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Sample records for indirect mechanism involving

  1. Wavelength dependence of ultraviolet-induced DNA damage distribution: involvement of direct or indirect mechanisms and possible artefacts.

    PubMed

    Kuluncsics, Z; Perdiz, D; Brulay, E; Muel, B; Sage, E

    1999-03-01

    DNA damage profiles have been established in plasmid DNA using purified DNA repair enzymes and a plasmid relaxation assay, following exposure to UVC, UVB, UVA or simulated sunlight (SSL). Cyclobutane pyrimidine dimers (CPDs) are revealed as T4 endonuclease V-sensitive sites, oxidation products at purine and pyrimidine as Fpg- and Nth-sensitive sites, and abasic sites are detected by Nfo protein from Escherichia coli. CPDs are readily detected after UVA exposure, though produced 10(3) and 10(5) times less efficiently than by UVB or UVC, respectively. We demonstrate that CPDs are induced by UVA radiation and not by contaminating UVB wavelengths. Furthermore, they are produced at doses compatible with human exposure and are likely to contribute to the mutagenic specificity of UVA [E. Sage et al., Proc. Natl. Acad. Sci. USA 93 (1996) 176-180]. Oxidative damage is induced with a linear dose dependence, for each region of the solar spectrum, with the exception of oxidized pyrimidine and abasic sites, which are not detectable after UVB irradiation. The distribution of the different classes of photolesions varies markedly, depending on wavelengths. However, the unexpectedly high yield of oxidative lesions, as compared to CPDs, by UVA and SSL led us to investigate their production mechanism. An artificial formation of hydroxyl radicals is observed, which depends on the material of the sample holder used for UVA irradiation and is specific for long UV wavelengths. Our study sheds light on a possible artefact in the production of oxidative damage by UVA radiation. Meanwhile, after eliminating some potential sources of the artefact ratios of CPDs to oxidized purine of three and five upon irradiation with UVA and SSL, respectively, are still observed, whereas these ratios are about 140 and 200 after UVC and UVB irradiation.

  2. Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein.

    PubMed

    Palermo, Christine M; Westlake, Claire A; Gasiewicz, Thomas A

    2005-04-05

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known to mediate the toxic effects of numerous environmental contaminants, including the polycyclic aromatic hydrocarbons (PAHs). Historically, binding of PAHs to the AhR and the events leading to the generation of DNA adducts have been associated with chemical carcinogenesis. Previous investigations have implicated green tea (GT) as affording protection against PAH-induced cancers in animal models. Investigations in our laboratory have demonstrated that the GT polyphenol epigallocatechin gallate (EGCG) is capable of antagonizing AhR-mediated gene transcription, implicating inhibition of AhR signaling as a potential chemopreventive mechanism. This line of investigation was directed at elucidating the molecular mechanism of this antagonism. Competitive binding assays strongly suggest that EGCG does not bind to the AhR ligand binding site, indicating this compound functions through a mechanism unlike that of typical AhR antagonists. Affinity chromatography experiments implicate an indirect mechanism of action involving direct binding of EGCG to the AhR chaperone protein, hsp90. This induces an AhR conformation capable of nuclear localization but incapable of binding DNA. These altered signaling events correlate with the formation of a complex with sedimentation characteristics different from those of the latent or ligand-activated AhR. These data implicate a model in which EGCG inhibits release of hsp90 from the AhR, stabilizing the complex in an intermediary state associated with XAP2. This is the first time EGCG has been demonstrated to directly bind hsp90 and the first indication that GT may exert its chemopreventive effects through an interaction with the common chaperone hsp90.

  3. Two distinct neural mechanisms underlying indirect reciprocity.

    PubMed

    Watanabe, Takamitsu; Takezawa, Masanori; Nakawake, Yo; Kunimatsu, Akira; Yamasue, Hidenori; Nakamura, Mitsuhiro; Miyashita, Yasushi; Masuda, Naoki

    2014-03-18

    Cooperation is a hallmark of human society. Humans often cooperate with strangers even if they will not meet each other again. This so-called indirect reciprocity enables large-scale cooperation among nonkin and can occur based on a reputation mechanism or as a succession of pay-it-forward behavior. Here, we provide the functional and anatomical neural evidence for two distinct mechanisms governing the two types of indirect reciprocity. Cooperation occurring as reputation-based reciprocity specifically recruited the precuneus, a region associated with self-centered cognition. During such cooperative behavior, the precuneus was functionally connected with the caudate, a region linking rewards to behavior. Furthermore, the precuneus of a cooperative subject had a strong resting-state functional connectivity (rsFC) with the caudate and a large gray matter volume. In contrast, pay-it-forward reciprocity recruited the anterior insula (AI), a brain region associated with affective empathy. The AI was functionally connected with the caudate during cooperation occurring as pay-it-forward reciprocity, and its gray matter volume and rsFC with the caudate predicted the tendency of such cooperation. The revealed difference is consistent with the existing results of evolutionary game theory: although reputation-based indirect reciprocity robustly evolves as a self-interested behavior in theory, pay-it-forward indirect reciprocity does not on its own. The present study provides neural mechanisms underlying indirect reciprocity and suggests that pay-it-forward reciprocity may not occur as myopic profit maximization but elicit emotional rewards.

  4. Two distinct neural mechanisms underlying indirect reciprocity

    PubMed Central

    Watanabe, Takamitsu; Takezawa, Masanori; Nakawake, Yo; Kunimatsu, Akira; Yamasue, Hidenori; Nakamura, Mitsuhiro; Miyashita, Yasushi; Masuda, Naoki

    2014-01-01

    Cooperation is a hallmark of human society. Humans often cooperate with strangers even if they will not meet each other again. This so-called indirect reciprocity enables large-scale cooperation among nonkin and can occur based on a reputation mechanism or as a succession of pay-it-forward behavior. Here, we provide the functional and anatomical neural evidence for two distinct mechanisms governing the two types of indirect reciprocity. Cooperation occurring as reputation-based reciprocity specifically recruited the precuneus, a region associated with self-centered cognition. During such cooperative behavior, the precuneus was functionally connected with the caudate, a region linking rewards to behavior. Furthermore, the precuneus of a cooperative subject had a strong resting-state functional connectivity (rsFC) with the caudate and a large gray matter volume. In contrast, pay-it-forward reciprocity recruited the anterior insula (AI), a brain region associated with affective empathy. The AI was functionally connected with the caudate during cooperation occurring as pay-it-forward reciprocity, and its gray matter volume and rsFC with the caudate predicted the tendency of such cooperation. The revealed difference is consistent with the existing results of evolutionary game theory: although reputation-based indirect reciprocity robustly evolves as a self-interested behavior in theory, pay-it-forward indirect reciprocity does not on its own. The present study provides neural mechanisms underlying indirect reciprocity and suggests that pay-it-forward reciprocity may not occur as myopic profit maximization but elicit emotional rewards. PMID:24591599

  5. Indirect Acquisition of Information in Quantum Mechanics

    NASA Astrophysics Data System (ADS)

    Ballesteros, M.; Fraas, M.; Fröhlich, J.; Schubnel, B.

    2016-02-01

    Long sequences of successive direct (projective) measurements or observations of just a few "uninteresting" physical quantities pertaining to a quantum system, such as clicks of some detectors, may reveal indirect, but precise and unambiguous information on the values of some very "interesting" observables of the system. In this paper, the mathematics underlying this claim is developed; i.e., we attempt to contribute to a mathematical theory of indirect and, in particular, non-demolition observations and measurements in quantum mechanics. Our attempt leads us to make some novel uses of classical notions and results of probability theory, such as the "algebra of functions measurable at infinity", the Central Limit Theorem, results concerning relative entropy and its role in the theory of large deviations, etc.

  6. Mechanisms of Xenobiotic Receptor Activation: Direct vs. Indirect

    PubMed Central

    Mackowiak, Bryan; Wang, Hongbing

    2016-01-01

    The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of genes encoding drug-metabolizing enzymes and transporters, as well as those involving energy homeostasis, cell proliferation, and/or immune responses. Unlike prototypical steroid hormone receptors, XRs are activated through both direct ligand-binding and ligand-independent (indirect) mechanisms by a plethora of structurally unrelated chemicals. This review covers research literature that discusses direct vs. indirect activation of XRs. A particular focus is centered on the signaling control of the constitutive androstane receptor (CAR), the pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AhR). We expect that this review will shed light on both the common and distinct mechanisms associated with activation of these three XRs. PMID:26877237

  7. Mechanical analysis of Drosophila indirect flight and jump muscles

    PubMed Central

    Swank, Douglas M.

    2011-01-01

    The genetic advantages of Drosophila make it a very appealing choice for investigating muscle development, muscle physiology and muscle protein structure and function. To take full advantage of this model organism, it has been vital to develop isolated Drosophila muscle preparations that can be mechanically evaluated. We describe techniques to isolate, prepare and mechanically analyze skinned muscle fibers from two Drosophila muscle types, the indirect flight muscle and the jump muscle. The function of the indirect flight muscle is similar to vertebrate cardiac muscle, to generate power in an oscillatory manner. The indirect flight muscle is ideal for evaluating the influence of protein mutations on muscle and cross-bridge stiffness, oscillatory power, and deriving cross-bridge rate constants. Jump muscle physiology and structure are more similar to skeletal vertebrate muscle than indirect flight muscle, and it is ideal for measuring maximum shortening velocity, force-velocity characteristics and steady-state power generation. PMID:22079350

  8. [Mechanisms of imiquimod indirect antiviral activity].

    PubMed

    Hober, D; Ajram, L; Chehadeh, W; Lazrek, M; Goffard, A; Dewilde, A; Wattré, P

    2005-01-01

    The potential role of an immune response in HPV-related anogenital disorders had already been anticipated by clinicians. Indeed the lesions efflorescence and the relapsing HPV infection in HIV positive patients as well as the lack of recurrence in patients with spontaneous cure, provided relevant clues for a likely immune mechanism. At present time, the role of the immune system in the development of HPV-related anogenital disorders is well established : HPV induce a humoral and cell mediated immune response. This response is mainly exerted towards infected cells; it is also exerted at the systemic level, through antibodies synthesis, but this pathway remains a secondary one. Due to the limits of the present therapies (either purely destructive and characterized by the rate of recurrences, or antiviral, but difficult to use), it was necessary to find a new treatment type which enhances the local immune response, results in the disappearance of lesions and allows for a decrease in the risk of recurrences. The original mechanism of action of the first cell-mediated immune response modifier: imiquimod, for local use (Aldara 5 % cream) is an answer to this need. The first positive results observed in vitro and in animals were confirmed in patients with HPV anogenital warts in a double blind placebo-controlled study: imiquimod inhibits HPV replication and results in the condyloma regression. Its action is based on the combined activation of the natural local immunity, by stimulating interferon alpha; and of the acquired immunity, by stimulating a T-cell mediated immune response. Thus imiquimod appears to be an original antiviral compound, because it does not act directly on the virus itself.

  9. The Potential Neural Mechanisms of Acute Indirect Vibration

    PubMed Central

    2011-01-01

    There is strong evidence to suggest that acute indirect vibration acts on muscle to enhance force, power, flexibility, balance and proprioception suggesting neural enhancement. Nevertheless, the neural mechanism(s) of vibration and its potentiating effect have received little attention. One proposal suggests that spinal reflexes enhance muscle contraction through a reflex activity known as tonic vibration stretch reflex (TVR), which increases muscle activation. However, TVR is based on direct, brief, and high frequency vibration (>100 Hz) which differs to indirect vibration, which is applied to the whole body or body parts at lower vibration frequency (5-45 Hz). Likewise, muscle tuning and neuromuscular aspects are other candidate mechanisms used to explain the vibration phenomenon. But there is much debate in terms of identifying which neural mechanism(s) are responsible for acute vibration; due to a number of studies using various vibration testing protocols. These protocols include: different methods of application, vibration variables, training duration, exercise types and a range of population groups. Therefore, the neural mechanism of acute vibration remain equivocal, but spinal reflexes, muscle tuning and neuromuscular aspects are all viable factors that may contribute in different ways to increasing muscular performance. Additional research is encouraged to determine which neural mechanism(s) and their contributions are responsible for acute vibration. Testing variables and vibration applications need to be standardised before reaching a consensus on which neural mechanism(s) occur during and post-vibration. Key points There is strong evidence to suggest that acute indirect vibration acts on muscle to enhance force, power, flexibility, balance and proprioception, but little attention has been given to the neural mechanism(s) of acute indirect vibration. Current findings suggest that acute vibration exposure may cause a neural response, but there is little

  10. Indirect Abuse Involving Children During the Separation Process.

    PubMed

    Hayes, Brittany E

    2015-07-27

    Separation is believed to be an antidote to risk abusers pose to their partners and children and underlines many interventions in family, juvenile, and criminal court proceedings. Countering this belief is the claim that many abusers respond to the felt loss of power and control occasioned by separation by changing or escalating abusive tactics. This study complements research on post-separation by asking whether separation is associated with an increase in threats of indirect abuse, which relies on third parties to manipulate the victim. Children, and threats made against them, can be used as a proxy to control or intimidate the victim. Using data from the Chicago Women Health Risk Study (N = 339), the current study examined whether mothers who were separated were at greater risk of abuse through threats against the children when compared with mothers who were still in a relationship with their abuser. Results indicated that separated mothers were four times more likely to report threats to take and threats to harm the children, Exp(B) = 4.05, p < .05; Exp(B) = 3.93, p < .05, than non-separated mothers. Findings can be used to inform child custody procedures and the design of Family Justice Centers.

  11. Direct and indirect coupling mechanisms in a chiral plasmonic system

    NASA Astrophysics Data System (ADS)

    Wang, Yongkai; Wen, Xiaojing; Qu, Yu; Fu, Tong; Zhang, Zhongyue

    2016-10-01

    Artificial chiral plasmonic nanostructures (ACPNs) are widely studied and used in biological monitoring, analytical chemistry, and negative-refractive-index media. The mechanism of direct coupling between two twist metal nanorods has been obtained in usual ACPNs. In this work, we proposed a nanosystem of twist nanorods separated by a metal film (TNMF). By analyzing the charge distributions, a new indirect coupling mechanism is found. According to the equivalent LC resonant circuits, gold nanorods on the two sides of the gold film can be regarded as a receiver and an emitter. These components enhanced transmittance and provided direct and indirect coupling mechanisms for the circular dichroism (CD). The direct coupling mode cannot be explained by impedance matching and can be tuned monotonously by monotonously varying geometric dimensions. However, the CD signal of indirect coupling can be explained by impedance matching and can be tuned to its maximum by varying geometric dimensions when the impedances of both sides of the gold film match. These results can help design novel chiral optical structures and promote combined applications between photons and electrons when a gold film is powered on.

  12. Impact of Father Involvement: A Closer Look at Indirect Effects Models Involving Marriage and Child Adjustment

    ERIC Educational Resources Information Center

    Goeke-Morey, Marcie C.; Cummings, E. Mark

    2007-01-01

    In this article we present a framework for understanding the indirect effects of fathering on child development in the context of the marriage. We discuss three central pathways of influence: through relations between marital quality and fathering, through children's exposure to father expressions of marital discord, and through relations between…

  13. Profiling Social, Emotional and Behavioural Difficulties of Children Involved in Direct and Indirect Bullying Behaviours

    ERIC Educational Resources Information Center

    Smith, H.; Polenik, K.; Nakasita, S.; Jones, A. P.

    2012-01-01

    Being involved in bullying places a child at risk of poor psychosocial and educational outcomes. This study aimed to examine the profile of behavioural, emotional and social functioning for two subtypes of bullying: direct and indirect (relational). Pupils aged between 7 and 11 years completed sociometric measures of social inclusion and bullying…

  14. Profiling Social, Emotional and Behavioural Difficulties of Children Involved in Direct and Indirect Bullying Behaviours

    ERIC Educational Resources Information Center

    Smith, H.; Polenik, K.; Nakasita, S.; Jones, A. P.

    2012-01-01

    Being involved in bullying places a child at risk of poor psychosocial and educational outcomes. This study aimed to examine the profile of behavioural, emotional and social functioning for two subtypes of bullying: direct and indirect (relational). Pupils aged between 7 and 11 years completed sociometric measures of social inclusion and bullying…

  15. Linking Mother and Youth Parenting Attitudes: Indirect Effects via Maltreatment, Parent Involvement, and Youth Functioning

    PubMed Central

    Thompson, Richard; Jones, Deborah J.; Litrownik, Alan J.; English, Diana J.; Kotch, Jonathan B.; Lewis, Terri; Dubowitz, Howard

    2014-01-01

    Evidence suggests that parenting attitudes are transmitted within families. However, limited research has examined this prospectively. The current prospective study examined direct effects of early maternal attitudes toward parenting (as measured at child age 4 by the Adult-Adolescent Parenting Inventory [AAPI]) on later youth parenting attitudes (as measured by the AAPI at youth age 18). Indirect effects via child maltreatment (physical abuse, sexual abuse, neglect, and emotional maltreatment), parent involvement, and youth functioning (internalizing and externalizing problems) were also assessed. Analyses were conducted on data from 412 families enrolled in the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). There were significant direct effects for three of the four classes of mother parenting attitudes (appropriate developmental expectations of children, empathy toward children, and appropriate family roles) on youth attitudes but not for rejection of punishment. In addition, the following indirect effects were obtained: Mother expectations influenced youth expectations via neglect; mother empathy influenced youth empathy via both parental involvement and youth externalizing problems; and mother rejection of punishment influenced youth rejection of punishment via youth internalizing problems. None of the child or family process variables, however, affected the link between mother and youth attitudes about roles. PMID:25113632

  16. Linking mother and youth parenting attitudes: indirect effects via maltreatment, parent involvement, and youth functioning.

    PubMed

    Thompson, Richard; Jones, Deborah J; Litrownik, Alan J; English, Diana J; Kotch, Jonathan B; Lewis, Terri; Dubowitz, Howard

    2014-01-01

    Evidence suggests that parenting attitudes are transmitted within families. However, limited research has examined this prospectively. The current prospective study examined direct effects of early maternal attitudes toward parenting (as measured at child age 4 by the Adult-Adolescent Parenting Inventory [AAPI]) on later youth parenting attitudes (as measured by the AAPI at youth age 18). Indirect effects via child maltreatment (physical abuse, sexual abuse, neglect, and emotional maltreatment), parent involvement, and youth functioning (internalizing and externalizing problems) were also assessed. Analyses were conducted on data from 412 families enrolled in the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). There were significant direct effects for three of the four classes of mother parenting attitudes (appropriate developmental expectations of children, empathy toward children, and appropriate family roles) on youth attitudes but not for rejection of punishment. In addition, the following indirect effects were obtained: Mother expectations influenced youth expectations via neglect; mother empathy influenced youth empathy via both parental involvement and youth externalizing problems; and mother rejection of punishment influenced youth rejection of punishment via youth internalizing problems. None of the child or family process variables, however, affected the link between mother and youth attitudes about roles. © The Author(s) 2014.

  17. Lung mechanical changes following bronchoaspiration in a porcine model: differentiation of direct and indirect mechanisms.

    PubMed

    Fodor, Gergely H; Peták, Ferenc; Erces, Dániel; Balogh, Adám L; Babik, Barna

    2014-08-01

    Bronchoaspiration results in local deterioration of lung function through direct damage and/or indirect systemic effects related to neurohumoral pathways. We distinguished these effects by selectively intubating the two main bronchi in pigs while a PEEP of 4 or 10cm H2O was maintained. Gastric juice was instilled only into the right lung. Lung mechanical and ventilation defects were assessed by measuring unilateral pulmonary input impedance (ZL,s) and the third phase slope of the capnogram (SIII) for each lung side separately before the aspiration and for 120min thereafter. Marked transient elevations in ZL,s parameters and SIII were observed in the affected lung after aspiration. Elevating PEEP did not affect these responses in the ZL,s parameters, whereas it prevented the SIII increases. None of these indices changed in the intact left lung. These findings furnish evidence of the predominance of the local direct damage over the indirect systemic effects in the development of the deterioration of lung function, and demonstrate the benefit of an initially elevated PEEP following aspiration.

  18. Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics

    NASA Astrophysics Data System (ADS)

    Riley, Blake T.; Ilyichova, Olga; Costa, Mauricio G. S.; Porebski, Benjamin T.; de Veer, Simon J.; Swedberg, Joakim E.; Kass, Itamar; Harris, Jonathan M.; Hoke, David E.; Buckle, Ashley M.

