogene-related research.

  9. Augustine, his sermons, and their significance

    Directory of Open Access Journals (Sweden)

    Johannes Van Oort

    2009-09-01

    Full Text Available Augustine’s sermons provide a unique source in explaining his influence from the 5th century onwards as a theologian and pastor, a minister of the Word preached and celebrated in the sacrament. Of particular value in this regard are his sermons on the Psalms. Issues of authenticity are also considered in this article. The influence of Augustine’s sermons was widespread through their tradition and adaptation by others. A substantial and reliable corpus of his sermons is available today. As a pastor, Augustine was anxious to challenge heresy in his preaching, especially to confront the Donatists, Manichaeans and Pelagians. His preaching is considered in the wider context of congregational worship with its origins in the synagogue. Of special importance are his preaching techniques, while his doctrine of ‘the inner teacher’ (magister interior is equally significant. Essential elements of Augustine’s theory and practice became influential in the early days of the Protestant Reformation (Luther, Calvin and others. The author briefly touches on the question of their relevance for today’s congregational worship.

  10. Significance of nanotechnology in medical sciences

    Directory of Open Access Journals (Sweden)

    Gaur Ajay

    2008-01-01

    Full Text Available Nanotechnology refers broadly to a field of applied science and technology whose unifying theme is the control of matter on the molecular level in scales smaller than 1 µm, normally 1-100 nm, and the fabrication of devices within that size range. Two main approaches are used in nanotechnology. In the "bottom-up" approach, materials and devices are built from molecular components, which assemble themselves chemically by principles of molecular recognition. In the "top-down" approach, nano-objects are constructed from larger entities without atomic-level control. In addition, as the need for the development of new medicines is pressing, and given the inherent nanoscale functions of the biological components of living cells, nanotechnology has been applied to diverse medical fields such as oncology, cardiovascular medicine, and in treatment of other chronic diseases. Indeed, nanotechnology is being used to refine discovery of biomarkers, molecular diagnostics, and drug discovery and drug delivery, which could be applicable to management of these patients. In this review, we will focus upon significance of nanotechnology in medical sciences, as well as the plausible side effects related to their use.

  11. Phenotypic plasticity: molecular mechanisms and adaptive significance.

    Science.gov (United States)

    Kelly, Scott A; Panhuis, Tami M; Stoehr, Andrew M

    2012-04-01

    Phenotypic plasticity can be broadly defined as the ability of one genotype to produce more than one phenotype when exposed to different environments, as the modification of developmental events by the environment, or as the ability of an individual organism to alter its phenotype in response to changes in environmental conditions. Not surprisingly, the study of phenotypic plasticity is innately interdisciplinary and encompasses aspects of behavior, development, ecology, evolution, genetics, genomics, and multiple physiological systems at various levels of biological organization. From an ecological and evolutionary perspective, phenotypic plasticity may be a powerful means of adaptation and dramatic examples of phenotypic plasticity include predator avoidance, insect wing polymorphisms, the timing of metamorphosis in amphibians, osmoregulation in fishes, and alternative reproductive tactics in male vertebrates. From a human health perspective, documented examples of plasticity most commonly include the results of exercise, training, and/or dieting on human morphology and physiology. Regardless of the discipline, phenotypic plasticity has increasingly become the target of a plethora of investigations with the methodological approaches utilized ranging from the molecular to whole organsimal. In this article, we provide a brief historical outlook on phenotypic plasticity; examine its potential adaptive significance; emphasize recent molecular approaches that provide novel insight into underlying mechanisms, and highlight examples in fishes and insects. Finally, we highlight examples of phenotypic plasticity from a human health perspective and underscore the use of mouse models as a powerful tool in understanding the genetic architecture of phenotypic plasticity.

  12. Taxonomic significance of trichomes micromorphology in cucurbits.

    Science.gov (United States)

    Ali, Mohammad Ajmal; Al-Hemaid, Fahad M A

    2011-01-01

    Studies on trichomes micromorphology using Scanning Electron Microscope (SEM) were undertaken in 23 species with one variety under 13 genera of the family Cucurbitaceae (viz., Benincasa hispida (Thunb.) Cogn., Citrullus lanatus (Thunb.) Matsum. & Nakai, Cucumis melo var. agrestis Naudin, Cucumis sativus L., Diplocyclos palmatus (L.) C. Jeffrey, Edgaria dargeelingensis C.B. Clarke, Gynostemma burmanicum King ex Chakr., Gynostemma pentaphyllum (Thunb.) Makino, Gynostemma pubescens (Gagnep.) C.Y. Wu, Hemsleya dipterygia Kuang & A.M. Lu, Lagenaria siceraria (Molina) Standl., Luffa acutangula (L.) Roxb., Luffa cylindrica M. Roem., Luffa echinata Roxb., Melothria heterophylla (Lour.) Cogn., Melothria leucocarpa (Blume) Cogn., Melothria maderspatana (L.) Cogn., Sechium edule (Jacq.) Sw., Thladiantha cordifolia (Blume) Cogn., Trichosanthes cucumerina L., T. cucumerina var. anguina (L.) Haines, Trichosanthes dioica Roxb., Trichosanthes lepiniana (Naudin) Cogn. and T. tricuspidata Lour.). The trichomes in the family Cucurbitaceae vary from unicellular to multicellular, conical to elongated, smooth to ridges, with or without flattened disk at base and cyctolithic appendages, thin to thick walled, curved at apices to blunt. Trichomes micromorphology in the family Cucurbitaceae was found significant taxonomically.

  13. Measurement and significance of sperm morphology

    Institute of Scientific and Technical Information of China (English)

    Roelof Menkveld; Cas AG Holleboom; Johann PT Rhemrev

    2011-01-01

    The measurement or evaluation and clinical significance of human sperm morphology has always been and still is a controversial aspect of the semen analysis for the determination of a male's fertility potential.In this review the background of the development of the evaluation criteria for sperm morphology will be discussed.Aspects of criticism on the strict criteria definition and use of the criteria for sperm morphology evaluation will be discussed as well as possible reasons for the decline in normal sperm morphology values and how we can compromise for this phenomenon resulting in the very low normal reference value as published in the 2010 WHO manual for the Examination and Processing of Human Semen.One of the possible solutions may be to give more attention to a limited number of abnormal sperm morphology categories and the inclusion of sperm morphology patterns.It is concluded in this review that if done correctly and with care and with strict application of existing guidelines as outlined in the 2010 WHO manual,sperm morphology measurement still has a very important role to play in the clinical evaluation of male fertility potential.

  14. Coliforms in processed mango: significance and control.

    Science.gov (United States)

    O'Connor-Shaw, R E; Guthrie, J A; Dunlop, K J; Roberts

    1995-03-01

    The aims of this investigation were to enumerate coliforms in fresh mangoes, puree, cheeks, and cheeks-in-puree in order to determine the source of these organisms in the processed products, to determine methods for their control, and to identify coliforms isolated from cheeks-in-puree to determine whether they have any public health significance. Product from four processors was tested on two occasions. The retail packs of cheeks-in-puree having the highest coliform counts were those in which raw puree was added to the cheeks. Coliform counts in these samples ranged between 1.4 x 10(3) and 5.4 x 10(4) cfu/g. Pasteurisation reduced the coliform count of raw puree to Klebsiella pneumoniae using the ATB 32E Identification System. Klebsiella strains were tested for growth at 10 degrees C, faecal coliform response, and fermentation of D-melizitose, to differentiate the three phenotypically similar strains, K. pneumoniae, K. terrigena and K planticola. Results indicated that 41% of K. pneumoniae isolates gave reactions typical of K. pneumoniae. A further 44% of strains gave an atypical reaction pattern for these tests and were designed 'psychrotrophic' K. pneumoniae. Klebsiella pneumoniae counts of between 2.1 x 10(3) and 4.9 x 10(4) cfu/g were predicted to occur in the retail packs of mango cheeks-in-puree produced by the processors who constituted this product with raw puree. In view of the opportunistic pathogenic nature of K. pneumoniae, its presence in these products is considered undesirable and steps, such as pasteurisation of puree, should be taken in order to inactivate it.

  15. Practical significance of weld strength matching

    Energy Technology Data Exchange (ETDEWEB)

    Sloterdijk, W. [N.V. Nederlandse Gasunie, Groningen (Netherlands); Schipaanboord, W.N. [N.V. Nederlandse Gasunie, Groningen (Netherlands)

    1996-10-01

    Defect tolerance in welds in pipelines constructed in modern high strength material depends on the balance in strength between weld material and pipe material. The Guidelines on the assessment of girth weld defects published by the European Pipeline Research Group (EPRG) define in Tier 2 defect limits assuming that the (actual) weld metal yield strength is equal or greater than the yield strength of the parent material. The defect limits according to Tier 2 exceed the defect limits in `workmanship standards` (l>25 mm). Nevertheless, the draft European welding standard EN 288 does not yet require a test to measure and verify the weld metal yield strength. Gasunie has performed a test program with the aim to look at the practical significance of weld strength matching in a strain controlled situation and to verify the relevance of limits given in the European welding and line pipe codes, in combination with the EPRG Guidelines. It is concluded that the results of the tests confirm the defect acceptance limits according to Tier 2 of the EPRG Guidelines. (orig.) [Deutsch] Die Zulaessigkeit von Fehlern in Rundschweissnaehten in Rohrleitungen aus modernen hochfesten Baustaehlen haengt von dem Verhaeltnis der Werkstofffestigkeit des Schweissgutes zu der des Grundwerkstoffs ab. Die von der European Pipeline Research Group (EPRG) veroeffentlichte Richtlinie zur Bewertung von Schweissnahtfehlern gibt in der zweiten Bewertungsstufe (Tier 2) Werte fuer zulaessige Schweissnahtfehlergroessen unter der Bedingung an, dass die Dehngrenze des Schweissgutes groesser oder gleich der Dehngrenze des Grundwerkstoffs ist. Die nach Tier 2 zulaessigen Fehler sind groesser als die in `Good-workmanship`-Regelwerken angegebenen Fehlerlaenge (l>25 mm). Demgegenueber fehlt im Entwurf der europaeischen Schweissnorm EN 288 bislang ein solcher Dehngrenzennachweis. Gasunie hat ein Versuchsprogramm durchgefuehrt, um die Bedeutung der Schweissgutfestigkeit bei dehnungskontrollierter Belastung sowie

  16. Inhibition of Midkine Augments Osteoporotic Fracture Healing.

    Directory of Open Access Journals (Sweden)

    Melanie Haffner-Luntzer

    Full Text Available The heparin-binding growth and differentiation factor midkine (Mdk is proposed to negatively regulate osteoblast activity and bone formation in the adult skeleton. As Mdk-deficient mice were protected from ovariectomy (OVX-induced bone loss, this factor may also play a role in the pathogenesis of postmenopausal osteoporosis. We have previously demonstrated that Mdk negatively influences bone regeneration during fracture healing. Here, we investigated whether the inhibition of Mdk using an Mdk-antibody (Mdk-Ab improves compromised bone healing in osteoporotic OVX-mice. Using a standardized femur osteotomy model, we demonstrated that Mdk serum levels were significantly enhanced after fracture in both non-OVX and OVX-mice, however, the increase was considerably greater in osteoporotic mice. Systemic treatment with the Mdk-Ab significantly improved bone healing in osteoporotic mice by increasing bone formation in the fracture callus. On the molecular level, we demonstrated that the OVX-induced reduction of the osteoanabolic beta-catenin signaling in the bony callus was abolished by Mdk-Ab treatment. Furthermore, the injection of the Mdk-Ab increased trabecular bone mass in the skeleton of the osteoporotic mice. These results implicate that antagonizing Mdk may be useful for the therapy of osteoporosis and osteoporotic fracture-healing complications.

  17. Latent inhibition in human adults without masking.

    Science.gov (United States)

    Escobar, Martha; Arcediano, Francisco; Miller, Ralph R

    2003-09-01

    Latent inhibition refers to attenuated responding to Cue X observed when the X-outcome pairings are preceded by X-alone presentations. It has proven difficult to obtain in human adults unless the preexposure (X-alone) presentations are embedded within a masking (i.e., distracting) task. The authors hypothesized that the difficulty in obtaining latent inhibition with unmasked tasks is related to the usual training procedures, in which the preexposure and conditioning experiences are separated by a set of instructions. Experiment 1 reports latent inhibition without masking in a task in which preexposure and conditioning occur without interruption. Experiments 2 and 3 demonstrate that this attenuation in responding to target Cue X does not pass a summation test for conditioned inhibition and is context specific, thereby confirming that it is latent inhibition. Experiments 3 and 4 confirm that introducing instructions between preexposure and conditioning disrupts latent inhibition.

  18. Response inhibition signals and miscoding of direction in dorsomedial striatum

    Directory of Open Access Journals (Sweden)

    Daniel W Bryden

    2012-09-01

    Full Text Available The ability to inhibit action is critical for everyday behavior and is affected by a variety of disorders. Behavioral control and response inhibition is thought to depend on a neural circuit that includes the dorsal striatum, yet the neural signals that lead to response inhibition and its failure are unclear. To address this issue, we recorded from neurons in rat dorsomedial striatum (mDS in a novel task in which rats responded to a spatial cue that signaled that reward would be delivered either to the left or to the right. On 80% of trials rats were instructed to respond in the direction cued by the light (GO. On 20% of trials a second light illuminated instructing the rat to refrain from making the cued movement and move in the opposite direction (STOP. Many neurons in mDS encoded direction, firing more or less strongly for GO movements made ipsilateral or contralateral to the recording electrode. Neurons that fired more strongly for contralateral GO responses were more active when rats were faster, showed reduced activity on STOP trials, and miscoded direction on errors, suggesting that when these neurons were overly active, response inhibition failed. Neurons that decreased firing for contralateral movement were excited during trials in which the rat was required to stop the ipsilateral movement. For these neurons activity was reduced when errors were made and was negatively correlated with movement time suggesting that when these neurons were less active on STOP trials, response inhibition failed. Finally, the activity of a significant number of neurons represented a global inhibitory signal, firing more strongly during response inhibition regardless of response direction. Breakdown by cell type suggests that putative medium spiny neurons tended to fire more strongly under STOP trials, whereas putative interneurons exhibited both activity patterns. 

  19. Response inhibition signals and miscoding of direction in dorsomedial striatum

    Science.gov (United States)

    Bryden, Daniel W.; Burton, Amanda C.; Kashtelyan, Vadim; Barnett, Brian R.; Roesch, Matthew R.

    2012-01-01

    The ability to inhibit action is critical for everyday behavior and is affected by a variety of disorders. Behavioral control and response inhibition is thought to depend on a neural circuit that includes the dorsal striatum, yet the neural signals that lead to response inhibition and its failure are unclear. To address this issue, we recorded from neurons in rat dorsomedial striatum (mDS) in a novel task in which rats responded to a spatial cue that signaled that reward would be delivered either to the left or to the right. On 80% of trials rats were instructed to respond in the direction cued by the light (GO). On 20% of trials a second light illuminated instructing the rat to refrain from making the cued movement and move in the opposite direction (STOP). Many neurons in mDS encoded direction, firing more or less strongly for GO movements made ipsilateral or contralateral to the recording electrode. Neurons that fired more strongly for contralateral GO responses were more active when rats were faster, showed reduced activity on STOP trials, and miscoded direction on errors, suggesting that when these neurons were overly active, response inhibition failed. Neurons that decreased firing for contralateral movement were excited during trials in which the rat was required to stop the ipsilateral movement. For these neurons activity was reduced when errors were made and was negatively correlated with movement time suggesting that when these neurons were less active on STOP trials, response inhibition failed. Finally, the activity of a significant number of neurons represented a global inhibitory signal, firing more strongly during response inhibition regardless of response direction. Breakdown by cell type suggests that putative medium spiny neurons (MSNs) tended to fire more strongly under STOP trials, whereas putative interneurons exhibited both activity patterns. PMID:22973206

  20. R-lipoic acid inhibits mammalian pyruvate dehydrogenase kinase.

    Science.gov (United States)

    Korotchkina, Lioubov G; Sidhu, Sukhdeep; Patel, Mulchand S

    2004-10-01

    The four pyruvate dehydrogenase kinase (PDK) and two pyruvate dehydrogenase phosphatase (PDP) isoenzymes that are present in mammalian tissues regulate activity of the pyruvate dehydrogenase complex (PDC) by phosphorylation/dephosphorylation of its pyruvate dehydrogenase (E1) component. The effect of lipoic acids on the activity of PDKs and PDPs was investigated in purified proteins system. R-lipoic acid, S-lipoic acid and R-dihydrolipoic acid did not significantly affect activities of PDPs and at the same time inhibited PDKs to different extents (PDK1>PDK4 approximately PDK2>PDK3 for R-LA). Since lipoic acids inhibited PDKs activity both when reconstituted in PDC and in the presence of E1 alone, dissociation of PDK from the lipoyl domains of dihydrolipoamide acetyltransferase in the presence of lipoic acids is not a likely explanation for inhibition. The activity of PDK1 towards phosphorylation sites 1, 2 and 3 of E1 was decreased to the same extent in the presence of R-lipoic acid, thus excluding protection of the E1 active site by lipoic acid from phosphorylation. R-lipoic acid inhibited autophosphorylation of PDK2 indicating that it exerted its effect on PDKs directly. Inhibition of PDK1 by R-lipoic acid was not altered by ADP but was decreased in the presence of pyruvate which itself inhibits PDKs. An inhibitory effect of lipoic acid on PDKs would result in less phosphorylation of E1 and hence increased PDC activity. This finding provides a possible mechanism for a glucose (and lactate) lowering effect of R-lipoic acid in diabetic subjects.

  1. Neural signature of behavioural inhibition in women with bulimia nervosa.

    Science.gov (United States)

    Skunde, Mandy; Walther, Stephan; Simon, Joe J; Wu, Mudan; Bendszus, Martin; Herzog, Wolfgang; Friederich, Hans-Christoph

    2016-08-01

    Impaired inhibitory control is considered a behavioural phenotype in patients with bulimia nervosa. However, the underlying neural correlates of impaired general and food-specific behavioural inhibition are largely unknown. Therefore, we investigated brain activation during the performance of behavioural inhibition to general and food-related stimuli in adults with bulimia nervosa. Women with bulimia and healthy control women underwent event-related fMRI while performing a general and a food-specific no-go task. We included 28 women with bulimia nervosa and 29 healthy control women in our study. On a neuronal level, we observed significant group differences in response to general no-go stimuli in women with bulimia nervosa with high symptom severity; compared with healthy controls, the patients showed reduced activation in the right sensorimotor area (postcentral gyrus, precentral gyrus) and right dorsal striatum (caudate nucleus, putamen). The present results are limited to adult women with bulimia nervosa. Furthermore, it remains unclear whether impaired behavioural inhibition in patients with this disorder are a cause or consequence of chronic illness. Our findings suggest that diminished frontostriatal brain activation in patients with bulimia nervosa contribute to the severity of binge eating symptoms. Gaining further insight into the neural mechanisms of behavioural inhibition problems in individuals with this disorder may inform brain-directed treatment approaches and the development of response inhibition training approaches to improve inhibitory control in patients with bulimia nervosa. The present study does not support greater behavioural and neural impairments to food-specific behavioural inhibition in these patients.

  2. Enhanced latent inhibition in high schizotypy individuals

    OpenAIRE

    Granger, Kiri T.; Moran, Paula M.; Buckley, Matthew G.; Haselgrove, Mark

    2016-01-01

    Latent inhibition refers to a retardation in learning about a stimulus that has been rendered familiar by non-reinforced preexposure, relative to a non-preexposed stimulus. Latent inhibition has been shown to be inversely correlated with schizotypy, and abnormal in people with schizophrenia, but these findings are inconsistent. One potential contributing factor to this inconsistency is that many tasks that purport to measure latent inhibition are confounded by alternative effects that also re...

  3. FASN Inhibition and Taxane Treatment Combine to Enhance Anti-tumor Efficacy in Diverse Xenograft Tumor Models through Disruption of Tubulin Palmitoylation and Microtubule Organization and FASN Inhibition-Mediated Effects on Oncogenic Signaling and Gene Expression.

    Science.gov (United States)

    Heuer, Timothy S; Ventura, Richard; Mordec, Kasia; Lai, Julie; Fridlib, Marina; Buckley, Douglas; Kemble, George

    2017-02-01

    Palmitate, the enzymatic product of FASN, and palmitate-derived lipids support cell metabolism, membrane architecture, protein localization, and intracellular signaling. Tubulins are among many proteins that are modified post-translationally by acylation with palmitate. We show that FASN inhibition with TVB-3166 or TVB-3664 significantly reduces tubulin palmitoylation and mRNA expression. Disrupted microtubule organization in tumor cells is an additional consequence of FASN inhibition. FASN inhibition combined with taxane treatment enhances inhibition of in vitro tumor cell growth compared to treatment with either agent alone. In lung, ovarian, prostate, and pancreatic tumor xenograft studies, FASN inhibition and paclitaxel or docetaxel combine to inhibit xenograft tumor growth with significantly enhanced anti-tumor activity. Tumor regression was observed in 3 of 6 tumor xenograft models. FASN inhibition does not affect cellular taxane concentration in vitro. Our data suggest a mechanism of enhanced anti-tumor activity of the FASN and taxane drug combination that includes inhibition of tubulin palmitoylation and disruption of microtubule organization in tumor cells, as well as a sensitization of tumor cells to FASN inhibition-mediated effects that include gene expression changes and inhibition of β-catenin. Together, the results strongly support investigation of combined FASN inhibition and taxane treatment as a therapy for a variety of human cancers. Copyright © 2016 3-V Biosciences. Published by Elsevier B.V. All rights reserved.

  4. FASN Inhibition and Taxane Treatment Combine to Enhance Anti-tumor Efficacy in Diverse Xenograft Tumor Models through Disruption of Tubulin Palmitoylation and Microtubule Organization and FASN Inhibition-Mediated Effects on Oncogenic Signaling and Gene Expression

    Directory of Open Access Journals (Sweden)

    Timothy S. Heuer

    2017-02-01

    Full Text Available Palmitate, the enzymatic product of FASN, and palmitate-derived lipids support cell metabolism, membrane architecture, protein localization, and intracellular signaling. Tubulins are among many proteins that are modified post-translationally by acylation with palmitate. We show that FASN inhibition with TVB-3166 or TVB-3664 significantly reduces tubulin palmitoylation and mRNA expression. Disrupted microtubule organization in tumor cells is an additional consequence of FASN inhibition. FASN inhibition combined with taxane treatment enhances inhibition of in vitro tumor cell growth compared to treatment with either agent alone. In lung, ovarian, prostate, and pancreatic tumor xenograft studies, FASN inhibition and paclitaxel or docetaxel combine to inhibit xenograft tumor growth with significantly enhanced anti-tumor activity. Tumor regression was observed in 3 of 6 tumor xenograft models. FASN inhibition does not affect cellular taxane concentration in vitro. Our data suggest a mechanism of enhanced anti-tumor activity of the FASN and taxane drug combination that includes inhibition of tubulin palmitoylation and disruption of microtubule organization in tumor cells, as well as a sensitization of tumor cells to FASN inhibition-mediated effects that include gene expression changes and inhibition of β-catenin. Together, the results strongly support investigation of combined FASN inhibition and taxane treatment as a therapy for a variety of human cancers.

  5. Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation

    Directory of Open Access Journals (Sweden)

    Lu Li

    2014-01-01

    Full Text Available This study aimed to investigate the role of 5-lipoxygenase (5-LO in acute liver failure (ALF and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN/lipopolysaccharide (LPS. Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor, 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT, aspartate transaminase (AST, total bilirubin (Tbil, and tumor necrosis factor- (TNF-α. Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF-α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.

  6. Biological significance of soluble IL-2 receptor

    Directory of Open Access Journals (Sweden)

    Calogero Caruso

    1993-01-01

    Full Text Available A NUMBER of receptors for growth factors and differentiation antigens have been found to be secreted or released by cells. Following mononuclear cell (MNC activation and interleukin-2 receptor (IL-2R expression, a soluble form of the Alpha;-chain of IL-2R (sIL-2R is released. The sIL-2R has been shown to be present in the culture supernatants of activated MNCs as well as in normal sera and, in higher amounts, in sera from subjects affected by several diseases including neoplastic, infectious and autoimmune ones, and in sera from transplanted patients suffering allograft rejection. The blood sIL-2R levels depend on the number of producing cells and the number of molecules per cell, so that sIL-2R blood values may represent an index of the number and the functional state of producing cells, both normal and neoplastic. Thus, monitoring of the immune system, mostly T-cells and haematological malignancies might be targets for the measurement of sIL-2R. Since many conditions may influence sIL-2R production, little diagnostic use may result from these measurements. However, since blood sIL-2R levels may correlate with disease progression and/or response to therapy, their measurement may be a useful index of activity and extent of disease. The precise biological role of the soluble form of the IL-2R is still a matter of debate. However, we know that increased sIL-2R levels may be observed in association with several immunological abnormalities and that sIL-2R is able to bind IL-2. It is conceivable then that in these conditions the excess sIL-2R released in vivo by activated lymphoid cells or by neoplastic cells may somehow regulate IL-2-dependent processes. On the other hand, it cannot exclude that sIL-2R is a by-product without biological significance. Finally, it is puzzling that in many conditions in which an increase of blood sIL-2R values has been observed, MNCs display a decreased in vitro capacity to produce sIL-2R. These seemingly contrasting

  7. Prognostic significance of erythropoietin in pancreatic adenocarcinoma.

    Science.gov (United States)

    Welsch, Thilo; Zschäbitz, Stefanie; Becker, Verena; Giese, Thomas; Bergmann, Frank; Hinz, Ulf; Keleg, Shereen; Heller, Anette; Sipos, Bence; Klingmüller, Ursula; Büchler, Markus W; Werner, Jens; Giese, Nathalia A

    2011-01-01

    Erythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC). The clinico-pathological relevance of hemoglobin (Hb, n = 150), serum Epo (sEpo, n = 87) and tissue expression of Epo/Epo receptor (EpoR, n = 104) was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05) and PDAC (p<0.001), reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46), 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99) but not in PDAC (O/P = 0.85). Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01)--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml) were not significantly different in M0 (20%) and M1 (30%) groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05). The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold ≥16 mU/ml by endogenous or exogenous means may predispose to or

  8. Inverse agonism and its therapeutic significance

    Directory of Open Access Journals (Sweden)

    Gurudas Khilnani

    2011-01-01

    Full Text Available A large number of G-protein-coupled receptors (GPCRs show varying degrees of basal or constitutive activity. This constitutive activity is usually minimal in natural receptors but is markedly observed in wild type and mutated (naturally or induced receptors. According to conventional two-state drug receptor interaction model, binding of a ligand may initiate activity (agonist with varying degrees of positive intrinsic activity or prevent the effect of an agonist (antagonist with zero intrinsic activity. Inverse agonists bind with the constitutively active receptors, stabilize them, and thus reduce the activity (negative intrinsic activity. Receptors of many classes (α-and β-adrenergic, histaminergic, GABAergic, serotoninergic, opiate, and angiotensin receptors have shown basal activity in suitable in vitro models. Several drugs that have been conventionally classified as antagonists (β-blockers, antihistaminics have shown inverse agonist effects on corresponding constitutively active receptors. Nearly all H 1 and H 2 antihistaminics (antagonists have been shown to be inverse agonists. Among the β-blockers, carvedilol and bucindolol demonstrate low level of inverse agonism as compared to propranolol and nadolol. Several antipsychotic drugs (D 2 receptors antagonist, antihypertensive (AT 1 receptor antagonists, antiserotoninergic drugs and opioid antagonists have significant inverse agonistic activity that contributes partly or wholly to their therapeutic value. Inverse agonism may also help explain the underlying mechanism of beneficial effects of carvedilol in congestive failure, naloxone-induced withdrawal syndrome in opioid dependence, clozapine in psychosis, and candesartan in cardiac hypertrophy. Understanding inverse agonisms has paved a way for newer drug development. It is now possible to develop agents, which have only desired therapeutic value and are devoid of unwanted adverse effect. Pimavanserin (ACP-103, a highly selective 5-HT

  9. Therapeutic Non Thermal Plasma, Significance and Challenges

    Directory of Open Access Journals (Sweden)

    Wameath Sh. Abdul-Majeed

    2014-06-01

    Full Text Available Plasma is an electrically neutral, highly ionized gas that consists of several species (electrons, ions, reactive species, and UV light and classified into localized thermal equilibrium (LTE plasmas and non-localized thermal equilibrium (n-LTE plasmas. In LTE plasmas, the electron temperature exists in equilibrium with the gas temperature. In contrast, the electron temperature in (n- LTE plasmas can reach temperatures of 1-10 (eV while the gas temperature is kept as low as room temperature, which makes it useful for a wide range of industrial applications (e.g. ozone generation, surface treatment, .., etc. In the past decade, non thermal (cold atmospheric pressure plasmas were developed and emerged as a promising new tool for medical applications as it’s proved to be more selective in its application (e.g. selective killing of microbes. Accordingly, developments of cold atmospheric plasma devices led to the possibility to apply plasma species to heat-sensitive surfaces (e.g. human skin with precise tuning, controllability and without damage of surrounding tissue. On this basis, medical plasma proved effective for skin sterilization, wound healing and tissue regeneration, cancer treatment, malignant cell apoptosis and blood coagulation. Moreover, cold plasma is known to inactivate a wide range of pathogens such as bacteria, viruses, fungi, spores and biofilms. Therefore it has been considered a very efficient alternative to superficially applied antibiotics or disinfectants. It’s worth noting that histological evaluation for the skin treated with atmospheric cold plasma showed that no morphological changes and no significant degree of necrosis or apoptosis were detectable after plasma treatment. Other studies denoted that a limited increase in the number of DNA double-strand breaks was observed in plasma-treated excised human skin. However, varieties of a new generation handheld and battery-operated devices makes it difficult to interpret the

  10. Collaborative inhibition in spatial memory retrieval

    National Research Council Canada - National Science Library

    Sjolund, Lori A; Erdman, Matthew; Kelly, Jonathan W

    2014-01-01

    .... Two experiments were designed to explore whether collaborative inhibition, which has heretofore been studied using traditional memory stimuli such as word lists, also characterizes spatial memory retrieval...