    2016-10-01

    The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel. These structures offer a structural rationalization for the potency and selectivity of these inhibitors, and together with MD simulation and computational analysis, reveal a dynamic pathway between the metal binding exosite and the active site, providing key details of a previously proposed allosteric mode of inhibition. Collectively, this work provides insight into both direct and indirect mechanisms of inhibition for KLK4 that have broad implications for the enzymology of the serine protease superfamily, and may potentially be exploited for the design of therapeutic inhibitors.

  19. Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics

    PubMed Central

    Riley, Blake T.; Ilyichova, Olga; Costa, Mauricio G. S.; Porebski, Benjamin T.; de Veer, Simon J.; Swedberg, Joakim E.; Kass, Itamar; Harris, Jonathan M.; Hoke, David E.; Buckle, Ashley M.

    2016-01-01

    The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel. These structures offer a structural rationalization for the potency and selectivity of these inhibitors, and together with MD simulation and computational analysis, reveal a dynamic pathway between the metal binding exosite and the active site, providing key details of a previously proposed allosteric mode of inhibition. Collectively, this work provides insight into both direct and indirect mechanisms of inhibition for KLK4 that have broad implications for the enzymology of the serine protease superfamily, and may potentially be exploited for the design of therapeutic inhibitors. PMID:27767076

  20. Photoinactivation of Eight Health-Relevant Bacterial Species: Determining the Importance of the Exogenous Indirect Mechanism.

    PubMed

    Maraccini, Peter A; Wenk, Jannis; Boehm, Alexandria B

    2016-05-17

    It is presently unknown to what extent the endogenous direct, endogenous indirect, and exogenous indirect mechanisms contribute to bacterial photoinactivation in natural surface waters. In this study, we investigated the importance of the exogenous indirect mechanism by conducting photoinactivation experiments with eight health-relevant bacterial species (Bacteroides thetaiotaomicron, Campylobacter jejuni, Enterococcus faecalis, Escherichia coli K12, E. coli O157:H7, Salmonella enterica serovar Typhimurium LT2, Staphylococcus aureus, and Streptococcus bovis). We used three synthetic photosensitizers (methylene blue, rose bengal, and nitrite) and two model natural photosensitizers (Suwannee River natural organic matter and dissolved organic matter isolated from a wastewater treatment wetland) that generated singlet oxygen and hydroxyl radical. B. thetaiotaomicron had larger first order rate constants than all other organisms under all conditions tested. The presence of the synthetic photosensitizers generally enhanced photoinactivation of Gram-positive facultative anaerobes (Ent. faecalis, Staph. aureus, and Strep. bovis). Among Gram-negative bacteria, only methylene blue with E. coli K12 and rose bengal with C. jejuni showed an enhancing effect. The presence of model natural photosensitizers either reduced or did not affect photoinactivation rate constants. Our findings highlight the importance of the cellular membrane and photosensitizer properties in modulating the contribution of the exogenous indirect mechanism to the overall bacterial photoinactivation.

  1. Involvement of Mechanical Stress in Androgenetic Alopecia

    PubMed Central

    Tellez-Segura, Rafael

    2015-01-01

    Context: Androgenetic alopecia (AGA) is a frequent disorder characterized by progressive hair miniaturization in a very similar pattern among all affected men. The pathogenesis is related to androgen-inducible overexpression of transforming growth factor β-1 from balding dermal papilla cells, which is involved in epithelial inhibition and perifollicular fibrosis. Recent research shows that hair follicle androgen sensitivity is regulated by Hic-5, an androgen receptor co-activator which may be activated by the mechanical stimulation. Moreover, the dermis of scalp susceptible to be affected by AGA is firmly bounded to the galea aponeurotica, so the physical force exerted by the occipitofrontalis muscle is transmitted to the scalp skin. Aims: To know whether mechanical stress supported by hair follicles is involved in AGA phenomenon. Materials and Methods: It is performed with a finite element analysis of a galea model and a schematic representation of AGA progression according to Hamilton–Norwood scale in order to establish the correlation between elastic deformation in scalp and clinical progression of male pattern baldness. Results: The result was a highly significant correlation (r: −0.885, P < 0.001) that clearly identifies a mechanical factor in AGA development. Conclusions: All these data suggest that mechanical stress determines AGA patterning and a stretch-induced and androgen-mediated mechanotransduction in dermal papilla cells could be the primary mechanism in AGA pathogenesis. PMID:26622151

  2. Enantioselective pharmacokinetics of ibuprofen and involved mechanisms.

    PubMed

    Hao, Haiping; Wang, Guangji; Sun, Jianguo

    2005-01-01

    Although dexibuprofen (S-ibuprofen) was marketed in Austria and Switzerland, the racemate at various formulations is still extensively used worldwide, and there are no indications that the racemate will be replaced by the single enantiomer. Thus, elucidation of the characteristics and involved mechanisms of the chiral pharmacokinetics of racemic ibuprofen is of special importance for the understanding of the pharmacological and toxicological consequences, and for prediction of the clinically potential drug interactions and influence of the pathological states. Stereoselective pharmacokinetics and metabolism are common features for chiral nonsteroidal antiinflammatory drugs (NSAIDs) and especially for 2-arylpropionic acid derivatives characterized with a chiral center adjacent to the carboxyl group. Although the enantioselective pharmacokinetic characteristics of different NSAIDs should be treated case by case, they share similar mechanisms underlying the protein binding, metabolism and chiral inversion. Ibuprofen was the most extensively researched drug in terms of chiral characteristics and mechanisms. Therefore, elucidation of the mechanisms derived from research on ibuprofen may provide better understanding and prediction of other chiral drugs. This article attempts to elucidate the chiral pharmacokinetics and involved mechanisms of ibuprofen in comparison with other NSAIDs based on recent developments. Topics on history of ibuprofen, enantioselective analysis method, absorption, protein binding, conventional metabolism, metabolic chiral inversion, gene polymorphism, and biochemical developments were included. It is worth mentioning that some underlying biochemical mechanisms, especially for the metabolic chiral inversion and ethnic differences still remain to be seen. Further research is required to develop human-resourced researching model and to provide more evidence concerning the site of inversion, species variation, CYP450 gene polymorphisms, and

  3. [Signaling mechanisms involved in resolution of inflammation].

    PubMed

    Cervantes-Villagrana, Rodolfo Daniel; Cervantes-Villagrana, Alberto Rafael; Presno-Bernal, José Miguel

    2014-01-01

    Inflammation is a physiological process, which eliminates pathogens and induces repair of damaged tissue. This process is controlled by negative feedback mechanisms, but if the inflammation persists, it generates a deleterious autoimmune process or can to contribute with diseases such as obesity or cancer. The inflammation resolution involves mechanisms such as decrease of proliferation and maturation of immune cells, phagocytosis and apoptosis of immune cells, and decrease of proinflammatory mediators. Therefore, is relevant to study the physiological effects of specific receptors that participate in inflammation resolution and the design of specific agonists as conventional anti-inflammatory therapeutics, without dramatic collateral effects. In this review, we study some mechanisms associated with inflammation inhibition, particularly the transduction of receptors for ligands with anti-inflammatory effects and that are relevant for their potential therapeutic.

  4. DNA deformation energy as an indirect recognition mechanism in protein-DNA interactions.

    PubMed

    Aeling, Kimberly A; Steffen, Nicholas R; Johnson, Matthew; Hatfield, G Wesley; Lathrop, Richard H; Senear, Donald F

    2007-01-01

    Proteins that bind to specific locations in genomic DNA control many basic cellular functions. Proteins detect their binding sites using both direct and indirect recognition mechanisms. Deformation energy, which models the energy required to bend DNA from its native shape to its shape when bound to a protein, has been shown to be an indirect recognition mechanism for one particular protein, Integration Host Factor (IHF). This work extends the analysis of deformation to two other DNA-binding proteins, CRP and SRF, and two endonucleases, I-CreI and I-PpoI. Known binding sites for all five proteins showed statistically significant differences in mean deformation energy as compared to random sequences. Binding sites for the three DNA-binding proteins and one of the endonucleases had mean deformation energies lower than random sequences. Binding sites for I-PpoI had mean deformation energy higher than random sequences. Classifiers that were trained using the deformation energy at each base pair step showed good cross-validated accuracy when classifying unseen sequences as binders or nonbinders. These results support DNA deformation energy as an indirect recognition mechanism across a wider range of DNA-binding proteins. Deformation energy may also have a predictive capacity for the underlying catalytic mechanism of DNA-binding enzymes.

  5. Indirect Measurement of Energy Density of Soft PZT Ceramic Utilizing Mechanical Stress

    NASA Astrophysics Data System (ADS)

    Unruan, Muangjai; Unruan, Sujitra; Inkong, Yutthapong; Yimnirun, Rattikorn

    2017-07-01

    This paper reports on an indirect measurement of energy density of soft PZT ceramic utilizing mechanical stress. The method works analogous to the Olsen cycle and allows for a large amount of electro-mechanical energy conversion. A maximum energy density of 350 kJ/m3/cycle was found under 0-312 MPa and 1-20 kV/cm of applied mechanical stress and electric field, respectively. The obtained result is substantially higher than the results reported in previous studies of PZT materials utilizing a direct piezoelectric effect.

  6. Indirect estimation of electrical resistivity by abrasion and physico-mechanical properties of rocks

    NASA Astrophysics Data System (ADS)

    Su, Okan; Momayez, Moe

    2017-08-01

    This paper attempts to estimate electrical resistivity from physico-mechanical and abrasion properties of rocks. For this purpose, the electrical properties of rock samples collected from igneous and metamorphic formations were initially measured in a laboratory by employing the two-electrode method. In addition, physical, mechanical, and abrasion properties of the rocks were determined. Then, an attempt was made to examine the possibility of estimation of electrical resistivity from other rock properties. In this sense, it was found that water content, porosity, and the ratio of Vp/Vs have significant effects on the electrical resistivity. Moreover, we report that indirect tensile strength and static elastic modulus indirectly control the electrical characteristics of rocks, since reasonable correlations exist between them. Nevertheless, the reliability of the effect of rock abrasion on the resistivity could not be confirmed with a high degree of certainty. More data are needed to check its validity. Thus, we conclude in light of statistical analyses that the results of the tests and the relationships are statistically significant. For this reason, the electrical resistivity of the intact rock can be indirectly estimated by accounting for the physico-mechanical properties for a given formation. However, rock abrasion cannot be considered for the same purpose.

  7. Density functional theory study of direct and indirect photodegradation mechanisms of sulfameter.

    PubMed

    Shah, Shaheen; Hao, Ce

    2016-10-01

    Sulfonamide antibiotics (SAs) have been observed to undergo direct and indirect photodegradation in natural water environments. In this study, the density functional theory (DFT) method was employed for the study of direct and indirect photodegradation mechanisms of sulfameter (SME) with excited triplet states of dissolved organic matter ((3)DOM(*)) and metal ions. SME was adopted as a representative of SAs, and SO2 extrusion product was obtained with different energy paths in the triplet-sensitized photodegradation of the neutral (SME(0)) and the anionic (SME(-)) form of SME. The selected divalent metal ions (Ca(2+), Mg(2+), and Zn(2+)) promoted the triplet-sensitized photodegradation of SME(0) but showed an inhibitory effect in triplet-sensitized photodegradation of SME(-). The triplet-sensitized indirect photodegradation mechanism of SME was investigated with the three DOM analogues, i.e., 2-acetonaphthone (2-AN), fluorenone (FN), and thioxanthone (TN). Results indicated that the selected DOM analogues are highly responsible for the photodegradation via attacking on amine moiety of SME. According to the natural bond orbital (NBO) analysis, the triplet-sensitized photodegradation mechanism of SME(0) with 2-AN, FN, and TN was H-transfer, and the SME(-) was proton plus electron transfer with these DOM analogues.

  8. Cavity excavation and enlargement as mechanisms for indirect interactions in an avian community.

    PubMed

    Blanc, Lori A; Walters, Jeffrey R

    2008-02-01

    Direct and indirect species interactions within ecological communities may play a strong role in influencing or maintaining community structure. Complex community interactions pose a major challenge to predicting ecosystem responses to environmental change because predictive frameworks require identification of mechanisms by which community interactions arise. Cavity-nesting communities are well suited for mechanistic studies of species interactions because cavity nesters interact through the creation of and competition for cavity-nest sites. In this study, we use a cavity-nest web as a predictive framework for identifying potential indirect species interactions within a cavity-nesting community. From 2002 to 2005, we monitored abundance and nests of cavity-nesting birds in the longleaf pine (Pinus palustris) ecosystem. Using a nest-web approach, we identified a potential indirect interaction between the Red-cockaded Woodpecker (Picoides borealis) and large secondary cavity nesters, mediated by the Northern Flicker (Colaptes auratus). We used structural equation modeling to test a path model of this interaction, using cavity excavation and enlargement as mechanisms which drive the relationship between these species. Through experimental manipulation of cavity availability, we blocked links described in our model, confirming cavity creation and enlargement as processes that influence community structure. We found that a single-species management technique could potentially disrupt this indirect relationship by affecting Northern Flicker cavity-excavation behavior. This study is the first demonstration of how experimental cavity manipulation can be used to test inferred processes derived from a nest web and highlights the need to understand how mechanisms underlying species interactions can complicate ecosystem responses to environmental change.

  9. Major regulatory mechanisms involved in sperm motility.

    PubMed

    Pereira, Rute; Sá, Rosália; Barros, Alberto; Sousa, Mário

    2017-01-01

    The genetic bases and molecular mechanisms involved in the assembly and function of the flagellum components as well as in the regulation of the flagellar movement are not fully understood, especially in humans. There are several causes for sperm immotility, of which some can be avoided and corrected, whereas other are related to genetic defects and deserve full investigation to give a diagnosis to patients. This review was performed after an extensive literature search on the online databases PubMed, ScienceDirect, and Web of Science. Here, we review the involvement of regulatory pathways responsible for sperm motility, indicating possible causes for sperm immotility. These included the calcium pathway, the cAMP-dependent protein kinase pathway, the importance of kinases and phosphatases, the function of reactive oxygen species, and how the regulation of cell volume and osmolarity are also fundamental components. We then discuss main gene defects associated with specific morphological abnormalities. Finally, we slightly discuss some preventive and treatments approaches to avoid development of conditions that are associated with unspecified sperm immotility. We believe that in the near future, with the development of more powerful techniques, the genetic causes of sperm immotility and the regulatory mechanisms of sperm motility will be better understand, thus enabling to perform a full diagnosis and uncover new therapies.

  10. Major regulatory mechanisms involved in sperm motility

    PubMed Central

    Pereira, Rute; Sá, Rosália; Barros, Alberto; Sousa, Mário

    2017-01-01

    The genetic bases and molecular mechanisms involved in the assembly and function of the flagellum components as well as in the regulation of the flagellar movement are not fully understood, especially in humans. There are several causes for sperm immotility, of which some can be avoided and corrected, whereas other are related to genetic defects and deserve full investigation to give a diagnosis to patients. This review was performed after an extensive literature search on the online databases PubMed, ScienceDirect, and Web of Science. Here, we review the involvement of regulatory pathways responsible for sperm motility, indicating possible causes for sperm immotility. These included the calcium pathway, the cAMP-dependent protein kinase pathway, the importance of kinases and phosphatases, the function of reactive oxygen species, and how the regulation of cell volume and osmolarity are also fundamental components. We then discuss main gene defects associated with specific morphological abnormalities. Finally, we slightly discuss some preventive and treatments approaches to avoid development of conditions that are associated with unspecified sperm immotility. We believe that in the near future, with the development of more powerful techniques, the genetic causes of sperm immotility and the regulatory mechanisms of sperm motility will be better understand, thus enabling to perform a full diagnosis and uncover new therapies. PMID:26680031

  11. [Brain mechanisms involved in decision-making].

    PubMed

    Martínez-Selva, J M; Sánchez-Navarro, J P; Bechara, A; Román, F

    To review the studies on brain mechanisms in decision making within the framework of the somatic marker hypothesis, and based on experiments employing the Iowa Gambling Task. An overview of the somatic marker hypothesis is presented together with the review of the main results obtained from research in brain damaged patients, and normal subjects with functional neuroimaging studies, that have led to the identification of the neural structures involved in decision making in humans. The main region involved in decision making is the ventromedial prefrontal cortex, that integrates sensory, mnesic and emotional information relevant to the task. Other structures intervening in the various relevant processes in decision making are the amygdala (processing and encoding of the emotional signal and its association with contextual stimuli) and the cingulate cortex (process monitoring and response inhibition, especially in situations of uncertainty). The prefrontal dorsolateral cortex would also be involved through the necessary activation of the working memory in the decision making process, especially in the case of complex tasks.

  12. Parent Involvement in Head Start and Children's Development: Indirect Effects Through Parenting.

    PubMed

    Ansari, Arya; Gershoff, Elizabeth

    2016-04-01

    The authors examined the extent to which parent involvement in Head Start programs predicted changes in both parent and child outcomes over time, using a nationally representative sample of 1,020 three-year-old children over 3 waves of the Family and Child Experiences Survey. Center policies that promote involvement predicted greater parent involvement, and parents who were more involved in Head Start centers demonstrated increased cognitive stimulation and decreased spanking and controlling behaviors. In turn, these changes in parenting behaviors were associated with gains in children's academic and behavioral skills. These findings suggest that Head Start programs should do even more to facilitate parent involvement because it can serve as an important means for promoting both parent and child outcomes.

  13. Parent Involvement in Head Start and Children’s Development: Indirect Effects Through Parenting

    PubMed Central

    Ansari, Arya; Gershoff, Elizabeth

    2015-01-01

    The authors examined the extent to which parent involvement in Head Start programs predicted changes in both parent and child outcomes over time, using a nationally representative sample of 1,020 three-year-old children over 3 waves of the Family and Child Experiences Survey. Center policies that promote involvement predicted greater parent involvement, and parents who were more involved in Head Start centers demonstrated increased cognitive stimulation and decreased spanking and controlling behaviors. In turn, these changes in parenting behaviors were associated with gains in children’s academic and behavioral skills. These findings suggest that Head Start programs should do even more to facilitate parent involvement because it can serve as an important means for promoting both parent and child outcomes. PMID:27022200

  14. T cell responses to human platelet antigen–1a involve a unique form of indirect allorecognition

    PubMed Central

    Ahlen, Maria Therese; Husebekk, Anne; Killie, Ida Løken; Skogen, Bjørn

    2016-01-01

    Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-related condition caused by maternal antibodies binding an alloantigen on fetal platelets. In most cases the alloantigen is formed by a single amino acid, integrin β3 Leu33, referred to as human platelet antigen–1a (HPA-1a). Production of anti–HPA-1a antibodies likely depends on CD4+ T cells that recognize the same alloantigen in complex with the HLA-DRA/DRB3*01:01 molecule. While this complex is well characterized, T cell recognition of it is not. Here, to examine the nature of antigen recognition by HPA-1a–specific T cells, we assayed native and synthetic variants of the integrin β3 peptide antigen for binding to DRA/DRB3*01:01-positive antigen-presenting cells and for T cell activation. We found that HPA-1a–specific T cells recognize non-allogeneic integrin β3 residues anchored to DRA/DRB3*01:01 by the allogeneic Leu33, which itself is not directly recognized by these T cells. Furthermore, these T cell responses are diverse, with different T cells depending on different residues for recognition. This represents a unique form of indirect allorecognition in which a non-allogeneic peptide sequence becomes immunogenic by stable anchoring to MHC by an allogeneic residue. PMID:27699233

  15. Molecular Mechanisms Involved in Schwann Cell Plasticity

    PubMed Central

    Boerboom, Angélique; Dion, Valérie; Chariot, Alain; Franzen, Rachelle

    2017-01-01

    Schwann cell incredible plasticity is a hallmark of the utmost importance following nerve damage or in demyelinating neuropathies. After injury, Schwann cells undergo dedifferentiation before redifferentiating to promote nerve regeneration and complete functional recovery. This review updates and discusses the molecular mechanisms involved in the negative regulation of myelination as well as in the reprogramming of Schwann cells taking place early following nerve lesion to support repair. Significant advance has been made on signaling pathways and molecular components that regulate SC regenerative properties. These include for instance transcriptional regulators such as c-Jun or Notch, the MAPK and the Nrg1/ErbB2/3 pathways. This comprehensive overview ends with some therapeutical applications targeting factors that control Schwann cell plasticity and highlights the need to carefully modulate and balance this capacity to drive nerve repair. PMID:28261057

  16. Brain mechanisms involved in processing unreal perceptions.

    PubMed

    Ku, Jeonghun; Kim, Jae-Jin; Jung, Young Chul; Park, Il Ho; Lee, Hyeongrae; Han, Kiwan; Yoon, Kang Jun; Kim, In Young; Kim, Sun I

    2008-12-01

    Individuals sometimes experience an illusory or hallucinatory perception. This unreal perception is usually resolved after the individual recognizes that the perception was not real. In this study, we investigated the brain mechanisms involved in the process to an illusory or hallucinatory perception through 'obtaining insight into unreality'. We used a novel and intuitive paradigm designed by combining functional magnetic resonance imaging and augmented reality technology to simulate visual illusory stimuli that mimic hallucinations during brain scanning. The results showed various brain activations, predominantly in the amygdala in the early phase, the medial frontal cortex and the occipitotemporal junction in the middle phase, and the thalamus in the late phase, which correlated with a subject's proneness to hallucinating. These activations may correspond to a 'responding stage' for a perception-based immediate emotional reaction, a 'monitoring stage' for integration and recalibration to ascertain that the perception was not real, and a 'resolving stage' for controlling the information and finally settling it, respectively. Our paradigm and findings may be useful in understanding the mechanisms for discriminating and coping with hallucinatory perceptions.

  17. Bottom-up and top-down mechanisms indirectly mediate interactions between benthic biotic ecosystem components

    NASA Astrophysics Data System (ADS)

    Van Colen, Carl; Thrush, Simon F.; Parkes, Samantha; Harris, Rachel; Woodin, Sally A.; Wethey, David S.; Pilditch, Conrad A.; Hewitt, Judi E.; Lohrer, Andrew M.; Vincx, Magda

    2015-04-01

    The loss or decline in population size of key species can instigate a cascade of effects that have implications for interacting species, therewith impacting biodiversity and ecosystem functioning. We examined how top-down and bottom-up interactions may mediate knock-on effects of a coastal deposit-feeding clam, Macomona liliana (hereafter Macomona), on sandflat meiobenthos densities. Therefore we manipulated densities of Macomona in combination with predator exclusion and experimental shading that was expected to alter microphytobenthos biomass. We show that Macomona regulated densities of meiobenthic (38-500 μm) nematodes, copepods, polychaetes, turbellarians, and ostracodes during the three months of incubation via indirect mechanisms. Predator pressure on Macomona by eagle rays (Myliobatis tenuicaudatus) was found to have a negative effect on densities of some meiobenthic taxa. Furthermore, experimental shading resulted in the loss of a positive relation between Macomona and microphytobenthos biomass, while concurrently increasing the density of some meiobenthic taxa. We suggest that this observation can be explained by the release from bioturbation interference effects of the cockle Austrovenus stutchburyi that was found to thrive in the presence of Macomona under non-shaded conditions. Our results highlight the importance of interactions between macrofaunal bioturbation, microphyte biomass, sediment stability, and predation pressure for the structuring of benthic communities. This experiment illustrates that manipulative field experiments may be particularly suitable to study such multiple indirect mechanisms that regulate ecosystem diversity and related functioning because such approaches may best capture the complex feedbacks and processes that determine ecosystem dynamics.

  18. An Indirect and Dynamically Induced Energy Mechanism in a Plasma-Neutral Atmosphere

    NASA Astrophysics Data System (ADS)

    Hsu, Vicki W.

    Plasma-neutral interactions play an integral role in governing the dynamics and energy of an upper atmosphere. In the Earth's ionosphere-thermosphere (I/T) region, these interactions can produce significant structure in neutral temperature, winds, mass density, and composition. External sources of momentum and energy that directly affect these properties of the upper atmosphere have been extensively investigated, but these investigations are not sufficient to fully describe thermosphere phenomenology. Considering the strong plasma-neutral coupling in the I/T region, an internal and indirect energy mechanism, or a feedback exchange between hydrodynamics and thermodynamics, can contribute to the resultant structure. The complex, indirect consequences of internal momentum changes on neutral gas properties have not been thoroughly assessed due to the multivariate nature of the problem and limited observations. Through the use of the National Center for Atmospheric Research Thermosphere-Ionosphere-Electrodynamics General Circulation Model, this thesis seeks to simulate, understand, and quantify how plasma-neutral interactions affect the energy distribution of the upper thermosphere via an indirect, dynamically induced mechanism, and to establish that this mechanism can explain the existence of thermospheric density features. The main conclusions that stem from this dissertation are as follows: (1) Changes in the field-aligned ion drag force alter neutral temperature and mass density by means of a divergent neutral wind field, commanding the formation, local time, and solar cycle variations of the equatorial thermosphere anomaly trough; (2) Ion and viscous drag forces produce balanced motion with sustained, divergent winds that change thermal and mass density structure through adiabatic heating; (3) A boundary that delineates the lower and upper thermosphere is recognized and deemed the "thermopause", and helium is demonstrated to be an effective dynamic tracer for a

  19. Effect of tooth brush abrasion and thermo-mechanical loading on direct and indirect veneer restorations.

    PubMed

    Rosentritt, Martin; Sawaljanow, Alexander; Behr, Michael; Kolbeck, Carola; Preis, Verena

    2015-01-01

    This study investigated toothbrush abrasion and in vitro aging on ceramic (indirect technique) and composite veneers (direct technique). Identical composite and individual human incisors were restored with industrially preformed composite veneers, indirectly produced ceramic veneers, and direct composite restorations. Surface roughness was determined before and after tooth brushing. A 5-year period of oral service was simulated by thermal cycling and mechanical loading (TCML). After TCML, all specimens were examined with microscopy and scanning electron microscopy. Specimens without failures during TCML were loaded until failure. analysis of variance; Bonferroni's post hoc analysis, Kaplan-Meier-Log Rank test (α = 0.05). Tooth brushing yielded a non-significant increase (p = 0.560) in roughness in all materials (industrial veneer, 0.12+/-0.07 μm, direct restoration, 0.18+/-0.14 μm, ceramic, 0.35+/-0.16 μm). No significant differences in roughness could be determined between the materials, neither before nor after testing (p < 0.001). After TCML of artificial teeth, direct and preformed composite veneers on composite teeth showed no failures or damages. Two ceramic veneers showed cracking in the labial area. After TCML of human teeth, transmission microscopy indicated a facial crack in a ceramic veneer and chipping in the cervical area of a preformed veneer. Two direct composite veneers lost retention. No significantly different survival rates were found between the three veneer groups. Fracture force on human teeth varied between 527.8+/-132.4 N (ceramic), 478.3+/-165.4 N (preformed composite), and 605.0+/-263.5 N (direct composite). All materials revealed comparable wear resistance. Indirect ceramic, direct restorative composite, and preformed composite veneers showed comparable failure rates and satisfying longevity. The results indicate similar longevity of the chosen materials for veneer restorations.

  20. Indirect effects and traditional trophic cascades: a test involving wolves, coyotes, and pronghorn.

    PubMed

    Berger, Kim Murray; Gese, Eric M; Berger, Joel

    2008-03-01

    The traditional trophic cascades model is based on consumer resource interactions at each link in a food chain. However, trophic-level interactions, such as mesocarnivore release resulting from intraguild predation, may also be important mediators of cascades. From September 2001 to August 2004, we used spatial and seasonal heterogeneity in wolf distribution and abundance in the southern Greater Yellowstone Ecosystem to evaluate whether mesopredator release of coyotes (Canis latrans), resulting from the extirpation of wolves (Canis lupus), accounts for high rates of coyote predation on pronghorn (Antilocapra americana) fawns observed in some areas. Results of this ecological perturbation in wolf densities, coyote densities, and pronghorn neonatal survival at wolf-free and wolf-abundant sites support the existence of a species-level trophic cascade. That wolves precipitated a trophic cascade was evidenced by fawn survival rates that were four-fold higher at sites used by wolves. A negative correlation between coyote and wolf densities supports the hypothesis that interspecific interactions between the two species facilitated the difference in fawn survival. Whereas densities of resident coyotes were similar between wolf-free and wolf-abundant sites, the abundance of transient coyotes was significantly lower in areas used by wolves. Thus, differential effects of wolves on solitary coyotes may be an important mechanism by which wolves limit coyote densities. Our results support the hypothesis that mesopredator release of coyotes contributes to high rates of coyote predation on pronghorn fawns, and demonstrate the importance of alternative food web pathways in structuring the dynamics of terrestrial systems.

  1. Interleukin-19 induces angiogenesis in the absence of hypoxia by direct and indirect immune mechanisms

    PubMed Central

    Kako, Farah; Gabunia, Khatuna; Ray, Mitali; Kelemen, Sheri E.; England, Ross N.; Kako, Bashar; Scalia, Rosario G.

    2016-01-01

    Neovascularization and inflammation are independent biological processes but are linked in response to injury. The role of inflammation-dampening cytokines in the regulation of angiogenesis remains to be clarified. The purpose of this work was to test the hypothesis that IL-19 can induce angiogenesis in the absence of tissue hypoxia and to identify potential mechanisms. Using the aortic ring model of angiogenesis, we found significantly reduced sprouting capacity in aortic rings from IL-19−/− compared with wild-type mice. Using an in vivo assay, we found that IL-19−/− mice respond to vascular endothelial growth factor (VEGF) significantly less than wild-type mice and demonstrate decreased capillary formation in Matrigel plugs. IL-19 signals through the IL-20 receptor complex, and IL-19 induces IL-20 receptor subunit expression in aortic rings and cultured human vascular smooth muscle cells, but not endothelial cells, in a peroxisome proliferator-activated receptor-γ-dependent mechanism. IL-19 activates STAT3, and IL-19 angiogenic activity in aortic rings is STAT3-dependent. Using a quantitative RT-PCR screening assay, we determined that IL-19 has direct proangiogenic effects on aortic rings by inducing angiogenic gene expression. M2 macrophages participate in angiogenesis, and IL-19 has indirect angiogenic effects, as IL-19-stimulated bone marrow-derived macrophages secrete proangiogenic factors that induce greater sprouting of aortic rings than unstimulated controls. Using a quantitative RT-PCR screen, we determined that IL-19 induces expression of angiogenic cytokines in bone marrow-derived macrophages. Together, these data suggest that IL-19 can promote angiogenesis in the absence of hypoxia by at least two distinct mechanisms: 1) direct effects on vascular cells and 2) indirect effects by stimulation of macrophages. PMID:27053520

  2. Gunshot induced indirect femoral fracture: mechanism of injury and fracture morphology.

    PubMed

    Kieser, David C; Carr, D J; Leclair, S C J; Horsfall, I; Theis, J C; Swain, M V; Kieser, J A

    2013-12-01

    Indirect ballistic fractures occur when a projectile passes close to, but not contacting, the bone. The mechanism of how these fractures occur is not yet proven, but recently the acoustic shockwave has been excluded as a cause. The objective of this study is to determine whether the expanding temporary cavity, the collapse of this cavity or its oscillation causes these fractures. In addition, we describe the fracture morphology and biomechanical causes of this injury. 40 fresh deer femora were strain gauged and embedded in ballistic gelatin before being shot with four different projectiles with varying distances off the bone. Pressure recordings, chronographs and radar allowed assessment of local pressures and energy transfer. High-speed video allowed the temporal relationship between the temporary cavity and fracture formation to be analysed, while sample dissection allowed the fracture morphology to be described. The fractures produced were consistently wedge-shaped and caused by the expansion of the temporary cavity, flexing the bone beyond its yield point, causing tension failure on the cortex opposite the expanding temporary cavity and a compression wedge on the side of the cavity. Local pressure was not predictive of fracture formation but the energy transfer to the gelatin block was predictive. Indirect fractures are caused by the expansion of the temporary cavity and relate to the proximity of this cavity to the bone. Fractures occur from flexion of the bone and classically display wedge-shaped fracture patterns with the apex of the wedge pointing away from the expanding cavity.

  3. Inhibition of the Mitochondrial Permeability Transition for Cytoprotection: Direct versus Indirect Mechanisms

    PubMed Central

    Martel, Cécile; Huynh, Le Ha; Garnier, Anne; Ventura-Clapier, Renée; Brenner, Catherine

    2012-01-01

    Mitochondria are fascinating organelles, which fulfill multiple cellular functions, as diverse as energy production, fatty acid β oxidation, reactive oxygen species (ROS) production and detoxification, and cell death regulation. The coordination of these functions relies on autonomous mitochondrial processes as well as on sustained cross-talk with other organelles and/or the cytosol. Therefore, this implies a tight regulation of mitochondrial functions to ensure cell homeostasis. In many diseases (e.g., cancer, cardiopathies, nonalcoholic fatty liver diseases, and neurodegenerative diseases), mitochondria can receive harmful signals, dysfunction and then, participate to pathogenesis. They can undergo either a decrease of their bioenergetic function or a process called mitochondrial permeability transition (MPT) that can coordinate cell death execution. Many studies present evidence that protection of mitochondria limits disease progression and severity. Here, we will review recent strategies to preserve mitochondrial functions via direct or indirect mechanisms of MPT inhibition. Thus, several mitochondrial proteins may be considered for cytoprotective-targeted therapies. PMID:22675634

  4. Ionic mechanisms involved in the nodal swelling of myelinated axons caused by marine toxins.

    PubMed

    Benoit, Evelyne; Mattei, Cesar; Ouanounou, Gilles; Meunier, Frederic A; Suput, Dusan; Le Gall, Frederic; Marquais, Michel; Dechraoui, Marie Y; Molgo, Jordi

    2002-01-01

    This review describes the ionic mechanisms involved in the nodal swelling of frog myelinated axons caused by specific marine neurotoxins (ciguatoxins, brevetoxins, Conus consors toxin and equinatoxin-II), analysed using confocal laser scanning microscopy. We have focussed on toxins that either target neuronal voltage-dependent Na+ channels, or that form cation-selective pores and indirectly affect the functioning of the Na(+)-Ca(++)exchanger.

  5. Epigenetic mechanisms involved in developmental nutritional programming

    PubMed Central

    Gabory, Anne; Attig, Linda; Junien, Claudine

    2011-01-01

    The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result in modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, position and functions of epigenetic marks. Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks, at the global or individual gene level, of environmental stressors in humans and animal models. In parallel, increasing numbers of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes, by highlighting the importance of crosstalk between the different epigenetic marks. A number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition, epigenetic processes and long-term illness. The existence of a self-propagating epigenetic cycle has been demonstrated. Moreover, recent studies demonstrate an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult. Despite recent progress, we are still far from understanding how, when and where environmental stressors disturb key epigenetic mechanisms. Thus, identifying the original key marks and their changes throughout development during an individual’s lifetime or over several generations remains a challenging issue. PMID:22010058

  6. Microstructure and mechanical properties of 7075 aluminum alloy nanostructured composites processed by mechanical milling and indirect hot extrusion

    SciTech Connect

    Flores-Campos, R.; Estrada-Guel, I.; Miki-Yoshida, M.; Martinez-Sanchez, R.; Herrera-Ramirez, J.M.

    2012-01-15

    Nanostructured composites of 7075 aluminum alloy and carbon coated silver nanoparticles were produced by mechanical milling and indirect hot extrusion. The milling products were obtained in a high energy SPEX ball mill, and then were compacted by uniaxial load and pressure-less sintered under argon atmosphere. Finally, the sintered product was hot extruded. Carbon coated silver nanoparticles were well distributed in the matrix of the extruded material. Tensile tests were carried out to corroborate the hypothesis that second phase particles, well dispersed in the matrix, improve the strength of the material. High resolution transmission electron microscopy was employed to locate and make sure that the silver nanoparticles were homogeneously and finely dispersed. Highlights: Black-Right-Pointing-Pointer 7075 Al nanostructured composites can be produced by mechanical milling. Black-Right-Pointing-Pointer Carbon coated silver nanoparticles are well dispersed into aluminum matrix. Black-Right-Pointing-Pointer Ductile Ag-C NP's improve the mechanical properties of the 7075 Al-alloy. Black-Right-Pointing-Pointer Ag-C NP's content has an important effect in the particle and crystallite size. Black-Right-Pointing-Pointer Ag-C NP's keep their morphology after milling and conformation processes.

  7. The reaction mechanisms and kinetics of removing azo reactive dye by indirect photolysis approaches.

    PubMed

    Tsui, S M; Chu, W

    2002-01-01

    The photodegradation of azo reactive dye (RR2) in the presence of acetone (ACE) or triethylamine (TEA) via indirect photolysis was investigated. Photolytic experiments were conducted in a merry-go-round photoreactor with 253.7-nm monochromatic UV lamps. The photodegradation of RR2 in aqueous ACE or TEA solution was found to be kinetically controlled by pseudo-first- and zero-order kinetics, respectively. Typically, the photodegradation reaction is more favorable at higher pH. In the presence of TEA, the rate enhancement primarily is a result of the electron transfer from TEA to RR2 and results in the photoreduction of dye chromophore. Photosensitization is likely the dominant mechanism in the presence of ACE. With respect to the decoloration rate, ACE proved to be a promising rate enhancer at elevated concentrations, and the solution color faded rapidly within 5 minutes of retention time. The photodecoloration of RR2 was found to co-occur with photodechlorination and was followed by photodesulfonation at a later stage in which the mineralized end products, including hydrogen, chloride, and sulphorate ions, were detected in approximately stoichiometric amounts.

  8. Indirect adaptive output feedback control of a biorobotic AUV using pectoral-like mechanical fins.

    PubMed

    Naik, Mugdha S; Singh, Sahjendra N; Mittal, Rajat

    2009-06-01

    This paper treats the question of servoregulation of autonomous underwater vehicles (AUVs) in the yaw plane using pectoral-like mechanical fins. The fins attached to the vehicle have oscillatory swaying and yawing motion. The bias angle of the angular motion of the fin is used for the purpose of control. Of course, the design approach considered here is applicable to AUVs for other choices of oscillation patterns of the fins, which produce periodic forces and moments. It is assumed that the vehicle parameters, hydrodynamic coefficients, as well the fin forces and moments are unknown. For the trajectory control of the yaw angle, a sampled-data indirect adaptive control system using output (yaw angle) feedback is derived. The control system has a modular structure, which includes a parameter identifier and a stabilizer. For the control law derivation, an internal model of the exosignals (reference signal (constant or ramp) and constant disturbance) is included. Unlike the direct adaptive control scheme, the derived control law is applicable to minimum as well as nonminimum phase biorobotic AUVs (BAUVs). This is important, because for most of the fin locations on the vehicle, the model is a nonminimum phase. In the closed-loop system, the yaw angle trajectory tracking error converges to zero and the remaining state variables remain bounded. Simulation results are presented which show that the derived modular control system accomplishes precise set point yaw angle control and turning maneuvers in spite of the uncertainties in the system parameters using only yaw angle feedback.

  9. Is consolidation drainage an indirect mechanism for increased abundance of cattail in northern prairie wetlands?

    USGS Publications Warehouse

    Wiltermuth, Mark T.; Anteau, Michael J.

    2016-01-01

    In the Prairie Pothole Region of North America, disturbances to wetlands that disrupt water-level fluctuations in response to wet–dry climatic conditions have the potential to alter natural vegetative communities in favor of species that proliferate in stable environments, such as cattail (Typha spp.). We evaluated the effect of water-level dynamics during a recent fluctuation in wet–dry conditions on cattail coverage within semipermanently and permanently ponded wetlands situated in watersheds with different land use and amounts of wetland drainage. We found that ponded water depth increase was significantly greater in wetlands where water levels were not near the spill point of the topographic basin, where banks were steeper, and in larger wetlands where past dry conditions had less influence on change in pond area. Proportion of the wetland covered by cattail was negatively correlated with increased water depth, bank slope and pond area. Our observations provide evidence that cattail coverage in prairie wetlands is regulated by water-level fluctuations and that land use surrounding the wetland might have an indirect effect on cattail coverage by altering water-level response to wet–dry climate conditions. For example, drainage of smaller wetlands into larger wetlands that are characterized by more permanent hydroperiods, leads to stabilized water levels near their spill point and is therefore a potential mechanism for increased cattail abundance in the northern prairie region.