  11. The Significance of Adolescents' Relationships with Significant Others and School Failure

    Science.gov (United States)

    Domagala-Zysk, Ewa

    2006-01-01

    This article demonstrates the importance of social support from students' significant others (parents, peers and teachers) in the process of doing well at school. The main focus of the research project was to find correlations between the quality of adolescents' relationships with significant others and their school success or school failure, as…

  12. Acetazolamide inhibits aquaporin-1 protein expression and angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Yang XIANG; Bing MA; Tao LI; Jun-wei GAO; He-ming YU; Xue-jun LI

    2004-01-01

    AIM: To study effects of acetazolamide on aquaporin-1 (AQP1) protein expression and angiogenesis. METHODS:Establishing Lewis-lung-carcinoma model, the localization of AQP1 in tumor tissues was investigated by immunohistochemical methods; The biological activity of acetazolamide was detected by endothelial cells proliferation test (MTT) assay and chorioallantoic membrane (CAM) vascular inhibition test. RESULTS: Immunohistochemical localization of AQP1 in mice tumor was labeled in capillaries, post capillary venules endothelial cells. After being treated with acetazolamide, the number of capillaries and post capillary venules was significantly decreased in tumor tissue. Acetazolamide showed significant inhibitory effect on angiogenesis in CAM and endothelial cell proliferation.CONCLUSION: Acetazolamide might be identified and developed as one of potential lead compounds for a new therapeutic intervention in inhibiting cancer angiogenesis.

  13. Inhibition of Leukemic Cell Telomerase Activity by Antisense Phosphorothioate Oligodeoxynucleotides

    Institute of Scientific and Technical Information of China (English)

    HEDongmei; ZHANGYuan

    2002-01-01

    Objective To evaluate the effect of human telomerase reverse transcriptase(hTERT) gene antisense oligodeoxynucleotide (ASON) on telomerase activity in K562 cells.Methods Telomerase activity was detemined by polymerase chain reaction enzyme-linked immunoassay (PCR-ELISA) in K562 cells treated with ASODN and hTERTmRNA expression was detected by reverse transcriptase polymerase chain reaction (RT-PCR). Results The hTERTmRNA level was decreased,and telomerase activity was significantly inhibited when the K562 cells were treated with ASODN for 48 h. Conclusion It is suggested that hTETR ASODN might specifically inhibit telomrase activity of K562 cells at translation level,and it is further proved that hTERT gene has significant correlation with telopmerase activity.

  14. HEPES inhibits the conversion of prion protein in cell culture.

    Science.gov (United States)

    Delmouly, Karine; Belondrade, Maxime; Casanova, Danielle; Milhavet, Ollivier; Lehmann, Sylvain

    2011-05-01

    HEPES is a well-known buffering reagent used in cell-culture medium. Interestingly, this compound is also responsible for significant modifications of biological parameters such as uptake of organic molecules, alteration of oxidative stress mechanisms or inhibition of ion channels. While using cell-culture medium supplemented with HEPES on prion-infected cells, it was noticed that there was a significant concentration-dependent inhibition of accumulation of the abnormal isoform of the prion protein (PrP(Sc)). This effect was present only in live cells and was thought to be related to modification of the PrP environment or biology. These results could modify the interpretation of cell-culture assays of prion therapeutic agents, as well as of previous cell biology results obtained in the field using HEPES buffers. This inhibitory effect of HEPES could also be exploited to prevent contamination or propagation of prions in cell culture.

  15. Extraction conditions of white rose petals for the inhibition of enzymes related to skin aging.

    Science.gov (United States)

    Choi, Ehn-Kyoung; Guo, Haiyu; Choi, Jae-Kwon; Jang, Su-Kil; Shin, Kyungha; Cha, Ye-Seul; Choi, Youngjin; Seo, Da-Woom; Lee, Yoon-Bok; Joo, Seong-So; Kim, Yun-Bae

    2015-09-01

    In order to assess inhibitory potentials of white rose petal extracts (WRPE) on the activities of enzymes related to dermal aging according to the extraction conditions, three extraction methods were adopted. WRPE was prepared by extracting dried white rose (Rosa hybrida) petals with 50% ethanol (WRPE-EtOH), Pectinex® SMASH XXL enzyme (WRPE-enzyme) or high temperature-high pressure (WRPE-HTHP). In the inhibition of matrix metalloproteinase-1, although the enzyme activity was fully inhibited by all 3 extracts at 100 µg/mL in 60 min, partial inhibition (50-70%) was achieved only by WRPE-EtOH and WRPE-enzyme at 50 µg/mL. High concentrations (≥250 µg/mL) of all 3 extracts markedly inhibited the elastase activity. However, at low concentrations (15.6-125 µg/mL), only WRPE-EtOH inhibited the enzyme activity. Notably, WRPE-EtOH was superior to WRPE-enzyme and WRPE-HTHP in the inhibition of tyrosinase. WRPE-EtOH significantly inhibited the enzyme activity from 31.2 µM, reaching 80% inhibition at 125 µM. In addition to its strong antioxidative activity, the ethanol extract of white rose petals was confirmed to be effective in inhibiting skin aging-related enzymes. Therefore, it is suggested that WRPE-EtOH could be a good candidate for the improvement of skin aging such as wrinkle formation and pigmentation.

  16. Relationships between presynaptic inhibition and static postural sway in subjects with and without diabetic neuropathy.

    Science.gov (United States)

    Chun, Jihyun; Hong, Junggi

    2015-09-01

    [Purpose] Diabetic peripheral neuropathy can often lead to balance impairment. The spinal reflex is a mechanism that is reportedly important for balance, but it has not been investigated in diabetic peripheral neuropathy patients. Moreover, inhibitory or facilitatory behavior of the spinal reflex-known as presynaptic inhibition-is essential for controlling postural sway. The purpose of this study was to compare the differences in as presynaptic inhibition and balance in subjects with and without diabetic peripheral neuropathy to determine the influence of presynaptic inhibition on balance in diabetic peripheral neuropathy patients. [Subjects and Methods] Presynaptic inhibition and postural sway were tested in eight patients (mean age, 58±6 years) and eight normal subjects (mean age, 59±7 years). The mean percent difference in conditioned reflex amplitude relative to the unconditioned reflex amplitude was assessed to calculate as presynaptic inhibition. The single-leg balance index was measured using a computerized balance-measuring device. [Results] The diabetic peripheral neuropathy group showed lower presynaptic inhibition (47±30% vs. 75±22%) and decreased balance (0.65±0.24 vs. 0.38±0.06) as compared with the normal group. No significant correlation was found between as presynaptic inhibition and balance score (R=0.37). [Conclusion] Although the decreased as presynaptic inhibition observed in diabetic peripheral neuropathy patients may suggest central nervous system involvement, further research is necessary to explore the role of presynaptic inhibition in decreased balance in diabetic peripheral neuropathy patients.

  17. Combined MET inhibition and topoisomerase I inhibition block cell growth of small cell lung cancer.

    Science.gov (United States)

    Rolle, Cleo E; Kanteti, Rajani; Surati, Mosmi; Nandi, Suvobroto; Dhanasingh, Immanuel; Yala, Soheil; Tretiakova, Maria; Arif, Qudsia; Hembrough, Todd; Brand, Toni M; Wheeler, Deric L; Husain, Aliya N; Vokes, Everett E; Bharti, Ajit; Salgia, Ravi

    2014-03-01

    Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC. ©2013 AACR.

  18. Inhibition of the dorsal premotor cortex does not repair surround inhibition in writer's cramp patients.

    Science.gov (United States)

    Veugen, Lidwien C; Hoffland, Britt S; Stegeman, Dick F; van de Warrenburg, Bart P

    2013-03-01

    Writer's cramp is a task-specific form of focal dystonia, characterized by abnormal movements and postures of the hand and arm during writing. Two consistent abnormalities in its pathophysiology are a loss of surround inhibition and overactivity of the dorsal premotor cortex (PMd). This study aimed to assess a possible link between these two phenomena by investigating whether PMd inhibition leads to an improvement of surround inhibition, in parallel with previously demonstrated writing improvement. Fifteen writer's cramp patients and ten controls performed a simple motor hand task during which surround inhibition was measured using transcranial magnetic stimulation. Motor cortical excitability was measured of the active and surround muscles at three phases of the task. Surround inhibition and writing performance were assessed before and after PMd inhibitory continuous theta burst stimulation. In contrast to healthy controls, patients did not show inhibition of the abductor digiti minimi muscle during movement initiation of the first dorsal interosseus muscle, confirming the loss of surround inhibition. PMd inhibition led to an improvement of writing speed in writer's cramp patients. However, in both groups, no changes in surround inhibition were observed. The results confirm a role for the PMd in the pathophysiology of writer's cramp. We show that PMd inhibition does not lead to restoration of the surround inhibition defect in writer's cramp, despite the improvement in writing. This questions the involvement of the PMd in the loss of surround inhibition, and perhaps also the direct link between surround inhibition and dystonia.

  19. Combination of rapamycin, CI-1040, and 17-AAG inhibits metastatic capacity of prostate cancer via Slug inhibition.

    Directory of Open Access Journals (Sweden)

    Guanxiong Ding

    Full Text Available Though prostate cancer (PCa has slow progression, the hormone refractory (HRCP and metastatic entities are substantially lethal and lack effective treatments. Transcription factor Slug is critical in regulating metastases of various tumors including PCa. Here we studied targeted therapy against Slug using combination of 3 drugs targeting 3 pathways respectively converging via Slug and further regulating PCa metastasis. Using in vitro assays we confirmed that Slug up-regulation incurred inhibition of E-cadherin that was anti-metastatic, and inhibited Bim-regulated cell apoptosis in PCa. Upstream PTEN/Akt, mTOR, Erk, and AR/Hsp90 pathways were responsible for Slug up-regulation and each of these could be targeted by rapamycin, CI-1040, and 17-AAG respectively. In 4 PCa cell lines with different traits in terms of PTEN loss and androgen sensitivity we tested the efficacy of mono- and combined therapy with the drugs. We found that metastatic capacity of the cells was maximally inhibited only when all 3 drugs were combined, due to the crosstalk between the pathways. 17-AAG decreases Slug expression via blockade of HSP90-dependent AR stability. Combination of rapamycin and CI-1040 diminishes invasiveness more potently in PCa cells that are androgen insensitive and with PTEN loss. Slug inhibited Bim-mediated apoptosis that could be rescued by mTOR/Erk/HSP90 inhibitors. Using mouse models for circulating PCa DNA quantification, we found that combination of mTOR/Erk/HSP90 inhibitors reduced circulating PCa cells in vivo significantly more potently than combination of 2 or monotherapy. Conclusively, combination of mTOR/Erk/Hsp90 inhibits metastatic capacity of prostate cancer via Slug inhibition.

  20. Discriminating anisometropic amblyopia from myopia based on interocular inhibition.

    Science.gov (United States)

    Jia, Wuli; Zhou, Jiawei; Lu, Zhong-Lin; Lesmes, Luis A; Huang, Chang-Bing

    2015-09-01

    Amblyopia screening during childhood is critical for early detection and successful treatment. In the current study, we develop and evaluate a screening method that exploits the imbalanced interocular inhibition between amblyopic and fellow eyes. In nineteen subjects with anisometropic amblyopia and twenty-two age-matched subjects with myopia, we measured the area under the contrast sensitivity functions (AUCSFs) in eight monocular conditions defined by the tested eye (left, right), patching of the untested eye (translucent, opaque), and refractive status (corrected, uncorrected). For each tested eye, we defined the inhibition index as the ratio between the AUCSF values obtained in the translucent and opaque patching conditions of the untested eye. To evaluate the screening potential of the inhibition index, we compared results from patients with amblyopia and myopia. With and without optical correction, the index was significantly lower in the amblyopic eye than in the fellow eye of the amblyopic subjects and both eyes of the myopic subjects. No significant difference was found among the two eyes of the myopic subjects and the fellow eyes of the amblyopic subjects. With the inhibition index as the predictor, a logistic regression model successfully discriminated amblyopic eyes from myopic eyes with 100% accuracy in the uncorrected condition. In the corrected condition, with the inhibition index and interocular visual acuity difference as predictors, amblyopic eyes were likewise discriminated from myopic eyes with 100% accuracy. This pattern of CSF changes, caused by the different patching modes of the untested eye, provides a potential CSF signature to discriminate anisometropic amblyopia from myopia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Reinforcement and Stimulant Medication Ameliorate Deficient Response Inhibition in Children with Attention-Deficit/Hyperactivity Disorder.

    Science.gov (United States)

    Rosch, Keri S; Fosco, Whitney D; Pelham, William E; Waxmonsky, James G; Bubnik, Michelle G; Hawk, Larry W

    2016-02-01

    This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n = 111, 25 girls) and typically-developing (TD) controls (n = 33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions.

  2. Biochemical requirements for inhibition of Connexin26-containing channels by natural and synthetic taurine analogs.

    Science.gov (United States)

    Tao, Liang; Harris, Andrew L

    2004-09-10

    Previous work has shown that protonated taurine and aminosulfonate pH buffers, including HEPES, can directly and reversibly inhibit connexin channels that contain connexin26 (Cx26) (Bevans, C. G., and Harris, A. L. (1999) J. Biol. Chem. 274, 3711-3719). The structural requirements for this inhibition were explored by studies of the effects of structural analogs of taurine on the activity of Cx26-containing reconstituted hemichannels from native tissue. Several analogs inhibited the channels, with a range of relative affinities and efficacies. Each active compound contains a protonated amine separated from an ionized sulfonate or sulfinate moiety by several methylene groups. The inhibition is eliminated if the sulfonate/sulfinate moiety or the amine is not present. Compounds that contain a protonated amine but lack a sulfonate/sulfinate moiety do not inhibit but do competitively block the effect of the active compounds. Compounds that lack the protonated amine do not significantly inhibit or antagonize inhibition. The results suggest involvement of the protonated amine in binding and of the ionized sulfur-containing moiety in effecting the inhibition. The maximal effect of the inhibitory compounds is enhanced when a carboxyl group is linked to the alpha-carbon. Inhibition but not binding is stereospecific, with l-isomers being inhibitory and the corresponding d-isomers being inactive but able to antagonize inhibition by the l-isomers. Whereas not all connexins are sensitive to aminosulfonates, the well defined structural requirements described here argue strongly for a highly specific regulatory interaction with some connexins. The finding that cytoplasmic aminosulfonates inhibit connexin channels whereas other cytoplasmic compounds antagonize the inhibition suggests that gap junction channels are regulated by a complex interplay of cytoplasmic ligands.

  3. a -Difluoromethylornithine Inhibits the Growth of Fungus Macrophomina phaseoli

    OpenAIRE

    PALAVAN-ÜNSAL, Narçin

    2014-01-01

    a -Difluoromethylornithine (DFMO), a specific enzyme activated inhibitor of ornithine decarboxylase (ODC), significantly inhibited the mycelial growth of the fungus Macrophomina phaseoli (Tassi) Goidanich. Putrescine (Put), when added to the nutrient medium at a concentration of 0.25 mM, decreased the inhibitory effect of DFMO. These results suggest that polyamines (PAs) are essential for the growth of fungi and that DFMO is applicable to the alleviation or prevention of crop losses due to ph...

  4. Inhibition of N-Type Calcium Channels by Fluorophenoxyanilide Derivatives

    Directory of Open Access Journals (Sweden)

    Ellen C. Gleeson

    2015-04-01

    Full Text Available A set of fluorophenoxyanilides, designed to be simplified analogues of previously reported ω-conotoxin GVIA mimetics, were prepared and tested for N-type calcium channel inhibition in a SH-SY5Y neuroblastoma FLIPR assay. N-type or Cav2.2 channel is a validated target for the treatment of refractory chronic pain. Despite being significantly less complex than the originally designed mimetics, up to a seven-fold improvement in activity was observed.

  5. Azithromycin Inhibits Mucus Hypersecretion from Airway Epithelial Cells

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    Takeshi Shimizu

    2012-01-01

    Full Text Available To examine the in vivo effects of the 15-member macrolide, azithromycin (AZM, on mucus hypersecretion, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal instillation of ovalbumin (OVA in OVA-sensitized rats, or by intranasal lipopolysaccharides (LPS instillation. Oral administration of AZM (5–10 mg/kg or clarithromycin (CAM, 5–10 mg/kg significantly inhibited OVA- and LPS-induced mucus production, whereas josamycin (JM or ampicillin (ABPC showed no effect. In vitro effects of AZM on airway epithelial cells were examined using NCI-H292 cells and human nasal epithelial cells cultured in air-liquid interface. Mucus secretion was evaluated by enzyme-linked immunosorbent assay using an anti-MUC5AC monoclonal antibody. AZM or CAM significantly inhibited tumor necrosis factor-α (TNF-α (20 ng/mL-induced MUC5AC secretion from NCI-H292 cells at 10−6–10−7 M, whereas JM or ABPC showed no effect. AZM significantly inhibited TNF- (20 ng/mL-induced MUC5AC secretion from human nasal epithelial cells at 10−4 M. MUC5AC mRNA expression was also significantly inhibited. These results indicate that the 15-member macrolide, AZM, exerts direct inhibitory effects on mucus secretion from airway epithelial cells and that it may be useful for the treatment of mucus hypersecretion caused by allergic inflammation and LPS stimulation.

  6. Perioperative platelet inhibition in transurethral interventions: TURP/TURB

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    Michael Wenders

    2012-10-01

    Full Text Available PURPOSE: To determine whether transurethral surgery under platelet inhibition is a feasible procedure. Before transurethral resection of prostate (TURP or bladder tumours (TURB, the administration of platelet-inhibiting medication is often interrupted due to possible bleeding complications. We studied the performance of TURP and TURB under the current recommendations of the American College of Chest Physicians (ACCP on perioperative platelet inhibition. MATERIALS AND METHODS: Patients assigned for transurethral intervention were preoperatively divided into the following risk groups: low, medium and high cardio- or cerebrovascular risk. In patients with a low-risk profile, acetylsalicylic acid (ASA was discontinued. Patients of the medium risk group continued taking 100 mg of ASA. Patients of the high-risk group receiving dual platelet inhibition (ASA + clopidogrel were not treated operatively. In total 346 patients from the low and medium risk groups underwent transurethral intervention. RESULTS: Forty-two out of 198 TURP were performed under 100 mg of ASA. Without ASA, a significantly shorter length of stay and earlier removal of the transurethral catheter was documented. In the parameters postoperative haemorrhage and operative revision, no significant differences were observed. Thirty-two out of 148 TURB were performed under 100 mg of ASA. Regarding the length of stay, time until catheter removal, postoperative haemorrhage and operative revision, no significant differences were found under ASA. Only significantly longer continuous irrigation was documented under ASA. CONCLUSION: In the case of a verified indication for use of platelet inhibitors, it is possible to avoid discontinuation and the consequent increased risk of thromboembolic incidents in transurethral surgery is admissible.

  7. Competitive inhibition bacteria of bovine origin against Salmonella serovars.

    Science.gov (United States)

    Danyluk, Michelle D; Zhao, Tong; Doyle, Michael P

    2007-08-01

    Studies were conducted to isolate bacteria inhibitory to Salmonella enterica serovar Typhimurium definitive type (DT) 104 in vitro from cattle not carrying Salmonella and to determine the inhibitory activity of the isolated bacteria through competitive growth in cattle feces artificially contaminated with Salmonella Typhimurium DT104 and S. enterica serovar Newport. Fecal samples (108) were obtained from dairy and beef cows. S. enterica serovars were isolated from 9.25% of the samples and included Salmonella Newport (4), Salmonella Bareilly (1), Salmonella Mbandaka (1), Salmonella Montevideo (1), Salmonella Meleagridis (1), and monophasic Salmonella (2). All four Salmonella Newport isolates were resistant to at least nine antibiotics. Of 1,097 bacterial isolates from cattle feces screened, 30 were inhibitory to Salmonella Typhimurium DT104 in vitro. The inhibitory isolates included 22 Escherichia coli, 6 Bacillus circulans, 1 Serratia fonticola, and 1 Enterobacter cloacae. Typing by pulsed-field gel electrophoresis showed 17 distinguishable profiles among the 22 E. coli. Competitive inhibition isolates did not significantly reduce Salmonella Typhimurium DT104 during 21 days of storage at 37 degrees C in cattle feces. B. circulans (10(5) CFU/g of inoculum) significantly reduced Salmonella Newport on days 3 and 5 and on day 21 with 10(8) CFU/g of inoculum at 37 degrees C. At 21degrees C, significant reductions of Salmonella Typhimurium DT104 occurred with 10(8) CFU of gram-negative competitive inhibition bacteria per g and 10(5) CFU of B. circulans per g on day 5 only. No significant reductions were observed with Salmonella Newport at 21 degrees C. The 25 competitive inhibition bacteria identified in this study offer a first step in identifying competitive inhibition bacteria that may reduce the level of intestinal carriage and fecal shedding of Salmonella Typhimurium DT104 and Salmonella Newport in cattle.

  8. Atomoxetine restores the response inhibition network in Parkinson's disease.

    Science.gov (United States)

    Rae, Charlotte L; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E; Jones, P Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

    2016-08-01

    Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction

  9. Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Eunsun Jung

    2013-12-01

    Full Text Available Madecassoside (MA, a pentacyclic triterpene isolated from Centella asitica (L., is used as a therapeutic agent in wound healing and also as an anti-inflammatory and anti-aging agent. However, the involvement of MA in skin-pigmentation has not been reported. This study was conducted to investigate the effects of MA on ultraviolet (UV-induced melanogenesis and mechanisms in a co-culture system of keratinocytes and melanocytes. MA significantly inhibited UVR-induced melanin synthesis and melanosome transfer in the co-culture system. These effects were further demonstrated by the MA-induced inhibition of protease-activated receptor-2 expression and its signaling pathway, cyclooxygenase-2, prostaglandin E2 and prostaglandin F2 alpha in keratinocytes. The clinical efficacy of MA was confirmed on artificially tanned human skin. MA significantly reduced UV-induced melanin index at 8 weeks after topical application. Overall, the study demonstrated significant benefits of MA use in the inhibition of hyperpigmentation caused by UV irradiation.

  10. Effect of oxygen inhibition on composite repair strength over time.

    Science.gov (United States)

    Dall'Oca, Susanna; Papacchini, Federica; Goracci, Cecilia; Cury, Alvaro H; Suh, Byoung I; Tay, Franklin R; Polimeni, Antonella; Ferrari, Marco

    2007-05-01

    The study was aimed at examining whether an oxygen inhibition layer is required for bonding a repairing to a pre-existing composite, and to determine the time required for free radicals within a composite substrate to decay to the extent that the composite repair strength drops significantly. Ten slabs of Gradia Direct Anterior (GC Corp.) were divided into (1) control group: an interfacial oxygen inhibition layer was created by applying and light-curing two layers of bonding resin (D/E Resin, Bisco) to the slabs surface in atmospheric air; (2) experimental group: the absence of an interfacial oxygen inhibition layer was obtained by light-curing the second bonding resin layer in a nitrogen atmosphere. After 1 and 2 h, 1, 14, and 30 days of air storage, a composite repair was layered over the bonding resin. Microtensile bond strengths were measured and statistically analyzed. The curing atmosphere was not a significant factor for bond strength (p = 0.82), and time and curing atmosphere-time interaction were significant (p composite, and it takes more than 14 days before the bond strength between a pre-existing and a fresh composite drops.

  11. Inhibition of human immunodeficiency virus type-1 by cdk inhibitors

    Directory of Open Access Journals (Sweden)

    Kehn-Hall Kylene

    2010-03-01

    Full Text Available Abstract Current therapy for human immunodeficiency virus (HIV-1 infection relies primarily on the administration of anti-retroviral nucleoside analogues, either alone or in combination with HIV-protease inhibitors. Although these drugs have a clinical benefit, continuous therapy with the drugs leads to drug-resistant strains of the virus. Recently, significant progress has been made towards the development of natural and synthetic agents that can directly inhibit HIV-1 replication or its essential enzymes. We previously reported on the pharmacological cyclin-dependent kinase inhibitor (PCI r-roscovitine as a potential inhibitor of HIV-1 replication. PCIs are among the most promising novel antiviral agents to emerge over the past few years. Potent activity on viral replication combined with proliferation inhibition without the emergence of resistant viruses, which are normally observed in HAART patients; make PCIs ideal candidates for HIV-1 inhibition. To this end we evaluated twenty four cdk inhibitors for their effect on HIV-1 replication in vitro. Screening of these compounds identified alsterpaullone as the most potent inhibitor of HIV-1 with activity at 150 nM. We found that alsterpaullone effectively inhibits cdk2 activity in HIV-1 infected cells with a low IC50 compared to control uninfected cells. The effects of alsterpaullone were associated with suppression of cdk2 and cyclin expression. Combining both alsterpaullone and r-roscovitine (cyc202 in treatment exhibited even stronger inhibitory activities in HIV-1 infected PBMCs.