  10. Effect of polymerization under pressure on indirect tensile mechanical properties of light-polymerized composites.

    PubMed

    Brosh, Tamar; Ferstand, Nechama; Cardash, Harold; Baharav, Haim

    2002-10-01

    Flaws developed during polymerization of restorative materials cause a decrease in mechanical properties. The aim of this study was to determine the effect of polymerization under pressure on the indirect tensile mechanical properties (stiffness and diametral tensile strength) of several light-polymerized composites. Five light-polymerized composites were tested: Brilliant, Z100, TPH Spectrum, Prodigy, and Pertac Hybrid. A total of 80 cylindrical disk specimens (6 mm x 2 mm) were prepared for each material in a special mold that enabled polymerization under pressure (PUP). An equal number of specimens were polymerized under surface pressures of 0,.35,.71 and 1.06 MPa (n = 20). Stiffness (N/mm) and diametral tensile strength (DTS) (MPa) were analyzed while loading the specimen to failure with a loading machine. Two-way analysis of variance and Weibull analyses were applied (alpha=5%). Material type had a statistically significant influence on both DTS and stiffness (P<.0001). Differences up to 33% in DTS and up to 70% in stiffness values were found among the tested materials. Loading (PUP) had a significant influence on stiffness (P<.03) and DTS (P<.0001). PUP caused an increase in DTS values for Brilliant, Z100, and Prodigy of about 20% (P<.001) and increased stiffness only for Brilliant (15%). However, the amount of pressure needed for the improvement was different between materials (interaction between materials and loadings) (P<.0005). Weibull statistics showed that PUP improved the chances for reducing flaws in a material. Polymerizing material under pressure can improve its DTS and stiffness. However, the pressure needed for the procedure is material dependent.

  11. Mechanical work as an indirect measure of subjective costs influencing human movement.

    PubMed

    Zelik, Karl E; Kuo, Arthur D

    2012-01-01

    To descend a flight of stairs, would you rather walk or fall? Falling seems to have some obvious disadvantages such as the risk of pain or injury. But the preferred strategy of walking also entails a cost for the use of active muscles to perform negative work. The amount and distribution of work a person chooses to perform may, therefore, reflect a subjective valuation of the trade-offs between active muscle effort and other costs, such as pain. Here we use a simple jump landing experiment to quantify the work humans prefer to perform to dissipate the energy of landing. We found that healthy normal subjects (N = 8) preferred a strategy that involved performing 37% more negative work than minimally necessary (P<0.001) across a range of landing heights. This then required additional positive work to return to standing rest posture, highlighting the cost of this preference. Subjects were also able to modulate the amount of landing work, and its distribution between active and passive tissues. When instructed to land softly, they performed 76% more work than necessary (P<0.001), with a higher proportion from active muscles (89% vs. 84%, P<0.001). Stiff-legged landings, performed by one subject for demonstration, exhibited close to the minimum of work, with more of it performed passively through soft tissue deformations (at least 30% in stiff landings vs. 16% preferred). During jump landings, humans appear not to minimize muscle work, but instead choose to perform a consistent amount of extra work, presumably to avoid other subjective costs. The degree to which work is not minimized may indirectly quantify the relative valuation of costs that are otherwise difficult to measure.

  12. Modelling the Thermo-Mechanical Behavior of Magnesium Alloys during Indirect Extrusion

    SciTech Connect

    Steglich, D.; Ertuerk, S.; Bohlen, J.; Letzig, D.; Brocks, W.

    2010-06-15

    One of the basic metal forming process for semi-finished products is extrusion. Since extrusion involves complex thermo-mechanical and multiaxial loading conditions resulting in large strains, high strain rates and an increase in temperature due to deformation, a proper yield criterion and hardening law should be used in the numerical modelling of the process. A phenomenological model based on a plastic potential has been proposed that takes strain, strain rate and temperature dependency on flow behaviour into consideration. A hybrid methodology of experiment and finite element simulation has been adopted in order to obtain necessary model parameters. The anisotropy/asymmetry in yielding was quantified by tensile and compression tests of specimens prepared from different directions. The identification of the corresponding model parameters was performed by a genetic algorithm. A fully coupled thermo-mechanical analysis has been used in extrusion simulations for calculation of the temperature field by considering heat fluxes and heat generated due to plastic deformation. The results of the approach adopted in this study appeared to be successful showing promising predictions of the experiments and thus may be extended to be applicable to other magnesium alloys or even other hcp metals.

  13. Organophosphorus Pesticides Decrease M2 Muscarinic Receptor Function in Guinea Pig Airway Nerves via Indirect Mechanisms

    PubMed Central

    Proskocil, Becky J.; Bruun, Donald A.; Thompson, Charles M.; Fryer, Allison D.; Lein, Pamela J.

    2010-01-01

    Background Epidemiological studies link organophosphorus pesticide (OP) exposures to asthma, and we have shown that the OPs chlorpyrifos, diazinon and parathion cause airway hyperreactivity in guinea pigs 24 hr after a single subcutaneous injection. OP-induced airway hyperreactivity involves M2 muscarinic receptor dysfunction on airway nerves independent of acetylcholinesterase (AChE) inhibition, but how OPs inhibit neuronal M2 receptors in airways is not known. In the central nervous system, OPs interact directly with neurons to alter muscarinic receptor function or expression; therefore, in this study we tested whether the OP parathion or its oxon metabolite, paraoxon, might decrease M2 receptor function on peripheral neurons via similar direct mechanisms. Methodology/Principal Findings Intravenous administration of paraoxon, but not parathion, caused acute frequency-dependent potentiation of vagally-induced bronchoconstriction and increased electrical field stimulation (EFS)-induced contractions in isolated trachea independent of AChE inhibition. However, paraoxon had no effect on vagally-induced bradycardia in intact guinea pigs or EFS-induced contractions in isolated ileum, suggesting mechanisms other than pharmacologic antagonism of M2 receptors. Paraoxon did not alter M2 receptor expression in cultured cells at the mRNA or protein level as determined by quantitative RT-PCR and radio-ligand binding assays, respectively. Additionally, a biotin-labeled fluorophosphonate, which was used as a probe to identify molecular targets phosphorylated by OPs, did not phosphorylate proteins in guinea pig cardiac membranes that were recognized by M2 receptor antibodies. Conclusions/Significance These data indicate that neither direct pharmacologic antagonism nor downregulated expression of M2 receptors contributes to OP inhibition of M2 function in airway nerves, adding to the growing evidence of non-cholinergic mechanisms of OP neurotoxicity. PMID:20479945

  14. A Dominant Social Comparison Heuristic Unites Alternative Mechanisms for the Evolution of Indirect Reciprocity.

    PubMed

    Whitaker, Roger M; Colombo, Gualtiero B; Allen, Stuart M; Dunbar, Robin I M

    2016-08-12

    Cooperation is a fundamental human trait but our understanding of how it functions remains incomplete. Indirect reciprocity is a particular case in point, where one-shot donations are made to unrelated beneficiaries without any guarantee of payback. Existing insights are largely from two independent perspectives: i) individual-level cognitive behaviour in decision making, and ii) identification of conditions that favour evolution of cooperation. We identify a fundamental connection between these two areas by examining social comparison as a means through which indirect reciprocity can evolve. Social comparison is well established as an inherent human disposition through which humans navigate the social world by self-referential evaluation of others. Donating to those that are at least as reputable as oneself emerges as a dominant heuristic, which represents aspirational homophily. This heuristic is found to be implicitly present in the current knowledge of conditions that favour indirect reciprocity. The effective social norms for updating reputation are also observed to support this heuristic. We hypothesise that the cognitive challenge associated with social comparison has contributed to cerebral expansion and the disproportionate human brain size, consistent with the social complexity hypothesis. The findings have relevance for the evolution of autonomous systems that are characterised by one-shot interactions.

  15. A Dominant Social Comparison Heuristic Unites Alternative Mechanisms for the Evolution of Indirect Reciprocity

    NASA Astrophysics Data System (ADS)

    Whitaker, Roger M.; Colombo, Gualtiero B.; Allen, Stuart M.; Dunbar, Robin I. M.

    2016-08-01

    Cooperation is a fundamental human trait but our understanding of how it functions remains incomplete. Indirect reciprocity is a particular case in point, where one-shot donations are made to unrelated beneficiaries without any guarantee of payback. Existing insights are largely from two independent perspectives: i) individual-level cognitive behaviour in decision making, and ii) identification of conditions that favour evolution of cooperation. We identify a fundamental connection between these two areas by examining social comparison as a means through which indirect reciprocity can evolve. Social comparison is well established as an inherent human disposition through which humans navigate the social world by self-referential evaluation of others. Donating to those that are at least as reputable as oneself emerges as a dominant heuristic, which represents aspirational homophily. This heuristic is found to be implicitly present in the current knowledge of conditions that favour indirect reciprocity. The effective social norms for updating reputation are also observed to support this heuristic. We hypothesise that the cognitive challenge associated with social comparison has contributed to cerebral expansion and the disproportionate human brain size, consistent with the social complexity hypothesis. The findings have relevance for the evolution of autonomous systems that are characterised by one-shot interactions.

  16. A Dominant Social Comparison Heuristic Unites Alternative Mechanisms for the Evolution of Indirect Reciprocity

    PubMed Central

    Whitaker, Roger M.; Colombo, Gualtiero B.; Allen, Stuart M.; Dunbar, Robin I. M.

    2016-01-01

    Cooperation is a fundamental human trait but our understanding of how it functions remains incomplete. Indirect reciprocity is a particular case in point, where one-shot donations are made to unrelated beneficiaries without any guarantee of payback. Existing insights are largely from two independent perspectives: i) individual-level cognitive behaviour in decision making, and ii) identification of conditions that favour evolution of cooperation. We identify a fundamental connection between these two areas by examining social comparison as a means through which indirect reciprocity can evolve. Social comparison is well established as an inherent human disposition through which humans navigate the social world by self-referential evaluation of others. Donating to those that are at least as reputable as oneself emerges as a dominant heuristic, which represents aspirational homophily. This heuristic is found to be implicitly present in the current knowledge of conditions that favour indirect reciprocity. The effective social norms for updating reputation are also observed to support this heuristic. We hypothesise that the cognitive challenge associated with social comparison has contributed to cerebral expansion and the disproportionate human brain size, consistent with the social complexity hypothesis. The findings have relevance for the evolution of autonomous systems that are characterised by one-shot interactions. PMID:27515119

  17. Mechanisms of poliovirus inactivation by the direct and indirect effects of ionizing radiation

    SciTech Connect

    Ward, R.L.

    1980-08-01

    This study was designed to measure the effects of ionizing radiation on poliovirus particles when given under conditions where either direct (in broth) or indirect (in water) effects were predominant. Under direct conditions, inactivation of poliovirus was found to be due primarily to RNA damage, although capsid damage could account for about one-third of the viral inactivation. RNA damage did not appear to be due to strand breakage and therefore was probably caused primarily by base damage or crosslink formation. Capsid damage under direct irradiation conditions did not result in significant alterations of either the sedimentation coefficients or the isoelectric points of the poliovirus particles or detectable modification of the sizes of the viral proteins. It did, however, cause loss of availability to bind to host cells. Under indirect conditions no more than 25% of viral inactivation appeared to be due to RNA damage. However, the sedimentation coefficients and isoelectric points of the viral particles were greatly altered, and their abilities to bind to cells were lost at about three-fourths the rate of loss of infectivity. Capsid damage in this case did result in changes in the sizes of capsid proteins. Therefore, the majority of the radiation inactivation under indirect conditions appeared to be due to protein damage.

  18. Mechanical stress on tensioned wires at direct and indirect loading: a biomechanical study on the Ilizarov external fixator.

    PubMed

    Gessmann, Jan; Jettkant, Birger; Schildhauer, Thomas Armin; Seybold, Dominik

    2011-10-01

    The biomechanical effect of indirect weight loading with the Ilizarov ring fixator using a weight-bearing platform has not yet been investigated. The problem of wire loosening and breakage occurs more frequently when patients are mobilised with a weight-bearing platform. Therefore, the aim of this research was to compare the influence of direct and indirect weight loading on the tensioned wires. A universal testing machine (UTS, Germany) was used in this study. A composite tibia model with a standard four-ring Ilizarov fixator and 1.8-mm wires in anatomical position was used to simulate a clinical situation. Wire strain was measured with two strain gauges positioned at the ring-wire interface of each wire. After a standardised 2-mm mid-diaphyseal osteotomy, an axial load of up to 1000 N was applied to the bone; the different methods of weight loading were evaluated in two experimental set-ups. A higher axial load was necessary to achieve an osteotomy gap closure at indirect loading. Mechanical stress on the tensioned wires was 400% higher on the proximal wires and 250% higher on the distal wires at a maximum axial loading of 1000 N. Mechanical stress remained on the wires in indirect loading, even after bone end contact, and led to excessive stress under higher weight-bearing amounts. There is a substantial change in the biomechanical characteristics of the Ilizarov ring fixator when mobilising a patient with a weight-bearing platform. The considerable higher mechanical stress on the wires needs to be considered when patients are mobilised with a weight-bearing platform. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. The effect of mechanical loading on the cusp defection of premolars restored with direct and indirect techniques.

    PubMed

    Zamboni, Sandra Costa; Nogueira, Lafayette; Bottino, Marco Antonio; Sobrinho, Lourenço Correr; Valandro, Luiz Felipe

    2014-01-01

    This study assessed the effect of fatigue load cycling on human premolars restored with MOD restorations (direct and indirect approaches) on cuspal defection, compared to intact teeth (unprepared) and unrestored teeth with an inlay preparation. MOD inlay preparations were performed on sixty premolars with their roots embedded in acrylic resin. These teeth were divided into six groups (n = 10): (1) intact teeth; (2) unrestored and prepared teeth; (3) teeth restored with direct composite resin; (4) teeth restored with an indirect composite resin; (5) teeth restored with injected ceramic inlays (IPS Empress 2 (Ivoclar); (6) teeth restored with CAD/CAM inlays made of feldspathic ceramic (Vita Mark II). All of the indirect restorations were adhesively cemented. Strain-gauges were bonded to the buccal and lingual surfaces of the specimens. Compressive axial loading of 100N was applied on the occlusal face of the specimens to measure the cuspal deflection (microstrain) under compressive loading. These measurements were obtained before and after mechanical cycling (1 Hz, 37°C, 100,000x). Comparing the results obtained before and after fatiguing, the cuspal defection increased only in the CAD/CAM approach. The prepared tooth group had the highest cuspal defection, before and after mechanical cycling. The evaluated restoring approaches decrease the cuspal defection, consequently appear to improve the cuspal reinforcement.

  20. FSD-C10, a Fasudil derivative, promotes neuroregeneration through indirect and direct mechanisms

    PubMed Central

    Li, Yan-Hua; Xie, Chong; Zhang, Yuan; Li, Xing; Zhang, Hai-fei; Wang, Qing; Chai, Zhi; Xiao, Bao-guo; Thome, Rodolfo; Zhang, Guang-Xian; Ma, Cun-gen

    2017-01-01

    FSD-C10, a Fasudil derivative, was shown to reduce severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through the modulation of the immune response and induction of neuroprotective molecules in the central nervous system (CNS). However, whether FSD-C10 can promote neuroregeneration remains unknown. In this study, we further analyzed the effect of FSD-C10 on neuroprotection and remyelination. FSD-C10-treated mice showed a longer, thicker and more intense MAP2 and synaptophysin positive signal in the CNS, with significantly fewer CD4+ T cells, macrophages and microglia. Importantly, the CNS of FSD-C10-treated mice showed a shift of activated macrophages/microglia from the type 1 to type 2 status, elevated numbers of oligodendrocyte precursor cells (OPCs) and oligodendrocytes, and increased levels of neurotrophic factors NT-3, GDNF and BDNF. FSD-C10-treated microglia significantly inhibited Th1/Th17 cell differentiation and increased the number of IL-10+ CD4+ T cells, and the conditioned medium from FSD-C10-treated microglia promoted OPC survival and oligodendrocyte maturation. Addition of FSD-C10 directly promoted remyelination in a chemical-induced demyelination model on organotypic slice culture, in a BDNF-dependent manner. Together, these findings demonstrate that FSD-C10 promotes neural repair through mechanisms that involved both immunomodulation and induction of neurotrophic factors. PMID:28112256

  1. Mechanism of surface plasmon resonance sensing by indirect competitive inhibition immunoassay using Au nanoparticle labeled antibody.

    PubMed

    Kabiraz, Dulal C; Morita, Kinichi; Sakamoto, Kazuhira; Kawaguchi, Toshikazu

    2017-09-01

    We investigated the use of a surface plasmon resonance (SPR) biosensor using an antibody (Ab) labeled with Au-nanoparticle (Ab-AuNP conjugate). As clenbuterol is a small molecule, an indirect competitive inhibition immunoassay was used. The SPR immunoassay using Ab-AuNP conjugate had an extremely low limit of the detection (LOD) with a magnitude of 0.05 ppt (0.05pgmL(-1)), which was 40 times lower than that of unlabeled Ab. To identify the key factor in determining the LOD of the indirect competitive inhibition immunoassay, affinity constants of the surface immunoreaction (K1) and of the premixed solution (αK2) were evaluated. We found that the dielectric constant change due to AuNP labeling of Ab did not affect on the affinity constants, because all the amplification magnitude terms canceled out in the equations. Thus, the K1 and αK2 values were determined to 3.0×10(11)M(-1) and 2.9×10(12)M(-1), respectively, which were three and four orders of magnitude higher, respectively, than those of unlabeled Ab. The simulation plot of LOD with respect to K1 and αK2 showed that a K1 one order of magnitude lower than αK2 produced a ppt level LOD. Because the affinity constants are determined by the molar concentrations of reactant and product, the molar mass of the Ab or Ab-AuNP conjugate in the sample solution containing 1ppm (1μgmL(-1)) highly affects the constants. Consequently, molar mass adjustment can be used to adjust the LOD in an indirect competitive inhibition immunoassay as needed for a practical application. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Extracorporeal shock waves stimulate frog sciatic nerves indirectly via a cavitation-mediated mechanism.

    PubMed Central

    Schelling, G.; Delius, M.; Gschwender, M.; Grafe, P.; Gambihler, S.

    1994-01-01

    Shock waves (SWs) are single pressure pulses with amplitudes up to over 100 MPa, a rise time of only a few nanoseconds, and a short duration of approximately 2 microseconds. Their clinical application for stone destruction causes pain, indicating nerve stimulation by SWs. To examine this phenomenon, sciatic nerves of frogs were exposed to SWs in an organ bath. The SWs were generated with an experimental Dornier lithotripter model XL1 at an operating voltage of 15 kV. The nerves were mounted in a chamber which allowed electrical nerve stimulation and the registration of electrically and SW-induced compound action potentials (SWCAPs). The chamber was filled with frog Ringer's solution. In a standardized protocol. The first experiment established that 95.0 +/- 4.7% of administered SWs induced action potentials which were lower in amplitude (1.45 +/- 1.14 versus 1.95 +/- 0.95 mV, p = 0.004) but similar in shape to electrically induced compound action potentials. In a second experiment, it was shown that the site of origin of the SWCAPs could be correctly determined by simultaneous recording of action potentials at both ends of the nerve. The mechanism of shock wave stimulation was examined by experiments 3 and 4. In experiment 3, in contrast to the previous experiments, SW exposure of the nerves was performed 6 cm outside the shock wave focus. This resulted in a mean probability of inducing a SWCAP of only 4%. After gas bubble administration, this probability increased to 86% for the first SW released immediately after bubble application and declined to 56% for the second, 21% for the third, to 0 for the 10th SW after fluid injection. This indicates that cavitation, the interaction between shock waves and gas bubbles in fluid or tissues, was involved in SWCAP generation. In experiment 4, nerves were again exposed in the focus, however, the Ringer's solution surrounding the nerve was replaced by polyvinyl alcohol (PVA). PVA is a solution with low cavitation activity

  3. Posttraumatic torsional injury as an indirect cause of fibular intraneural ganglion cysts: case illustrations and potential mechanisms.

    PubMed

    Spinner, Robert J; Ibrahim Elshiekh, Mohanad Ahmed; Tubbs, R Shane; Turner, Norman S; Amrami, Kimberly K

    2012-07-01

    Trauma has been loosely associated with the development of fibular intraneural ganglion cysts. Sporadic reports of direct trauma to the proximal lateral leg in the region of the superior tibiofibular joint (STFJ) capsule support the development of a capsular rent and the subsequent egress of joint fluid from the articular joint. This report provides evidence to suggest that indirect trauma from torsion can link concomitant ankle injury and fibular nerve palsy (foot drop) and fibular intraneural ganglion cysts. We present two cases to illustrate different potential mechanisms. One patient sustained an ankle ligamentous injury which was translated through the interosseous membrane (IOM) to the proximal leg region, affecting the STFJ and the fibular nerve (ascending pathway). The second patient had blunt injury to the popliteal fossa in combination with a twisting injury to the leg. In this latter case we offer two plausible explanations: (1) combined knee and ankle injury resulting in an ascending pathway mechanism; and (2) a knee injury which disrupted the STFJ, resulting in a translational force down the leg (descending pathway). We believe that fibular intraneural cysts from the STFJ result from direct and indirect trauma. Additional reports of similar cases and sophisticated biomechanical testing will allow us to delineate the exact mechanisms for these injury patterns.