  12. Proteasome Inhibition Suppresses Dengue Virus Egress in Antibody Dependent Infection.

    Directory of Open Access Journals (Sweden)

    Milly M Choy

    2015-11-01

    Full Text Available The mosquito-borne dengue virus (DENV is a cause of significant global health burden, with an estimated 390 million infections occurring annually. However, no licensed vaccine or specific antiviral treatment for dengue is available. DENV interacts with host cell factors to complete its life cycle although this virus-host interplay remains to be fully elucidated. Many studies have identified the ubiquitin proteasome pathway (UPP to be important for successful DENV production, but how the UPP contributes to DENV life cycle as host factors remains ill defined. We show here that proteasome inhibition decouples infectious virus production from viral RNA replication in antibody-dependent infection of THP-1 cells. Molecular and imaging analyses in β-lactone treated THP-1 cells suggest that proteasome function does not prevent virus assembly but rather DENV egress. Intriguingly, the licensed proteasome inhibitor, bortezomib, is able to inhibit DENV titers at low nanomolar drug concentrations for different strains of all four serotypes of DENV in primary monocytes. Furthermore, bortezomib treatment of DENV-infected mice inhibited the spread of DENV in the spleen as well as the overall pathological changes. Our findings suggest that preventing DENV egress through proteasome inhibition could be a suitable therapeutic strategy against dengue.

  13. Modelling sodium inhibition on the anaerobic digestion process.

    Science.gov (United States)

    Hierholtzer, A; Akunna, J C

    2012-01-01

    Sodium is a known process inhibitor in anaerobic systems and impacts on methanogens through an increase of osmotic pressure or complete dehydration of microorganisms. In this study, a combination of experimental and modelling approaches has been employed to determine and simulate sodium inhibition on the anaerobic digestion process. The ADM1, which has been successfully used in modelling anaerobic processes, has been modified to include an extra inhibition function that considers the effect of sodium on acetoclastic methanogens and the impact on biogas production and composition. A non-competitive inhibition function was added to the rate of acetate uptake for the model to take into account sodium toxicity. Experimental studies consisted of both batch and reactor tests to obtain parameters for model calibration and validation. The calibrated model was used to predict the effect of ammonia nitrogen on sodium toxicity. It was found that relatively low sodium levels can bring about significant levels of process inhibition in the presence of high levels of ammonia. On the other hand, where the concentration of ammonia is relatively low, the tolerance threshold for sodium ions increases. Hence, care must be taken in the use of sodium hydroxide for pH adjustment during anaerobic digestion of protein-rich substrates.

  14. Inhibition of coral recruitment by macroalgae and cyanobacteria

    Science.gov (United States)

    Kuffner, I.B.; Walters, L.J.; Becerro, M.A.; Paul, V.J.; Ritson-Williams, R.; Beach, K.S.

    2006-01-01

    Coral recruitment is a key process in the maintenance and recovery of coral reef ecosystems. While intense competition between coral and algae is often assumed on reefs that have undergone phase shifts from coral to algal dominance, data examining the competitive interactions involved, particularly during the larval and immediate post-settlement stage, are scarce. Using a series of field and outdoor seawater table experiments, we tested the hypothesis that common species of macroalgae and cyanobacteria inhibit coral recruitment. We examined the effects of Lyngbya spp., Dictyota spp., Lobophora variegata (J. V. Lamouroux) Womersley, and Chondrophycus poiteaui (J. V. Lamouroux) Nam (formerly Laurencia poiteaui) on the recruitment success of Porites astreoides larvae. All species but C. poiteaui caused either recruitment inhibition or avoidance behavior in P. astreoides larvae, while L. confervoides and D. menstrualis significantly increased mortality rates of P. astreoides recruits. We also tested the effect of some of these macrophytes on larvae of the gorgonian octocoral Briareum asbestinum. Exposure to Lyngbya majuscula reduced survival and recruitment in the octocoral larvae. Our results provide evidence that algae and cyanobacteria use tactics beyond space occupation to inhibit coral recruitment. On reefs experiencing phase shifts or temporary algal blooms, the restocking of adult coral populations may be slowed due to recruitment inhibition, thereby perpetuating reduced coral cover and limiting coral community recovery. ?? Inter-Research 2006.

  15. The Theaflavin Monomers Inhibit the Cancer Cells Growth in Vitro

    Institute of Scientific and Technical Information of China (English)

    You-Ying TU; An-Bin TANG; Naoharu WATANABE

    2004-01-01

    The inhibition effects of tea theaflavins complex (TFs), theaflavin-3-3 '-digallate (TFDG),theaflavin-3'-gallate (TF2B), and an unidentified compound (UC) on the growth of human liver cancer BEL-7402 cells, gastric cancer MKN-28 cells and acute promyelocytic leukemia LH-60 cells were investigated.TFs was obtained through the catalysis of catechins with immobilized polyphenols oxidase. TFDG, TF2B and UC were isolated from TFs with high speed countercurrent chromatography (HSCCC). The results showed that TF2B significantly inhibited the growth of all three kinds of cancer cells, TFs, TFDG and UC had some effect on BEL-7402 and MKN-28, but little activity on LH-60. The inhibition effects of TF2B, TFDG, and UC on BEL-7402 and MKN-28 were stronger than TFs. The relationship coefficients between monomer concentration and its inhibition rate against MKN-28 and BEL-7402 were 0.87 and 0.98 for TF2B, 0.96 and 0.98 for UC, respectively. The IC50 values ofTFs, TF2B, and TFDG were 0.18, 0.11, and 0.16 mM on BEL-7402 cells, and 1.11, 0.22, and 0.25 mM on MKN-28 cells respectively.

  16. Inhibition of endogenous lactate turnover with lactate infusion in humans

    Energy Technology Data Exchange (ETDEWEB)

    Searle, G.L.; Feingold, K.R.; Hsu, F.S.; Clark, O.H.; Gertz, E.W.; Stanley, W.C. (Veterans Administration Medical Center, San Francisco, CA (USA))

    1989-11-01

    The extent to which lactate infusion may inhibit endogenous lactate production, though previously considered, has never been critically assessed. To examine this proposition, single injection tracer methodology (U-{sup 14}C Lactate) has been used for the estimation of lactate kinetics in 12 human subjects under basal conditions and with the infusion of sodium lactate. The basal rate of lactate turnover was measured on a day before the study with lactate infusion, and averaged 63.7 + 5.5 mg/kg/h. Six of these individuals received a stable lactate infusion at an approximate rate of 160 mg/kg/h, while the remaining six individuals were infused at the approximate rate of 100 mg/kg/h. It has been found that stable lactate infused at rates approximating 160 mg/kg/h consistently produced a complete inhibition of endogenous lactate production. Infusion of lactate at 100 mg/kg/h caused a lesser and more variable inhibition of endogenous lactate production (12% to 64%). In conclusion, lactate infusion significantly inhibits endogenous lactate production.

  17. Phytotoxicity of nanoparticles: Inhibition of seed germination and root growth

    Energy Technology Data Exchange (ETDEWEB)

    Lin Daohui [Department of Environmental Science, Zhejiang University, Hangzhou 310028 (China); Department of Plant, Soil and Insect Sciences, University of Massachusetts, Stockbridge Hall, Amherst, MA 01003 (United States); Xing Baoshan [Department of Plant, Soil and Insect Sciences, University of Massachusetts, Stockbridge Hall, Amherst, MA 01003 (United States)], E-mail: bx@pssci.umass.edu

    2007-11-15

    Plants need to be included to develop a comprehensive toxicity profile for nanoparticles. Effects of five types of nanoparticles (multi-walled carbon nanotube, aluminum, alumina, zinc, and zinc oxide) on seed germination and root growth of six higher plant species (radish, rape, ryegrass, lettuce, corn, and cucumber) were investigated. Seed germination was not affected except for the inhibition of nanoscale zinc (nano-Zn) on ryegrass and zinc oxide (nano-ZnO) on corn at 2000 mg/L. Inhibition on root growth varied greatly among nanoparticles and plants. Suspensions of 2000 mg/L nano-Zn or nano-ZnO practically terminated root elongation of the tested plant species. Fifty percent inhibitory concentrations (IC{sub 50}) of nano-Zn and nano-ZnO were estimated to be near 50 mg/L for radish, and about 20 mg/L for rape and ryegrass. The inhibition occurred during the seed incubation process rather than seed soaking stage. These results are significant in terms of use and disposal of engineered nanoparticles. - Engineered nanoparticles can inhibit the seed germination and root growth.

  18. Inhibition of auxin-induced ethylene production by lycoricidinol

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Bin-G.; Lee, June-S.; Oh, Seung-Eun (Yonsei Univ., Seoul (Republic of Korea)); Horiuchi, Yuko; Imaseki, Hidemasa

    1984-03-01

    Lycoricidinol, a natural growth inhibitor isolated from bulbs of Lycoris radiata Herb. strongly suppressed auxin-induced ethylene production from the hypocotyl segments of etiolated mung bean (Vigna radiata Wilczek) seedlings. The inhibitor did not significantly inhibit ethylene formation from its immediate precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), during short-term (up to 4h) incubation. The ACC content in tissue treated with IAA was reduced by lycoricidinol in close parallel with the inhibition of ethylene production. Examination of radioactive metabolites in tissues labeled with 3,4-/sup 14/C-methionine indicated that reduction of the ACC content was not due to any possible promotive effect of lycoricidinol on conjugation of ACC with malonate. Lycoricidinol showed no inhibitory effect on the activity of ACC synthase if applied in vitro, but it almost completely abolished the increase in the enzyme activity when applied in vivo during incubation of the tissue with IAA. Lycoricidinol also strongly inhibited incorporation of /sup 14/C-leucine into protein in the tissue. The suppression of the enzyme induction and, in turn, that of ethylene production by lycoricidinol were interpreted as being due to the inhibition of protein synthesis.

  19. Defective urinary crystallization inhibition and urinary stone formation

    Directory of Open Access Journals (Sweden)

    Mauricio Carvalho

    2006-06-01

    Full Text Available INTRODUCTION: Nephrocalcin (NC is a glycoprotein produced in the kidney and inhibits calcium oxalate crystal formation. It has been separated into 4 isoforms (A, B, C, and D and found that (A + B are more abundant than (C + D in urine of healthy subjects, but the reverse is seen in human urine of kidney stone patients. To further examine the role of this protein in inhibition of urinary crystallization, nephrocalcin isoforms were purified from 2 genetically pure dog species. MATERIALS AND METHODS: We studied healthy Beagles, known to be non-stone forming dogs, and Mini-Schnauzers, known to be calcium oxalate stone formers. NC was isolated and purified from each group. Urinary biochemistry and calcium oxalate crystal growth inhibition were measured. RESULTS: Specific crystal growth inhibition activity was significantly higher in non-stone forming dogs (9.79 ± 2.25 in Beagles vs. 2.75 ± 1.34 of Mini-Schnauzers, p < 0.005. Dissociation constants toward calcium oxalate monohydrate were 10-fold different, with Beagles' isoforms being 10 times stronger inhibitors compare to those of Mini-Schnauzers'. Isoforms C + D of NC were the main isoforms isolated in stone-forming dogs. CONCLUSION: NC of these two species of dogs differently affects calcium oxalate crystallization and might have a role in determining ulterior urinary stone formation.

  20. Low levels of inorganic lead noncompetitively inhibit mu-calpain.

    Science.gov (United States)

    Audesirk, T; Pedersen, C; Audesirk, G; Kern, M

    1998-11-16

    Calpain is a ubiquitous calcium-dependent cysteine protease, whose cytoskeletal protein substrates suggest that it may be important in neuronal differentiation. Lead (Pb2+) is known to substitute for Ca2+ in a variety of intracellular processes, and interferes with the development of hippocampal neurons in vitro. We found that free Pb2+ at 1 nM does not activate calpain in the absence of Ca2+. Pb2+ inhibited the activity of calpain; the degree of calpain inhibition was dependent on an interaction between concentrations of both Ca2+ and Pb2+. In the presence of 1 microM free Ca2+, 10 pM free Pb2+ reduced calpain activity, but in the presence of 100 microM free Ca2+, 1 nM free Pb2+ failed to inhibit calpain. This provides evidence that Pb2+ competes for the Ca2+ binding sites on calpain. In the presence of 40 microM free Ca2+, 1 nM free Pb2+ significantly reduces Vmax without altering Km, suggesting that Pb2+ acts as a noncompetitive inhibitor of calpain. Inhibition of calpain is one mechanism by which Pb2+ may interfere with neuronal development.

  1. Interleukin-10 inhibits autonomous myelopoiesis in patients with myelofibrosis.

    Science.gov (United States)

    Geissler, Klaus; Jäger, Eva; Öhler, Leopold; Gisslinger, Heinz; Jäger, Ulrich; Lechner, Klaus

    2015-09-01

    The spontaneous formation of colony-forming units granulocyte/macrophage (CFU-GM) in semisolid cultures has been shown to be due to the endogenous release of cytokines and/or to the hypersensitivity of cells against growth factors. We have reported that increased autonomous CFU-GM growth is an in vitro characteristic of myelofibrosis (MF) which may reflect aberrant hematopoiesis in vivo. Because of its cytokine synthesis-inhibiting action, we speculated that interleukin-10 (IL-10) may inhibit pathological overproduction of myeloid cells in MF by suppression of autonomous myelopoiesis. In this study, IL-10 significantly inhibited autonomous CFU-GM formation in vitro from peripheral blood mononuclear cells (PB MNC) in 10 of 11 patients with MF tested. In all patients, there was a mean inhibition of 69% ranging from 35% to 100%. Suppression of autonomous CFU-GM formation by IL-10 was dose dependent and reversible by the addition of anti-IL-10 antibodies. Our results indicate that IL-10 is a potentially useful molecule to affect aberrant myelopoiesis in patients with MF.

  2. Maturation of cognitive control: delineating response inhibition and interference suppression.

    Directory of Open Access Journals (Sweden)

    Christopher R Brydges

    Full Text Available Cognitive control is integral to the ability to attend to a relevant task whilst suppressing distracting information or inhibiting prepotent responses. The current study examined the development of these two subprocesses by examining electrophysiological indices elicited during each process. Thirteen 18 year-old adults and thirteen children aged 8-11 years (mean=9.77 years completed a hybrid Go/Nogo flanker task while continuous EEG data were recorded. The N2 topography for both response inhibition and interference suppression changed with increasing age. The neural activation associated with response inhibition became increasingly frontally distributed with age, and showed decreases of both amplitude and peak latency from childhood to adulthood, possibly due to reduced cognitive demands and myelination respectively occurring during this period. Interestingly, a significant N2 effect was apparent in adults, but not observed in children during trials requiring interference suppression. This could be due to more diffuse activation in children, which would require smaller levels of activation over a larger region of the brain than is reported in adults. Overall, these results provide evidence of distinct maturational processes occurring throughout late childhood and adolescence, highlighting the separability of response inhibition and interference suppression.

  3. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels.

    Science.gov (United States)

    Smith, M Ryan; Vayalil, Praveen K; Zhou, Fen; Benavides, Gloria A; Beggs, Reena R; Golzarian, Hafez; Nijampatnam, Bhavitavya; Oliver, Patsy G; Smith, Robin A J; Murphy, Michael P; Velu, Sadanandan E; Landar, Aimee

    2016-08-01

    Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP), decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231) breast adenocarcinoma cells up to 6 days after an initial 24h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR) in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10µM) of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC) protein levels, although other protein levels were unaffected. This study

  4. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels

    Directory of Open Access Journals (Sweden)

    M. Ryan Smith

    2016-08-01

    Full Text Available Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP, decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231 breast adenocarcinoma cells up to 6 days after an initial 24 h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10 µM of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC protein levels, although other protein levels were

  5. Reactor design for minimizing product inhibition during enzymatic lignocellulose hydrolysis: II. Quantification of inhibition and suitability of membrane reactors.

    Science.gov (United States)

    Andrić, Pavle; Meyer, Anne S; Jensen, Peter A; Dam-Johansen, Kim

    2010-01-01

    Product inhibition of cellulolytic enzymes affects the efficiency of the biocatalytic conversion of lignocellulosic biomass to ethanol and other valuable products. New strategies that focus on reactor designs encompassing product removal, notably glucose removal, during enzymatic cellulose conversion are required for alleviation of glucose product inhibition. Supported by numerous calculations this review assesses the quantitative aspects of glucose product inhibition on enzyme-catalyzed cellulose degradation rates. The significance of glucose product inhibition on dimensioning of different ideal reactor types, i.e. batch, continuous stirred, and plug-flow, is illustrated quantitatively by modeling different extents of cellulose conversion at different reaction conditions. The main operational challenges of membrane reactors for lignocellulose conversion are highlighted. Key membrane reactor features, including system set-up, dilution rate, glucose output profile, and the problem of cellobiose are examined to illustrate the quantitative significance of the glucose product inhibition and the total glucose concentration on the cellulolytic conversion rate. Comprehensive overviews of the available literature data for glucose removal by membranes and for cellulose enzyme stability in membrane reactors are given. The treatise clearly shows that membrane reactors allowing continuous, complete, glucose removal during enzymatic cellulose hydrolysis, can provide for both higher cellulose hydrolysis rates and higher enzyme usage efficiency (kg(product)/kg(enzyme)). Current membrane reactor designs are however not feasible for large scale operations. The report emphasizes that the industrial realization of cellulosic ethanol requires more focus on the operational feasibility within the different hydrolysis reactor designs, notably for membrane reactors, to achieve efficient enzyme-catalyzed cellulose degradation. (c) 2010 Elsevier Inc. All rights reserved.

  6. Cellulase Inhibition by High Concentrations of Monosaccharides

    DEFF Research Database (Denmark)

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

    2014-01-01

    that low free water availability contributes to cellulase inhibition. Of the hydrolytic enzymes involved, those acting on the cellulose substrate, that is, exo- and endoglucanases, were the most inhibited. The β -glucosidases were shown to be less sensitive to high monosaccharide concentrations except...

  7. 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…

  8. 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…

  9. Quorum Sensing Inhibition, Relevance to Periodontics

    OpenAIRE

    Yada, Sudheer; Kamalesh, B; Sonwane, Siddharth; Guptha, Indra; Swetha, R K

    2015-01-01

    Quorum sensing helps bacteria to communicate with each other and in coordinating their behavior. Many diseases of human beings, plants, and animals are mediated by quorum sensing. Various approaches are being tried to inhibit this communication to control the diseases caused by bacteria. Periodontal pathogens also communicate through quorum sensing and new approaches to treat periodontal disease using quorum sensing inhibition need to explored.

  10. 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…

  11. Quorum sensing inhibition, relevance to periodontics.

    Science.gov (United States)

    Yada, Sudheer; Kamalesh, B; Sonwane, Siddharth; Guptha, Indra; Swetha, R K

    2015-01-01

    Quorum sensing helps bacteria to communicate with each other and in coordinating their behavior. Many diseases of human beings, plants, and animals are mediated by quorum sensing. Various approaches are being tried to inhibit this communication to control the diseases caused by bacteria. Periodontal pathogens also communicate through quorum sensing and new approaches to treat periodontal disease using quorum sensing inhibition need to explored.

  12. Inhibition in Autism: Children with Autism Have Difficulty Inhibiting Irrelevant Distractors but Not Prepotent Responses

    Science.gov (United States)

    Adams, Nena C.; Jarrold, Christopher

    2012-01-01

    Resistance to distractor inhibition tasks have previously revealed impairments in children with autism. However, on the classic Stroop task and other prepotent response tasks, children with autism show intact inhibition. These data may reflect a distinction between prepotent response and resistance to distractor inhibition. The current study…

  13. Inhibition of neutral sphingomyelinase decreases elevated levels of inducible nitric oxide synthase and apoptotic cell death in ocular hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Aslan, Mutay, E-mail: mutayaslan@akdeniz.edu.tr [Department of Medical Biochemistry, Akdeniz University Faculty of Medicine, Antalya (Turkey); Basaranlar, Goksun [Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya (Turkey); Unal, Mustafa [Department of Ophthalmology, Akdeniz University Faculty of Medicine, Antalya (Turkey); Ciftcioglu, Akif [Department of Pathology, Akdeniz University Faculty of Medicine, Antalya (Turkey); Derin, Narin [Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya (Turkey); Mutus, Bulent [Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario (Canada)

    2014-11-01

    Endoplasmic reticulum (ER) stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS2) have been implicated in the pathogenesis of neuronal retinal cell death in ocular hypertension. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression, hence this study determined the role of selective neutral sphingomyelinase (N-SMase) inhibition on retinal NOS2 levels, ER stress, apoptosis and visual evoked potentials (VEPs) in a rat model of elevated intraocular pressure (EIOP). NOS2 expression and retinal protein nitration were significantly greater in EIOP and significantly decreased with N-SMase inhibition. A significant increase was observed in retinal ER stress markers pPERK, CHOP and GRP78 in EIOP, which were not significantly altered by N-SMase inhibition. Retinal TUNEL staining showed increased apoptosis in all EIOP groups; however N-SMase inhibition significantly decreased the percent of apoptotic cells in EIOP. Caspase-3, -8 and -9 activities were significantly increased in EIOP and returned to baseline levels following N-SMase inhibition. Latencies of all VEP components were significantly prolonged in EIOP and shortened following N-SMase inhibition. Data confirm the role of nitrative injury in EIOP and highlight the protective effect of N-SMase inhibition in EIOP via down-regulation of NOS2 levels and nitrative stress. - Highlights: • Inhibition of N-SMase decreases NOS2 levels in ocular hypertension. • Inhibition of N-SMase decreases protein nitration in ocular hypertension. • Inhibition of N-SMase decreases caspase activation in ocular hypertension. • Inhibition of N-SMase decreases apoptosis in ocular hypertension.

  14. PRSS8 methylation and its significance in esophageal squamous cell carcinoma

    Science.gov (United States)

    Bao, Yonghua; Wang, Qian; Guo, Yongchen; Chen, Zhiguo; Li, Kai; Yang, Yiqiong; Zhang, Huijuan; Dong, Huali; Shen, Kui; Yang, Wancai

    2016-01-01

    Esophageal cancer is one of the most common cancers worldwide, and the incidence and mortality is increasing rapidly in recent years in China, but the underlying mechanisms are largely unclear. Herein we found that the expression of PRSS8, a serine protease prostasin, is significantly decreased in esophageal squamous cell carcinomas (ESCC) at mRNA and protein levels. The reduction of PRSS8 was well correlated with poor differentiation and shorter survival time. Interestingly, ESCC stromal expression of PRSS8 was significantly correlated with stromal lymphocyte infiltration and cancer progression. Methylation specific PCR showed that PRSS8 was hypermethylated in ESCC tissues and ESCC cell lines, which was linked to the downregulation of PRSS8 expression and decreased activities of PRSS8 promoter. De-methylation agent decitabine was able to restore PRSS8 expression, leading to the inhibition of cancer cell proliferation, motility, migration and cell cycle arrest. However, the restored PRSS8 and its tumor inhibition could be reversed by small interfering RNA targeting PRSS8. Mechanistic study showed that tumor inhibition of PRSS8 may be associated with proliferation- and epithelial mesenchymal transition - related proteins in ESCC cells. In conclusion, our finding showed that PRSS8 methylation and its stromal expression had important clinical significance in ESCC. PMID:27081034

  15. Clinical and biological significance of PIM1 kinase in osteosarcoma.

    Science.gov (United States)

    Liao, Yunfei; Feng, Yong; Shen, Jacson; Gao, Yan; Cote, Gregory; Choy, Edwin; Harmon, David; Mankin, Henry; Hornicek, Francis; Duan, Zhenfeng

    2016-07-01

    Osteosarcoma is the most prevalent histological form of primary malignant bone tumor. The majority of osteosarcoma patients have limited alternative therapeutic options and metastatic patients generally have a poor prognosis. Proto-oncogene serine/threonine-protein kinase PIM1 is associated with growth and survival of many kinds of tumor cells. However, the role of PIM1 in osteosarcoma remains largely unknown. In this study, we investigated the functional and therapeutic relevance of PIM1 as a putative target in osteosarcoma. We found PIM1 was highly expressed in various osteosarcoma cell lines and in tumor tissues from osteosarcoma patients. Tissue microarray and immunohistochemistry analysis showed that the overall and disease-free survival rate of patients with high levels of PIM1 protein expression were significantly shorter than patients with low levels. High levels of PIM1 were also associated with present metastasis and can be considered as an independent prognostic factor in osteosarcoma patients. Knockdown of PIM1 expression by synthetic siRNA or shRNA greatly inhibited cell growth, migration, and invasion. Moreover, these changes accompanied with down-regulation of anti-apoptotic protein Bcl-2. The similar results were obtained in osteosarcoma cells treated with PIM1 specific inhibitor (SMI-4a). These results suggest that PIM1 kinase is critical for the growth and metastasis of osteosarcoma cells and can be a potential therapeutic target for osteosarcoma treatment. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1185-1194, 2016. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  16. Clinical significance of PHPT1 protein expression in lung cancer

    Institute of Scientific and Technical Information of China (English)

    XU An-jian; XIA Xiang-hou; DU Song-tao; GU Jun-chao

    2010-01-01

    Background in our previous studies, we found the expression of 14-kD phosphohistidine phosphatase (PHPT1) was associated with lung cancer cells migration and invasion, and PHPT1 mRNA expression level in lung cancer tissues clinically correlated with lymph node metastasis. in the present study, we aimed to further investigate the expression of PHPT1 protein in lung cancer.Methods Expression of PHPT1 protein in tissue samples from 146 lung cancers and 30 normal tissues adjacent to lung cancers was assessed using immunohistochemical method. Fisher's exact test was used to analyze expression patterns of PHPT1 protein in these tissue types. Meanwhile, we studied the correlation between expression of PHPT1 protein and clinicopathological features in lung cancer.Results Significantly higher expression levels of PHPT1 protein were found in lung cancer samples (53.42%) than in normal tissues adjacent to lung cancer (23.33%) (P=0.003). Fisher's exact test showed that lung cancer stage positively correlated with expression of PHPT1 protein (P=0.02), and lung cancer samples with lymph node metastasis showed higher PHPT1 protein expression (P=0.016) than the samples without lymph node metastasis.Conclusions The results of this study agree with findings from our previous study of PHPT1 mRNA expression in lung cancer tissues, and strongly suggest that PHPT1 protein is closely associated with the carcinogenesis and metastasis of lung cancer. Thus, therapy targeting PHPT1 (inhibition or silencing) could be potentially benefited for lung cancer patients.

  17. Inhibition of ethylene production by rhizobitoxine

    Energy Technology Data Exchange (ETDEWEB)

    Owens, L.D.; Lieberman, M.; Kunishi, A.

    1970-01-01

    Rhizobitoxine, an inhibitor of methionine biosynthesis in Salmonella typhimurium, inhibited ethylene production about 75% in light-grown sorghum seedlings and in senescent apple tissue. Ethylene production stimulated by indoleacetic acid and kinetin in sorghum was similarly inhibited. With both apple and sorghum, the inhibition could only be partially relieved by additions of methionine. A methionine analogue, ..cap alpha..-keto-..gamma..-methylthiobutyric acid, which has been suggested as an intermediate between methionine and ethylene, had no effect on the inhibition. Incorporation of /sup 14/C from added methionine-/sup 14/C into ethylene was curtailed by rhizobitoxine to about the same extent as was ethylene production. These results suggest that rhizobitoxine interferes with ethylene biosynthesis by blocking the conversion of methionine to ethylene and not indirectly by inhibiting the biosynthesis of methionine. Ethylene production by Penicillium digitatum, a fungus which produces ethylene via pathways not utilizing methionine as a precursor, was not affected by rhizobitoxine. 16 references, 2 figures, 4 tables.

  18. Inositol hexaphosphate (IP6) inhibits cellular proliferation in melanoma.

    Science.gov (United States)

    Rizvi, Irfan; Riggs, Dale R; Jackson, Barbara J; Ng, Alex; Cunningham, Cynthia; McFadden, David W

    2006-06-01

    Inositol Hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate found in food sources high in fiber content. We have previously reported IP6 to have significant inhibitory effects against pancreatic cancer in vitro. We hypothesized that the IP6 would significantly inhibit cell growth of cutaneous melanoma in vitro. The melanoma line HTB68 was cultured using standard techniques and treated with IP6 at doses ranging from 0.2 to 1.0 mM/well. Cell viability was measured by MTT at 72 h. VEGF production was measured in the cell supernatants by ELISA. Apoptosis was evaluated by Annexin V-FITC and results calculated using FACS analysis. Statistical analysis was performed by ANOVA. Significant reductions (P IP6. Overall, IP6 exhibited a mean inhibition of cell growth of 52.1 +/- 11.5% (range, 1.6-83.0%) at 72 h of incubation. VEGF production was significantly reduced (P IP6 (7.5 pg/ml) compared to control (40.9 pg/ml). IP6 significantly increased (P = 0.029) late apoptosis from 5.3 to 7.0% gated events. No changes in necrosis or early apoptosis were observed. Adjuvant treatment of melanoma continues to challenge clinicians and patients. Our findings that IP6 significantly decreased cellular growth, VEGF production and increased late apoptosis in melanoma suggest its potential therapeutic value. Further in vivo studies are planned to evaluate safety and clinical utility of this agent.

  19. Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

    Indian Academy of Sciences (India)

    David Alan Thompson; Bruce D Hammock

    2007-03-01

    The leukotoxins [9(10)- and 12(13)-EpOME] are produced by activated inflammatory leukocytes such as neutrophils. High EpOME levels are observed in disorders such as acute respiratory distress syndrome and in patients with extensive burns. Although the physiological significance of the EpOMEs remains poorly understood, in some systems, the EpOMEs act as a protoxin, with their corresponding epoxide hydrolase metabolites, 9,10- and 12,13-DiHOME, specifically exerting toxicity. Both the EpOMEs and the DiHOMEs were also recently shown to have neutrophil chemotactic activity. We evaluated whether the neutrophil respiratory burst, a surge of oxidant production thought to play an important role in limiting certain bacterial and fungal infections, is modulated by members of the EpOME metabolic pathway. We present evidence that the DiHOMEs suppress the neutrophil respiratory burst by a mechanism distinct from that of respiratory burst inhibitors such as cyclosporin H or lipoxin A4, which inhibit multiple aspects of neutrophil activation.

  20. Inhibition of Complement Retards Ankylosing Spondylitis Progression

    Science.gov (United States)

    Yang, Chaoqun; Ding, Peipei; Wang, Qingkai; Zhang, Long; Zhang, Xin; Zhao, Jianquan; Xu, Enjie; Wang, Na; Chen, Jianfeng; Yang, Guang; Hu, Weiguo; Zhou, Xuhui

    2016-01-01

    Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-β1 in serum. The combined treatment with a bacteria-derived complement inhibitor Efb-C (C-terminal of extracellular fibrinogen-binding protein of Staphylococcus aureus) remarkably retarded the progression of mouse AS by reducing osteoblast differentiation. Furthermore, we demonstrated that two important modulators involved in AS disease, TGF-β1 and RANKL, were elevated upon in vitro complement attack in osteoblast and/or osteoclast cells. These findings further unravel that complement activation is closely related with the pathogenesis of AS, and suggest that complement inhibition may hold great potential for AS therapy. PMID:27698377

  1. Mortalin inhibition in experimental Parkinson's disease.

    Science.gov (United States)

    Chiasserini, Davide; Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Susta, Federica; Orvietani, Pier Luigi; Koya, Keizo; Binaglia, Luciano; Calabresi, Paolo

    2011-08-01

    Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6-hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT-077, a rhodamine-123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham-operated, and 6-hydroxydopamine-denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6-hydroxydopamine-treated rats in comparison with sham-operated animals. MKT-077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT-077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease.

  2. Obesity inhibits lymphangiogenesis in prostate tumors.

    Science.gov (United States)

    Moreira, Ângela; Pereira, Sofia S; Machado, Christiane L; Morais, Tiago; Costa, Madalena; Monteiro, Mariana P

    2014-01-01

    Lymphangiogenesis is the process that leads to new lymphatic vessels formation from preexisting blood vessels in the presence of appropriate inducing signals, which in pathologic conditions such as cancer, may contribute to tumor cells dissemination. The aim of the present study was to study the role of obesity, leptin and insulin in tumor lymphangiogenesis. For that, we have quantified the lymphatic vessels in prostate tumors through their immunohistochemistry staining by Lyve-1 in RM1 prostate tumors induced in different obese mice models (ob/ob, db/db and diet induced obese (DIO) and in normal weight C57BL/6J mice (control). Lymph vessels density was determined by Lyve-1 immunohistochemistry of prostate adenocarcinomas, while the percentage of the Lyve-1 stained area and lymphatic vessels number were obtained using a morphometric computerized tool. Obese ob/ob and DIO mice presented prostate tumors that were significantly larger (pprostate tumors of DIO mice compared to tumors of db/db mice (pobesity may have a protective effect against prostate cancer dissemination by inhibiting lymphangiogenesis through a still unidentified mechanism that appears not to involve leptin or insulin.

  3. Vagus nerve stimulation inhibits cortical spreading depression.

    Science.gov (United States)

    Chen, Shih-Pin; Ay, Ilknur; de Morais, Andreia Lopes; Qin, Tao; Zheng, Yi; Sadeghian, Homa; Oka, Fumiaki; Simon, Bruce; Eikermann-Haerter, Katharina; Ayata, Cenk

    2016-04-01

    Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation speed of spreading depression was reduced by ∼15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy.

  4. Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

    Science.gov (United States)

    Rossi, Antonietta; Caiazzo, Elisabetta; Bilancia, Rossella; Riemma, Maria A.; Pagano, Ester; Cicala, Carla; Ialenti, Armando; Zjawiony, Jordan K.; Izzo, Angelo A.; Capasso, Raffaele; Roviezzo, Fiorentina

    2017-01-01

    Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma. PMID

  5. Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization.

    Science.gov (United States)

    Rossi, Antonietta; Caiazzo, Elisabetta; Bilancia, Rossella; Riemma, Maria A; Pagano, Ester; Cicala, Carla; Ialenti, Armando; Zjawiony, Jordan K; Izzo, Angelo A; Capasso, Raffaele; Roviezzo, Fiorentina

    2016-01-01

    Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma.

  6. Spinal inhibition of descending command to soleus motoneurons is removed prior to dorsiflexion

    DEFF Research Database (Denmark)

    Geertsen, Svend Sparre; van de Ruit, Mark; Grey, Michael James;

    2011-01-01

    of 40-45 ms, the LLF was significantly more inhibited compared to the SLF when taking the effect on the H-reflex into account. Finally, we investigated how the CPN-induced inhibition and facilitation of the soleus MEP were modulated prior to dorsiflexion. Whereas the late facilitation (CT interval: 55...... stimulation of the posterior tibial nerve (PTN) were conditioned by prior stimulation of the common peroneal nerve (CPN) at a variety of conditioning-test (CT) intervals.MEPs in the precontracted soleus muscle were inhibited when the TMS pulse was preceded by CPN stimulation with a CT interval of 35 ms......, and they were facilitated for CT intervals of 50-55 ms. A similar inhibition of the soleus H-reflex was not observed. To investigate which descending pathways might be responsible for the afferent-evoked inhibition and facilitation, we examined the effect of CPN stimulation on short-latency facilitation (SLF...

  7. Bacterial toxins can inhibit host cell autophagy through cAMP generation.

    Science.gov (United States)

    Shahnazari, Shahab; Namolovan, Anton; Mogridge, Jeremy; Kim, Peter K; Brumell, John H

    2011-09-01

    Autophagy plays a significant role in innate and adaptive immune responses to microbial infection. Some pathogenic bacteria have developed strategies to evade killing by host autophagy. These include the use of 'camouflage' proteins to block targeting to the autophagy pathway and the use of pore-forming toxins to block autophagosome maturation. However, general inhibition of host autophagy by bacterial pathogens has not been observed to date. Here we demonstrate that bacterial cAMP-elevating toxins from B. anthracis and V. cholera can inhibit host anti-microbial autophagy, including autophagic targeting of S. Typhimurium and latex bead phagosomes. Autophagy inhibition required the cAMP effector protein kinase A. Formation of autophagosomes in response to rapamycin and the endogenous turnover of peroxisomes was also inhibited by cAMP-elevating toxins. These findings demonstrate that cAMP-elevating toxins, representing a large group of bacterial virulence factors, can inhibit host autophagy to suppress immune responses and modulate host cell physiology.

  8. Inhibition of human lanosterol synthase by the constituents of Colocasia esculenta (taro).

    Science.gov (United States)

    Sakano, Yuichi; Mutsuga, Motoh; Tanaka, Rie; Suganuma, Hiroyuki; Inakuma, Takahiro; Toyoda, Masatake; Goda, Yukihiro; Shibuya, Masaaki; Ebizuka, Yutaka

    2005-02-01

    Ethanol extracts of lyophilized vegetables were tested for inhibition of human lanosterol synthase (hOSC) in order to find the compounds to suppress cholesterol biosynthesis. Of 130 samples tested, twelve samples showed significant inhibition. Among them, Colocasia esculenta (taro) showed the highest inhibition (55% inhibition at 300 microg/ml). Examination of activity variation among eight taro cultivars indicated that "Aichi-wase" and "Yatsugashira" had the most potent activity for hOSC inhibition. In order to identify the active constituent of taro, ethanol extracts of "Aichi-wase" were partitioned with hexane and aqueous methanol, and fractionated by silica gel column chromatography. Inhibitory activity was concentrated in two major active fractions. Further purification of these fractions by preparative HPLC gave three monogalactosyldiacylglycerols and five digalactosyldiacylglycerols as active compounds that showed 28 to 67% inhibitory activities at the concentration 300 microg/ml.

  9. Haloperidol treatment at pre-exposure phase reduces the disturbance of latent inhibition in rats with neonatal ventral hippocampus lesions.

    Science.gov (United States)

    Ouhaz, Zakaria; Ba-M'hamed, Saadia; Bennis, Mohamed

    2014-10-01

    Animals with neonatal ventral hippocampal lesions develop during or after adolescence abnormal behaviors related to schizophrenia such as anxiety and latent inhibition disruption. The aim of this study was to test whether haloperidol injection prior to pre-exposure session in the latent inhibition test would facilitate latent inhibition. Lesioned animals showed a significant decrease in the number and duration of social interactions, a decrease in the marbles buried, a significant increase in locomotor activity, and a disruption of latent inhibition. In the conditioned taste aversion test, injection of haloperidol produced the recovery of latent inhibition. These findings demonstrate that neonatal lidocaine lesion of the ventral hippocampus can induce behavioral changes related to schizophrenia, and injection of haloperidol, when restricted only to a three-day pre-exposure, is sufficient to facilitate latent inhibition.

  10. Significant Life Experiences and Environmental Justice: Positionality and the Significance of Negative Social/Environmental Experiences

    Science.gov (United States)

    Ceaser, Donovon

    2015-01-01

    Significant life experiences (SLE) research has been criticized for a disproportionate focus on privileged groups and positive experiences. In this paper, I use textual analysis to examine the SLEs within the Environmental Justice (EJ) literature. Theoretically, I blend feminist theory, the sociology of disaster, and research on EJ motives for…

  11. Pirfenidone inhibits post-traumatic proliferative vitreoretinopathy.

    Science.gov (United States)

    Khanum, B N M K; Guha, R; Sur, V P; Nandi, S; Basak, S K; Konar, A; Hazra, S

    2017-03-17

    PurposeThe purpose of the study was to evaluate the efficacy and safety of intravitreal pirfenidone for inhibition of proliferative vitreoretinopathy (PVR) in a model of penetrating ocular injury.Patients and methodsPenetrating trauma was induced on the retina of rabbit and treated either with 0.1 ml of phosphate-buffered saline (PBS) or 0.1 ml of 0.5% pirfenidone, and development of PVR was evaluated clinically and graded after 1 month. Histopathology and immunohistochemistry with transforming growth factor beta (TGFβ), alpha smooth muscle actin (αSMA), and collagen-1 were performed to assess the fibrotic changes. Expression of cytokines in the vitro-retinal tissues at different time points following pirfenidone and PBS injection was examined by RT-PCR. Availability of pirfenidone in the vitreous of rabbit at various time points was determined by high-performance liquid chromatography following injection of 0.1 ml of 0.5% pirfenidone. In normal rabbit eye, 0.1 ml of 0.5% pirfenidone was injected to evaluate any toxic effect.ResultsClinical assessment and grading revealed prevention of PVR formation in pirfenidone-treated animals, gross histology, and histopathology confirmed the observation. Immunohistochemistry showed prevention in the expression of collagen-I, αSMA, and TGFβ in the pirfenidone-treated eyes compared to the PBS-treated eyes. Pirfenidone inhibited increased gene expression of cytokines observed in control eyes. Pirfenidone could be detected up to 48 h in the vitreous of rabbit eye following single intravitreal injection. Pirfenidone did not show any adverse effect following intravitreal injection; eyes were devoid of any abnormal clinical sign, intraocular pressure, and electroretinography did not show any significant change and histology of retina remained unchanged.ConclusionThis animal study shows that pirfenidone might be a potential therapy for PVR. Further clinical study will be useful to evaluate the clinical application of

  12. Volatile hydrocarbons inhibit methanogenic crude oil degradation

    Directory of Open Access Journals (Sweden)

    Angela eSherry

    2014-04-01

    Full Text Available Methanogenic degradation of crude oil in subsurface sediments occurs slowly, but without the need for exogenous electron acceptors, is sustained for long periods and has enormous economic and environmental consequences. Here we show that volatile hydrocarbons are inhibitory to methanogenic oil biodegradation by comparing degradation of an artificially weathered crude oil with volatile hydrocarbons removed, with the same oil that was not weathered. Volatile hydrocarbons (nC5-nC10, methylcyclohexane, benzene, toluene and xylenes were quantified in the headspace of microcosms. Aliphatic (n-alkanes nC12-nC34 and aromatic hydrocarbons (4-methylbiphenyl, 3-methylbiphenyl, 2-methylnaphthalene, 1-methylnaphthalene were quantified in the total hydrocarbon fraction extracted from the microcosms. 16S rRNA genes from key microorganisms known to play an important role in methanogenic alkane degradation (Smithella and Methanomicrobiales were quantified by quantitative PCR. Methane production from degradation of weathered oil in microcosms was rapid (1.1 ± 0.1 µmol CH4/g sediment/day with stoichiometric yields consistent with degradation of heavier n-alkanes (nC12-nC34. For non-weathered oil, degradation rates in microcosms were significantly lower (0.4 ± 0.3 µmol CH4/g sediment/day. This indicated that volatile hydrocarbons present in the non-weathered oil inhibit, but do not completely halt, methanogenic alkane biodegradation. These findings are significant with respect to rates of biodegradation of crude oils with abundant volatile hydrocarbons in anoxic, sulphate-depleted subsurface environments, such as contaminated marine sediments which have been entrained below the sulfate-reduction zone, as well as crude oil biodegradation in petroleum reservoirs and contaminated aquifers.

  13. Rapid inhibition of vasoconstriction in renal afferent arterioles by aldosterone.

    Science.gov (United States)

    Uhrenholt, T R; Schjerning, J; Hansen, P B; Nørregaard, R; Jensen, B L; Sorensen, G L; Skøtt, O

    2003-12-12

    Aldosterone has been suggested to elicit vessel contraction via a nongenomic mechanism. We tested this proposal in microdissected, perfused rabbit renal afferent arterioles. Aldosterone had no effect on internal diameter in concentrations from 10(-10) to 10(-5) mol/L, but aldosterone abolished the ability of 100 mmol/L KCl to induce vascular contraction. The inhibitory effect of aldosterone was observed from 1 pmol/L. The inhibitory effect was significant after 5 minutes and maximal after 20 minutes and was fully reversible. Actinomycin D (10(-6) mol/L) prolonged the effect of aldosterone. The effect was abolished by the mineralocorticoid receptor antagonist spironolactone (10(-7) mol/L) but not by the glucocorticoid receptor antagonist mifepristone (10(-6) mol/L). The K+-mediated increase of intracellular calcium concentration in afferent arterioles was not affected by aldosterone. Mineralocorticoid receptor was detected by reverse transcription-polymerase chain reaction and immunohistochemistry in rat renal vasculature and rabbit endothelial cells. Inhibition of phosphatidylinositol (PI)-3 kinase with LY 294002 (3x10(-6) mol/L) restored sensitivity to K+ in the presence of aldosterone, and afferent arterioles were immunopositive for PI-3 kinase subunit p110alpha. Inhibition of NO formation by L-NAME (10(-4) mol/L) or inhibition of soluble guanylyl cyclase with 1H-(1,2,4)Oxadiazolo[4,3-a]quinoxaline-1-one restored K+-induced vasoreactivity in the presence of aldosterone. Similar to aldosterone, the NO donor sodium nitroprusside inhibited K+-induced vascular contraction. Geldanamycin (10(-6) mol/L), an inhibitor of heat shock protein 90, abolished aldosterone-induced vasorelaxation. We conclude that aldosterone inhibits depolarization-induced vasoconstriction in renal afferent arterioles by a rapid nongenomic mechanism that is initiated by mineralocorticoid receptor activation and involves PI-3 kinase, protein kinase B, and heat shock protein 90-mediated

  14. Porphyromonas gingivalis Lipids Inhibit Osteoblastic Differentiation and Function▿

    Science.gov (United States)

    Wang, Yu-Hsiung; Jiang, Jin; Zhu, Qiang; AlAnezi, Amer Z.; Clark, Robert B.; Jiang, Xi; Rowe, David W.; Nichols, Frank C.

    2010-01-01

    Porphyromonas gingivalis produces unusual sphingolipids that are known to promote inflammatory reactions in gingival fibroblasts and Toll-like receptor 2 (TLR2)-dependent secretion of interleukin-6 from dendritic cells. The aim of the present study was to examine whether P. gingivalis lipids inhibit osteoblastic function. Total lipids from P. gingivalis and two fractions, phosphoglycerol dihydroceramides and phosphoethanolamine dihydroceramides, were prepared free of lipid A. Primary calvarial osteoblast cultures derived from 5- to 7-day-old CD-1 mice were used to examine the effects of P. gingivalis lipids on mineralized nodule formation, cell viability, apoptosis, cell proliferation, and gene expression. P. gingivalis lipids inhibited osteoblast differentiation and fluorescence expression of pOBCol2.3GFP in a concentration-dependent manner. However, P. gingivalis lipids did not significantly alter osteoblast proliferation, viability, or apoptosis. When administered during specific intervals of osteoblast growth, P. gingivalis total lipids demonstrated inhibitory effects on osteoblast differentiation only after the proliferation stage of culture. Reverse transcription-PCR confirmed the downregulation of osteoblast marker genes, including Runx2, ALP, OC, BSP, OPG, and DMP-1, with concurrent upregulation of RANKL, tumor necrosis factor alpha, and MMP-3 genes. P. gingivalis total lipids and lipid fractions inhibited calvarial osteoblast gene expression and function in vivo, as determined by the loss of expression of another osteoblast differentiation reporter, pOBCol3.6GFPcyan, and reduced uptake of Alizarin complexone stain. Finally, lipid inhibition of mineral nodule formation in vitro was dependent on TLR2 expression. Our results indicate that inhibition of osteoblast function and gene expression by P. gingivalis lipids represents a novel mechanism for altering alveolar bone homeostasis at periodontal disease sites. PMID:20584977

  15. Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPσ.

    Science.gov (United States)

    Pendleton, James C; Shamblott, Michael J; Gary, Devin S; Belegu, Visar; Hurtado, Andres; Malone, Misti L; McDonald, John W

    2013-09-01

    CNS damage often results in demyelination of spared axons due to oligodendroglial cell death and dysfunction near the injury site. Although new oligodendroglia are generated following CNS injury and disease, the process of remyelination is typically incomplete resulting in long-term functional deficits. Chondroitin sulfate proteoglycans (CSPGs) are upregulated in CNS grey and white matter following injury and disease and are a major component of the inhibitory scar that suppresses axon regeneration. CSPG inhibition of axonal regeneration is mediated, at least in part, by the protein tyrosine phosphatase sigma (PTPσ) receptor. Recent evidence demonstrates that CSPGs inhibit OL process outgrowth, however, the means by which their effects are mediated remains unclear. Here we investigate the role of PTPσ in CSPG inhibition of OL function. We found that the CSPGs, aggrecan, neurocan and NG2 all imposed an inhibitory effect on OL process outgrowth and myelination. These inhibitory effects were reversed by degradation of CSPGs with Chondroitinase ABC prior to OL exposure. RNAi-mediated down-regulation of PTPσ reversed the inhibitory effect of CSPGs on OL process outgrowth and myelination. Likewise, CSPG inhibition of process outgrowth and myelination was significantly reduced in cultures containing PTPσ(-/-) OLs. Finally, inhibition of Rho-associated kinase (ROCK) increased OL process outgrowth and myelination during exposure to CSPGs. These results suggest that in addition to their inhibitory effects on axon regeneration, CSPGs have multiple inhibitory actions on OLs that result in incomplete remyelination following CNS injury. The identification of PTPσ as a receptor for CSPGs, and the participation of ROCK downstream of CSPG exposure, reveal potential therapeutic targets to enhance white matter repair in the damaged CNS.

  16. Magnolol inhibits migration of vascular smooth muscle cells via cytoskeletal remodeling pathway to attenuate neointima formation

    Energy Technology Data Exchange (ETDEWEB)

    Karki, Rajendra [Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City (United States); Department of Oriental Medicine Resources, Mokpo National University (Korea, Republic of); Kim, Seong-Bin [Jeollanamdo Development Institute for Korean Traditional Medicine, Jangheung gun, Jeollanamdo (Korea, Republic of); Kim, Dong-Wook, E-mail: dbkim@mokpo.ac.kr [Department of Oriental Medicine Resources, Mokpo National University (Korea, Republic of)

    2013-12-10

    Background: Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration. Methods: The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury. Results: VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity. Conclusions: Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation. General significance: This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis. - Highlights: • Magnolol strongly inhibited migration of VSMCs. • Magnolol inhibited stress fibers formation. • MLC20 phosphorylation was also inhibited by magnolol. • Anti

  17. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Xiaopeng; Du, Jie; Hua, Song; Zhang, Haowen; Gu, Cheng; Wang, Jie; Yang, Lei; Huang, Jianfeng; Yu, Jiahua, E-mail: yujiahua@suda.edu.cn; Liu, Fenju, E-mail: fangsh@suda.edu.cn

    2015-01-15

    Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly, combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.

  18. Advanced Glycation End Products Inhibit the Proliferation of Human Umbilical Vein Endothelial Cells by Inhibiting Cathepsin D

    Science.gov (United States)

    Li, Yuan; Chang, Ye; Ye, Ning; Dai, Dongxue; Chen, Yintao; Zhang, Naijin; Sun, Guozhe; Sun, Yingxian

    2017-01-01

    We aimed to investigate the effect of advanced glycation end products (AGEs) on the proliferation and migration ability of human umbilical vein endothelial cells (HUVECs). Cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay, real-time cell analyzer and 5-Ethynyl-2′-deoxyuridine (EdU) staining. Cell migration was detected by wound-healing and transwell assay. AGEs significantly inhibited the proliferation and migration of HUVECs in a time-and dose-dependent way. Western blotting revealed that AGEs dramatically increased the expression of microtubule-associated protein 1 light chain 3 (LC3) II/I and p62. Immunofluorescence of p62 and acridine orange staining revealed that AGEs significantly increased the expression of p62 and the accumulation of autophagic vacuoles, respectively. Chloroquine (CQ) could further promote the expression of LC3 II/I and p62, increase the accumulation of autophagic vacuoles and promote cell injury induced by AGEs. In addition, AGEs reduced cathepsin D (CTSD) expression in a time-dependent way. Overexpression of wild-type CTSD significantly decreased the ratio of LC 3 II/I as well as p62 accumulation induced by AGEs, but overexpression of catalytically inactive mutant CTSD had no such effects. Only overexpression of wild-type CTSD could restore the proliferation of HUVECs inhibited by AGEs. However, overexpression of both wild-type CTSD and catalytically inactive mutant CTSD could promote the migration of HUVECs inhibited by AGEs. Collectively, our study found that AGEs inhibited the proliferation and migration in HUVECs and promoted autophagic flux, which in turn played a protective role against AGEs-induced cell injury. CTSD, in need of its catalytic activity, may promote proliferation in AGEs-treated HUVECs independent of the autophagy-lysosome pathway. Meanwhile, CTSD could improve the migration of AGEs-treated HUVECs regardless of its enzymatic activity. PMID:28218663

  19. Advanced Glycation End Products Inhibit the Proliferation of Human Umbilical Vein Endothelial Cells by Inhibiting Cathepsin D

    Directory of Open Access Journals (Sweden)

    Yuan Li

    2017-02-01

    Full Text Available We aimed to investigate the effect of advanced glycation end products (AGEs on the proliferation and migration ability of human umbilical vein endothelial cells (HUVECs. Cell proliferation was detected by methyl thiazolyl tetrazolium (MTT assay, real-time cell analyzer and 5-Ethynyl-2′-deoxyuridine (EdU staining. Cell migration was detected by wound-healing and transwell assay. AGEs significantly inhibited the proliferation and migration of HUVECs in a time-and dose-dependent way. Western blotting revealed that AGEs dramatically increased the expression of microtubule-associated protein 1 light chain 3 (LC3 II/I and p62. Immunofluorescence of p62 and acridine orange staining revealed that AGEs significantly increased the expression of p62 and the accumulation of autophagic vacuoles, respectively. Chloroquine (CQ could further promote the expression of LC3 II/I and p62, increase the accumulation of autophagic vacuoles and promote cell injury induced by AGEs. In addition, AGEs reduced cathepsin D (CTSD expression in a time-dependent way. Overexpression of wild-type CTSD significantly decreased the ratio of LC 3 II/I as well as p62 accumulation induced by AGEs, but overexpression of catalytically inactive mutant CTSD had no such effects. Only overexpression of wild-type CTSD could restore the proliferation of HUVECs inhibited by AGEs. However, overexpression of both wild-type CTSD and catalytically inactive mutant CTSD could promote the migration of HUVECs inhibited by AGEs. Collectively, our study found that AGEs inhibited the proliferation and migration in HUVECs and promoted autophagic flux, which in turn played a protective role against AGEs-induced cell injury. CTSD, in need of its catalytic activity, may promote proliferation in AGEs-treated HUVECs independent of the autophagy-lysosome pathway. Meanwhile, CTSD could improve the migration of AGEs-treated HUVECs regardless of its enzymatic activity.

  20. Fear inhibition in high trait anxiety.

    Science.gov (United States)

    Kindt, Merel; Soeter, Marieke

    2014-01-01

    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.

  1. BST2/Tetherin Inhibition of Alphavirus Exit

    Directory of Open Access Journals (Sweden)

    Yaw Shin Ooi

    2015-04-01

    Full Text Available Alphaviruses such as chikungunya virus (CHIKV and Semliki Forest virus (SFV are small enveloped RNA viruses that bud from the plasma membrane. Tetherin/BST2 is an interferon-induced host membrane protein that inhibits the release of many enveloped viruses via direct tethering of budded particles to the cell surface. Alphaviruses have highly organized structures and exclude host membrane proteins from the site of budding, suggesting that their release might be insensitive to tetherin inhibition. Here, we demonstrated that exogenously-expressed tetherin efficiently inhibited the release of SFV and CHIKV particles from host cells without affecting virus entry and infection. Alphavirus release was also inhibited by the endogenous levels of tetherin in HeLa cells. While rubella virus (RuV and dengue virus (DENV have structural similarities to alphaviruses, tetherin inhibited the release of RuV but not DENV. We found that two recently identified tetherin isoforms differing in length at the N-terminus exhibited distinct capabilities in restricting alphavirus release. SFV exit was efficiently inhibited by the long isoform but not the short isoform of tetherin, while both isoforms inhibited vesicular stomatitis virus exit. Thus, in spite of the organized structure of the virus particle, tetherin specifically blocks alphavirus release and shows an interesting isoform requirement.