  4. Effects of feral horses in Great Basin landscapes on soils and ants: Direct and indirect mechanisms

    USGS Publications Warehouse

    Beever, E.A.; Herrick, J.E.

    2006-01-01

    We compared soil-surface penetration resistance and abundance of ant mounds at 12 western Great Basin sites (composed of 19 plots) either grazed by feral horses (Equus caballus) or having had horses removed for the last 10–14 years. Across this broad spatial domain (3.03 million ha), we minimized confounding due to abiotic factors by selecting horse-occupied and horse-removed sites with similar aspect, slope, fire history, grazing pressure by cattle (minimal to none), and dominant vegetation (Artemisia tridentata). During both 1997 and 1998, we found 2.2–8.4 times greater abundance of ant mounds and 3.0–15.4 times lower penetration resistance in soil surfaces at horse-removed sites. In 1998, thatched Formica ant mounds, which existed predominately at high elevations, were 3.3 times more abundant at horse-removed sites, although abundance varied widely among sites within treatments. Several types of analyses suggested that horses rather than environmental variability were the primary source of treatment differences we observed in ecosystem components. Tests of several predictions suggest that alterations occurred through not only direct effects, but also indirect effects and potentially feedback loops. Free-roaming horses as well as domestic grazers should be considered in conservation planning and land management in the Great Basin, an ecoregion that represents both an outstanding conservation opportunity and challenge.

  5. Mechanisms for indirect effects from aerosol pollution on mixed-phase clouds

    NASA Astrophysics Data System (ADS)

    Phillips, Vaughan

    2015-04-01

    Aerosol pollution can have various effects on mixed-phase clouds. They can alter coalescence and raindrop-freezing for droplet activation by CCN aerosols. They can alter aggregation of ice crystals and snow formation. This can alter the lifetime of mixed-phase clouds, as well as the reflectivity for solar radiation. Simulations of observed cases of mixed-phase clouds have been performed to examine the mechanisms for effects from aerosol pollution on them. Such mechanisms are discussed in the presentation.

  6. A Review of Molecular Mechanisms Involved in Toxicity of Nanoparticles

    PubMed Central

    Khalili Fard, Javad; Jafari, Samira; Eghbal, Mohammad Ali

    2015-01-01

    In recent decades, the use of nanomaterials has received much attention in industrial and medical fields. However, some reports have mentioned adverse effects of these materials on the biological systems and cellular components. There are several major mechanisms for cytotoxicity of nanoparticles (NPs) such as physicochemical properties, contamination with toxic element, fibrous structure, high surface charge and radical species generation. In this review, a brief key mechanisms involved in toxic effect of NPs are given, followed by the in vitro toxicity assays of NPs and prooxidant effects of several NPs such as carbon nanotubes, titanium dioxide NPs, quantum dots, gold NPs and silver NPs. PMID:26819915

  7. Effect of different mechanical and chemical surface treatments on the repaired bond strength of an indirect composite resin.

    PubMed

    Kimyai, Soodabeh; Oskoee, Siavash Savadi; Mohammadi, Narmin; Rikhtegaran, Sahand; Bahari, Mahmoud; Oskoee, Parnian Alizadeh; Vahedpour, Hafez

    2015-02-01

    This study compared the effects of two mechanical surface preparation techniques, air abrasion and Nd:YAG laser, with the use of two adhesive systems, self-etch and etch and rinse, on the repair bond strengths of an indirect composite resin. One hundred fifty cylindrical samples of an indirect composite resin were prepared and randomly divided into six groups (n = 25). In groups 1-3, the composite resin surfaces were respectively prepared as follows: no roughening, roughening by air abrasion, and roughening by Nd:YAG laser, followed by application of an etch-and-rinse adhesive. In groups 4-6, the preparation techniques were respectively the same as those in groups 1-3, followed by application of a self-etch adhesive. Subsequently, a direct composite resin was added and repair bond strengths were measured. Data were analyzed with two-way ANOVA and post hoc Tukey's test. Mean bond strength value was significant based on the preparation technique (P < 0.001), i.e., in air abrasion and Nd:YAG laser groups, bond strengths were significantly higher compared to no-preparation groups (P < 0.0005). There were significant differences in bond strength values between air abrasion and Nd:YAG laser groups, with significantly higher values in air abrasion groups (P < 0.0005). However, there were no significant differences in bond strength values between the adhesive systems. Furthermore, the cumulative effects of the adhesive system and the surface preparation technique were not significant. Surface preparation of the indirect composite resin with air abrasion and Nd:YAG laser resulted in a significant increase in the repair bond strength, with air abrasion being more effective. There were no significant differences in bond strength between the two adhesives.

  8. Mechanisms of and facility types involved in hazardous materials incidents.

    PubMed Central

    Kales, S N; Polyhronopoulos, G N; Castro, M J; Goldman, R H; Christiani, D C

    1997-01-01

    The purpose of this study was to systematically investigate hazardous materials (hazmat) releases and determine the mechanisms of these accidents, and the industries/activities and chemicals involved. We analyzed responses by Massachusetts' six district hazmat teams from their inception through May 1996. Information from incident reports was extracted onto standard coding sheets. The majority of hazardous materials incidents were caused by spills, leaks, or escapes of hazardous materials (76%) and occurred at fixed facilities (80%). Transportation-related accidents accounted for 20% of incidents. Eleven percent of hazardous materials incidents were at schools or health care facilities. Petroleum-derived fuels were involved in over half of transportation-related accidents, and these accounted for the majority of petroleum fuel releases. Chlorine derivatives were involved in 18% of all accidents and were associated with a wide variety of facility types and activities. In conclusion, systematic study of hazardous materials incidents allows the identification of preventable causes of these incidents. PMID:9300926

  9. A study of indirect reciprocity involving a reputation system or a simple tag system in a one-shot, multi-player game.

    PubMed

    Tanimoto, Jun

    2007-01-01

    The possibility of the evolution of cooperation backed by indirect reciprocity (IDR) in a one-shot, multi-player game is investigated focusing on two mechanisms. First of all, the reputation system with image score (RS with IS), as proposed by Nowak and Sigmund [Nowak, M.A., Sigmund, K., 1998. Evolution of indirect reciprocity by image scoring. Nature 393, 573-577], is investigated in various game structures. A numerical experiment demonstrates that the RS with IS is a robust mechanism for the support of IDR in various dilemma games, but whose effectiveness decreases with an increase in the number of players in a game. It is fair to say that the RS is an information mapping function to relate between player's cooperative fraction on his action and IS. As the second mechanism, a simple tag system which could be applicable to animals having no cognitive complexity is considered to support IDR. Computer simulations of the tag system's strategy for invading a population initially consisting of AllD, AllC, and Random strategies suggest several novel facts. The Tag strategy with plausible crossover and mutation probabilities can only invade to settle down if the game structure is not Trivial and contains a moderate dilemma. The Tag strategy's evolutionary competition takes place mainly in the presence of the AllD strategy. During the competition, the Tag strategy frequently metamorphoses to shake off the AllD strategy, but stops after winning in order to avoid a shrinking payoff due to fragmentation.

  10. Molecular Mechanisms in Mood Regulation Involving the Circadian Clock

    PubMed Central

    Albrecht, Urs

    2017-01-01

    The circadian system coordinates activities and functions in cells and tissues in order to optimize body functions in anticipation to daily changes in the environment. Disruption of the circadian system, due to irregular lifestyle such as rotating shift work, frequent travel across time-zones, or chronic stress, is correlated with several diseases such as obesity, cancer, and neurological disorders. Molecular mechanisms linking the circadian clock with neurological functions have been uncovered suggesting that disruption of the clock may be critically involved in the development of mood disorders. In this mini-review, I will summarize molecular mechanisms in which clock components play a central role for mood regulation. Such mechanisms have been identified in the monoaminergic system, the HPA axis, and neurogenesis. PMID:28223962

  11. Molecular Mechanisms in Mood Regulation Involving the Circadian Clock.

    PubMed

    Albrecht, Urs

    2017-01-01

    The circadian system coordinates activities and functions in cells and tissues in order to optimize body functions in anticipation to daily changes in the environment. Disruption of the circadian system, due to irregular lifestyle such as rotating shift work, frequent travel across time-zones, or chronic stress, is correlated with several diseases such as obesity, cancer, and neurological disorders. Molecular mechanisms linking the circadian clock with neurological functions have been uncovered suggesting that disruption of the clock may be critically involved in the development of mood disorders. In this mini-review, I will summarize molecular mechanisms in which clock components play a central role for mood regulation. Such mechanisms have been identified in the monoaminergic system, the HPA axis, and neurogenesis.

  12. Prevalence of Underprescription or Overprescription of Energy Needs in Critically Ill Mechanically Ventilated Adults as Determined by Indirect Calorimetry: A Systematic Literature Review.

    PubMed

    Tatucu-Babet, Oana A; Ridley, Emma J; Tierney, Audrey C

    2016-02-01

    Underfeeding and overfeeding has been associated with adverse patient outcomes. Resting energy expenditure can be measured using indirect calorimetry. In its absence, predictive equations are used. A systematic literature review was conducted to determine the prevalence of underprescription and overprescription of energy needs in adult mechanically ventilated critically ill patients by comparing predictive equations to indirect calorimetry measurements. Ovid MEDLINE, CINAHL Plus, Scopus, and EMBASE databases were searched in May 2013 to identify studies that used both predictive equations and indirect calorimetry to determine energy expenditure. Reference lists of included publications were also searched. The number of predictive equations that underestimated or overestimated energy expenditure by ±10% when compared to indirect calorimetry measurements were noted at both an individual and group level. In total, 2349 publications were retrieved, with 18 studies included. Of the 160 variations of 13 predictive equations reviewed at a group level, 38% underestimated and 12% overestimated energy expenditure by more than 10%. The remaining 50% of equations estimated energy expenditure to within ±10 of indirect calorimetry measurements. On an individual patient level, predictive equations underestimated and overestimated energy expenditure in 13-90% and 0-88% of patients, respectively. Differences of up to 43% below and 66% above indirect calorimetry values were observed. Large discrepancies exist between predictive equation estimates and indirect calorimetry measurements in individuals and groups. Further research is needed to determine the influence of indirect calorimetry and predictive equation limitations in contributing to these observed differences. © 2015 American Society for Parenteral and Enteral Nutrition.

  13. Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review

    PubMed Central

    Borges, Juliana Pereira; Lessa, Marcos Adriano

    2015-01-01

    Background Acute myocardial infarction is the leading cause of morbidity and mortality worldwide. Furthermore, research has shown that exercise, in addition to reducing cardiovascular risk factors, can also protect the heart against injury due to ischemia and reperfusion through a direct effect on the myocardium. However, the specific mechanism involved in exerciseinduced cardiac preconditioning is still under debate. Objective To perform a systematic review of the studies that have addressed the mechanisms by which aerobic exercise promotes direct cardioprotection against ischemia and reperfusion injury. Methods A search was conducted using MEDLINE, Literatura Latino-Americana e do Caribe de Informação em Ciências da Saúde, and Scientific Electronic Library Online databases. Data were extracted in a standardized manner by two independent researchers, who were responsible for assessing the methodological quality of the studies. Results The search retrieved 78 studies; after evaluating the abstracts, 30 studies were excluded. The manuscripts of the remaining 48 studies were completely read and, of these, 20 were excluded. Finally, 28 studies were included in this systematic review. Conclusion On the basis of the selected studies, the following are potentially involved in the cardioprotective response to exercise: increased heat shock protein production, nitric oxide pathway involvement, increased cardiac antioxidant capacity, improvement in ATP-dependent potassium channel function, and opioid system activation. Despite all the previous investigations, further research is still necessary to obtain more consistent conclusions. PMID:25830711

  14. Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review.

    PubMed

    Borges, Juliana Pereira; Lessa, Marcos Adriano

    2015-07-01

    Acute myocardial infarction is the leading cause of morbidity and mortality worldwide. Furthermore, research has shown that exercise, in addition to reducing cardiovascular risk factors, can also protect the heart against injury due to ischemia and reperfusion through a direct effect on the myocardium. However, the specific mechanism involved in exerciseinduced cardiac preconditioning is still under debate. To perform a systematic review of the studies that have addressed the mechanisms by which aerobic exercise promotes direct cardioprotection against ischemia and reperfusion injury. A search was conducted using MEDLINE, Literatura Latino-Americana e do Caribe de Informação em Ciências da Saúde, and Scientific Electronic Library Online databases. Data were extracted in a standardized manner by two independent researchers, who were responsible for assessing the methodological quality of the studies. The search retrieved 78 studies; after evaluating the abstracts, 30 studies were excluded. The manuscripts of the remaining 48 studies were completely read and, of these, 20 were excluded. Finally, 28 studies were included in this systematic review. On the basis of the selected studies, the following are potentially involved in the cardioprotective response to exercise: increased heat shock protein production, nitric oxide pathway involvement, increased cardiac antioxidant capacity, improvement in ATP-dependent potassium channel function, and opioid system activation. Despite all the previous investigations, further research is still necessary to obtain more consistent conclusions.

  15. Cardioproteomics: advancing the discovery of signaling mechanisms involved in cardiovascular diseases

    PubMed Central

    Cui, Ziyou; Dewey, Shannamar; Gomes, Aldrin V

    2011-01-01

    Cardioproteomics (Cardiovascular proteomics) is fast becoming an indispensible technique in deciphering changes in signaling pathways that occur in cardiovascular diseases (CVDs). The quality and availability of the instruments and bioinformatics software used for cardioproteomics continues to improve, and these techniques are now available to most cardiovascular researchers either directly or indirectly via university core centers. The heart and aorta are specialized tissues which present unique challenges to investigate. Currently, the diverse range of proteomic techniques available for cardiovascular research makes the choice of the best method or best combination of methods for the disease parameter(s) being investigated as important as the equipment used. This review focuses on proteomic techniques and their applications which have advanced our understanding of the signaling mechanisms involved in CVDs at the levels of protein complex/protein-protein interaction, post-translational modifications and signaling induced protein changes. PMID:22254205

  16. Mechanisms Involved in the Aging-Induced Vascular Dysfunction

    PubMed Central

    El Assar, Mariam; Angulo, Javier; Vallejo, Susana; Peiró, Concepción; Sánchez-Ferrer, Carlos F.; Rodríguez-Mañas, Leocadio

    2012-01-01

    Vascular aging is a key process determining health status of aged population. Aging is an independent cardiovascular risk factor associated to an impairment of endothelial function, which is a very early and important event leading to cardiovascular disease. Vascular aging, formerly being considered an immutable and inexorable risk factor, is now viewed as a target process for intervention in order to achieve a healthier old age. A further knowledge of the mechanisms underlying the age-related vascular dysfunction is required to design an adequate therapeutic strategy to prevent or restore this impairment of vascular functionality. Among the proposed mechanisms that contribute to age-dependent endothelial dysfunction, this review is focused on the following aspects occurring into the vascular wall: (1) the reduction of nitric oxide (NO) bioavailability, caused by diminished NO synthesis and/or by augmented NO scavenging due to oxidative stress, leading to peroxynitrite formation (ONOO−); (2) the possible sources involved in the enhancement of oxidative stress; (3) the increased activity of vasoconstrictor factors; and (4) the development of a low-grade pro-inflammatory environment. Synergisms and interactions between all these pathways are also analyzed. Finally, a brief summary of some cellular mechanisms related to endothelial cell senescence (including telomere and telomerase, stress-induced senescence, as well as sirtuins) are implemented, as they are likely involved in the age-dependent endothelial dysfunction, as well as in the lower vascular repairing capacity observed in the elderly. Prevention or reversion of those mechanisms leading to endothelial dysfunction through life style modifications or pharmacological interventions could markedly improve cardiovascular health in older people. PMID:22783194

  17. Mechanisms involved in the aging-induced vascular dysfunction.

    PubMed

    El Assar, Mariam; Angulo, Javier; Vallejo, Susana; Peiró, Concepción; Sánchez-Ferrer, Carlos F; Rodríguez-Mañas, Leocadio

    2012-01-01

    Vascular aging is a key process determining health status of aged population. Aging is an independent cardiovascular risk factor associated to an impairment of endothelial function, which is a very early and important event leading to cardiovascular disease. Vascular aging, formerly being considered an immutable and inexorable risk factor, is now viewed as a target process for intervention in order to achieve a healthier old age. A further knowledge of the mechanisms underlying the age-related vascular dysfunction is required to design an adequate therapeutic strategy to prevent or restore this impairment of vascular functionality. Among the proposed mechanisms that contribute to age-dependent endothelial dysfunction, this review is focused on the following aspects occurring into the vascular wall: (1) the reduction of nitric oxide (NO) bioavailability, caused by diminished NO synthesis and/or by augmented NO scavenging due to oxidative stress, leading to peroxynitrite formation (ONOO(-)); (2) the possible sources involved in the enhancement of oxidative stress; (3) the increased activity of vasoconstrictor factors; and (4) the development of a low-grade pro-inflammatory environment. Synergisms and interactions between all these pathways are also analyzed. Finally, a brief summary of some cellular mechanisms related to endothelial cell senescence (including telomere and telomerase, stress-induced senescence, as well as sirtuins) are implemented, as they are likely involved in the age-dependent endothelial dysfunction, as well as in the lower vascular repairing capacity observed in the elderly. Prevention or reversion of those mechanisms leading to endothelial dysfunction through life style modifications or pharmacological interventions could markedly improve cardiovascular health in older people.

  18. In vitro adventitious shoot regeneration via indirect organogenesis from inflorescence explants and peroxidase involvement in morphogenesis of Populus euphratica Olivier.

    PubMed

    Zhou, Yan; Gao, Ziyang; Gao, Shumin; Sun, Fangfang; Cheng, Pengjun; Li, Fenglan

    2012-12-01

    The inflorescences as explants for rapid propagation in vitro remained unknown in Populus euphratica Olivier. Here, we reported that multiple shoots were initiation from calli of both male and female inflorescences. The optimum medium for shoot induction from male inflorescences was lactose sulfite medium containing 1.0 mg L(-1) 6-benzylaminopurine (BA) and 0.5 mg L(-1) α-naphthalene acetic acid (NAA) or Murashige and Skoog (MS) medium containing 0.5 mg L(-1) BA and 0.2 mg L(-1) NAA. The optimum medium of shoot induction from female inflorescence calli was the MS medium containing 0.5 mg L(-1) BA and 0.2 mg L(-1) NAA. Rooting of regenerated shoots was obtained on 1/2 MS medium supplemented with 0.5∼1.0 mg L(-1) indole-3-butyric acid (IBA) and the highest frequency rooting was on medium containing 0.5 mg L(-1) IBA. No shoots were obtained on medium without BA and NAA. Peroxidase (POD) activity was measured by polyacrylamide gel electrophoresis during shoot induction and differentiation stages. The results showed that two bands of POD (2a and 2b) activity appeared lowest during the early 8 days at the dedifferentiation phase of leaves inducing calli, whereas POD 2a, 2b activity appeared to be increasing at the homeochronous dedifferentiation phase of inflorescence. Five most intensive bands, POD 1a, 1b, 1c, 2a, and ab, appeared in 8th and 28th days at the redifferentiation phase during shoot morphogenesis. These results demonstrated that the POD was involved in shoot morphogenesis from both leaf and inflorescence explants of Populus euphratica.

  19. Indirect role of alpha2-adrenoreceptors in anti-ulcer effect mechanism of nimesulide in rats.

    PubMed

    Suleyman, Halis; Halici, Zekai; Cadirci, Elif; Hacimuftuoglu, Ahmet; Keles, Sait; Gocer, Fatma

    2007-05-01

    Nimesulide, a non-steroidal, anti-inflammatory drug, produces ulcerogenic effects in adrenalectomized rats but is gastro-protective in intact rats. The objective of this study was to determine whether adrenal gland hormones are involved in the anti-ulcer effects of nimesulide. The results revealed that 100 mg/kg nimesulide produces gastric ulceration in adrenalectomized rats, which is prevented by prednisolone and adrenaline. The anti-ulcer effects of adrenaline and prednisolone in adrenalectomized rats were in turn antagonized by yohimbine, a selective alpha(2)-receptor blocker, but not by doxazosine (alpha(1)-receptor blocker) or propranolol (beta-blocker). Adrenaline prevented the formation of indomethacin-induced ulcers in both adrenalectomized and intact rats, but prednisolone increased the indomethacin-induced ulcerous area in intact rats, whereas it decreased the size of the ulcers in adrenalectomized rats. In addition, prednisolone prevented ulcer formation in intact rats in which the adrenaline concentration had been decreased by metyrosine. These results suggest that glucocorticoids are anti-ulcerogenic in not only adrenalectomized rats but also in intact rats with diminished circulating levels of adrenaline. In the light of these data, the effect of nimesulide on plasma adrenaline concentrations was studied. In comparison to the adrenaline levels found in intact control rats, the administration of nimesulide at doses of 10, 20, 40 and 100 mg/kg decreased adrenaline concentrations by 12.8, 22.6, 30.4, and 58.2%, respectively, without affecting blood corticosterone concentrations. The anti-ulcer effect of nimesulide was observed to be dose-dependent, and the strength of this effect was directly correlated the decreasing concentration of adrenaline. The concentration of adrenaline was decreased by 60.9% in rats treated with 300 mg/kg metyrosine in which prednisolone produced anti-ulcer effects. In summary, we have shown that nimesulide produces its anti

  20. Indirection and computer security.

    SciTech Connect

    Berg, Michael J.