  2. Use of bacillus subtilis strains to inhibit postharvest pathogenic fungi; Attivita` antagonista di alcuni ceppi di bacillus subtilis nei confronti di funghi patogeni

    Energy Technology Data Exchange (ETDEWEB)

    Arras, G.; Gambella, F.; Demontis, S.; Petretto, A.

    1995-09-01

    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.

  3. HIV-1 inhibition by extracts of Clusiaceae species from Mexico.

    Science.gov (United States)

    Huerta-Reyes, Maira; Basualdo, Maria del Carmen; Lozada, Lucio; Jimenez-Estrada, Manuel; Soler, Carmen; Reyes-Chilpa, Ricardo

    2004-06-01

    The organic plant extracts of 21 species of Clusiaceae from Mexico were screened for anti HIV-1 reverse transcriptase activity in a non-radioactive immuno colorimetric assay. The extracts of 5 species (23.8%) exhibited significant inhibition (> or =70%) of HIV-1 RT activity; of these, only 4 extracts showed reduced toxicity to human lymphocytic MT2 cells and were further tested as inhibitors of HIV-1 IIIb/LAV replication in a cellular system. The best extracts were Calophyllum brasiliense (hexane) and Clusia quadrangula (CH(2)Cl(2)-MeOH) which inhibited HIV-1 RT (IC(50)=29.6 microg/ml and 42 microg/ml), and showed an EC(50)=92.5 microg/ml and 91 microg/ml, respectively, on MT2 cells. However, only Calophyllum brasiliense hexane extract showed significant inhibition on viral replication (ED(50)=37.1 microg/ml), while Clusia quadrangula was less active (ED(50)=124 microg/ml). These results support the idea that plant extracts represent a valuable source of potential anti HIV compounds.

  4. Inhibition of sortase A by chalcone prevents Listeria monocytogenes infection.

    Science.gov (United States)

    Li, Hongen; Chen, Yutao; Zhang, Bing; Niu, Xiaodi; Song, Meng; Luo, Zhaoqing; Lu, Gejin; Liu, Bowen; Zhao, Xiaoran; Wang, Jianfeng; Deng, Xuming

    2016-04-15

    The critical role of sortase A in gram-positive bacterial pathogenicity makes this protein a good potential target for antimicrobial therapy. In this study, we report for the first time the crystal structure of Listeria monocytogenes sortase A and identify the active sites that mediate its transpeptidase activity. We also used a sortase A (SrtA) enzyme activity inhibition assay, simulation, and isothermal titration calorimetry analysis to discover that chalcone, an agent with little anti-L. monocytogenes activity, could significantly inhibit sortase A activity with an IC50 of 28.41 ± 5.34 μM by occupying the active site of SrtA. The addition of chalcone to a co-culture of L. monocytogenes and Caco-2 cells significantly inhibited bacterial entry into the cells and L. monocytogenes-mediated cytotoxicity. Additionally, chalcone treatment decreased the mortality of infected mice, the bacterial burden in target organs, and the pathological damage to L. monocytogenes-infected mice. In conclusion, these findings suggest that chalcone is a promising candidate for the development of treatment against L. monocytogenes infection.

  5. Inhibition of the gravitropic bending response of flowering shoots by salicylic acid.

    Science.gov (United States)

    Friedman, Haya; Meir, Shimon; Halevy, Abraham H; Philosoph-Hadas, Sonia

    2003-10-01

    The upward gravitropic bending of cut snapdragon, lupinus and anemone flowering shoots was inhibited by salicylic acid (SA) applied at 0.5 mM and above. This effect was probably not due to acidification of the cytoplasm, since other weak acids did not inhibit bending of snapdragon shoots. In order to study its mode of inhibitory action, we have examined in cut snapdragon shoots the effect of SA on three processes of the gravity-signaling pathway, including: amyloplast sedimentation, formation of ethylene gradient across the stem, and differential growth response. The results show that 1 mM SA inhibited differential ethylene production rates across the horizontal stem and the gravity-induced growth, without significantly inhibiting vertical growth or amyloplast sedimentation following horizontal placement. However, 5 mM SA inhibited all three gravity-induced processes, as well as the growth of vertical shoots, while increasing flower wilting. It may, therefore, be concluded that SA inhibits bending of various cut flowering shoots in a concentration-dependent manner. Thus, at a low concentration SA exerts its effect in snapdragon shoots by inhibiting processes operating downstream to stimulus sensing exerted by amyloplast sedimentation. At a higher concentration SA inhibits bending probably by exerting general negative effects on various cellular processes.

  6. Ingested (oral) SIRS peptide 1-21 inhibits acute EAE by inducing Th2-like cytokines.

    Science.gov (United States)

    Brod, Staley A; Hood, Zachary

    2007-02-01

    Ingested type I IFN inhibits clinical attacks, relapses and inflammation in murine chronic relapsing EAE by inhibiting Th1-like cytokines. Type I IFN activates human suppressor T cells that produce SIRS. We examined whether oral (ingested) SIRS peptide inhibits EAE by decreasing Th1-like cytokines. Parenteral SIRS peptide 1-21 showed a significant inhibition of disease severity in murine EAE. Ingested SIRS peptide at 10 and 100 microg SIRS peptide showed a significant inhibition of disease severity but also a prolonged delay in the onset of disease compared to placebo. There were significantly less inflammatory foci in the SIRS peptide fed group compared to the control mock fed group. Splenocytes from SIRS peptide 1-21 fed mice showed increased production of Th2-like CD30L, IL-13, TCA-3 cytokines/chemokines and decreased production of Th1-like cytokine lymphotactin. Ingested (oral) SIRS peptide significantly inhibits both clinical EAE and inflammation predominately via counter-regulatory type 2-like cytokines/chemokines IL-13, CD30L and TCA-3.

  7. Bovine Muc1 inhibits binding of enteric bacteria to Caco-2 cells.

    Science.gov (United States)

    Parker, Phillip; Sando, Lillian; Pearson, Roger; Kongsuwan, Kritaya; Tellam, Ross L; Smith, Stuart

    2010-01-01

    Inhibition of bacterial adhesion to intestinal epithelial receptors by the consumption of natural food components is an attractive strategy for the prevention of microbial related gastrointestinal illness. We hypothesised that Muc1, a highly glycosylated mucin present in cows' milk, may be one such food component. Purified bovine Muc1 was tested for its ability to inhibit binding of common enteric bacterial pathogens to Caco-2 cells grown in vitro. Muc1 caused dose-dependent binding inhibition of Escherichia coli, Salmonella enterica serovar Typhimurium (S. Typhimurium), Staphylococcus aureus and Bacillus subtilis. This inhibition was more pronounced for the Gram negative compared with Gram positive bacteria. It was also demonstrated that Muc1, immobilised on a membrane, bound all these bacterial species in a dose-dependent manner, although there was greater interaction with the Gram negative bacteria. A range of monosaccharides, representative of the Muc1 oligosaccharide composition, were tested for their ability to prevent binding of E. coli and S. Typhimurium to Caco-2 cells. Inhibition was structure dependent with sialic acid, L(-) fucose and D(+) mannose significantly inhibiting binding of both Gram negative species. N-acetylglucosamine and N-acetylgalactosamine significantly inhibited binding of E. coli whilst galactose, one of the most abundant Muc1 monosaccharides, showed the strongest inhibition against S. Typhimurium. Treatment with sialidase significantly decreased the inhibitory properties of Muc1, demonstrating the importance of sialic acid in adhesion inhibition. It is concluded that bovine Muc1 prevents binding of bacteria to human intestinal cells and may have a role in preventing the binding of common enteropathogenic bacteria to human intestinal epithelial surfaces.

  8. The IFITMs Inhibit Zika Virus Replication

    Directory of Open Access Journals (Sweden)

    George Savidis

    2016-06-01

    Full Text Available Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.

  9. Reversible Inhibition of Cellular Metabolism by Ribavirin

    Science.gov (United States)

    Larsson, Alf; Stenberg, Kjell; Öberg, Bo

    1978-01-01

    The broad spectrum antiviral drug ribavirin (Virazole, 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) inhibits cellular macromolecular synthesis as well as cell division in eucaryotic cells. The concentration and time dependence have been studied. One-hour treatment with 25 μM ribavirin or 18 h with 2 μM inhibited the deoxyribonucleic acid synthesis to 50%. Higher concentrations of ribavirin were required to obtain a similar inhibition of ribonucleic acid and protein synthesis. This effect on cell metabolism and cell division can be reversed by removing the drug from the cells. PMID:646339

  10. Environmental "Omics" of International Space Station: Insights, Significance, and Consequences

    Science.gov (United States)

    Venkateswaran, Kasthuri

    2016-07-01

    detected. The nine-erythromycin sensitive S. aureus strains exhibited spontaneous mutation when rifampin was tested. Some of the S. aureus strains tolerated gentamycin and tobramycin but cefazolin, cefoxitin, ciprofloxacin and oxacillin inhibited the growth of the S. aureus. Whole genome sequencing (WGS) of 21 ISS strains, exhibiting resistance to various antibiotics, was carried out. The antibiotic resistant genes deduced from the WGS were compared with the resistomes generated directly from the gene pool of the environmental samples. Using a targeted amplification panel consisting of over 500 antimicrobial resistance genes, we were able to confirm the results of the phenotypic assays. Specifically, the presence of multiple β-lactamase genes was observed. The class A β-lactamase genes, tem-1 (ampicillin-resistance) and ctx-M-14 (cefotaxime conferring gene), were found in multiple sites of ISS. In addition, presence of mecA gene (penicillin clusters) was confirmed in several sampling locations from both ISS flights. Finally, the existence of the ermA gene (erythromycin) was established. These results suggest widespread and consistent distribution of multiple antibiotic resistance genes throughout the ISS. The resistome data generated via molecular methods will be extremely important in determining the microbial significance to the crew health and the ISS maintenance. These data sets will be placed in the NASA GeneLab bioinformatics environment - consisting of a database, computational tools, and improved methods - that would subsequently be made open to the scientific research community to encourage innovation.

  11. Kinetic evaluation of the inhibition of protein glycation during heating.

    Science.gov (United States)

    Akıllıoğlu, H Gül; Gökmen, Vural

    2016-04-01

    This study aimed to investigate the kinetics of early stage of the Maillard reaction by a reversible bimolecular reaction mechanism and also to evaluate the compatibility of enzyme inhibition kinetics for calculating the inhibitory activity of protein anti-glycation agents. Model systems composed of ovalbumin, glucose, and anti-glycation agents (tannic acid or calcium ion) at different molar ratios were heated at 90 °C for different times in dry state or in solution. Heated samples were analysed for furosine, acid derivative of N-ε-fructoselysine (FL), to monitor the progression of the early glycation stage. Compared to a control, presence of calcium ions and tannic acid decreased FL formation significantly (pglycation of ovalbumin by a mixed non-competitive mechanism in both dry and in solution conditions; while the mode of inhibition by tannic acid was found to be purely non-competitive in the dry state.

  12. Probing inhibitory effects of nanocrystalline cellulose: inhibition versus surface charge

    Science.gov (United States)

    Male, Keith B.; Leung, Alfred C. W.; Montes, Johnny; Kamen, Amine; Luong, John H. T.

    2012-02-01

    NCC derived from different biomass sources was probed for its plausible cytotoxicity by electric cell-substrate impedance sensing (ECIS). Two different cell lines, Spodoptera frugiperda Sf9 insect cells and Chinese hamster lung fibroblast V79, were exposed to NCC and their spreading and viability were monitored and quantified by ECIS. Based on the 50%-inhibition concentration (ECIS50), none of the NCC produced was judged to have any significant cytotoxicity on these two cell lines. However, NCC derived from flax exhibited the most pronounced inhibition on Sf9 compared to hemp and cellulose powder. NCCs from flax and hemp pre-treated with pectate lyase were also less inhibitory than NCCs prepared from untreated flax and hemp. Results also suggested a correlation between the inhibitory effect and the carboxylic acid contents on the NCC.

  13. Inhibition of transfected PTEN on human colon cancer

    Institute of Scientific and Technical Information of China (English)

    Shou-Shui Xu; Wen-Lu Shen; Song-Ying Ouyang

    2004-01-01

    AIM: To study the inhibitory effect of transfected PTEN on LoVo cells.METHODS: Human PTEN cDNA was transferred into LoVo cells via lipofectin and PTEN mRNA levels and its expression were analyzed by Western blot and flow cytometry. Before or after transfection, the effects of 5-Fu on inhibiting cell proliferation and inducing apoptosis were measured by flow cytometry, DNA bands and MTT.RESULTS: PTEN transfection significantly up-regulated PTEN expression in LoVo cells. 5-Fu inhibited cell proliferation and induced apoptosis in transfected LoVo cells.CONCLUSION: Transfected PTEN can remark ably up-regulate PTEN expression in LoVo cells and promote the apoptosis.PTEN transfection is associated with 5-Fu treatment effect and has a cooperatively cytotoxic effect.

  14. Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer

    Science.gov (United States)

    Reusser, Nicole M; Dalton, Heather J; Pradeep, Sunila; Gonzalez-Villasana, Vianey; Jennings, Nicholas B; Vasquez, Hernan G; Wen, Yunfei; Rupaimoole, Rajesh; Nagaraja, Archana S; Gharpure, Kshipra; Miyake, Takahito; Huang, Jie; Hu, Wei; Lopez-Berestein, Gabriel; Sood, Anil K

    2014-01-01

    Purpose Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations. Experimental Design Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis. Results Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density. Conclusions Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer. PMID:24841852

  15. Syk Inhibition with Fostamatinib Leads to Transitional B Lymphocyte Depletion

    Science.gov (United States)

    Barr, Paul M.; Wei, Chungwen; Roger, James; Schaefer-Cutillo, Julia; Kelly, Jennifer L.; Rosenberg, Alexander F.; Jung, John; Sanz, Iñaki; Friedberg, Jonathan W.

    2012-01-01

    Cell signaling initiated by the B cell receptor is critical to normal development of B lymphocytes, most notably at the transitional B cell stage. Inhibition of this signaling pathway with the syk inhibitor, fostamatinib, has produced significant efficacy in lymphoid malignancies and autoimmune conditions. Here, we demonstrate that short-term use of fostamatinib impairs B lymphocyte development at the transitional stage without affecting mature B cell populations. Additionally, IL-10 producing B cells remained relatively constant throughout the treatment period. These findings provide insight into the mechanism of action of B cell receptor inhibition in autoimmune disease. As the development of agents targeting B cell receptor signaling proceeds, monitoring for long-term consequences as well as functional evaluation of B cell subsets may further improve our understanding of this rapidly growing class of novel agents. PMID:22284392

  16. Some heterocyclic thione derivatives exhibit anticoccidial activity by inhibiting glycosidases.

    Science.gov (United States)

    Balbaa, Mahmoud; Abd El-Hady, Neama; Taha, Nabil; El Ashry, El Sayed H

    2012-01-01

    Coccidiosis is one of the most common parasitic diseases affecting many species of domestic animals. This disease has a major economic significance and the search for new compounds having anticoccidial activity is of great importance. In this article, different levels of protection from coccidian infection by Eimeria stiedae were developed in rabbits by treatment with compounds incorporating the skeleton of thiourea. These compounds include 4,5-diphenylimidazole-2-thione (1), 4,5-Diphenyl-1,2,4-triazole-3-thiol (2) and 5-(2-Hydroxyphenyl)-4-phenyl-1,2,4-triazole-3-thiol (3) compared to the anticoccidial drug toltrazuril as a reference compound. Compounds 1-3 inhibit coccidiosis-induced activity of α-glucosidase. The protection from coccidial infection by compound 1 was higher than that shown for compounds 2 and 3. These data suggest that diazole and triazole thione derivatives have a mimetic effect for anticoccidial drugs through their inhibition of glycosidases.

  17. Corrosion inhibition of mild steel by aerobic biofilm

    Energy Technology Data Exchange (ETDEWEB)

    Chongdar, Shobhana [Naval Materials Research Laboratory, Addl. Ambarnath 421506 (India); Gunasekaran, G. [Naval Materials Research Laboratory, Addl. Ambarnath 421506 (India)]. E-mail: gunanmrl@rediffmail.com; Kumar, Pradeep [Naval Materials Research Laboratory, Addl. Ambarnath 421506 (India)

    2005-08-30

    Mild steel electrodes were incubated in phosphate-buffered basal salt solution (BSS) having two different aerobic bacteria, viz. Pseudomonas alcaligenes and Pseudomonas cichorii. In the medium containing P. cichorii, significant reduction in the corrosion rate was observed due to the surface reaction leading to the formation of corrosion inhibiting bacterial biofilm. With a view to understand the mechanism of microbially influenced corrosion/corrosion inhibition, electrochemical and biological experiments such as electrochemical impedance spectroscopy (EIS) measurements and biochemical analysis were made. The exposed surfaces were examined using scanning electron micrographs (SEM), energy dispersive spectroscopy (EDS) and electron spectroscopy for chemical analysis (ESCA). The scraped surface film was also examined using FT-IR spectroscopy. The results suggested that mild steel surface contained iron oxide-phosphate layer covered with bacteria and exo polymeric substance (EPS)/iron-EPS complex for P. cichorii and iron oxides and iron phosphate for P. alcaligenes.

  18. Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer's disease.

    Science.gov (United States)

    Yan, Riqiang; Fan, Qingyuan; Zhou, John; Vassar, Robert

    2016-06-01

    Over the past two decades, many studies have identified significant contributions of toxic β-amyloid peptides (Aβ) to the etiology of Alzheimer's disease (AD), which is the most common age-dependent neurodegenerative disease. AD is also recognized as a disease of synaptic failure. Aβ, generated by sequential proteolytic cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, is one of major culprits that cause this failure. In this review, we summarize current findings on how BACE1-cleaved APP products impact learning and memory through proteins localized on glutamatergic, GABAergic, and dopaminergic synapses. Considering the broad effects of Aβ on all three types of synapses, BACE1 inhibition emerges as a practical approach for ameliorating Aβ-mediated synaptic dysfunctions. Since BACE1 inhibitory drugs are currently in clinical trials, this review also discusses potential complications arising from BACE1 inhibition. We emphasize that the benefits of BACE1 inhibitory drugs will outweigh the concerns.

  19. ATF3 represses PPARγ expression and inhibits adipocyte differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Min-Kyung; Jung, Myeong Ho, E-mail: jung0603@pusan.ac.kr

    2014-11-07

    Highlights: • ATF3 decrease the expression of PPARγ and its target gene in 3T3-L1 adipocytes. • ATF3 represses the promoter activity of PPARγ2 gene. • ATF/CRE (−1537/−1530) is critical for ATF3-mediated downregulation of PPARγ. • ATF3 binds to the promoter region containing the ATF/CRE. • ER stress inhibits adipocyte differentiation through downregulation of PPARγ by ATF3. - Abstract: Activating transcription factor 3 (ATF3) is a stress-adaptive transcription factor that mediates cellular stress response signaling. We previously reported that ATF3 represses CCAAT/enhancer binding protein α (C/EBPα) expression and inhibits 3T3-L1 adipocyte differentiation. In this study, we explored potential role of ATF3 in negatively regulating peroxisome proliferator activated receptor-γ (PPARγ). ATF3 decreased the expression of PPARγ and its target gene in 3T3-L1 adipocytes. ATF3 also repressed the activity of −2.6 Kb promoter of mouse PPARγ2. Overexpression of PPARγ significantly prevented the ATF3-mediated inhibition of 3T3-L1 differentiation. Transfection studies with 5′ deleted-reporters showed that ATF3 repressed the activity of −2037 bp promoter, whereas it did not affect the activity of −1458 bp promoter, suggesting that ATF3 responsive element is located between the −2037 and −1458. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds to ATF/CRE site (5′-TGACGTTT-3′) between −1537 and −1530. Mutation of the ATF/CRE site abrogated ATF3-mediated transrepression of the PPARγ2 promoter. Treatment with thapsigargin, endoplasmic reticulum (ER) stress inducer, increased ATF3 expression, whereas it decreased PPARγ expression. ATF3 knockdown significantly blocked the thapsigargin-mediated downregulation of PPARγ expression. Furthermore, overexpression of PPARγ prevented inhibition of 3T3-L1 differentiation by thapsigargin. Collectively, these results suggest that ATF3-mediated

  20. Reflex inhibition of normal cramp following electrical stimulation of the muscle tendon.

    Science.gov (United States)

    Khan, Serajul I; Burne, John A

    2007-09-01

    Muscle cramp was induced in one head of the gastrocnemius muscle (GA) in eight of thirteen subjects using maximum voluntary contraction when the muscle was in the shortened position. Cramp in GA was painful, involuntary, and localized. Induction of cramp was indicated by the presence of electromyographic (EMG) activity in one head of GA while the other head remained silent. In all cramping subjects, reflex inhibition of cramp electrical activity was observed following Achilles tendon electrical stimulation and they all reported subjective relief of cramp. Thus muscle cramp can be inhibited by stimulation of tendon afferents in the cramped muscle. When the inhibition of cramp-generated EMG and voluntary EMG was compared at similar mean EMG levels, the area and timing of the two phases of inhibition (I(1), I(2)) did not differ significantly. This strongly suggests that the same reflex pathway was the source of the inhibition in both cases. Thus the cramp-generated EMG is also likely to be driven by spinal synaptic input to the motorneurons. We have found that the muscle conditions that appear necessary to facilitate cramp, a near to maximal contraction of the shortened muscle, are also the conditions that render the inhibition generated by tendon afferents ineffective. When the strength of tendon inhibition in cramping subjects was compared with that in subjects that failed to cramp, it was found to be significantly weaker under the same experimental conditions. It is likely that reduced inhibitory feedback from tendon afferents has an important role in generating cramp.

  1. In vitro evaluation of single- and multi-strain probiotics: Inter-species inhibition between probiotic strains, and inhibition of pathogens.

    Science.gov (United States)

    Chapman, C M C; Gibson, G R; Rowland, I

    2012-08-01

    Many studies comparing the effects of single- and multi-strain probiotics on pathogen inhibition compare treatments with different concentrations. They also do not examine the possibility of inhibition between probiotic strains with a mixture. We tested the ability of 14 single-species probiotics to inhibit each other using a cross-streak assay, and agar spot test. We then tested the ability of 15 single-species probiotics and 5 probiotic mixtures to inhibit Clostridium difficile, Escherichia coli and S. typhimurium, using the agar spot test. Testing was done with mixtures created in two ways: one group contained component species incubated together, the other group of mixtures was made using component species which had been incubated separately, equalised to equal optical density, and then mixed in equal volumes. Inhibition was observed for all combinations of probiotics, suggesting that when used as such there may be inhibition between probiotics, potentially reducing efficacy of the mixture. Significant inter-species variation was seen against each pathogen. When single species were tested against mixtures, the multi-species preparations displayed significantly (p probiotic species will inhibit each other when incubated together in vitro, in many cases a probiotic mixture was more effective at inhibiting pathogens than its component species when tested at approximately equal concentrations of biomass. This suggests that using a probiotic mixture might be more effective at reducing gastrointestinal infections, and that creating a mixture using species with different effects against different pathogens may have a broader spectrum of action that a single provided by a single strain.

  2. Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli.

    Directory of Open Access Journals (Sweden)

    Tasuku Akiyama

    Full Text Available Scratching relieves itch, but the underlying neural mechanisms are poorly understood. We presently investigated a role for the inhibitory neurotransmitters GABA and glycine in scratch-evoked inhibition of spinal itch-signaling neurons in a mouse model of chronic dry skin itch. Superficial dorsal horn neurons ipsilateral to hindpaw dry skin treatment exhibited a high level of spontaneous firing that was significantly attenuated by cutaneous scratching, pinch and noxious heat. Scratch-evoked inhibition was nearly abolished by spinal delivery of the glycine antagonist, strychnine, and was markedly attenuated by respective GABA(A and GABA(B antagonists bicuculline and saclofen. Scratch-evoked inhibition was also significantly attenuated (but not abolished by interruption of the upper cervical spinal cord, indicating the involvement of both segmental and suprasegmental circuits that engage glycine- and GABA-mediated inhibition of spinal itch-signaling neurons by noxious counterstimuli.

  3. A Review of CO2 Corrosion Inhibition by Imidazoline-based Inhibitor

    Directory of Open Access Journals (Sweden)

    Jaal Rafida Ahmad

    2014-07-01

    Full Text Available Carbon dioxide (CO2 corrosion is one of the most significant forms of attack in the oil and gas production and transportation systems. Corrosion inhibitors have been widely used in an effort to reduce the detrimental effect of the corrosion process. Different types of corrosion inhibitors have been applied for this purpose. The most frequent is the imidazoline-based inhibitors (IM, owing to their good adsorption characteristics and film-forming capability. Albeit their extensive use, their inhibition mechanism is not fully understood. This paper highlights the inhibition mechanism of IM and also the factors that contribute to its inhibition mechanism.

  4. IN VITRO ANTIOXIDANT AND α-AMYLASE INHIBITION ACTIVITIES OF PANCHSAKAR CHURNA

    Directory of Open Access Journals (Sweden)

    Ashok Kumar B.S.

    2013-12-01

    Full Text Available Panchsakar Churna is the composition of Cassia angustifolia, Terminalia chebula, Zingiber officinale, Foeniculum vulgare and Saindhava lavana. Aqueous extract of churna was used to investigate antioxidant activity by ferrous ion chelating assay and ferric reducing power and alpha amylase inhibition activity by dinitrosalicylic acid method (DNSA. Aqueous extract of churna showed maximum ferrous chelating activity - 42.01 and ferric reducing power - 1.5 and 83.33 % of inhibition protein denaturation at 1000 µg/ml. Panchsakar churna showed significant antioxidant and alpha amylase inhibition activities.

  5. PARP-1 inhibition alleviates diabetic cardiac complications in experimental animals.

    Science.gov (United States)

    Zakaria, Esraa M; El-Bassossy, Hany M; El-Maraghy, Nabila N; Ahmed, Ahmed F; Ali, Abdelmoneim A

    2016-11-15

    Cardiovascular complications are the major causes of mortality among diabetic population. Poly(ADP-ribose) polymerase-1 enzyme (PARP-1) is activated by oxidative stress leading to cellular damage. We investigated the implication of PARP-1 in diabetic cardiac complications. Type 2 diabetes was induced in rats by high fructose-high fat diet and low streptozotocin dose. PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for ten weeks after diabetes induction. At the end of study, surface ECG, blood pressure and vascular reactivity were studied. PARP-1 activity, reduced glutathione (GSH) and nitrite contents were assessed in heart muscle. Fasting glucose, fructosamine, insulin, and tumor necrosis factor alpha (TNF-α) levels were measured in serum. Finally, histological examination and collagen deposition detection in rat ventricular and aortic sections were carried out. Hearts isolated from diabetic animals showed increased PARP-1 enzyme activity compared to control animals while significantly reduced by 4-AB administration. PARP-1 inhibition by 4-AB alleviated cardiac ischemia in diabetic animals as indicated by ECG changes. PARP-1 inhibition also reduced cardiac inflammation in diabetic animals as evidenced by histopathological changes. In addition, 4-AB administration improved the elevated blood pressure and the associated exaggerated vascular contractility, endothelial destruction and vascular inflammation seen in diabetic animals. Moreover, PARP-1 inhibition decreased serum levels of TNF-α and cardiac nitrite but increased cardiac GSH contents in diabetic animals. However, PARP-1 inhibition did not significantly affect the developed hyperglycemia. Our findings prove that PARP-1 enzyme plays an important role in diabetic cardiac complications through combining inflammation, oxidative stress, and fibrosis mechanisms.