    2011-09-01

    The discipline of computer science is built on indirection. David Wheeler famously said, 'All problems in computer science can be solved by another layer of indirection. But that usually will create another problem'. We propose that every computer security vulnerability is yet another problem created by the indirections in system designs and that focusing on the indirections involved is a better way to design, evaluate, and compare security solutions. We are not proposing that indirection be avoided when solving problems, but that understanding the relationships between indirections and vulnerabilities is key to securing computer systems. Using this perspective, we analyze common vulnerabilities that plague our computer systems, consider the effectiveness of currently available security solutions, and propose several new security solutions.

  1. Neurophysiological mechanisms involved in language learning in adults

    PubMed Central

    Rodríguez-Fornells, Antoni; Cunillera, Toni; Mestres-Missé, Anna; de Diego-Balaguer, Ruth

    2009-01-01

    Little is known about the brain mechanisms involved in word learning during infancy and in second language acquisition and about the way these new words become stable representations that sustain language processing. In several studies we have adopted the human simulation perspective, studying the effects of brain-lesions and combining different neuroimaging techniques such as event-related potentials and functional magnetic resonance imaging in order to examine the language learning (LL) process. In the present article, we review this evidence focusing on how different brain signatures relate to (i) the extraction of words from speech, (ii) the discovery of their embedded grammatical structure, and (iii) how meaning derived from verbal contexts can inform us about the cognitive mechanisms underlying the learning process. We compile these findings and frame them into an integrative neurophysiological model that tries to delineate the major neural networks that might be involved in the initial stages of LL. Finally, we propose that LL simulations can help us to understand natural language processing and how the recovery from language disorders in infants and adults can be accomplished. PMID:19933142

  2. [Ocular involvement in spondylarthritis--new mechanisms, new therapies].

    PubMed

    Itulescu, T C M; Alexandrescu, Cristina; Voinea, Liliana-Mary

    2014-01-01

    Spondyloarthrites (SPA) represent a group of heterogenous rheumatic diseases (ankylosing spondylitis/SA, psoriatic arthritis/PsA, reactive arthritis/ReA, spondyloarthritis in bowel inflammatory diseases/BID, undifferentiated spondyloarthritis/undif SpA) with distinct clinical features and common genetic predisposition (HLA-B27). SpA may also affect other organs, ocular involvement, represented by uveitis and conjunctivitis, being one of the most important extraskeletal manifestations. Pathogenic mechanisms of ocular involment in SpA are not entirely known; nevertheless, the inflammatory process which characterizes the main rheumatic diseases seems to be responsible for this extraskeletal manifestation. SpA treatment targeted at clinical remission has a favourable effect not only on articular but also on ocular involvement. The discovery of new pathogenic mechanisms of both rheumatic and eye disease in SpA have contributed to identification of new pathogenic therapies. The interdisciplinary team work of rheumatologists and ophtalmologists have prove essential for the management of SpA patients with ocular manifestations.

  3. MP-4 Contributes to Snake Venom Neutralization by Mucuna pruriens Seeds through an Indirect Antibody-mediated Mechanism.

    PubMed

    Kumar, Ashish; Gupta, Chitra; Nair, Deepak T; Salunke, Dinakar M

    2016-05-20

    Mortality due to snakebite is a serious public health problem, and available therapeutics are known to induce debilitating side effects. Traditional medicine suggests that seeds of Mucuna pruriens can provide protection against the effects of snakebite. Our aim is to identify the protein(s) that may be important for snake venom neutralization and elucidate its mechanism of action. To this end, we have identified and purified a protein from M. pruriens, which we have named MP-4. The full-length polypeptide sequence of MP-4 was obtained through N-terminal sequencing of peptide fragments. Sequence analysis suggested that the protein may belong to the Kunitz-type protease inhibitor family and therefore may potentially neutralize the proteases present in snake venom. Using various structural and biochemical tools coupled with in vivo assays, we are able to show that MP-4 does not afford direct protection against snake venom because it is actually a poor inhibitor of serine proteases. Further experiments showed that antibodies generated against MP-4 cross-react with the whole venom and provide protection to mice against Echis carinatus snake venom. This study shows that the MP-4 contributes significantly to the snake venom neutralization activity of M. pruriens seeds through an indirect antibody-mediated mechanism.

  4. Açaí (Euterpe oleracea Mart.) Modulates Oxidative Stress Resistance in Caenorhabditis elegans by Direct and Indirect Mechanisms

    PubMed Central

    Bonomo, Larissa de Freitas; Silva, David Nunes; Boasquivis, Patrícia Ferreira; Paiva, Franciny Aparecida; Guerra, Joyce Ferreira da Costa; Martins, Talita Alves Faria; de Jesus Torres, Álvaro Gustavo; de Paula, Igor Thadeu Borges Raposo; Caneschi, Washington Luiz; Jacolot, Philippe; Grossin, Nicolas; Tessier, Frederic J.; Boulanger, Eric; Silva, Marcelo Eustáquio; Pedrosa, Maria Lúcia; de Paula Oliveira, Riva

    2014-01-01

    Açaí (Euterpe oleracea Mart.) has recently emerged as a promising source of natural antioxidants. Despite its claimed pharmacological and nutraceutical value, studies regarding the effects of açaí in vivo are limited. In this study, we use the Caenorhabditis elegans model to evaluate the in vivo antioxidant properties of açaí on an organismal level and to examine its mechanism of action. Supplementation with açaí aqueous extract (AAE) increased both oxidative and osmotic stress resistance independently of any effect on reproduction and development. AAE suppressed bacterial growth, but this antimicrobial property did not influence stress resistance. AAE-increased stress resistance was correlated with reduced ROS production, the prevention of sulfhydryl (SH) level reduction and gcs-1 activation under oxidative stress conditions. Our mechanistic studies indicated that AAE promotes oxidative stress resistance by acting through DAF-16 and the osmotic stress response pathway OSR-1/UNC-43/SEK-1. Finally, AAE increased polyglutamine protein aggregation and decreased proteasome activity. Our findings suggest that natural compounds available in AAE can improve the antioxidant status of a whole organism under certain conditions by direct and indirect mechanisms. PMID:24594796

  5. Multiple direct and indirect mechanisms drive estrogen-induced tumor growth in high grade serous ovarian cancers.

    PubMed

    Ciucci, Alessandra; Zannoni, Gian Franco; Buttarelli, Marianna; Lisi, Lucia; Travaglia, Daniele; Martinelli, Enrica; Scambia, Giovanni; Gallo, Daniela

    2016-02-16

    The notion that menopausal estrogen replacement therapy increases ovarian cancer risk, but only for the two more common types (i.e. serous and endometrioid), while possibly decreasing risk for clear cell tumors, is strongly suggestive of causality. However, whether estradiol (E2) is tumorigenic or promotes development of occult preexisting disease is unknown. The present study investigated molecular and cellular mechanisms by which E2 modulates the growth of high grade serous ovarian cancer (HGSOC). Results showed that ERα expression was necessary and sufficient to induce the growth of HGSOC cells in in vitro models. Conversely, in vivo experimental studies demonstrated that increasing the levels of circulating estrogens resulted in a significant growth acceleration of ERα-negative HGSOC xenografts, as well. Tumors from E2-treated mice had significantly higher proliferation rate, angiogenesis, and density of tumor-associated macrophage (TAM) compared to ovariectomized females. Accordingly, immunohistochemical analysis of ERα-negative tissue specimens from HGSOC patients showed a significantly greater TAM infiltration in premenopausal compared to postmenopausal women. This study describes novel insights into the impact of E2 on tumor microenvironment, independently of its direct effect on tumor cell growth, thus supporting the idea that multiple direct and indirect mechanisms drive estrogen-induced tumor growth in HGSOC.

  6. Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches

    PubMed Central

    Hajishengallis, George; Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia; Lambris, John D.

    2015-01-01

    The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis. PMID:26306443

  7. Mechanism of Oligonucleotide Uptake by Cells: Involvement of Specific receptors?

    NASA Astrophysics Data System (ADS)

    Yakubov, Leonid A.; Deeva, Elena A.; Zarytova, Valentina F.; Ivanova, Eugenia M.; Ryte, Antonina S.; Yurchenko, Lyudmila V.; Vlassov, Valentin V.

    1989-09-01

    We have investigated the interaction of oligonucleotides and their alkylating derivatives with mammalian cells. In experiments with L929 mouse fibroblast and Krebs 2 ascites carcinoma cells, it was found that cellular uptake of oligodeoxynucleotide derivatives is achieved by an endocytosis mechanism. Uptake is considerably more efficient at low oligomer concentration (< 1 μ M), because at this concentration a significant percentage of the total oligomer pool is absorbed on the cell surface and internalized by a more efficient absorptive endocytosis process. Two modified proteins were detected in mouse fibroblasts that were treated with the alkylating oligonucleotide derivatives. The binding of the oligomers to the proteins is inhibited by other oligodeoxynucleotides, single- and double-stranded DNA, and RNA. The polyanions heparin and chondroitin sulfates A and B do not inhibit binding. These observations suggest the involvement of specific receptor proteins in binding of oligomers to mammalian cells.

  8. Complications involving the extensor mechanism after total knee arthroplasty.

    PubMed

    Papalia, Rocco; Vasta, Sebastiano; D'Adamio, Stefano; Albo, Erika; Maffulli, Nicola; Denaro, Vincenzo

    2015-12-01

    To overview the complications involving extensor apparatus of the knee following total knee arthroplasty (TKA) and to summarize which are the lines of treatment available and their reported outcomes in literature. A comprehensive search of several databases was performed using as basic keywords "complications after TKA", "extensor mechanism disruption", "periprosthetic patellar fracture", "quadriceps tendon rupture", "quadriceps tendon rupture" isolated or combined with other terms by using Boolean operators. The methodological quality of each article was also evaluated using the Coleman methodology score (CMS). Twenty-nine studies were evaluated. The mean CMS of the studies selected was 33.1/100. Patellar fractures, requiring surgical treatment when there is rupture of the extensor mechanism or loosening of the patellar component, were treated surgically in 28.1 % of patients. The patellar and quadriceps tendon ruptures were surgically treated with reconstruction or augmented repair, respectively, in 98.6 and 76.5 %. Complications involving the extensor apparatus of the knee following a TKA need early and appropriate management to avoid their devastating influence on joint functionality. Management has to be evaluated very carefully based on the site of the lesion, integrity of the prosthetic components and surrounding tissue to restore, and the patients' individual characteristics. The surgical approach for comminuted periprosthetic fractures and reconstruction of torn tendons of the extensor apparatus are needed to restore function and decrease pain, but, given the poor methodological quality of the studies published so far, it is not clear which surgical technique or graft leads to better outcomes. Therefore, there is an absolute need for better designed comparative trials producing clearer and stronger evidence on this critical matter. IV.

  9. Effects of distraction on muscle length: mechanisms involved in sarcomerogenesis.

    PubMed

    Caiozzo, Vincent J; Utkan, Ali; Chou, Richard; Khalafi, Afshin; Chandra, Heena; Baker, Michael; Rourke, Bryan; Adams, Greg; Baldwin, Ken; Green, Stuart

    2002-10-01

    Although a great deal of interest has been given to understanding the mechanisms involved in regulating the radial growth that occurs because of resistance training, much less has been given to studying the longitudinal growth of skeletal muscle that occurs because of passive stretch. The current authors provide a brief overview of key issues relevant to the longitudinal growth of skeletal muscle that occurs during distraction osteogenesis. Specifically, five key issues are addressed: (1) the pattern of sarcomerogenesis during distraction; (2) sarcomerogenesis and altered expression of sarcomeric and nonsarcomeric genes; (3) the satellite cell hypothesis; (4) mitogenic factors; and (5) new approaches for studying the longitudinal growth of skeletal muscle. A discussion is provided that revolves around the concept of a negative feedback loop. One of the most interesting issues to be resolved in muscle biology is the role of satellite cells in regulating the growth of skeletal muscle. Currently, it is not known whether satellite cell activation is a prerequisite for the longitudinal growth of skeletal muscle. Gene chip analyses provide a paradoxical view, showing that distraction osteogenesis results in the upregulation of a gene, GADD45, involved with growth arrest and deoxyribonucleic acid destruction.

  10. Ventralization of an indirect developing hemichordate by NiCl₂ suggests a conserved mechanism of dorso-ventral (D/V) patterning in Ambulacraria (hemichordates and echinoderms).

    PubMed

    Röttinger, E; Martindale, M Q

    2011-06-01

    One of the earliest steps in embryonic development is the establishment of the future body axes. Morphological and molecular data place the Ambulacraria (echinoderms and hemichordates) within the Deuterostomia and as the sister taxon to chordates. Extensive work over the last decades in echinoid (sea urchins) echinoderms has led to the characterization of gene regulatory networks underlying germ layer specification and axis formation during embryogenesis. However, with the exception of recent studies from a direct developing hemichordate (Saccoglossus kowalevskii), very little is known about the molecular mechanism underlying early hemichordate development. Unlike echinoids, indirect developing hemichordates retain the larval body axes and major larval tissues after metamorphosis into the adult worm. In order to gain insight into dorso-ventral (D/V) patterning, we used nickel chloride (NiCl₂), a potent ventralizing agent on echinoderm embryos, on the indirect developing enteropneust hemichordate, Ptychodera flava. Our present study shows that NiCl₂ disrupts the D/V axis and induces formation of a circumferential mouth when treated before the onset of gastrulation. Molecular analysis, using newly isolated tissue-specific markers, shows that the ventral ectoderm is expanded at expense of dorsal ectoderm in treated embryos, but has little effect on germ layer or anterior-posterior markers. The resulting ventralized phenotype, the effective dose, and the NiCl₂ sensitive response period of Ptychodera flava, is very similar to the effects of nickel on embryonic development described in larval echinoderms. These strong similarities allow one to speculate that a NiCl₂ sensitive pathway involved in dorso-ventral patterning may be shared between echinoderms, hemichordates and a putative ambulacrarian ancestor. Furthermore, nickel treatments ventralize the direct developing hemichordate, S. kowalevskii indicating that a common pathway patterns both larval and adult

  11. Cellular and Humoral Mechanisms Involved in the Control of Tuberculosis

    PubMed Central

    Zuñiga, Joaquin; Torres-García, Diana; Santos-Mendoza, Teresa; Rodriguez-Reyna, Tatiana S.; Granados, Julio; Yunis, Edmond J.

    2012-01-01

    Mycobacterium tuberculosis (Mtb) infection is a major international public health problem. One-third of the world's population is thought to have latent tuberculosis, a condition where individuals are infected by the intracellular bacteria without active disease but are at risk for reactivation, if their immune system fails. Here, we discuss the role of nonspecific inflammatory responses mediated by cytokines and chemokines induced by interaction of innate receptors expressed in macrophages and dendritic cells (DCs). We also review current information regarding the importance of several cytokines including IL-17/IL-23 in the development of protective cellular and antibody-mediated protective responses against Mtb and their influence in containment of the infection. Finally, in this paper, emphasis is placed on the mechanisms of failure of Mtb control, including the immune dysregulation induced by the treatment with biological drugs in different autoimmune diseases. Further functional studies, focused on the mechanisms involved in the early host-Mtb interactions and the interplay between host innate and acquired immunity against Mtb, may be helpful to improve the understanding of protective responses in the lung and in the development of novel therapeutic and prophylactic tools in TB. PMID:22666281

  12. Introduction to Special Section: Mechanical Involvement of Fluids in Faulting

    NASA Astrophysics Data System (ADS)

    Hickman, Stephen; Sibson, Richard; Bruhn, Ronald

    1995-07-01

    A growing body of evidence suggests that fluids are intimately linked to a variety of faulting processes. These include the long term structural and compositional evolution of fault zones; fault creep; and the nucleation, propagation, arrest, and recurrence of earthquake ruptures. Besides the widely recognized physical role of fluid pressures in controlling the strength of crustal fault zones, it is also apparent that fluids can exert mechanical influence through a variety of chemical effects. The United States Geological Survey sponsored a Conference on the Mechanical Effects of Fluids in Faulting under the auspices of the National Earthquake Hazards Reduction Program at Fish Camp, California, from June 6 to 10, 1993. The purpose of the conference was to draw together and to evaluate the disparate evidence for the involvement of fluids in faulting; to establish communication on the importance of fluids in the mechanics of faulting between the different disciplines concerned with fault zone processes; and to help define future critical investigations, experiments, and observational procedures for evaluating the role of fluids in faulting. This conference drew together a diverse group of 45 scientists, with expertise in electrical and magnetic methods, geochemistry, hydrology, ore deposits, rock mechanics, seismology, and structural geology. Some of the outstanding questions addressed at this workshop included the following: 1. What are fluid pressures at different levels within seismically active fault zones? Do they remain hydrostatic throughout the full depth extent of the seismogenic regime, or are they generally superhydrostatic at depths in excess of a few kilometers? 2. Are fluid pressures at depth within fault zones constant through an earthquake cycle, or are they time-dependent? What is the spatial variability in fluid pressures? 3. What is the role of crustal fluids in the overall process of stress accumulation, release, and transfer during the earthquake

  13. Microtensile bond strength between indirect composite resin inlays and dentin: effect of cementation strategy and mechanical aging.

    PubMed

    Prochnow, Emília Pithan; Amaral, Marina; Bergoli, César Dalmolin; Silva, Tatiana Bernardon; Saavedra, Guilherme; Valandro, Luiz Felipe

    2014-08-01

    To evaluate the microtensile bond strength of indirect resin composite inlays to dentin using two cementation strategies, before and after mechanical aging. Standardized inlay cavities (bucco-lingual width: 3 mm; depth: 4 mm) were prepared in 32 human premolars. The teeth were embedded in self-curing acrylic resin up to 3 mm from the cementoenamel junction, impressions were made using a polyvinyl siloxane material, master dies were obtained using type 4 stone, and inlay composite resin restorations were fabricated (Sinfony, 3M ESPE). The teeth were randomly allocated into 4 groups according to the cementation strategy (conventional [C] and simplified [S]) and aging (mechanical cycling [MC] and not aged): C[G1]: Adper SingleBond + RelyX ARC without aging; CMC[G2]: conventional cementation + mechanical cycling (106 cycles, 88 N, 4 Hz, ± 37°C); S[G3]: self-adhesive resin cement (RelyX U-100) without aging; SMC[G4] self-adhesive cementation + mechanical cycling. Intaglio surfaces of composite inlays were treated by tribochemical silica coating in G1 and G2, while G3 and G4 received no surface treatment. Non-aged specimens were stored in a moist environment at ca 37°C for the same period as MC (3 days). Non-trimmed beam specimens (bonding area = 1 mm²) were produced by serial cutting, and microtensile testing was performed (0.5 mm/min). Two-way ANOVA showed that the microtensile bond strength was affected only by cementation strategy (p < 0.0001). Tukey's test showed that groups G1 (35.1 ± 9.1) and G2 (32.7 ± 10.7) presented significantly higher bond strength values than G3 (8.7 ± 6.3) and G4 (5.2 ± 4.6). The use of a conventional adhesive technique and tribochemical silica coating resulted in higher μTBS than the one-step simplified cementation, even after mechanical cycling.

  14. The impact of in vitro aging on the mechanical and optical properties of indirect veneering composite resins.

    PubMed

    Stawarczyk, Bogna; Egli, Roger; Roos, Malgorzata; Ozcan, Mutlu; Hämmerle, Christoph H F

    2011-12-01

    Flexural strength, hardness, surface roughness, discoloration, and abrasion resistance are important properties of veneering composite resins. Recently introduced veneering resins are purported to have enhanced mechanical properties due to their composition, but their long-term durability is not known. The purpose of this study was to test the impact of aging on 3 different veneering composite resins. Indirect composite resins, GC Gradia, VITA VM LC, and Sinfony were prepared for flexural strength (n=165 per group), Martens hardness (n=10), surface roughness (n=10), discoloration measurement (n=30), and abrasion resistance (n=6) testing. After initial flexural strength measurement, the remaining specimens were stored in water or subjected to thermocycling for 1, 7, 28, 90, or 180 days, and hardness and surface roughness (water stored: n=5 and thermocycling: n=5) were tested. The discoloration specimens were divided into 3 groups: coffee, black tea, and red wine; n=10), and age and discoloration were measured. Abrasion resistance was determined after 120,000, 240,000, 640,000, and 1,200,000 mechanical thermocycling loading. One-way ANOVA was used, followed by a post hoc Scheffé test and t test. The longitudinal observations were analyzed by using linear mixed models (α=.05). When considering all 5 of the properties tested, Sinfony demonstrated the best results, followed by GC Gradia and VITA VM LC. The veneering composite resin, Sinfony, showed the most stable properties. Copyright © 2011 The Editorial Council of the Journal of Prosthetic Dentistry. Published by Mosby, Inc. All rights reserved.

  15. Mechanisms involved in BACE upregulation associated to stress.

    PubMed

    Martisova, Eva; Solas, Maite; Gerenu, Gorka; Milagro, Fermin I; Campion, Javier; Ramirez, Maria J

    2012-09-01

    The objective of the present work was to study a purported involvement of stress in amyloid pathology through the modulation of BACE expression. Early-life stressed rats (maternal separation, MS) showed significant increases in corticosterone levels, BACE expression and Aβ levels. The CpG7 site of the BACE promoter was significantly hypomethylated in MS, and corticosterone levels negatively correlated to the methylation status of CpG7. The activation of the stress-activated protein kinase JNK was also increased in MS rats. In SHSY-5Y neuroblastoma cells, corticosterone induced a rapid increase in BACE expression that was abolished by specific inhibiton of JNK activation or by spironolactone, a mineralocorticoid receptor antagonist, but not by mifepristone, a glucocorticoid receptor antagonist. Corticosterone was also able to increase pJNK expression and this effect was fully reverted by spironolactone. Mice chronically treated with corticosterone showed increased BACE and pJNK expression. These increases were reverted by treatment with spironolactone or with a JNK inhibitor. It is suggested that increased corticosterone levels associated to stress lead to increase BACE transcription both through epigenetic mechanisms and activation of JNK.

  16. Physical activity and self-esteem: testing direct and indirect relationships associated with psychological and physical mechanisms.

    PubMed

    Zamani Sani, Seyed Hojjat; Fathirezaie, Zahra; Brand, Serge; Pühse, Uwe; Holsboer-Trachsler, Edith; Gerber, Markus; Talepasand, Siavash

    2016-01-01

    In the present study, we investigated the relationship between physical activity (PA) and self-esteem (SE), while introducing body mass index (BMI), perceived physical fitness (PPF), and body image (BI) in adults (N =264, M =38.10 years). The findings indicated that PA was directly and indirectly associated with SE. BMI predicted SE neither directly nor indirectly, but was directly associated with PPF and both directly and indirectly with BI. Furthermore, PPF was directly related to BI and SE, and a direct association was found between BI and SE. The pattern of results suggests that among a sample of adults, PA is directly and indirectly associated with SE, PPF, and BI, but not with BMI. PA, PPF, and BI appear to play an important role in SE. Accordingly, regular PA should be promoted, in particular, among adults reporting lower SE.

  17. Physical activity and self-esteem: testing direct and indirect relationships associated with psychological and physical mechanisms

    PubMed Central

    Zamani Sani, Seyed Hojjat; Fathirezaie, Zahra; Brand, Serge; Pühse, Uwe; Holsboer-Trachsler, Edith; Gerber, Markus; Talepasand, Siavash

    2016-01-01

    In the present study, we investigated the relationship between physical activity (PA) and self-esteem (SE), while introducing body mass index (BMI), perceived physical fitness (PPF), and body image (BI) in adults (N =264, M =38.10 years). The findings indicated that PA was directly and indirectly associated with SE. BMI predicted SE neither directly nor indirectly, but was directly associated with PPF and both directly and indirectly with BI. Furthermore, PPF was directly related to BI and SE, and a direct association was found between BI and SE. The pattern of results suggests that among a sample of adults, PA is directly and indirectly associated with SE, PPF, and BI, but not with BMI. PA, PPF, and BI appear to play an important role in SE. Accordingly, regular PA should be promoted, in particular, among adults reporting lower SE. PMID:27789950

  18. Involvement of mast cells and proteinase-activated receptor 2 in oxaliplatin-induced mechanical allodynia in mice.

    PubMed

    Sakamoto, Ayumi; Andoh, Tsugunobu; Kuraishi, Yasushi

    2016-03-01

    The chemotherapeutic agent oxaliplatin induces neuropathic pain, a dose-limiting side effect, but the underlying mechanisms are not fully understood. Here, we show the potential involvement of cutaneous mast cells in oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin induced mechanical allodynia, which peaked on day 10 after injection. Oxaliplatin-induced mechanical allodynia was almost completely prevented by congenital mast cell deficiency. The numbers of total and degranulated mast cells was significantly increased in the skin after oxaliplatin administration. Repetitive topical application of the mast cell stabilizer azelastine hydrochloride inhibited mechanical allodynia and the degranulation of mast cells without affecting the number of mast cells in oxaliplatin-treated mice. The serine protease inhibitor camostat mesilate and the proteinase-activated receptor 2 (PAR2) antagonist FSLLRY-NH2 significantly inhibited oxaliplatin-induced mechanical allodynia. However, it was not inhibited by the H1 histamine receptor antagonist terfenadine. Single oxaliplatin administration increased the activity of cutaneous serine proteases, which was attenuated by camostat and mast cell deficiency. Depletion of the capsaicin-sensitive primary afferents by neonatal capsaicin treatment almost completely prevented oxaliplatin-induced mechanical allodynia, the increase in the number of mast cells, and the activity of cutaneous serine proteases. These results suggest that serine protease(s) released from mast cells and PAR2 are involved in oxaliplatin-induced mechanical allodynia. Therefore, oxaliplatin may indirectly affect the functions of mast cells through its action on capsaicin-sensitive primary afferents.

  19. MECHANISMS INVOLVED IN MYCORRHIZAL WHEAT PROTECTION AGAINST POWDERY MILDEW.

    PubMed

    Mustafa, G; Tisserant, B; Randoux, B; Fontaine, J; Sahraoui, A Lounes-Hadj; Reignault, Ph

    2014-01-01

    In France, the Ecophyto 2018 national action plan will set out to reduce the use of pesticides by 50% by 2018, if possible. To achieve this goal, the use of arbuscular mycorrhizal (AM) fungi could be a potential alternative method allowing the control of crop diseases. The inoculation by AM fungi has been demonstrated to protect plants against soil-borne pathogens, but little is known about their effectiveness against aerial pathogens, such as the biotrophic fungus Blumeria graminis f.sp. tritici (Bgt) causing wheat (Triticum aestivum) powdery mildew. In the present study, wheat plants were grown in pots, under controlled conditions. Using various phosphorus (P) concentrations, the effectiveness of three AM inocula (Rhizophagus irregularis (Ri), Funneliformis mosseae (Fm)) and Solrize, a mixture of Ri and Fm) in Orvantis wheat cultivar, were tested. After 42 days of culture, mycorrhizal (M) and non-mycorrhizal (NM) wheat plants were infected by Bgt. A satisfactory mycorrhizal rate was obtained with the phosphorus concentration P/5 (P corresponding to the dose used in wheat fields in = 62 mg/L). Our work shows, for the first time, (i) a protective effect of AM inoculation against wheat powdery mildew, reaching up to 73% with Fm inocula, and (ii) its ability to induce a systemic resistance in wheat. Thereafter, we investigated mechanisms involved in this protection. Control plants, M plants, infected plants by Bgt, and M-infected plants were compared at: (i) cytological level, our results revealed that papillae and whole-fluorescent cells presence was induced, conversely fungal haustorium formation in epidermal cells was reduced within M plants leaves (ii) enzymatic level-by assessing defense enzyme activities (lipoxygenase, peroxidase) known as defense markers were measured 24, 48, 72 and 96 hours after infection (hai). The importance of these activities in the defense pathways induced in wheat by AM fungi will be discussed.

  20. Cooperative mechanisms involved in chronic antidiuretic response to bendroflumethiazide in rats with lithium-induced nephrogenic diabetes insipidus.

    PubMed

    Moosavi, S M S; Karimi, Z

    2014-03-01

    Previous studies of central diabetes insipidus suggested that thiazides acutely exerted a paradoxical antidiuresis by either indirectly activating volume-homeostatic reflexes to decrease distal fluid-delivery, or directly stimulating distal water-reabsorption. This study investigated whether the direct and indirect actions of bendroflumethiazide (BFTZ) simultaneously cooperated and also whether the renal nerves were involved in inducing long-term antidiuresis in nephrogenic diabetes insipidus (NDI). BFTZ or vehicle was gavaged into bilateral renal denervated and innervated rats with lithium-induced NDI for 10 days, constituting four groups. At one day before (D0) and one, five and ten days after starting administration of BFTZ or vehicle, rats were placed in metabolic cages to collect urine for 6 hours. BFTZ-treatment in both renal innervated and denervated rats caused equivalent reductions in urine-flow, creatinine clearance, lithium clearance and free-water clearance, but rises in urine-osmolality, fractional proximal reabsorption and fractional distal reabsorption at all days compared to D0, as well as to those of their relevant vehicle-received group. Therefore, the chronic antidiuretic response to BFTZ in conscious NDI rats was exerted through a concomitant cooperation of its direct distal effect of stimulating water-reabsorption and its indirect effect of reducing distal fluid-delivery by activating volume-homeostatic mechanisms, which appeared independent of the renal nerves.

  1. Technical key and mechanism of laser-involved therapy

    NASA Astrophysics Data System (ADS)

    Tian, Zhaobing; Zhang, Dan; Gao, Feng

    1997-06-01

    The method of laser-involved therapy can be classified as the following: (1) intravascular low level He-Ne laser irradiation therapy; (2) light-oxygen-blood therapy; (3) light-oxygen-blood therapy. The key of laser-involved therapy is the proper wavelength light. The use of energy in laser-involved therapy is different from that in laser acupuncture. Of all kinds of light-involved therapy, oxygen has direct influence on the curative effect. Oxygen can be thought as the carrier of laser energy. Having absorbed the photon, the oxygen get excited and reaches every part of the organism through blood circulation, which promotes physiological and biochemistry reaction and therefore improves the metabolism.

  2. Study of Mechanisms of Aerosol Indirect Effects on Glaciated Clouds: Progress during the Project Final Technical Report

    SciTech Connect

    Phillips, Vaughan T. J.

    2013-10-18

    This 3-year project has studied how aerosol pollution influences glaciated clouds. The tool applied has been an 'aerosol-cloud model'. It is a type of Cloud-System Resolving Model (CSRM) modified to include 2-moment bulk microphysics and 7 aerosol species, as described by Phillips et al. (2009, 2013). The study has been done by, first, improving the model and then performing sensitivity studies with validated simulations of a couple of observed cases from ARM. These are namely the Tropical Warm Pool International Cloud Experiment (TWP-ICE) over the tropical west Pacific and the Cloud and Land Surface Interaction Campaign (CLASIC) over Oklahoma. During the project, sensitivity tests with the model showed that in continental clouds, extra liquid aerosols (soluble aerosol material) from pollution inhibited warm rain processes for precipitation production. This promoted homogeneous freezing of cloud droplets and aerosols. Mass and number concentrations of cloud-ice particles were boosted. The mean sizes of cloud-ice particles were reduced by the pollution. Hence, the lifetime of glaciated clouds, especially ice-only clouds, was augmented due to inhibition of sedimentation and ice-ice aggregation. Latent heat released from extra homogeneous freezing invigorated convective updrafts, and raised their maximum cloud-tops, when aerosol pollution was included. In the particular cases simulated in the project, the aerosol indirect effect of glaciated clouds was twice than of (warm) water clouds. This was because glaciated clouds are higher in the troposphere than water clouds and have the first interaction with incoming solar radiation. Ice-only clouds caused solar cooling by becoming more extensive as a result of aerosol pollution. This 'lifetime indirect effect' of ice-only clouds was due to higher numbers of homogeneously nucleated ice crystals causing a reduction in their mean size, slowing the ice-crystal process of snow production and slowing sedimentation. In addition

  3. Mechanisms Involved in the Nociception Triggered by the Venom of the Armed Spider Phoneutria nigriventer

    PubMed Central

    Gewehr, Camila; Oliveira, Sara Marchesan; Rossato, Mateus Fortes; Trevisan, Gabriela; Dalmolin, Gerusa Duarte; Rigo, Flávia Karine; de Castro Júnior, Célio José; Cordeiro, Marta Nascimento; Ferreira, Juliano; Gomez, Marcus V.

    2013-01-01

    Background The frequency of accidental spider bites in Brazil is growing, and poisoning due to bites from the spider genus Phoneutria nigriventer is the second most frequent source of such accidents. Intense local pain is the major symptom reported after bites of P. nigriventer, although the mechanisms involved are still poorly understood. Therefore, the aim of this study was to identify the mechanisms involved in nociception triggered by the venom of Phoneutria nigriventer (PNV). Methodology/Principal Findings Twenty microliters of PNV or PBS was injected into the mouse paw (intraplantar, i.pl.). The time spent licking the injected paw was considered indicative of the level of nociception. I.pl. injection of PNV produced spontaneous nociception, which was reduced by arachnid antivenin (ArAv), local anaesthetics, opioids, acetaminophen and dipyrone, but not indomethacin. Boiling or dialysing the venom reduced the nociception induced by the venom. PNV-induced nociception is not dependent on glutamate or histamine receptors or on mast cell degranulation, but it is mediated by the stimulation of sensory fibres that contain serotonin 4 (5-HT4) and vanilloid receptors (TRPV1). We detected a kallikrein-like kinin-generating enzyme activity in tissue treated with PNV, which also contributes to nociception. Inhibition of enzymatic activity or administration of a receptor antagonist for kinin B2 was able to inhibit the nociception induced by PNV. PNV nociception was also reduced by the blockade of tetrodotoxin-sensitive Na+ channels, acid-sensitive ion channels (ASIC) and TRPV1 receptors. Conclusion/Significance Results suggest that both low- and high-molecular-weight toxins of PNV produce spontaneous nociception through direct or indirect action of kinin B2, TRPV1, 5-HT4 or ASIC receptors and voltage-dependent sodium channels present in sensory neurons but not in mast cells. Understanding the mechanisms involved in nociception caused by PNV are of interest not only for

  4. Homing orientation in salamanders: A mechanism involving chemical cues

    NASA Technical Reports Server (NTRS)

    Madison, D. M.

    1972-01-01

    A detailed description is given of experiments made to determine the senses and chemical cues used by salamanders for homing orientation. Sensory impairment and cue manipulative techniques were used in the investigation. All experiments were carried out at night. Results show that sense impaired animals did not home as readily as those who were blind but retained their sensory mechanism. This fact suggests that the olfactory mechanism is necessary for homing in the salamander. It was determined that after the impaired salamander regenerated its sensory mechanism it too returned home. It was concluded that homing ability in salamanders is direction independent, distant dependent, and vision independent.

  5. [Classical dengue transmission dynamics involving mechanical control and prophylaxis].

    PubMed

    Toro-Zapata, Hernán D; Restrepo, Leonardo D; Vergaño-Salazar, Juan G; Muñoz-Loaiza, Aníbal

    2010-12-01

    Dengue fever transmission dynamics were studied in an endemic region considering the use of preventative measures and mechanical control in reducing transmission of the disease. A system of ordinary differential equations was proposed, describing the dynamics and their evolution as determined by numerical simulation. Different mechanical control and prophylaxis strategies were compared to the situation without control. The basic reproduction number R₀ was determined R₀ to show that if R₀ > 1 there would be a risk of an epidemic and otherwise the disease would have low impact levels. The basic reproduction number helps determine the dynamics' future pattern and contrast the results so obtained with those obtained numerically. It was concluded that although prophylaxis and mechanical control alone provide effective results in controlling the disease, if both controls are combined then infection levels become significantly reduced. Around 60 % mechanical control and prevention levels are needed to provide suitable results in controlling dengue outbreaks.

  6. Cardiac involvement with amyloidosis: mechanisms of disease, diagnosis and management.

    PubMed

    Marcu, Constantin B; Niessen, Hans W; Beek, Aernout M; Brouwer, Wessel P; Robbers, Lourens F; Van Rossum, Albert C

    2011-01-01

    The amyloidoses represent a group of clinical disorders of diverse etiologies that have as a common pathophysiologic denominator the deposition of misfolded protein based amyloid fibrils in the interstitial space of various organs. They are uncommon diseases with protean clinical presentations. Cardiac involvement is the determining factor for a patient's prognosis. Clinicians have to maintain a high index of suspicion and actively search for signs and symptoms of cardiac involvement in patients with preexisting conditions known to be associated with the development of amyloidosis. Early diagnosis and accurate fibril typing are the first steps in managing the disease. Judicious use of various diagnostic modalities such as serum markers and imaging studies, and good communication among all the physicians involved in the care of these sick and frail patients, are keys to a better outcome.

  7. Molecular mechanism(s) involved in differential expression of vitamin C transporters along the intestinal tract.

    PubMed

    Subramanian, Veedamali S; Srinivasan, Padmanabhan; Wildman, Alexis J; Marchant, Jonathan S; Said, Hamid M

    2017-04-01

    Mammalian cells utilize two transporters for the uptake of ascorbic acid (AA), Na(+)-dependent vitamin C transporter SVCT-1 and SVCT-2. In the intestine, these transporters are involved in AA absorption and are expressed at the apical and basolateral membrane domains of the polarized epithelia, respectively. Little is known about the differential expression of these two transporters along the anterior-posterior axis of the intestinal tract and the molecular mechanism(s) that dictate this pattern of expression. We used mouse and human intestinal cDNAs to address these issues. The results showed a significantly lower rate of carrier-mediated AA uptake by mouse colon than jejunum. This was associated with a significantly lower level of expression of SVCT-1 and SVCT-2 at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels in the colon than the jejunum, implying the involvement of transcriptional mechanism(s). Similarly, expression levels of SVCT-1 and SVCT-2 mRNA and hnRNA were significantly lower in human colon. We also examined the levels of expression of hepatocyte nuclear factor 1α and specificity protein 1, which drive transcription of the Slc23a1 and Slc23a2 promoters, respectively, and found them to be markedly lower in the colon. Furthermore, significantly lower levels of the activating markers for histone (H3) modifications [H3 trimethylation of lysine 4 (H3K4me3) and H3 triacetylation of lysine 9 (H3K9ac)] were observed in the Slc23a1 and Slc23a2 promoters in the colon. These findings show, for the first time, that SVCT-1 and SVCT-2 are differentially expressed along the intestinal tract and that this pattern of expression is, at least in part, mediated via transcriptional/epigenetic mechanisms.NEW & NOTEWORTHY Our findings show, for the first time, that transporters of the water-soluble vitamin ascorbic acid (i.e., the vitamin C transporters SVCT-1 and SVCT-2) are differentially expressed along the length of the intestinal tract and that the

  8. Mechanisms Involved in Virus-Induced Neural Cell Death

    DTIC Science & Technology

    2001-09-01

    We are using experimental infection with reoviruses as a model to study how viruses induce cell death (apoptosis) and cause dysregulation of the cell...and their ligand (TRAIL). Apoptosis involves both death-receptor (DR) and mitochondrial-associated cell death pathways, and leads to the early

  9. Ochratoxin A carcinogenicity involves a complex network of epigenetic mechanisms.

    PubMed

    Marin-Kuan, Maricel; Cavin, Christophe; Delatour, Thierry; Schilter, Benoît

    2008-08-01

    Ochratoxin A (OTA) is a mycotoxin occurring in a wide range of food products. Because of the limitation of human epidemiological data, the safety significance of OTA in food has to rely on animal data, with renal toxicity and carcinogenicity being considered the pivotal effects. The elucidation of the mechanism of action would improve the use of experimental animal data for risk assessment. Direct genotoxicity versus epigenetic mechanisms appears to be a key question. In the present review, the increasingly documented epigenetic cellular effects of OTA and their potential toxicological relevance are discussed. The information available suggests that OTA is unlikely to act through a single, well-defined mechanism of action. Instead, it is proposed that a network of interacting epigenetic mechanisms, including protein synthesis inhibition, oxidative stress and the activation of specific cell signalling pathways, is responsible for OTA carcinogenicity. From a risk assessment perspective, it has to be noted that the mechanisms proposed above depend mainly upon gene expression and enzyme activation, and are, therefore, likely to be thresholded.