  6. Salmonella infection inhibits intestinal biotin transport: cellular and molecular mechanisms.

    Science.gov (United States)

    Ghosal, Abhisek; Jellbauer, Stefan; Kapadia, Rubina; Raffatellu, Manuela; Said, Hamid M

    2015-07-15

    Infection with the nontyphoidal Salmonella is a common cause of food-borne disease that leads to acute gastroenteritis/diarrhea. Severe/prolonged cases of Salmonella infection could also impact host nutritional status, but little is known about its effect on intestinal absorption of vitamins, including biotin. We examined the effect of Salmonella enterica serovar Typhimurium (S. typhimurium) infection on intestinal biotin uptake using in vivo (streptomycin-pretreated mice) and in vitro [mouse (YAMC) and human (NCM460) colonic epithelial cells, and human intestinal epithelial Caco-2 cells] models. The results showed that infecting mice with wild-type S. typhimurium, but not with its nonpathogenic isogenic invA spiB mutant, leads to a significant inhibition in jejunal/colonic biotin uptake and in level of expression of the biotin transporter, sodium-dependent multivitamin transporter. In contrast, infecting YAMC, NCM460, and Caco-2 cells with S. typhimurium did not affect biotin uptake. These findings suggest that the effect of S. typhimurium infection is indirect and is likely mediated by proinflammatory cytokines, the levels of which were markedly induced in the intestine of S. typhimurium-infected mice. Consistent with this hypothesis, exposure of NCM460 cells to the proinflammatory cytokines TNF-α and IFN-γ led to a significant inhibition of biotin uptake, sodium-dependent multivitamin transporter expression, and activity of the SLC5A6 promoter. The latter effects appear to be mediated, at least in part, via the NF-κB signaling pathway. These results demonstrate that S. typhimurium infection inhibits intestinal biotin uptake, and that the inhibition is mediated via the action of proinflammatory cytokines.

  7. Ginger extract inhibits LPS induced macrophage activation and function

    Directory of Open Access Journals (Sweden)

    Bruch David

    2008-01-01

    Full Text Available Abstract Background Macrophages play a dual role in host defence. They act as the first line of defence by mounting an inflammatory response to antigen exposure and also act as antigen presenting cells and initiate the adaptive immune response. They are also the primary infiltrating cells at the site of inflammation. Inhibition of macrophage activation is one of the possible approaches towards modulating inflammation. Both conventional and alternative approaches are being studied in this regard. Ginger, an herbal product with broad anti inflammatory actions, is used as an alternative medicine in a number of inflammatory conditions like rheumatic disorders. In the present study we examined the effect of ginger extract on macrophage activation in the presence of LPS stimulation. Methods Murine peritoneal macrophages were stimulated by LPS in presence or absence of ginger extract and production of proinflammatory cytokines and chemokines were observed. We also studied the effect of ginger extract on the LPS induced expression of MHC II, B7.1, B7.2 and CD40 molecules. We also studied the antigen presenting function of ginger extract treated macrophages by primary mixed lymphocyte reaction. Results We observed that ginger extract inhibited IL-12, TNF-α, IL-1β (pro inflammatory cytokines and RANTES, MCP-1 (pro inflammatory chemokines production in LPS stimulated macrophages. Ginger extract also down regulated the expression of B7.1, B7.2 and MHC class II molecules. In addition ginger extract negatively affected the antigen presenting function of macrophages and we observed a significant reduction in T cell proliferation in response to allostimulation, when ginger extract treated macrophages were used as APCs. A significant decrease in IFN-γ and IL-2 production by T cells in response to allostimulation was also observed. Conclusion In conclusion ginger extract inhibits macrophage activation and APC function and indirectly inhibits T cell activation.

  8. Lobelane inhibits methamphetamine-evoked dopamine release via inhibition of the vesicular monoamine transporter-2.

    Science.gov (United States)

    Nickell, Justin R; Krishnamurthy, Sairam; Norrholm, Seth; Deaciuc, Gabriela; Siripurapu, Kiran B; Zheng, Guangrong; Crooks, Peter A; Dwoskin, Linda P

    2010-02-01

    Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [(3)H]dihydrotetrabenazine binding, inhibition of [(3)H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (K(i) = 45 nM) inhibiting vesicular [(3)H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC(50) = 0.65 microM; I(max) = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC(50) = 0.42 microM, I(max) = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for

  9. Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2S⃞

    Science.gov (United States)

    Nickell, Justin R.; Krishnamurthy, Sairam; Norrholm, Seth; Deaciuc, Gabriela; Siripurapu, Kiran B.; Zheng, Guangrong; Crooks, Peter A.

    2010-01-01

    Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [3H]dihydrotetrabenazine binding, inhibition of [3H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (Ki = 45 nM) inhibiting vesicular [3H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC50 = 0.65 μM; Imax = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC50 = 0.42 μM, Imax = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a

  10. 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.

  11. Toxicants inhibiting anaerobic digestion: a review.

    Science.gov (United States)

    Chen, Jian Lin; Ortiz, Raphael; Steele, Terry W J; Stuckey, David C

    2014-12-01

    Anaerobic digestion is increasingly being used to treat wastes from many sources because of its manifold advantages over aerobic treatment, e.g. low sludge production and low energy requirements. However, anaerobic digestion is sensitive to toxicants, and a wide range of compounds can inhibit the process and cause upset or failure. Substantial research has been carried out over the years to identify specific inhibitors/toxicants, and their mechanism of toxicity in anaerobic digestion. In this review we present a detailed and critical summary of research on the inhibition of anaerobic processes by specific organic toxicants (e.g., chlorophenols, halogenated aliphatics and long chain fatty acids), inorganic toxicants (e.g., ammonia, sulfide and heavy metals) and in particular, nanomaterials, focusing on the mechanism of their inhibition/toxicity. A better understanding of the fundamental mechanisms behind inhibition/toxicity will enhance the wider application of anaerobic digestion.

  12. Glycerol inhibition of ruminal lipolysis in vitro

    Science.gov (United States)

    Supplemental glycerol inhibits rumen lipolysis, a prerequisite for rumen biohydrogenation, which is responsible for the saturation of dietary fatty acids consumed by ruminant animals. Feeding excess glycerol, however, adversely affects dry matter digestibility. To more clearly define the effect of...

  13. Bioengineered Hydrogel to Inhibit Post-Traumatic Central Nervous System Scarring

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0586 TITLE: Bioengineered Hydrogel to Inhibit Post-Traumatic Central Nervous System Scarring PRINCIPAL...Hydrogel to Inhibit Post-Traumatic Central Nervous System Scarring 5a. CONTRACT NUMBER W81XWH-14-1-0586 5b. GRANT NUMBER W81XWH- 14-1-0586 5c...barriers that prevent the optimal delivery of biologics and cells to the injured nervous system . A significant problem is the formation of scar tissue

  14. Anthocyanin Interactions with DNA: Intercalation, Topoisomerase I Inhibition and Oxidative Reactions

    OpenAIRE

    2008-01-01

    Anthocyanins and their aglycone anthocyanidins are pigmented flavonoids found in significant amounts in many commonly consumed foods. They exhibit a complex chemistry in aqueous solution, which makes it difficult to study their chemistry under physiological conditions. Here we used a gel electrophoresis assay employing supercoiled DNA plasmid to examine the ability of these compounds (1) to intercalate DNA, (2) to inhibit human topoisomerase I through both inhibition of plasmid relaxation act...

  15. INHIBITION OF APOPTOSIS BY bcr-abl FUSION GENE IN K562 CELLS

    Institute of Scientific and Technical Information of China (English)

    WANG Chun-hong; SUN Bing-zhong; YUAN Yue-chuan

    1999-01-01

    Objective: To investigate the effect of bcr-abl fusion gene on CML cell apoptosis. Methods: Apoptosis of exvivo cultured K562 cells were observed after exposure to synthetic 18 mer antisense oligodeoxynucleotide complementary to the bcr-abl junction (b3a2). Results: Apoptosis of K562 cells was significantly increased associated with inhibition of bcr-abl expression. Conclusion: bcr-abl fusion gene formation due to chromosome translocation may be the major mechanism of CML via inhibition of apoptosis.

  16. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.

    Directory of Open Access Journals (Sweden)

    Emmanuel S Onaivi

    Full Text Available BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R but not (H316Y polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.

  17. Curcumin inhibits amygdaloid kindled seizures in rats.

    Science.gov (United States)

    DU, Peng; Li, Xin; Lin, Hao-Jie; Peng, Wei-Feng; Liu, Jian-Ying; Ma, Yu; Fan, Wei; Wang, Xin

    2009-06-20

    Curcumin can reduce the severity of seizures induced by kainate acid (KA), but the role of curcumin in amygdaloid kindled models is still unknown. This study aimed to explore the effect of curcumin on the development of kindling in amygdaloid kindled rats. With an amygdaloid kindled Sprague-Dawley (SD) rat model and an electrophysiological method, different doses of curcumin (10 mgxkg(-1)xd(-1) and 30 mgxkg(-1)xd(-1) as low dose groups, 100 mgxkg(-1)xd(-1) and 300 mgxkg(-1)xd(-1) as high dose groups) were administrated intraperitoneally during the whole kindling days, by comparison with the course of kindling, afterdischarge (AD) thresholds and the number of ADs to reach the stages of class I to V seizures in the rats between control and experimental groups. One-way or two-way ANOVA and Fisher's least significant difference post hoc test were used for statistical analyses. Curcumin (both 100 mgxkg(-1)xd(-1) and 300 mgxkg(-1)xd(-1)) significantly inhibited the behavioral seizure development in the (19.80 +/- 2.25) and (21.70 +/- 2.21) stimulations respectively required to reach the kindled state. Rats treated with 100 mgxkg(-1)xd(-1) curcumin 30 minutes before kindling stimulation showed an obvious increase in the stimulation current intensity required to evoke AD from (703.3 +/- 85.9) microA to (960.0 +/- 116.5) microA during the progression to class V seizures. Rats treated with 300 mgxkg(-1)xd(-1) curcumin showed a significant increase in the stimulation current intensity required to evoke AD from (735.0 +/- 65.2) microA to (867.0 +/- 93.4) microA during the progression to class V seizures. Rats treated with 300 mgxkg(-1)xd(-1) curcumin required much more evoked ADs to reach the stage of class both IV (as (199.83 +/- 12.47) seconds) and V seizures (as (210.66 +/- 10.68) seconds). Rats treated with 100 mgxkg(-1)xd(-1) curcumin required much more evoked ADs to reach the stage of class V seizures (as (219.56 +/- 18.24) seconds). Our study suggests that curcumin has

  18. Neomycin inhibits angiogenin-induced angiogenesis

    OpenAIRE

    1998-01-01

    A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, an...

  19. Neomycin inhibits angiogenin-induced angiogenesis

    OpenAIRE

    Hu, Guo-fu

    1998-01-01

    A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, an...

  20. Inhibited solid propellant composition containing beryllium hydride

    Science.gov (United States)

    Thompson, W. W. (Inventor)

    1978-01-01

    An object of this invention is to provide a composition of beryllium hydride and carboxy-terminated polybutadiene which is stable. Another object of this invention is to provide a method for inhibiting the reactivity of beryllium hydride toward carboxy-terminated polybutadiene. It was found that a small amount of lecithin inhibits the reaction of beryllium hydride with the acid groups in carboxy terminated polybutadiene.

  1. The inhibition of monoamine oxidase by esomeprazole

    OpenAIRE

    2013-01-01

    Virtual screening of a library of drugs has suggested that esomeprazole, the S-enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomepra...

  2. Piperine, a dietary phytochemical, inhibits angiogenesis

    OpenAIRE

    2012-01-01

    Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induce...

  3. 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.

  4. Inhibition of Heme Peroxidases by Melamine

    Directory of Open Access Journals (Sweden)

    Pattaraporn Vanachayangkul

    2012-01-01

    Full Text Available In 2008 melamine-contaminated infant formula and dairy products in China led to over 50,000 hospitalizations of children due to renal injuries. In North America during 2007 and in Asia during 2004, melamine-contaminated pet food products resulted in numerous pet deaths due to renal failure. Animal studies have confirmed the potent renal toxicity of melamine combined with cyanuric acid. We showed previously that the solubility of melamine cyanurate is low at physiologic pH and ionic strength, provoking us to speculate how toxic levels of these compounds could be transported through the circulation without crystallizing until passing into the renal filtrate. We hypothesized that melamine might be sequestered by heme proteins, which could interfere with heme enzyme activity. Four heme peroxidase enzymes were selected for study: horseradish peroxidase (HRP, lactoperoxidase (LPO, and cyclooxygenase-1 and -2 (COX-1 and -2. Melamine exhibited noncompetitive inhibition of HRP (9.5±0.7mM, and LPO showed a mixed model of inhibition (14.5±4.7mM. The inhibition of HRP and LPO was confirmed using a chemiluminescent peroxidase assay. Melamine also exhibited COX-1 inhibition, but inhibition of COX-2 was not detected. Thus, our results demonstrate that melamine inhibits the activity of three heme peroxidases.

  5. Scale Inhibition of Green Inhibitor Polyepoxysuccinic Sodium

    Institute of Scientific and Technical Information of China (English)

    Feng Hui-xia; Wang Yi; Yu Shu-rong; Liang Bao-feng

    2004-01-01

    Polyepoxysuccinic acid (PESA) is the green water treatment agents recognized all over the world[1-3]. It is found that when PESA is used alone, it had good scale inhibition. PESA should be included in the category of green scale inhibitor.PESA is synthesized with maleicanhydride in the presence of catalysts. The effect on scale-in-hibiting property of the product from amount and feed times of catalyst, the reaction temperature, the reaction time were investigated. The optimum reaction conditions are as follows:n(maleic anhydride):n(Ca(OH)2):n(NaOH)=1:0.05-0.2:0.5, reaction temperature 95C, reaction time 4h.In all the references about PESA, PESA is researched as a kind of highly effective scale inhibitor or chelate. In this paper, the performance of scale inhibition of PESA is evaluated by scale static inhibitor.The results are shown in Figture1.It is evident from our experimental data (Figture1) that when inhibition for CaCO3.With the increase of PESA dosage, scale inhibition increases. When dosage is more than 6mg/L, inhibition efficiency is over 50%. The formulas give scale inhibition efficiency more than 95% at 12mg/L of total dosage.

  6. The antiplatelet activity of Geiji-Bokryung-Hwan, Korean traditional formulation, is mediated through inhibition of phospholipase C and inhibition of TxB(2) synthetase activity.

    Science.gov (United States)

    Park, Won-Hwan; Kim, Kyoung-Sook; Kim, Kyung-Ho; Kim, Dong-Soo; Kim, Cheorl-Ho

    2003-07-01

    Geiji-Bokryung-Hwan (GBH), consisting of herbes of Cinnamomi ramulus (Geiji), Poria cocos (Bokryun), Mountan cortex radicis (Mokdanpi), Paeoniae radix (Jakyak), and Persicae semen (Doin), on antiplatelet activity in human platelet suspensions was studied. The mechanism involved in the antiplatelet activity of GBH in human platelet suspensions was investigated. GBH did not significantly affect the thromboxane synthetase activity of aspirin-treated platelet microsomes and GBH (15 and 30 microg/ml) significantly inhibited [3H]arachidonic acid released in collagen-activated platelets but not in unactivated-platelets. Nitric oxide (NO) production in human platelets was measured by a chemiluminesence detection method in this study. GBH did not significantly affect nitrate production in collagen (10 microg/ml)-induced human platelet aggregation. Various concentrations of GBH (0, 5, 10, 15, and 30 microg/ml) dose-dependently inhibited [3H]inositol monophosphate formation stimulated by collagen (10 microg/ml) in [3H]myoinositol-loaded platelets at different incubation times (1, 2, 3, and 5 min). These results indicated that the antiplatelet activity of GBH may possibly be due to the inhibition of phospholipase C (PLC) activity, leading to reduce phosphoinositide breakdown, followed by the inhibition of thromboxane A(2) formation, and then inhibition of [Ca(2+)](i) mobilization of platelet aggregation stimulated by agonists. In conclusion, GBH suppressed PLC in a dose-dependent manner, and may have pharmaceutical applications. These data suggest that GBH extracts merit investigation as a potential anti-atherosclerogenic agent in humans.

  7. Curcumin inhibits imiquimod-induced psoriasis-like inflammation by inhibiting IL-1beta and IL-6 production in mice.

    Directory of Open Access Journals (Sweden)

    Jun Sun

    Full Text Available Curcumin, a selective phosphorylase kinase inhibitor, is a naturally occurring phytochemical present in turmeric. Curcumin has been confirmed to have anti-inflammatory properties in addition to the ability to decrease the expression of pro-inflammatory cytokines in keratinocytes. The interleukin-23 (IL-23/IL-17A cytokine axis plays a critical role in the pathogenesis of psoriasis. Here, we report that topical use of a curcumin gel formulation strongly inhibited imiquimod (IMQ-induced psoriasis-like inflammation, the development of which was based on the IL-23/IL-17A axis. IMQ-induced epidermal hyperplasia and inflammation in BALB/c mouse ear was significantly inhibited following curcumin treatment. Real-time PCR showed that mRNA levels of IL-17A, IL-17F, IL-22, IL-1β, IL-6 and TNF-α cytokines were decreased significantly by curcumin in ear skin, an effect similar to that of clobetasol. In addition, we found that curcumin may enhance the proliferation of epidermis γδ T cells but inhibit dermal γδ T cell proliferation. We inferred that curcumin was capable of impacting the IL-23/IL-17A axis by inhibiting IL-1β/IL-6 and then indirectly down-regulating IL-17A/IL-22 production. In conclusion, curcumin can relieve the IMQ-induced psoriasis-like inflammation in a mouse model, similar to the effects of clobetasol. Therefore, we have every reason to expect that curcumin will be used in the treatment of psoriasis in the future.

  8. Spatially reciprocal inhibition of inhibition within a stimulus selection network in the avian midbrain.

    Science.gov (United States)

    Goddard, C Alex; Mysore, Shreesh P; Bryant, Astra S; Huguenard, John R; Knudsen, Eric I

    2014-01-01

    Reciprocal inhibition between inhibitory projection neurons has been proposed as the most efficient circuit motif to achieve the flexible selection of one stimulus among competing alternatives. However, whether such a motif exists in networks that mediate selection is unclear. Here, we study the connectivity within the nucleus isthmi pars magnocellularis (Imc), a GABAergic nucleus that mediates competitive selection in the midbrain stimulus selection network. Using laser photostimulation of caged glutamate, we find that feedback inhibitory connectivity is global within the Imc. Unlike typical lateral inhibition in other circuits, intra-Imc inhibition remains functionally powerful over long distances. Anatomically, we observed long-range axonal projections and retrograde somatic labeling from focal injections of bi-directional tracers in the Imc, consistent with spatial reciprocity of intra-Imc inhibition. Together, the data indicate that spatially reciprocal inhibition of inhibition occurs throughout the Imc. Thus, the midbrain selection circuit possesses the most efficient circuit motif possible for fast, reliable, and flexible selection.

  9. Pain inhibits pain; human brainstem mechanisms.

    Science.gov (United States)

    Youssef, A M; Macefield, V G; Henderson, L A

    2016-01-01

    Conditioned pain modulation is a powerful analgesic mechanism, occurring when a painful stimulus is inhibited by a second painful stimulus delivered at a different body location. Reduced conditioned pain modulation capacity is associated with the development of some chronic pain conditions and the effectiveness of some analgesic medications. Human lesion studies show that the circuitry responsible for conditioned pain modulation lies within the caudal brainstem, although the precise nuclei in humans remain unknown. We employed brain imaging to determine brainstem sites responsible for conditioned pain modulation in 54 healthy individuals. In all subjects, 8 noxious heat stimuli (test stimuli) were applied to the right side of the mouth and brain activity measured using functional magnetic resonance imaging. This paradigm was then repeated. However, following the fourth noxious stimulus, a separate noxious stimulus, consisting of an intramuscular injection of hypertonic saline into the leg, was delivered (conditioning stimulus). During this test and conditioning stimulus period, 23 subjects displayed conditioned pain modulation analgesia whereas 31 subjects did not. An individual's analgesic ability was not influenced by gender, pain intensity levels of the test or conditioning stimuli or by psychological variables such as pain catastrophizing or fear of pain. Brain images were processed using SPM8 and the brainstem isolated using the SUIT toolbox. Significant increases in signal intensity were determined during each test stimulus and compared between subjects that did and did not display CPM analgesia (ppain modulation circuitry provides a framework for the future investigations into the neural mechanisms responsible for the maintenance of persistent pain conditions thought to involve altered analgesic circuitry.

  10. Risedronate inhibits human osteosarcoma cell invasion

    Directory of Open Access Journals (Sweden)

    Jung Sung

    2009-07-01

    Full Text Available Abstract Background Osteosarcoma is a highly malignant bone tumor and is the most commonly encountered malignant bone tumor in children and adolescents. Furthermore, significant numbers of patients eventually develop pulmonary metastases and succumb to the disease even after conventional multi-agent chemotherapy and surgical excision. Several solid tumors display enhanced expression of matrix metalloproteinases (MMPs, and recently clinical trials have been initiated on MMP-inhibitors. On the other hand, bisphosphonates (BPs, which have a profound effect on bone resorption, are widely used to treat osteoclast-mediated bone diseases. BPs are also known to inhibit tumor growths and metastases in some tumors such as breast cancer, renal cell carcinoma, and prostate cancer. Methods Two osteosarcoma cell lines (SaOS-2 and U2OS were treated with risedronate (0, 0.1, 1, 10 μM for 48 hours. Cell viabilities were determined using MTT assay, the mRNA levels of MMP-2 and MMP-9 were analyzed by reverse-transcription polymerase chain reaction, the amount of MMP-2 and MMP-9 protein were analyzed by Westernblot, the activities of MMP-2 and MMP-9 were observed by Gelatin zymography, and Matrigel invasion assays were used to investigate the invasive potential of osteosarcoma cell lines before and after risedronate treatment. Results The invasiveness of osteosarcoma cell lines (SaOS-2, U2OS were reduced in a dose dependent manner follow 48 hour treatment of up to 10 μM of the risedronate at which concentration no cytotoxicity occurred. Furthermore, the gelatinolytic activities and protein and mRNA levels of MMP-2 and MMP-9 were also suppressed by increasing risedronate concentrations. Conclusion Given that MMP-2 and MMP-9 are instrumental in tumor cell invasion, our results suggest the risedronate could reduce osteosarcoma cell invasion.

  11. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

    Science.gov (United States)

    Hubers, Scott A; Brown, Nancy J

    2016-03-15

    Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.

  12. Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis.

    Science.gov (United States)

    Lee, Tae-Sun; Lee, Joo-Young; Kyung, Jae Won; Yang, Yoosoo; Park, Seung Ju; Lee, Seulgi; Pavlovic, Igor; Kong, Byoungjae; Jho, Yong Seok; Jessen, Henning J; Kweon, Dae-Hyuk; Shin, Yeon-Kyun; Kim, Sung Hyun; Yoon, Tae-Young; Kim, Seyun

    2016-07-19

    Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6 Synaptotagmin 1 (Syt1), a Ca(2+) sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7 Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6 In addition, 5-IP7-dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca(2+) levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca(2+) These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.

  13. Combined intravitreal bevacizumab with phacoemulsification in visually significant cataract and visually significant exudative maculopathy

    Directory of Open Access Journals (Sweden)

    Ahmad Mansour

    2011-01-01

    Full Text Available Purpose : We investigated the visual outcome of combined phacoemulsification with intravitreal bevacizumab, in eyes with dense cataract and visually significant exudative maculopathy. Materials and Methods : Prospective longitudinal pilot study of consecutive patients treated by two surgeons in 2006, using intravitreal bevacizumab at the end of phacoemulsification. The historical control group consisted of consecutive subjects with exudative maculopathy and dense cataract treated by the same surgeons with the help of phacoemulsification without intravitreal bevacizumab prior to 2006. Results : Thirty-one treated patients had the mean (SD logMar best corrected visual acuity improving from - 1.48 (0.50 preoperatively to - 0.67 (0.38 in the first postoperative week ( p < 0.001, to - 0.64 (0.40 in the first postoperative month ( p < 0.001, and to - 0.62 (0.42 ( p < 0.001 on the last follow-up (mean 4.2 months, range 1 - 9 months. Fourteen control patients had the mean (SD logMar best corrected visual acuity improving from - 1.78 (0.79 preoperatively, to - 0.91 (0.53 in the first postoperative week ( p < 0.001, to - 0.86 (0.45 in the first postoperative month ( p < 0.001, and to - 0.90 (0.47 ( p < 0.001 on the last follow- up (mean 19.6 months, range 1 - 49 months. Initial visual acuities, final visual acuities, and percentage of visual improvement at one month were all not significantly better in the intervention compared to the control group at one month. In the study group, the fovea was flattened at the one-month follow-up, by 90-diopter slit lamp examination and / or Optical coherence tomography. Conclusion : The combination of intravitreal bevacizumab and phacoemulsification is beneficial for maximal visual rehabilitation in the first postoperative month.

  14. Determining the clinical significance of monoclonal gammopathy of undetermined significance: a SEER-Medicare population analysis.

    Science.gov (United States)

    Go, Ronald S; Gundrum, Jacob D; Neuner, Joan M

    2015-03-01

    Clinical guidelines have recommended annual follow-up examinations of most patients with monoclonal gammopathy of undetermined significance (MGUS); however, evidence supporting this practice is lacking. We performed a population-based study to examine the patterns of disease presentation and outcomes of patients with multiple myeloma, Waldenström macroglobulinemia, and lymphoplasmacytic lymphoma (monoclonal gammopathy-associated malignancies) comparing those with or without a previous MGUS follow-up examination. Patients with monoclonal gammopathy-associated malignancy from 1994 through 2007 were identified using the Surveillance, Epidemiology, and End Results-Medicare linked database and divided into 2 cohorts: those with follow-up (MGUS follow-up examination preceding the diagnosis) and those with no follow-up (no such follow-up examination). We compared the outcomes, including the rates of major complications at cancer diagnosis (acute kidney injury, cord compression, dialysis use, fracture, and hypercalcemia) and survival using propensity score adjustment and Cox proportional hazard models. All statistical tests were 2-sided. Of the 17,457 study patients, 6% had undergone MGUS follow-up. After multivariable modeling, the follow-up group had significantly fewer major complications at diagnosis (odds ratio 0.68; 95% confidence interval [CI], 0.57-0.80) and better disease-specific (median, 38 vs. 29 months, P < .001; hazard ratio [HR] 0.85; 95% CI, 0.76-0.94) and overall (median, 23 vs. 19 months, P < .001; HR 0.87; 95% CI, 0.80-0.95) survival. Patients with MGUS follow-up preceding the diagnosis of a monoclonal gammopathy-associated malignancy can experience fewer major complications and have longer survival than those without such follow-up examinations. Future studies replicating our findings in the non-Medicare population and determining the optimal schedule and cost-effectiveness of MGUS follow-up are warranted. Copyright © 2015 Elsevier Inc. All rights

  15. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, inhibits type I-IV allergic inflammation and pro-inflammatory enzymes.

    Science.gov (United States)

    Lee, Ji Yun; Kim, Chang Jong

    2010-06-01

    We previously reported that arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan isolated from Forsythia koreana, exhibits anti-inflammatory, antioxidant, and analgesic effects in animal models. In addition, arctigenin inhibited eosinophil peroxidase and activated myeloperoxidase in inflamed tissues. In this study, we tested the effects of arctigenin on type I-IV allergic inflammation and pro-inflammatory enzymes in vitro and in vivo. Arctigenin significantly inhibited the heterologous passive cutaneous anaphylaxis induced by ovalbumin in mice at 15 mg/kg, p.o., and compound 48/80-induced histamine release from rat peritoneal mast cells at 10 microM. Arctigenin (15 mg/kg, p.o.) significantly inhibited reversed cutaneous anaphylaxis. Further, arctigenin (15 mg/kg, p.o.) significantly inhibited the Arthus reaction to sheep's red blood cells, decreasing the hemolysis titer, the hemagglutination titer, and the plaque-forming cell number for SRBCs. In addition, arctigenin significantly inhibited delayed type hypersensitivity at 15 mg/kg, p.o. and the formation of rosette-forming cells at 45 mg/kg, p.o. Contact dermatitis induced by picrylchloride and dinitrofluorobenzene was significantly (p arctigenin (0.3 mg/ear). Furthermore, arctigenin dose-dependently inhibited pro-inflammatory enzymes, such as cyclooxygenase-1 and 2, 5-lipoxygenase, phospholipase A2, and phosphodiesterase. Our results show that arctigenin significantly inhibited B- and T-cell mediated allergic inflammation as well as pro-inflammatory enzymes.

  16. Arecoline inhibits catecholamine release from perfused rat adrenal gland

    Institute of Scientific and Technical Information of China (English)

    Dong-yoon LIM; Il-sik KIM

    2006-01-01

    Aim: To study the effect of arecoline, an alkaloid isolated from Areca catechu, on the secretion of catecholamines (CA) evoked by cholinergic agonists and the membrane depolarizer from isolated perfused rat adrenal gland. Methods: Adrenal glands were isolated from male Sprague-Dawley rats. The adrenal glands were perfused with Krebs bicarbonate solution by means of a peristaltic pump. The CA content of the perfusate was measured directly using the fluorometric method.Results: Arecoline (0.1-1.0 mmol/L) perfused into an adrenal vein for 60 min produced dose- and time-dependent inhibition in CA secretory responses evoked by acetylcholine (ACh) (5.32 mmol/L), 1.1-dimethyl-4-phenyl piperazinium iodide (DMPP) (100 μmol/L for 2 min) and 3-(m-choloro-phenyl-carbamoyl-oxy)-2-butynyl trimethyl ammonium chloride (McN-A-343) (100 μmol/L for 2 min). However, lower doses of arecoline did not affect CA secretion of high K+ (56 mmol/L); higher doses greatly reduced CA secretion of high K+. Arecoline also failed to affect basal catecholamine output. Furthermore, in adrenal glands loaded with arecoline (0.3 mmol/L), CA secretory response evoked by Bay-K-8644 (10 μmol/L), an activator of L-type Ca2+ channels, was markedly inhibited, whereas CA secretion by cyclopiazonic acid (10 μmol/L), an inhibitor of cytoplasmic Ca2+-ATPase, was not affected. Nicotine (30 μmol/L), which was peffused into the adrenal gland for 60min, however, initially enhanced ACh-evoked CA secretory responses. As time elapsed, these responses became more inhibited, whereas the initially enhanced high K+-evoked CA release diminished. CA secretion evoked by DMPP and McNA-343 was significantly depressed in the presence of nicotine. Conclusion:Arecoline dose-dependently inhibits CA secretion from isolated perfused rat adrenal gland evoked by activation of cholinergic receptors. At lower doses arecoline does not inhibit CA secretion through membrane depolarization, but at larger doses it does. This inhibitory

  17. White matter hyperintensities and prepulse inhibition in a mixed elderly population

    DEFF Research Database (Denmark)

    Salem, Lise C; Hejl, Anne-Mette; Garde, Ellen;

    2011-01-01

    rated visually on craniel MRI FLAIR images using the Fazekas scale. WMH were identified in 70% of all subjects. The latency to peak of the startle response increased significantly with increasing WMH load, whereas the inhibition of the startle response (PPI) was neither significantly related...

  18. Enzyme Inhibition by Molluscicidal Components of Myristica fragrans Houtt. in the Nervous Tissue of Snail Lymnaea acuminata

    Directory of Open Access Journals (Sweden)

    Preetee Jaiswal

    2010-01-01

    Full Text Available This study was designed to investigate the effects of molluscicidal components of Myristica fragrans Houtt. (Myristicaceae on certain enzymes in the nervous tissue of freshwater snail Lymnaea acuminata Lamarck (Lymnaeidae. In vivo and in vitro treatments of trimyristin and myristicin (active molluscicidal components of Myristica fragrans Houtt. significantly inhibited the acetylcholinesterase (AChE, acid and alkaline phosphatase (ACP/ALP activities in the nervous tissue of Lymnaea acuminata. The inhibition kinetics of these enzymes indicates that both the trimyristin and myristicin caused competitive noncompetitive inhibition of AChE. Trimyristin caused uncompetitive and competitive/noncompetitive inhibitions of ACP and ALP, respectively whereas the myristicin caused competitive and uncompetitive inhibition of ACP and ALP, respectively. Thus results from the present study suggest that inhibition of AChE, ACP, and ALP by trimyristin and myristicin in the snail Lymnaea acuminata may be the cause of the molluscicidal activity of Myristica fragrans.

  19. Inhibition of gastric H+, K(+)-ATPase by chalcone derivatives, xanthoangelol and 4-hydroxyderricin, from Angelica keiskei Koidzumi.

    Science.gov (United States)

    Murakami, S; Kijima, H; Isobe, Y; Muramatsu, M; Aihara, H; Otomo, S; Baba, K; Kozawa, M

    1990-10-01

    Two chalcone derivatives, xanthoangelol (1) and 4-hydroxyderricin (II) isolated from Angelica keiskei Koidzumi, inhibited pig gastric H+, K(+)-ATPase with IC50 values of 1.8 and 3.3 microM, respectively. The inhibition by I or II was competitive with respect to ATP and was non-competitive with respect to K+ I and II also inhibited K+, stimulated p-nitrophenyl phosphatase, with IC50 values of 1.3 and 3.5 microM, respectively. Proton transport in-vitro was inhibited by I or II, in a dose-dependent manner, 1 at 100 mg kg-1, i.p. significantly inhibited acid secretion and the formation of stress-induced gastric lesions. These results suggest that the antisecretory effect of 1 is due to the inhibition of gastric H+, K(+)-ATPase.

  20. GABA transmission in the ventral pallidum is not involved in the control of latent inhibition in the rat.

    Science.gov (United States)

    Lawrence, N S; Sharp, T; Peters, S P; Gray, J A; Young, A M J

    2003-01-01

    Latent inhibition describes a process of learning to ignore stimuli of no consequence, and is disrupted in acute, positive-symptomatic schizophrenia. Understanding the neural basis of latent inhibition in animals may help to elucidate the neural dysfunction underlying positive schizophrenic symptoms in man. Evidence suggests a crucial role for dopamine transmission in the nucleus accumbens in the control of latent inhibition. The present studies investigated the role of the GABA-ergic efferent from the nucleus accumbens to the ventral pallidum in latent inhibition. The GABA(A) agonist muscimol (4.56 ng/microl), and antagonist picrotoxin (0.2 microg/microl), were infused into the ventral pallidum, and effects on latent inhibition were assessed using a conditioned suppression procedure. Neither drug produced specific effects on latent inhibition when given alone and, in the case of muscimol, failed to reverse the disruption of latent inhibition induced by systemic amphetamine. In addition to significant non-specific drug effects, a positive control experiment revealed that intra-pallidal picrotoxin significantly enhanced locomotion, suggesting that our manipulations of ventral pallidal GABA function were behaviourally effective. We conclude that modulating ventral pallidal GABA transmission does not affect latent inhibition. The implications of this finding for theories of the neural circuitry mediating latent inhibition and for understanding the functional role of ventral pallidal GABA transmission are discussed.

  1. Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Blattmann, C. [Olgahospital, Stuttgart (Germany). Paediatrie 5; University Children' s Hospital of Heidelberg (Germany). Dept. of Pediatric Oncology, Hematology and Immunology; Thiemann, M. [German Cancer Research Center (DKFZ), Heidelberg (Germany). Dept. of Radiotherapy, Molecular- and Translational Radiation Oncology; Stenzinger, A. [Heidelberg Univ. (Germany). Inst. of Pathology; and others

    2013-11-15

    Background: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. Methods: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. Results: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. Conclusion: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS. (orig.)

  2. Intracortical modulation, and not spinal inhibition, mediates placebo analgesia.

    Science.gov (United States)

    Martini, M; Lee, M C H; Valentini, E; Iannetti, G D

    2015-02-01

    Suppression of spinal responses to noxious stimulation has been detected using spinal fMRI during placebo analgesia, which is therefore increasingly considered a phenomenon caused by descending inhibition of spinal activity. However, spinal fMRI is technically challenging and prone to false-positive results. Here we recorded laser-evoked potentials (LEPs) during placebo analgesia in humans. LEPs allow neural activity to be measured directly and with high enough temporal resolution to capture the sequence of cortical areas activated by nociceptive stimuli. If placebo analgesia is mediated by inhibition at spinal level, this would result in a general suppression of LEPs rather than in a selective reduction of their late components. LEPs and subjective pain ratings were obtained in two groups of healthy volunteers - one was conditioned for placebo analgesia while the other served as unconditioned control. Laser stimuli at three suprathreshold energies were delivered to the right hand dorsum. Placebo analgesia was associated with a significant reduction of the amplitude of the late P2 component. In contrast, the early N1 component, reflecting the arrival of the nociceptive input to the primary somatosensory cortex (SI), was only affected by stimulus energy. This selective suppression of late LEPs indicates that placebo analgesia is mediated by direct intracortical modulation rather than inhibition of the nociceptive input at spinal level. The observed cortical modulation occurs after the responses elicited by the nociceptive stimulus in the SI, suggesting that higher order sensory processes are modulated during placebo analgesia.

  3. Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress.

    Directory of Open Access Journals (Sweden)

    Xue Yu

    Full Text Available Homocysteine is an independent risk factor for coronary, cerebral, and peripheral vascular diseases. Recent studies have shown that levels of homocysteine are elevated in patients with impaired hepatic function, but the precise role of homocysteine in the development of hepatic dysfunction is unclear. In this study, we examined the effect of homocysteine on hepatocyte proliferation in vitro. Our results demonstrated that homocysteine inhibited hepatocyte proliferation by up-regulating protein levels of p53 as well as mRNA and protein levels of p21(Cip1 in primary cultured hepatocytes. Homocysteine induced cell growth arrest in p53-positive hepatocarcinoma cell line HepG2, but not in p53-null hepatocarcinoma cell line Hep3B. A p53 inhibitor pifithrin-α inhibited the expression of p21(Cip1 and attenuated homocysteine-induced cell growth arrest. Homocysteine induced TRB3 expression via endoplasmic reticulum stress pathway, resulting in Akt dephosphorylation. Knock-down of endogenous TRB3 significantly suppressed the inhibitory effect of homocysteine on cell proliferation and the phosphorylation of Akt. LiCl reversed homocysteine-mediated cell growth arrest by inhibiting TRB3-mediated Akt dephosphorylation. These results demonstrate that both TRB3 and p21(Cip1 are critical molecules in the homocysteine signaling cascade and provide a mechanistic explanation for impairment of liver regeneration in hyperhomocysteinemia.

  4. Mycotoxicogenic fungal inhibition by innovative cheese cover with aromatic plants.

    Science.gov (United States)

    Moro, Armando; Librán, Celia M; Berruga, M Isabel; Zalacain, Amaya; Carmona, Manuel

    2013-03-30

    The use of aromatic plants and their extracts with antimicrobial properties may be compromised in the case of cheese, as some type of fungal starter is needed during its production. Penicillium verrucosum is considered a common cheese spoiler. The aim of this study was to evaluate the innovative use of certain aromatic plants as natural cheese covers in order to prevent mycotoxicogenic fungal growth (P. verrucosum). A collection of 12 essential oils (EOs) was obtained from various aromatic plants by solvent-free microwave extraction technology, and volatile characterisation of the EOs was carried out by gas chromatography/mass spectrometry. The most effective EOs against P. verrucosum were obtained from Anethum graveolens, Hyssopus officinalis and Chamaemelum nobile, yielding 50% inhibition of fungal growth at concentration values lower than 0.02 µL mL⁻¹. All EOs showed high volatile heterogeneity, with α-phellandrene, pinocamphone, isopinocamphone, α-pinene, camphene, 1,8-cineole, carvacrol and trans-anethole being found to be statistically significant in the antifungal model. The use of these aromatic plants as natural covers on cheese can satisfactorily inhibit the growth of some mycotoxicogenic fungal spoilers. Among the volatile compounds present, α- and β-phellandrene were confirmed as the most relevant in the inhibition. © 2012 Society of Chemical Industry.

  5. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D. [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada); Pacher, Pal [National Institutes of Health, NIAAA, Laboratory of Physiologic Studies, Bethesda, MD (United States); Schulz, Richard, E-mail: richard.schulz@ualberta.ca [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada)

    2009-10-02

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC{sub 50} values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  6. Tea polyphenols inhibit rat osteoclast formation and differentiation.

    Science.gov (United States)

    Oka, Yoshiomi; Iwai, Shinichi; Amano, Hitoshi; Irie, Yuko; Yatomi, Kentaro; Ryu, Kakei; Yamada, Shoji; Inagaki, Katsunori; Oguchi, Katsuji

    2012-01-01

    Matrix metalloproteinases (MMPs) play an important role in degeneration of the matrix associated with bone and cartilage. Regulation of osteoclast activity is essential in the treatment of bone disease, including osteoporosis and rheumatoid arthritis. Polyphenols in green tea, particularly epigallocatechin-3-gallate (EGCG), inhibit MMPs expression and activity. However, the effects of the black tea polyphenol, theaflavin-3,3'-digallate (TFDG), on osteoclast and MMP activity are unknown. Therefore, we examined whether TFDG and EGCG affect MMP activity and osteoclast formation and differentiation in vitro. TFDG or EGCG (10 and 100 µM) was added to cultures of rat osteoclast precursors cells and mature osteoclasts. Numbers of multinucleated osteoclasts and actin rings decreased in polyphenol-treated cultures relative to control cultures. MMP-2 and MMP-9 activities were lower in TFDG- and EGCG-treated rat osteoclast precursor cells than in control cultures. MMP-9 mRNA levels declined significantly in TFDG-treated osteoclasts in comparison to control osteoclasts. TFDG and EGCG inhibited the formation and differentiation of osteoclasts via inhibition of MMPs. TFDG may suppress actin ring formation more effectively than EGCG. Thus, TFDG and EGCG may be suitable agents or lead compounds for the treatment of bone resorption diseases.

  7. Prolyl hydroxylase 3 inhibited the tumorigenecity of gastric cancer cells.

    Science.gov (United States)

    Cui, Lei; Qu, Jianguo; Dang, Shengchun; Mao, Zhengfa; Wang, Xuqing; Fan, Xin; Sun, Kang; Zhang, Jianxin

    2014-09-01

    Gastric cancer is one of the most common malignancies and the second leading cause of cancer-related death in the world, and it is very urgent to develop novel therapeutic strategies. Although HIF-1α is the most highly characterized target of prolyl hydroxylase 3 (PHD3), PHD3 has been shown to regulate several signal pathways independent of HIF-1α. Here, we found that the expression of PHD3 was decreased in the clinical gastric cancer samples and reversely correlated with tumor size and tumor stage. Over-expression of PHD3 in the gastric cancer cells significantly inhibited cell growth in vitro and in vivo, while knockdown the expression of PHD3 promoted the tumorigenecity of gastric cancer cells. Mechanistically, it showed that PHD3 downregulated the expression of beta-catenin and inhibited beta-catenin/T-cell factor (TCF) signaling. Taken together, our findings demonstrate that PHD3 inhibits gastric cancer by suppressing the beta-catenin/TCF signaling and PHD3 might be an important therapeutic target in gastric cancer.

  8. Potent Inhibition of Acid Ceramidase by Novel B-13 Analogues

    Directory of Open Access Journals (Sweden)

    Denny Proksch

    2011-01-01

    Full Text Available The lipid-signalling molecule ceramide is known to induce apoptosis in a variety of cell types. Inhibition of the lysosomal acid ceramidase can increase cellular ceramide levels and thus induce apoptosis. Indeed, inhibitors of acid ceramidase have been reported to induce cell death and to display potentiating effects to classical radio- or chemo therapy in a number of in vitro and in vivo cancer models. The most potent in vitro inhibitor of acid ceramidase, B-13, recently revealed to be virtually inactive towards lysosomal acid ceramidase in living cells. In contrast, a number of weakly basic B-13 analogues have been shown to accumulate in the acidic compartments of living cells and to efficiently inhibit lysosomal acid ceramidase. However, introduction of weakly basic groups at the ω-position of the fatty acid moiety of B-13 led to a significant reduction of potency towards acid ceramidase from cellular extracts. Herein, we report a novel B-13-derived scaffold for more effective inhibitors of acid ceramidase. Furthermore, we provide hints for an introduction of basic functional groups at an alternative site of the B-13 scaffold that do not interfere with acid ceramidase inhibition in vitro.

  9. Mini-review: Inhibition of biofouling by marine microorganisms.

    Science.gov (United States)

    Dobretsov, Sergey; Abed, Raeid M M; Teplitski, Max

    2013-01-01

    Any natural or artificial substratum exposed to seawater is quickly fouled by marine microorganisms and later by macrofouling species. Microfouling organisms on the surface of a substratum form heterogenic biofilms, which are composed of multiple species of heterotrophic bacteria, cyanobacteria, diatoms, protozoa and fungi. Biofilms on artificial structures create serious problems for industries worldwide, with effects including an increase in drag force and metal corrosion as well as a reduction in heat transfer efficiency. Additionally, microorganisms produce chemical compounds that may induce or inhibit settlement and growth of other fouling organisms. Since the last review by the first author on inhibition of biofouling by marine microbes in 2006, significant progress has been made in the field. Several antimicrobial, antialgal and antilarval compounds have been isolated from heterotrophic marine bacteria, cyanobacteria and fungi. Some of these compounds have multiple bioactivities. Microorganisms are able to disrupt biofilms by inhibition of bacterial signalling and production of enzymes that degrade bacterial signals and polymers. Epibiotic microorganisms associated with marine algae and invertebrates have a high antifouling (AF) potential, which can be used to solve biofouling problems in industry. However, more information about the production of AF compounds by marine microorganisms in situ and their mechanisms of action needs to be obtained. This review focuses on the AF activity of marine heterotrophic bacteria, cyanobacteria and fungi and covers publications from 2006 up to the end of 2012.

  10. Phytotoxicity of nanoparticles: inhibition of seed germination and root growth.

    Science.gov (United States)

    Lin, Daohui; Xing, Baoshan

    2007-11-01

    Plants need to be included to develop a comprehensive toxicity profile for nanoparticles. Effects of five types of nanoparticles (multi-walled carbon nanotube, aluminum, alumina, zinc, and zinc oxide) on seed germination and root growth of six higher plant species (radish, rape, ryegrass, lettuce, corn, and cucumber) were investigated. Seed germination was not affected except for the inhibition of nanoscale zinc (nano-Zn) on ryegrass and zinc oxide (nano-ZnO) on corn at 2000 mg/L. Inhibition on root growth varied greatly among nanoparticles and plants. Suspensions of 2000 mg/L nano-Zn or nano-ZnO practically terminated root elongation of the tested plant species. Fifty percent inhibitory concentrations (IC50) of nano-Zn and nano-ZnO were estimated to be near 50mg/L for radish, and about 20mg/L for rape and ryegrass. The inhibition occurred during the seed incubation process rather than seed soaking stage. These results are significant in terms of use and disposal of engineered nanoparticles.

  11. Inhibition of fatty acid metabolism reduces human myeloma cells proliferation.

    Directory of Open Access Journals (Sweden)

    José Manuel Tirado-Vélez

    Full Text Available Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40-70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma.

  12. Puerarin Alleviates Neuropathic Pain by Inhibiting Neuroinflammation in Spinal Cord

    Directory of Open Access Journals (Sweden)

    Ming Liu

    2014-01-01

    Full Text Available Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent of Puerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4–100 nM for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

  13. DBR1 siRNA inhibition of HIV-1 replication

    Directory of Open Access Journals (Sweden)

    Naidu Yathi

    2005-10-01

    Full Text Available Abstract Background HIV-1 and all retroviruses are related to retroelements of simpler organisms such as the yeast Ty elements. Recent work has suggested that the yeast retroelement Ty1 replicates via an unexpected RNA lariat intermediate in cDNA synthesis. The putative genomic RNA lariat intermediate is formed by a 2'-5' phosphodiester bond, like that found in pre-mRNA intron lariats and it facilitates the minus-strand template switch during cDNA synthesis. We hypothesized that HIV-1 might also form a genomic RNA lariat and therefore that siRNA-mediated inhibition of expression of the human RNA lariat de-branching enzyme (DBR1 expression would specifically inhibit HIV-1 replication. Results We designed three short interfering RNA (siRNA molecules targeting DBR1, which were capable of reducing DBR1 mRNA expression by 80% and did not significantly affect cell viability. We assessed HIV-1 replication in the presence of DBR1 siRNA and found that DBR1 knockdown led to decreases in viral cDNA and protein production. These effects could be reversed by cotransfection of a DBR1 cDNA indicating that the inhibition of HIV-1 replication was a specific effect of DBR1 underexpression. Conclusion These data suggest that DBR1 function may be needed to debranch a putative HIV-1 genomic RNA lariat prior to completion of reverse transcription.

  14. Optogenetic inhibition of neurons by internal light production

    Directory of Open Access Journals (Sweden)

    Benjamin eLand

    2014-04-01

    Full Text Available Optogenetics is an extremely powerful tool for selective neuronal activation/inhibition and dissection of neural circuits. However, a limitation of in vivo optogenetics is that an animal must be tethered to an optical fiber for delivery of light. Here, we describe a new method for in vivo, optogenetic inhibition of neural activity using an internal, animal-generated light source based on firefly luciferase. Two adeno-associated viruses encoding luciferase were tested and both produced concentration-dependent light after administration of the substrate, luciferin. Mice were co-infected with halorhodopsin- and luciferase-expressing viruses in the striatum, and luciferin administration significantly reduced Fos activity compared to control animals infected with halorhodopsin only. Recordings of neuronal activity in behaving animals confirmed that firing was greatly reduced after luciferin administration. Finally, amphetamine-induced locomotor activity was reduced in halorhodopsin/luciferase mice pre-injected with luciferin compared to controls. This demonstrates that virally encoded luciferase is able to generate sufficient light to activate halorhodopsin and suppress neural activity and change behavior. This approach could be used to generate inhibition in response to activation of specific molecular pathways.

  15. Antioxidant Activity and Acetylcholinesterase Inhibition of Grape Skin Anthocyanin (GSA

    Directory of Open Access Journals (Sweden)

    Mehnaz Pervin

    2014-07-01

    Full Text Available We aimed to investigate the antioxidant and acetylcholinesterase inhibitory activities of the anthocyanin rich extract of grape skin. Grape skin anthocyanin (GSA neutralized free radicals in different test systems, such as 2,-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS and 2,2-diphenyl-1-picrylhydrazyl (DPPH assays, to form complexes with Fe2+ preventing 2,2'-azobis(2-amidinopropane dihydrochloride (AAPH-induced erythrocyte hemolysis and oxidative DNA damage. Moreover, GSA decreased reactive oxygen species (ROS generation in isolated mitochondria thus inhibiting 2',-7'-dichlorofluorescin (DCFH oxidation. In an in vivo study, female BALB/c mice were administered GSA, at 12.5, 25, and 50 mg per kg per day orally for 30 consecutive days. Herein, we demonstrate that GSA administration significantly elevated the level of antioxidant enzymes in mice sera, livers, and brains. Furthermore, GSA inhibited acetylcholinesterase (AChE in the in vitro assay with an IC50 value of 363.61 µg/mL. Therefore, GSA could be an excellent source of antioxidants and its inhibition of cholinesterase is of interest with regard to neurodegenerative disorders such as Alzheimer’s disease.

  16. Dual effect of metformin on growth inhibition and oestradiol production in breast cancer cells.

    Science.gov (United States)

    Rice, S; Pellat, L; Ahmetaga, A; Bano, G; Mason, H D; Whitehead, S A

    2015-04-01

    Evidence has been accumulating for a role for metformin in reducing breast cancer risk in post-menopausal women. It inhibits growth of breast cancer cells via several mechanisms, primarily the AMPK/mTOR signalling pathway. Another possible protective mechanism may be the ability of metformin to inhibit aromatase activity. In the present study, we investigated the effects of metformin on the basal growth of MCF-7 cells, after oestradiol (E2) stimulation and after the inhibition of mTOR by rapamycin. Secondly, we investigated the effects of metformin on the activity of a number of steroidogenic enzymes and the mRNA expression of aromatase and steroid sulphatase (STS). High doses of metformin significantly inhibited both basal and oestrogen-stimulated cell division. Low-dose rapamycin (10-10 M) did not inhibit growth, but the addition of metformin induced a significant reduction in growth. High-dose rapamycin (10-8 M) inhibited growth, and this was further attenuated by the addition of metformin. Exposure to low (10-7 M) and high (10-4 M) doses of metformin for 7-10 days significantly reduced the conversion of androstenedione (ANDRO) and testosterone (TESTO) (both requiring aromatase), but not the conversion of oestrone or oestrone sulphate (ES) via 17β-hydroxysteroid dehydrogenase/sulphatase to E2. This attenuation was via a downregulation in the expression of total aromatase mRNA and promoter II, whilst the expression of sulphatase was unaffected by metformin. In conclusion, plasma levels of metformin have a dual therapeutic action, first by directly inhibiting cell proliferation which can be augmented by rapamycin analogues, and secondly, by inhibiting aromatase activity and reducing the local conversion of androgens to E2.

  17. Bcl6 promotes osteoblastogenesis through Stat1 inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fujie, Atsuhiro; Funayama, Atsushi; Miyauchi, Yoshiteru [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Sato, Yuiko [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Kobayashi, Tami [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Kanagawa, Hiroya; Katsuyama, Eri; Hao, Wu; Tando, Toshimi; Watanabe, Ryuichi [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Morita, Mayu [Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Miyamoto, Kana; Kanaji, Arihiko; Morioka, Hideo; Matsumoto, Morio; Toyama, Yoshiaki [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Miyamoto, Takeshi, E-mail: miyamoto@z5.keio.jp [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan)

    2015-02-13

    Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in significant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-deficient mice in vivo. Altered osteoblastogenesis in Bcl6-deficient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition. - Highlights: • Bcl6 is required for osteoblast differentiation. • Bcl6{sup −/−} mice exhibited altered osteoblastogenesis and reduced bone mass in vivo and in vitro. • We identified Stat1 as a direct target of Bcl6 in osteoblasts. • Bcl6 and Stat1 doubly deficient mice exhibited rescued bone phenotypes compared with Bcl6{sup −/−} mice.

  18. Inhibition of Neuroinflammation in LPS-Activated Microglia by Cryptolepine

    Science.gov (United States)

    Olajide, Olumayokun A.; Bhatia, Harsharan S.; de Oliveira, Antonio C. P.; Wright, Colin W.; Fiebich, Bernd L.

    2013-01-01

    Cryptolepine, an indoloquinoline alkaloid in Cryptolepis sanguinolenta, has anti-inflammatory property. In this study, we aimed to evaluate the effects of cryptolepine on lipopolysaccharide (LPS)- induced neuroinflammation in rat microglia and its potential mechanisms. Microglial activation was induced by stimulation with LPS, and the effects of cryptolepine pretreatment on microglial activation and production of proinflammatory mediators, PGE2/COX-2, microsomal prostaglandin E2 synthase and nitric oxide/iNOS were investigated. We further elucidated the role of Nuclear Factor-kappa B (NF-κB) and the mitogen-activated protein kinases in the antiinflammatory actions of cryptolepine in LPS-stimulated microglia. Our results showed that cryptolepine significantly inhibited LPS-induced production of tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-1beta (IL-1β), nitric oxide, and PGE2. Protein and mRNA levels of COX-2 and iNOS were also attenuated by cryptolepine. Further experiments on intracellular signalling mechanisms show that IκB-independent inhibition of NF-κB nuclear translocation contributes to the anti-neuroinflammatory actions of cryptolepine. Results also show that cryptolepine inhibited LPS-induced p38 and MAPKAPK2 phosphorylation in the microglia. Cell viability experiments revealed that cryptolepine (2.5 and 5 μM) did not produce cytotoxicity in microglia. Taken together, our results suggest that cryptolepine inhibits LPS-induced microglial inflammation by partial targeting of NF-κB signalling and attenuation of p38/MAPKAPK2. PMID:23737832

  19. Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction.

    Science.gov (United States)

    Guazzi, M D; Campodonico, J; Celeste, F; Guazzi, M; Santambrogio, G; Rossi, M; Trabattoni, D; Alimento, M

    1998-01-01

    Blockade of bradykinin breakdown and enhancement of prostaglandin release probably participate in the antihypertensive activity of angiotensin converting enzyme (ACE) inhibitors. Cyclooxygenase blockers may attenuate the efficacy of ACE inhibitors by interfering with prostaglandin synthesis, and patients taking aspirin may not benefit from ACE inhibition. This study was designed to evaluate the incidence of the counteractive phenomenon and to define minimal aspirin dosage that causes an antagonistic effect. These were 26 patients with mild to moderate hypertension (group 1) and 26 patients with severe untreated primary hypertension (group 2). Enalapril (20 mg twice a day) was used as a single drug in group 1 and was added to the combination of long-acting nifedipine (30 mg/day) and atenolol (50 mg/day) in group 2. Aspirin was tested at doses of 100 and 300 mg/day, and an attenuation of more than 20% of the mean blood pressure decrease produced by enalapril was the criteria that defined antagonism. The 100 mg dose was ineffective. However, 300 mg aspirin had an antagonistic effect in 57% of patients in group 1 and 50% of patients in group 2: mean arterial pressure was lowered by 63% and 91% less, respectively. Results were independent of the drug administration order. In "responders," aspirin significantly attenuated the renin rise associated with ACE inhibition. These findings suggest that a number of ACE-inhibited patients are susceptible to 300 mg/day aspirin, regardless of hypertension severity. Antagonism may be mediated through prostaglandin inhibition according to predominance, in an individual patient, of prostaglandin activation (also as a renin secretory stimulus) or angiotensin blockade by enalapril.

  20. Essential oil of Curcuma longa inhibits Streptococcus mutans biofilm formation.

    Science.gov (United States)

    Lee, Kwang-Hee; Kim, Beom-Su; Keum, Ki-Suk; Yu, Hyeon-Hee; Kim, Young-Hoi; Chang, Byoung-Soo; Ra, Ji-Young; Moon, Hae-Dalma; Seo, Bo-Ra; Choi, Na-Young; You, Yong-Ouk

    2011-01-01

    Curcuma longa (C. longa) has been used as a spice in foods and as an antimicrobial in Oriental medicine. In this study, we evaluated the inhibitory effects of an essential oil isolated from C. longa on the cariogenic properties of Streptococcus mutans (S. mutans), which is an important bacterium in dental plaque and dental caries formation. First, the inhibitory effects of C. longa essential oil on the growth and acid production of S. mutans were tested. Next, the effect of C. longa essential oil on adhesion to saliva-coated hydroxyapatite beads (S-HAs) was investigated. C. longa essential oil inhibited the growth and acid production of S. mutans at concentrations from 0.5 to 4 mg/mL. The essential oil also exhibited significant inhibition of S. mutans adherence to S-HAs at concentrations higher than 0.5 mg/mL. S. mutans biofilm formation was determined by scanning electron microscopy (SEM) and safranin staining. The essential oil of C. longa inhibited the formation of S. mutans biofilms at concentrations higher than 0.5 mg/mL. The components of C. longa essential oil were then analyzed by GC and GC-MS, and the major components were α-turmerone (35.59%), germacrone (19.02%), α-zingiberene (8.74%), αr-turmerone (6.31%), trans-β-elemenone (5.65%), curlone (5.45%), and β-sesquiphellandrene (4.73%). These results suggest that C. longa may inhibit the cariogenic properties of S. mutans.

  1. Structural Basis of GLUT1 Inhibition by Cytoplasmic ATP

    Science.gov (United States)

    Blodgett, David M.; De Zutter, Julie K.; Levine, Kara B.; Karim, Pusha; Carruthers, Anthony

    2007-01-01

    Cytoplasmic ATP inhibits human erythrocyte glucose transport protein (GLUT1)–mediated glucose transport in human red blood cells by reducing net glucose transport but not exchange glucose transport (Cloherty, E.K., D.L. Diamond, K.S. Heard, and A. Carruthers. 1996. Biochemistry. 35:13231–13239). We investigated the mechanism of ATP regulation of GLUT1 by identifying GLUT1 domains that undergo significant conformational change upon GLUT1–ATP interaction. ATP (but not GTP) protects GLUT1 against tryptic digestion. Immunoblot analysis indicates that ATP protection extends across multiple GLUT1 domains. Peptide-directed antibody binding to full-length GLUT1 is reduced by ATP at two specific locations: exofacial loop 7–8 and the cytoplasmic C terminus. C-terminal antibody binding to wild-type GLUT1 expressed in HEK cells is inhibited by ATP but binding of the same antibody to a GLUT1–GLUT4 chimera in which loop 6–7 of GLUT1 is substituted with loop 6–7 of GLUT4 is unaffected. ATP reduces GLUT1 lysine covalent modification by sulfo-NHS-LC-biotin by 40%. AMP is without effect on lysine accessibility but antagonizes ATP inhibition of lysine modification. Tandem electrospray ionization mass spectrometry analysis indicates that ATP reduces covalent modification of lysine residues 245, 255, 256, and 477, whereas labeling at lysine residues 225, 229, and 230 is unchanged. Exogenous, intracellular GLUT1 C-terminal peptide mimics ATP modulation of transport whereas C-terminal peptide-directed IgGs inhibit ATP modulation of glucose transport. These findings suggest that transport regulation involves ATP-dependent conformational changes in (or interactions between) the GLUT1 C terminus and the C-terminal half of GLUT1 cytoplasmic loop 6–7. PMID:17635959

  2. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  3. Inhibition of Neuroinflammation in LPS-Activated Microglia by Cryptolepine

    Directory of Open Access Journals (Sweden)

    Olumayokun A. Olajide

    2013-01-01

    Full Text Available Cryptolepine, an indoloquinoline alkaloid in Cryptolepis sanguinolenta, has anti-inflammatory property. In this study, we aimed to evaluate the effects of cryptolepine on lipopolysaccharide (LPS- induced neuroinflammation in rat microglia and its potential mechanisms. Microglial activation was induced by stimulation with LPS, and the effects of cryptolepine pretreatment on microglial activation and production of proinflammatory mediators, PGE2/COX-2, microsomal prostaglandin E2 synthase and nitric oxide/iNOS were investigated. We further elucidated the role of Nuclear Factor-kappa B (NF-κB and the mitogen-activated protein kinases in the antiinflammatory actions of cryptolepine in LPS-stimulated microglia. Our results showed that cryptolepine significantly inhibited LPS-induced production of tumour necrosis factor-alpha (TNFα, interleukin-6 (IL-6, interleukin-1beta (IL-1β, nitric oxide, and PGE2. Protein and mRNA levels of COX-2 and iNOS were also attenuated by cryptolepine. Further experiments on intracellular signalling mechanisms show that IκB-independent inhibition of NF-κB nuclear translocation contributes to the anti-neuroinflammatory actions of cryptolepine. Results also show that cryptolepine inhibited LPS-induced p38 and MAPKAPK2 phosphorylation in the microglia. Cell viability experiments revealed that cryptolepine (2.5 and 5 μM did not produce cytotoxicity in microglia. Taken together, our results suggest that cryptolepine inhibits LPS-induced microglial inflammation by partial targeting of NF-κB signalling and attenuation of p38/MAPKAPK2.

  4. Inhibition of polyphenol oxidases activity by various dipeptides.

    Science.gov (United States)

    Girelli, Anna M; Mattei, Enrico; Messina, Antonella; Tarola, Anna M

    2004-05-19

    In an effort to develop natural and nontoxic inhibitors on the activity of mushroom polyphenol oxidase (PPO) the effect of various glycyl-dipeptides (GlyAsp, GlyGly, GlyHis, GlyLeu, GlyLys, GlyPhe, GlyPro, GlyTyr) was investigated. The inhibition study with dihydroxyphenylalanine (DOPA) as substrate is based on separation of the enzymatic reaction components by reversed phase HPLC and the UV detection of the dopachrome formed. The results have evidenced that several of tested dipeptides inhibited PPO activity in the range of 20-40% while GlyPro and GlyLeu had no effect. The study has also permitted the characterization of the following kinetic pattern: a linear-mixed-type mechanism for GlyAsp, GlyGly, GlyLys, and GlyPhe and a hyperbolic-mixed-type for GlyTyr. It was not possible to identify the inhibition mechanism for GlyHis, although it affects PPO activity. In addition the effects of GlyAsp, GlyLys and GlyHis were evaluated for lessening the browning of fresh Golden Delicious apple and Irish White Skinned potato. The effectiveness of such inhibitors was determined by the difference between the colors observed in the dipeptide-treated sample and the controls using the color space CIE-Lab system. The % browning inhibition on potato (20-50%) was greater than of apple (20-30%) by the all tested dipeptides. Only GlyLys presented the significant value of 50%.

  5. Inhibition effect of engineered silver nanoparticles to bloom forming cyanobacteria

    Science.gov (United States)

    Thuy Duong, Thi; Son Le, Thanh; Thu Huong Tran, Thi; Kien Nguyen, Trung; Ho, Cuong Tu; Hien Dao, Trong; Phuong Quynh Le, Thi; Chau Nguyen, Hoai; Dang, Dinh Kim; Thu Huong Le, Thi; Thu Ha, Phuong

    2016-09-01

    Silver nanoparticle (AgNP) has a wide range antibacterial effect and is extensively used in different aspects of medicine, food storage, household products, disinfectants, biomonitoring and environmental remediation etc. In the present study, we examined the growth inhibition effect of engineered silver nanoparticles against bloom forming cyanobacterial M. aeruginosa strain. AgNPs were synthesized by a chemical reduction method at room temperature and UV-Vis spectroscopy, scanning electron microscopy (SEM), transmission electron microscope (TEM) showed that they presented a maximum absorption at 410 nm and size range between 10 and 18 nm. M. aeruginosa cells exposed during 10 d to AgNPs to a range of concentrations from 0 to 1 mg l-1. The changes in cell density and morphology were used to measure the responses of the M. aeruginosa to AgNPs. The control and treatment units had a significant difference in terms of cell density and growth inhibition (p < 0.05). Increasing the concentration of AgNPs, a reduction of the cell growths in all treatment was observed. The inhibition efficiency was reached 98.7% at higher concentration of AgNPs nanoparticles. The term half maximal effective concentration (EC50) based on the cell growth measured by absorbance at 680 nm (A680) was 0.0075 mg l-1. The inhibition efficiency was 98.7% at high concentration of AgNPs (1 mg l-1). Image of SEM and TEM reflected a shrunk and damaged cell wall indicating toxicity of silver nanoparticles toward M. aeruginosa.

  6. Ketamine inhibits human sperm function by Ca(2+)-related mechanism.

    Science.gov (United States)

    He, Yuanqiao; Zou, Qianxing; Li, Bingda; Chen, Houyang; Du, Xiaohong; Weng, Shiqi; Luo, Tao; Zeng, Xuhui

    2016-09-09

    Ketamine, a dissociative anesthetic, which was widely used in human and animal medicine, has become a popular recreational drug, as it can induce hallucinatory effects. Ketamine abuse can cause serious damage to many aspects of the organism, mainly reflected in the nervous system and urinary system. It has also been reported that ketamine can impair the male genital system. However, the detailed effect of ketamine on human spermatozoa remains unclear. Thus, we investigated the in vitro effects of ketamine on human sperm functions, to elucidate the underlying mechanism. Human sperm were treated in vitro with different concentrations of ketamine (0, 0.125, 0.25, 0.5, 1 g/L). The results showed that 0.25-1 g/L ketamine inhibited sperm total motility, progressive motility and linear velocity, in a dose-dependent manner. In addition, the sperm's ability to penetrate viscous medium and the progesterone-induced acrosome reaction were significantly inhibited by ketamine. Ketamine did not affect sperm viability, capacitation and spontaneous acrosome reaction. The intracellular calcium concentration ([Ca(2+)]i), which is a central factor in the regulation of human sperm function, was decreased by ketamine (0.125-1 g/L) in a dose-dependent manner. Furthermore, the currents of the sperm-specific Ca(2+) channel, CatSper, which modulates Ca(2+) influx in sperm, were inhibited by ketamine (0.125-1 g/L) in a dose-dependent manner. Our findings suggest that ketamine induces its toxic effects on human sperm functions by reducing sperm [Ca(2+)]i through inhibition of CatSper channel. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Inhibition of mouse peritoneal macrophage DNA synthesis by infection with the Arenavirus Pichinde. Interim report

    Energy Technology Data Exchange (ETDEWEB)

    Friedlander, A.M.; Jahrling, P.B.; Merrill, P.; Tobery, S.

    1983-01-19

    Macrophage DNA synthesis and proliferation occur during the development of cell-mediated immunity and in the early non-specific reaction to infection. Arenaviruses have a predilection for infection of cells of the reticuloendothelial system and in this study we have examined the effect of the arenavirus Pichinde on macrophage DNA synthesis. We have found that infection of mouse peritoneal macrophages with Pichinde caused a profound dose dependent inhibition of the DNA synthesis induced by macrophage growth factor/colony stimulating factor. At a multiplicity of inoculum of five there is a 75-95% inhibition of DNA synthesis. Viable virus is necessary for inhibition since Pichinde inactivated by heat or cobalt irradiation had no effect. Similarly, virus pre-treated with an antiserum to Pichinde was without inhibitory effect. Inhibition was demonstrated by measuring DNA synthesis spectrofluorometrically as well as by 3H-thymidine incorporation. The inhibition of DNA synthesis was not associated with any cytopathology. There was no evidence that the inhibition was due to soluble factors, such as prostaglandins or interferon, released by infected cells. These studies demonstrate, for the first time in vitro, a significant alteration in macrophage function caused by infection with an arenavirus. It is possible that inhibition of macrophage proliferation represents a mechanism by which some microorganisms interfere with host resistance.

  8. Inhibition of human gastric carcinoma cell growth by atofluding derivative N3-o-toluyl-fluorouracil

    Institute of Scientific and Technical Information of China (English)

    Jian Liu; Wei Tang; Xian-Jun Qu; Wen-Fang Xu; Shu-Xiang Cui; Yong Zhou; Yun-Xia Yuan; Ming-Hui Chen; Ruo-Han Wang; Ruo-Yan Gai; Masatoshi Makuuchi

    2006-01-01

    AIM:To evaluate the growth inhibition efficacy of atofluding derivative N3-o-toluyl-fluorouracil (TFU)on human gastric carcinoma cell lines SGC-7901 and MKN-45.METHODS:Cell growth inhibition by TFU was measured by MTT and clonogenic assays without or with liver microsomal enzymes. Xenografts of cancer cells in nude mice were employed to study the anti-proliferative effects of TFU in vivo,RESULTS:TFU inhibited the growth of SGC-7901 and MKN-45 cells. However, the inhibitory effects of TFU on cell growth were not significant. The inhibition rates were enhanced in the presence of liver microsomal enzymes, ranging 4.73%-48.57% in SGC-7901 cells and 9.0%-62.02% in MKN-45 cells. In vivo, TFU delayed the growth of SGC-7901 and MKN-45 cells in nude mice. The inhibition rates were 40.49%, 63.24%, and 75.98% in SGC-7901 cells and 40.76%, 61.41%, and 82.07% in MKN-45 cells when the oral doses were 25, 50, and 100 mg/kg, respectively. TFU treatment was generally well tolerated by mice with less than 20% reduction in body weight.CONCLUSION:TFU inhibits the growth of human gastric carcinoma cells. The inhibition rates are increased in the presence of liver microsomal enzymes. The efficacy of TFU may be associated with the sustaining release of 5-fluorouracil (5-FU) mediated by the enzymes.

  9. Study on the inhibition of methane production from anaerobic digestion of biodegradable solid waste.

    Science.gov (United States)

    Tiantao Zhao; Lijie Zhang; Youcai Zhao

    2010-04-01

    The inhibition effects and mechanisms of chlorinated methane, anthraquinone and acetylene on methanogenesis in the anaerobic digestion process of biodegradable solid wastes were investigated. It was found that both chloroform and acetylene could effectively inhibit methanogens. Acetylene inhibited the activity of methanogens, while chloroform inhibited metabolic process of methanogenesis. A central composite design (CCD) and response surface regression analysis (RSREG) were employed to determine the optimum conditions and interaction effects of chloroform and acetylene in terms of methane and hydrogen production. Acetylene promoted the inhibition efficiency (F = 31.14; P 0.05). In addition, a maximum hydrogen production of 1.6 ml was estimated under the optimum conditions of chloroform concentration of 6.69 mg kg(-1) and acetylene concentration of 3.08 x 10(-3) (v/v). Chloroform had a significant effect on enhancing the production of propionic acid and a minimum molar ratio of acetic acid to propionic acid of 0.707 was reached with the chloroform concentration of 9.24 mg kg(-1) and acetylene concentration of 4.0 x 10(-3) (v/v). Hence, methanogens can be inhibited while the stabilization process of solid wastes can still work well. Moreover, co-inhibition technology practice at landfills was feasible and the environmental damage was negligible, according to the analysis and experimental results.

  10. Co-inhibition of methanogens for methane mitigation in biodegradable wastes

    Institute of Scientific and Technical Information of China (English)

    ZHAO Tiantao; ZHANG Lijie; CHEN Haoquan; ZHAO Youcai

    2009-01-01

    The inhibition effects and mechanisms of chlorinated methane and acetylene on methanogenesis in the anaerobic digestion process of the biodegradable wastes were investigated.It was found that both chloroform and acetylene could effectively inhibit methanogens while the biodegradability of the wastes was not affected.Acetylene inhibited the activity of methanogens,while chloroform inhibited metabolic process of methanogenesis.A central composite design (CCD) and response surface regression analysis (RSREG) were employed to determine the optimum conditions and interaction effects of chloroform and acetylene in terms of inhibition efficiency,production of volatile fatty acids and molar ratio of propionic acid to acetic acid.Chloroform had significant effect on enhancing the production of VFA (F = 121.3;p0.05).In addition,a maximum molar ratio of propionic acid to acetic acid of 1.208 was estimated under the optimum conditions of chloroform concentration of 9.05 mg/kg and acetylene concentration of 3.6×10-3 (V/V).Hence,methanogens in the wastes can be inhibited while the stabilization process of the biodegradable wastes can still work well,as propionic acid generated during the inhibition process could hardly be utilized by methanogens.

  11. Probing the nature of AFEX-pretreated corn stover derived decomposition products that inhibit cellulase activity.

    Science.gov (United States)

    Humpula, James F; Uppugundla, Nirmal; Vismeh, Ramin; Sousa, Leonardo; Chundawat, Shishir P S; Jones, A Daniel; Balan, Venkatesh; Dale, Bruce E; Cheh, Albert M

    2014-01-01

    Sequential fractionation of AFEX-pretreated corn stover extracts was carried out using ultra-centrifugation, ultra-filtration, and solid phase extraction to isolate various classes of pretreatment products to evaluate their inhibitory effect on cellulases. Ultra-centrifugation removed dark brown precipitates that caused no appreciable enzyme inhibition. Ultra-filtration of ultra-centrifuged AFEX-pretreated corn stover extractives using a 10 kDa molecular weight cutoff (MWCO) membrane removed additional high molecular weight components that accounted for 24-28% of the total observed enzyme inhibition while a 3 kDa MWCO membrane removed 60-65%, suggesting significant inhibition is caused by oligomeric materials. Solid phase extraction (SPE) of AFEX-pretreated corn stover extractives after ultra-centrifugation removed 34-43% of the inhibition; ultra-filtration with a 5 kDa membrane removed 44-56% of the inhibition and when this ultra-filtrate was subjected to SPE a total of 69-70% of the inhibition were removed. Mass spectrometry found several phenolic compounds among the hydrophobic inhibition removed by SPE adsorption. Copyright © 2013. Published by Elsevier Ltd.

  12. The Hydrogen Sulfide Releasing Molecule Acetyl Deacylasadisulfide Inhibits Metastatic Melanoma

    Science.gov (United States)

    De Cicco, Paola; Panza, Elisabetta; Armogida, Chiara; Ercolano, Giuseppe; Taglialatela-Scafati, Orazio; Shokoohinia, Yalda; Camerlingo, Rosa; Pirozzi, Giuseppe; Calderone, Vincenzo; Cirino, Giuseppe; Ianaro, Angela

    2017-01-01

    Melanoma is the most common form of skin cancer. Given its high mortality, the interest in the search of preventive measures, such as dietary factors, is growing significantly. In this study we tested, in vitro and in vivo, the potential anti-cancer effect of the acetyl deacylasadisulfide (ADA), a vinyl disulfide compound, isolated and purified from asafoetida a foul-smelling oleo gum-resin of dietary and medicinal relevance. ADA markedly suppressed proliferation of human melanoma cell lines by inducing apoptosis. Moreover, treatment of melanoma cells with ADA reduced nuclear translocation and activation of NF-κB, decreased the expression of the anti-apoptotic proteins c-FLIP, XIAP, and Bcl-2 and inhibited the phosphorylation and activation of both AKT and ERK proteins, two of the most frequently deregulated pathways in melanoma. Finally, the results obtained in vitro were substantiated by the findings that ADA significantly and dose-dependently reduced lung metastatic foci formation in C57BL/6 mice. In conclusion, our findings suggest that ADA significantly inhibits melanoma progression in vivo and could represent an important lead compound for the development of new anti-metastatic agents. PMID:28289382

  13. Neomycin inhibits angiogenin-induced angiogenesis.

    Science.gov (United States)

    Hu, G F

    1998-08-18

    A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, and staurosporine, inhibitors of tyrosine kinase, phosphotyrosine phosphatase, and protein kinase C, respectively, do not inhibit nuclear translocation of angiogenin. Neomycin inhibits angiogenin-induced proliferation of human endothelial cells in a dose-dependent manner. At 50 microM, neomycin abolishes angiogenin-induced proliferation but does not affect the basal level of proliferation and cell viability. Other aminoglycoside antibiotics, including gentamicin, streptomycin, kanamycin, amikacin, and paromomycin, have no effect on angiogenin-induced cell proliferation. Most importantly, neomycin completely inhibits angiogenin-induced angiogenesis in the chicken chorioallantoic membrane at a dose as low as 20 ng per egg. These results suggest that neomycin and its analogs are a class of agents that may be developed for anti-angiogenin therapy.

  14. 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.

  15. Matrix metalloproteinase inhibition in atherosclerosis and stroke.

    Science.gov (United States)

    Roycik, M D; Myers, J S; Newcomer, R G; Sang, Q-X A

    2013-09-01

    Matrix metalloproteinases (MMPs) are a family of tightly regulated, zinc-dependent proteases that degrade extracellular matrix (ECM), cell surface, and intracellular proteins. Vascular remodeling, whether as a function of normal physiology or as a consequence of a myriad of pathological processes, requires degradation of the ECM. Thus, the expression and activity of many MMPs are up-regulated in numerous conditions affecting the vasculature and often exacerbate vascular dysfunction. A growing body of evidence supports the rationale of using MMP inhibitors for the treatment of cardiovascular diseases, stroke, and chronic vascular dementia. This manuscript will examine promising targets for MMP inhibition in atherosclerosis and stroke, reviewing findings in preclinical animal models and human patient studies. Strategies for MMP inhibition have progressed beyond chelating the catalytic zinc to functional blocking antibodies and peptides that target either the active site or exosites of the enzyme. While the inhibition of MMP activity presents a rational therapeutic avenue, the multiplicity of roles for MMPs and the non-selective nature of MMP inhibitors that cause unintended side-effects hinder full realization of MMP inhibition as therapy for vascular disease. For optimal therapeutic effects to be realized, specific targets for MMP inhibition in these pathologies must first be identified and then attacked by potent and selective agents during the most appropriate timepoint.

  16. Genistein inhibits differentiation of primary human adipocytes.

    Science.gov (United States)

    Park, Hea Jin; Della-Fera, Mary Anne; Hausman, Dorothy B; Rayalam, Srujana; Ambati, Suresh; Baile, Clifton A

    2009-02-01

    Genistein, a major soy isoflavone, has been reported to exhibit antiadipogenic and proapoptotic potential in vivo and in vitro. It is also a phytoestrogen which has high affinity to estrogen receptor beta. In this study, we determined the effect of genistein on adipogenesis and estrogen receptor (ER) alpha and beta expression during differentiation in primary human preadipocytes. Genistein inhibited lipid accumulation in a dose-dependent manner at concentrations of 6.25 microM and higher, with 50 microM genistein inhibiting lipid accumulation almost completely. Low concentrations of genistein (3.25 microM) increased cell viability and higher concentrations (25 and 50 microM) decreased it by 16.48+/-1.35% (P<.0001) and 50.68+/-1.34% (P<.0001). Oil Red O staining was used to confirm the effects on lipid accumulation. The inhibition of lipid accumulation was associated with inhibition of glycerol-3-phosphate dehydrogenase activity and down-regulation of expression of adipocyte-specific genes, including peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, glycerol-3-phosphate dehydrogenase, adipocyte fatty acid binding protein, fatty acid synthase, sterol regulatory element-binding protein 1, perilipin, leptin, lipoprotein lipase and hormone-sensitive lipase. These effects of genistein during the differentiation period were associated with down-regulation of ERalpha and ERbeta expression. This study adds to the elucidation of the molecular pathways involved in the inhibition of adipogenesis by phytoestrogens.

  17. Inhibition of eating behavior: negative cognitive effects of dieting.

    Science.gov (United States)

    Hart, K E; Chiovari, P

    1998-06-01

    This study tested the hypothesis that dieters would score higher than nondieters in terms of food rumination. Two hundred and thirty one college undergraduates completed the Eating Obsessive-Compulsiveness Scale (EOCS) and responded to a questionnaire that inquired about dieting status. Subjects also completed measures that tapped neuroticism and social desirability. Results showed that current dieters were significantly more obsessed with thoughts of eating and food than were nondieters. Neither dieting status nor EOCS scale scores were related to neuroticism or social desirability. These results are consistent with previous theory and research suggesting that inhibition of appetitive behaviors can have negative cognitive effects. Moreover, they indicate a potential target for therapeutic intervention.

  18. Influence of iron on sulfide inhibition in dark biohydrogen fermentation.

    Science.gov (United States)

    Dhar, Bipro Ranjan; Elbeshbishy, Elsayed; Nakhla, George

    2012-12-01

    Sulfide impact on biohydrogen production using dark fermentation of glucose at 37 °C was investigated. Dissolved sulfide (S(2-)) at a low concentration (25mg/L) increased biohydrogen production by 54% relative to the control (without iron addition). Whereas on initial dissolved S(2-) concentration of 500 mg/L significantly inhibited the biohydrogen production with total cumulative biohydrogen decreasing by 90% compared to the control (without iron addition). At sulfide concentrations of 500 mg S(2-)/L, addition of Fe(2+) at 3-4 times the theoretical requirement to precipitate 100% of the dissolved S(2-) entirely eliminated the inhibitory effect of sulfide.

  19. Zerumbone inhibits growth of hormone refractory prostate cancer cells by inhibiting JAK2/STAT3 pathway and increases paclitaxel sensitivity.