  10. A new hypothesis on the simultaneous direct and indirect proton pump mechanisms in NADH-quinone oxidoreductase (complex I).

    PubMed

    Ohnishi, Tomoko; Nakamaru-Ogiso, Eiko; Ohnishi, S Tsuyoshi

    2010-10-08

    Recently, Sazanov's group reported the X-ray structure of whole complex I [Nature, 465, 441 (2010)], which presented a strong clue for a "piston-like" structure as a key element in an "indirect" proton pump. We have studied the NuoL subunit which has a high sequence similarity to Na(+)/H(+) antiporters, as do the NuoM and N subunits. We constructed 27 site-directed NuoL mutants. Our data suggest that the H(+)/e(-) stoichiometry seems to have decreased from (4H(+)/2e(-)) in the wild-type to approximately (3H(+)/2e(-)) in NuoL mutants. We propose a revised hypothesis that each of the "direct" and the "indirect" proton pumps transports 2H(+) per 2e(-).

  11. Mechanisms Involved in Nematode Control by Endophytic Fungi.

    PubMed

    Schouten, Alexander

    2016-08-04

    Colonization of plants by particular endophytic fungi can provide plants with improved defenses toward nematodes. Evidently, such endophytes can be important in developing more sustainable agricultural practices. The mechanisms playing a role in this quantitative antagonism are poorly understood but most likely multifactorial. This knowledge gap obstructs the progress regarding the development of endophytes or endophyte-derived constituents into biocontrol agents. In part, this may be caused by the fact that endophytic fungi form a rather heterogeneous group. By combining the knowledge of the currently characterized antagonistic endophytic fungi and their effects on nematode behavior and biology with the knowledge of microbial competition and induced plant defenses, the various mechanisms by which this nematode antagonism operates or may operate are discussed. Now that new technologies are becoming available and more accessible, the currently unresolved mechanisms can be studied in greater detail than ever before.

  12. Rapid and reversible responses to IVIG in autoimmune neuromuscular diseases suggest mechanisms of action involving competition with functionally important autoantibodies

    PubMed Central

    Berger, Melvin; McCallus, Daniel E; Lin, Cindy Shin-Yi

    2013-01-01

    Intravenous immunoglobulin (IVIG) is widely used in autoimmune neuromuscular diseases whose pathogenesis is undefined. Many different effects of IVIG have been demonstrated in vitro, but few studies actually identify the mechanism(s) most important in vivo. Doses and treatment intervals are generally chosen empirically. Recent studies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy show that some effects of IVIG are readily reversible and highly dependent on the serum IgG level. This suggests that in some autoantibody-mediated neuromuscular diseases, IVIG directly competes with autoantibodies that reversibly interfere with nerve conduction. Mechanisms of action of IVIG which most likely involve direct competition with autoantibodies include: neutralization of autoantibodies by anti-idiotypes, inhibition of complement deposition, and increasing catabolism of pathologic antibodies by saturating FcRn. Indirect immunomodulatory effects are not as likely to involve competition and may not have the same reversibility and dose-dependency. Pharmacodynamic analyses should be informative regarding most relevant mechanism(s) of action of IVIG as well as the role of autoantibodies in the immunopathogenesis of each disease. Better understanding of the role of autoantibodies and of the target(s) of IVIG could lead to more efficient use of this therapy and better patient outcomes. PMID:24200120

  13. Mechanisms of molecular mimicry involving the microbiota in neurodegeneration.

    PubMed

    Friedland, Robert P

    2015-01-01

    The concept of molecular mimicry was established to explain commonalities of structure which developed in response to evolutionary pressures. Most examples of molecular mimicry in medicine have involved homologies of primary protein structure which cause disease. Molecular mimicry can be expanded beyond amino acid sequence to include microRNA and proteomic effects which are either pathogenic or salutogenic (beneficial) in regard to Parkinson's disease, Alzheimer's disease, and related disorders. Viruses of animal or plant origin may mimic nucleotide sequences of microRNAs and influence protein expression. Both Parkinson's and Alzheimer's diseases involve the formation of transmissible self-propagating prion-like proteins. However, the initiating factors responsible for creation of these misfolded nucleating factors are unknown. Amyloid patterns of protein folding are highly conserved through evolution and are widely distributed in the world. Similarities of tertiary protein structure may be involved in the creation of these prion-like agents through molecular mimicry. Cross-seeding of amyloid misfolding, altered proteostasis, and oxidative stress may be induced by amyloid proteins residing in bacteria in our microbiota in the gut and in the diet. Pathways of molecular mimicry induced processes induced by bacterial amyloid in neurodegeneration may involve TLR 2/1, CD14, and NFκB, among others. Furthermore, priming of the innate immune system by the microbiota may enhance the inflammatory response to cerebral amyloids (such as amyloid-β and α-synuclein). This paper describes the specific molecular pathways of these cross-seeding and neuroinflammatory processes. Evolutionary conservation of proteins provides the opportunity for conserved sequences and structures to influence neurological disease through molecular mimicry.

  14. The cytotoxic mechanism of glyoxal involves oxidative stress.

    PubMed

    Shangari, Nandita; O'Brien, Peter J

    2004-10-01

    Glyoxal is a reactive alpha-oxoaldehyde that is a physiological metabolite formed by lipid peroxidation, ascorbate autoxidation, oxidative degradation of glucose and degradation of glycated proteins. Glyoxal is capable of inducing cellular damage, like methylglyoxal (MG), but may also accelerate the rate of glycation leading to the formation of advanced glycation end-products (AGEs). However, the mechanism of glyoxal cytotoxicity has not been precisely defined. In this study we have focused on the cytotoxic effects of glyoxal and its ability to overcome cellular resistance to oxidative stress. Isolated rat hepatocytes were incubated with different concentrations of glyoxal. Glyoxal by itself was cytotoxic at 5mM, depleted GSH, formed reactive oxygen species (ROS) and collapsed the mitochondrial membrane potential. Glyoxal also induced lipid peroxidation and formaldehyde formation. Glycolytic substrates, e.g. fructose, sorbitol and xylitol inhibited glyoxal-induced cytotoxicity and prevented the decrease in mitochondrial membrane potential suggesting that mitochondrial toxicity contributed to the cytotoxic mechanism. Glyoxal cytotoxicity was prevented by the glyoxal traps d-penicillamine or aminoguanidine or ROS scavengers were also cytoprotective even when added some time after glyoxal suggesting that oxidative stress contributed to the glyoxal cytotoxic mechanism.

  15. Molecular mechanisms involved in mammalian primary sex determination.

    PubMed

    She, Zhen-Yu; Yang, Wan-Xi

    2014-08-01

    Sex determination refers to the developmental decision that directs the bipotential genital ridge to develop as a testis or an ovary. Genetic studies on mice and humans have led to crucial advances in understanding the molecular fundamentals of sex determination and the mutually antagonistic signaling pathway. In this review, we summarize the current molecular mechanisms of sex determination by focusing on the known critical sex determining genes and their related signaling pathways in mammalian vertebrates from mice to humans. We also discuss the underlying delicate balance between testis and ovary sex determination pathways, concentrating on the antagonisms between major sex determining genes.

  16. Mechanisms involved in antibody- and complement-mediated allograft rejection

    PubMed Central

    2010-01-01

    Antibody-mediated rejection has become critical clinically because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has been recognized as a major cause of allograft loss. Our group developed experimental animal models of vascularized organ transplantation to study pathogenesis of antibody- and complement-mediated endothelial cell injury leading to graft rejection. In this review, we discuss mechanisms of antibody-mediated graft rejection resulting from activation of complement by C1q- and MBL (mannose-binding lectin)-dependent pathways and interactions with a variety of effector cells, including macrophages and monocytes through Fcγ receptors and complement receptors. PMID:20135240

  17. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.

    PubMed

    Liu, Pengfei; Erez, Ayelet; Nagamani, Sandesh C Sreenath; Dhar, Shweta U; Kołodziejska, Katarzyna E; Dharmadhikari, Avinash V; Cooper, M Lance; Wiszniewska, Joanna; Zhang, Feng; Withers, Marjorie A; Bacino, Carlos A; Campos-Acevedo, Luis Daniel; Delgado, Mauricio R; Freedenberg, Debra; Garnica, Adolfo; Grebe, Theresa A; Hernández-Almaguer, Dolores; Immken, LaDonna; Lalani, Seema R; McLean, Scott D; Northrup, Hope; Scaglia, Fernando; Strathearn, Lane; Trapane, Pamela; Kang, Sung-Hae L; Patel, Ankita; Cheung, Sau Wai; Hastings, P J; Stankiewicz, Paweł; Lupski, James R; Bi, Weimin

    2011-09-16

    Complex genomic rearrangements (CGRs) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here, we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated, we observed localization and multiple copy number changes including deletions, duplications, and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism's life cycle.

  18. Mechanisms Involved in Osteoblast Response to Implant Surface Morphology

    NASA Astrophysics Data System (ADS)

    Boyan, Barbara D.; Lohmann, Christoph H.; Dean, David D.; Sylvia, Victor L.; Cochran, David L.; Schwartz, Zvi

    2001-08-01

    Osteoblasts respond to surface topography with altered morphology, proliferation, and differentiation. The effects observed vary with cell culture model and the topographical features of the surface. In general, increased surface roughness is associated with decreased proliferation and increased differentiation. Cell responses to hormones, growth factors, and cytokines are altered as well, as is autocrine production of these factors. The cells interact with the surface via integrin receptors, and their expression is also surface roughness-dependent. Integrin binding to cell attachment proteins activates signal transduction cascades, including those mediated by protein kinase C and phospholipase A2. These signaling pathways are also used by regulatory factors, which results in synergistic responses. Prostaglandins are important mediators of the surface effects, and both constitutive and inducible cyclooxygenase are involved.

  19. Involvement of thiol-based mechanisms in plant development.

    PubMed

    Rouhier, Nicolas; Cerveau, Delphine; Couturier, Jérémy; Reichheld, Jean-Philippe; Rey, Pascal

    2015-08-01

    Increasing knowledge has been recently gained regarding the redox regulation of plant developmental stages. The current state of knowledge concerning the involvement of glutathione, glutaredoxins and thioredoxins in plant development is reviewed. The control of the thiol redox status is mainly ensured by glutathione (GSH), a cysteine-containing tripeptide and by reductases sharing redox-active cysteines, glutaredoxins (GRXs) and thioredoxins (TRXs). Indeed, thiol groups present in many regulatory proteins and metabolic enzymes are prone to oxidation, ultimately leading to post-translational modifications such as disulfide bond formation or glutathionylation. This review focuses on the involvement of GSH, GRXs and TRXs in plant development. Recent studies showed that the proper functioning of root and shoot apical meristems depends on glutathione content and redox status, which regulate, among others, cell cycle and hormone-related processes. A critical role of GRXs in the formation of floral organs has been uncovered, likely through the redox regulation of TGA transcription factor activity. TRXs fulfill many functions in plant development via the regulation of embryo formation, the control of cell-to-cell communication, the mobilization of seed reserves, the biogenesis of chloroplastic structures, the metabolism of carbon and the maintenance of cell redox homeostasis. This review also highlights the tight relationships between thiols, hormones and carbon metabolism, allowing a proper development of plants in relation with the varying environment and the energy availability. GSH, GRXs and TRXs play key roles during the whole plant developmental cycle via their antioxidant functions and the redox-regulation of signaling pathways. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Mechanisms involved in the development of chemotherapy-induced neuropathy

    PubMed Central

    Boyette-Davis, Jessica A; Walters, Edgar T; Dougherty, Patrick M

    2015-01-01

    SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and painful condition seen in patients undergoing treatment with common agents such as vincristine, paclitaxel, oxaliplatin and bortezomib. The mechanisms of this condition are diverse, and include an array of molecular and cellular contributions. Current research implicates genetic predispositions to this condition, which then may influence cellular responses to chemotherapy. Processes found to be influenced during CIPN include increased expression of inflammatory mediators, primarily cytokines, which can create cascading effects in neurons and glia. Changes in ion channels and neurotransmission, as well as changes in intracellular signaling and structures have been implicated in CIPN. This review explores these issues and suggests considerations for future research. PMID:26087973

  1. Mechanisms involved in quinolone resistance in Mycoplasma mycoides subsp. capri.

    PubMed

    Antunes, Nuno T; Assunção, Patrícia; Poveda, José B; Tavío, María M

    2015-06-01

    Mycoplasma mycoides subsp. capri is a causative agent of contagious agalactia in goats. In this study, M. mycoides subsp. capri mutants were selected for resistance to fluoroquinolones (norfloxacin, enrofloxacin and ciprofloxacin) by serial passes in broth with increasing concentrations of antibiotic. Mutations conferring cross-resistance to the three fluoroquinolones were found in the quinolone resistance determining regions of the four genes encoding DNA gyrase and topoisomerase IV. Different mutations in the DNA gyrase GyrA subunit suggest a different mechanism of inhibition between norfloxacin and the other tested fluoroquinolones. The presence of an adenosine triphosphate-dependent efflux system was suggested through the use of the inhibitor orthovanadate. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Kinetics and mechanisms of reactions involving small aromatic reactive intermediates

    SciTech Connect

    Lin, M.C.

    1993-12-01

    Small aromatic radicals such as C{sub 6}H{sub 5}, C{sub 6}H{sub 5}O and C{sub 6}H{sub 4} are key prototype species of their homologs. C{sub 6}H{sub 5} and its oxidation product, C{sub 6}H{sub 5}O are believed to be important intermediates which play a pivotal role in hydrocarbon combustion, particularly with regard to soot formation. Despite their fundamental importance, experimental data on the reaction mechanisms and reactivities of these species are very limited. For C{sub 6}H{sub 5}, most kinetic data except its reactions with NO and NO{sub 2}, were obtained by relative rate measurements. For C{sub 6}H{sub 5}O, the authors have earlier measured its fragmentation reaction producing C{sub 5}H{sub 5} + CO in shock waves. For C{sub 6}H{sub 4}, the only rate constant measured in the gas phase is its recombination rate at room temperature. The authors have proposed to investigate systematically the kinetics and mechanisms of this important class of molecules using two parallel laser diagnostic techniques--laser resonance absorption (LRA) and resonance enhanced multiphoton ionization mass spectrometry (REMPI/MS). In the past two years, study has been focused on the development of a new multipass adsorption technique--the {open_quotes}cavity-ring-down{close_quotes} technique for kinetic applications. The preliminary results of this study appear to be quite good and the sensitivity of the technique is at least comparable to that of the laser-induced fluorescence method.

  3. Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

    PubMed Central

    H. WEIDLE, ULRICH; BIRZELE, FABIAN; KOLLMORGEN, GWENDLYN; RUEGER, RÜDIGER

    2016-01-01

    Ovarian carcinoma is associated with the highest death rate of all gynecological tumors. On one hand, its aggressiveness is based on the rapid dissemination of ovarian cancer cells to the peritoneum, the omentum, and organs located in the peritoneal cavity, and on the other hand, on the rapid development of resistance to chemotherapeutic agents. In this review, we focus on the metastatic process of ovarian cancer, which involves dissemination of, homing to and growth of tumor cells in distant organs, and describe promising molecular targets for possible therapeutic intervention. We provide an outline of the interaction of ovarian cancer cells with the microenvironment such as mesothelial cells, adipocytes, fibroblasts, endothelial cells, and other stromal components in the context of approaches for therapeutic interference with dissemination. The targets described in this review are discussed with respect to their validity as drivers of metastasis and to the availability of suitable efficient agents for their blockage, such as small molecules, monoclonal antibodies or antibody conjugates as emerging tools to manage this disease. PMID:27807064

  4. Mechanisms involved in the intrinsic isoniazid resistance of Mycobacterium avium.

    PubMed

    Mdluli, K; Swanson, J; Fischer, E; Lee, R E; Barry, C E

    1998-03-01

    Isoniazid (INH), which acts by inhibiting mycolic acid biosynthesis, is very potent against the tuberculous mycobacteria. It is about 100-fold less effective against Mycobacterium avium. This difference has often been attributed to a decreased permeability of the cell wall. We measured the rate of conversion of radiolabelled INH to 4-pyridylmethanol by whole cells and cell-free extracts and estimated the permeability barrier imposed by the cell wall to INH influx in Mycobacterium tuberculosis and M. avium. There was no significant difference in the relative permeability to INH between these two species. However, the total conversion rate in M. tuberculosis was found to be four times greater. Examination of in vitro-generated mutants revealed that the major resistance mechanism for both species is loss of the catalase-peroxidase KatG. Analysis of lipid and protein biosynthetic profiles demonstrated that the molecular target of activated INH was identical for both species. M. avium, however, formed colonies at INH concentrations inhibitory for mycolic acid biosynthesis. These mycolate-deficient M. avium exhibited altered colony morphologies, modified cell wall ultrastructure and were 10-fold more sensitive to treatment with hydrophobic antibiotics, such as rifampin. These findings may significantly impact the design of new therapeutic regimens for the treatment of infections with atypical mycobacteria.

  5. Mechanisms involved in cholesterol-induced neuronal insulin resistance.

    PubMed

    Taghibiglou, Changiz; Bradley, Clarrisa A; Gaertner, Tara; Li, Yuping; Wang, Yushan; Wang, Yu Tian

    2009-09-01

    Insulin receptors (IRs) are highly expressed in the central nervous system (CNS) and play an important role in normal brain functions, such as learning and memory. Due to the increasing rate of obesity in western societies and overall high fat diets, the incidents of neuronal insulin resistance is also on the rise, but the underlying mechanism is still poorly characterized. We found that cholesterol treatment produces robust insulin signaling resistance that is characterized by the marked reduction in insulin-stimulated tyrosine phosphorylation of the IR and its downstream targets insulin receptor substrate 1 (IRS1) and 2 (IRS2). Surface expression of IRs was also decreased and was correlated with an increase in facilitated receptor endocytosis. Membrane fractionation showed that after cholesterol treatment, the proportion of IRs localized in the lipid raft increased and correspondingly there was a reduction of IRs in the non-raft membrane. Interestingly, we found that IRs in the lipid rafts, unlike their counterparts in the non-raft membrane domain, were essentially unresponsive to insulin stimulation and that a high level of tyrosine phosphatase activity was associated with these raft fractions. Our results suggest that the lipid raft microdomain of the neuronal plasma membrane has a strong influence on IR signaling, and that incorporation of high levels of cholesterol may reduce IR signaling by increasing their representation in lipid rafts. The trapping of the IR in the lipid raft domain may result in its inactivation and promote its endocytosis: effects that could contribute to neuronal insulin resistance in obesity.

  6. Mechanisms involved in the developmental programming of adulthood disease.

    PubMed

    Warner, Matthew J; Ozanne, Susan E

    2010-04-14

    There are many instances in life when the environment plays a critical role in the health outcomes of an individual, yet none more so than those experienced in fetal and neonatal life. One of the most detrimental environmental problems encountered during this critical growth period are changes in nutrition to the growing fetus and newborn. Disturbances in the supply of nutrients and oxygen to the fetus can not only lead to adverse fetal growth patterns, but they have also been associated with the development of features of metabolic syndrome in adult life. This fetal response has been termed developmental programming or the developmental origins of health and disease. The present review focuses on the epidemiological studies that identified this association and the importance that animal models have played in studying this concept. We also address the potential mechanisms that may underpin the developmental programming of future disease. It also highlights (i) how developmental plasticity, although beneficial for short-term survival, can subsequently programme glucose intolerance and insulin resistance in adult life by eliciting changes in key organ structures and the epigenome, and (ii) how aberrant mitochondrial function can potentially lead to the development of Type 2 diabetes and other features of metabolic syndrome.

  7. Mechanism involved in enhancement of osteoblast differentiation by hyaluronic acid

    SciTech Connect

    Kawano, Michinao; Ariyoshi, Wataru; Iwanaga, Kenjiro; Okinaga, Toshinori; Habu, Manabu; Yoshioka, Izumi; Tominaga, Kazuhiro; Nishihara, Tatsuji

    2011-02-25

    Research highlights: {yields} In this study was to investigate the effects of HA on osteoblast differentiation induced by BMP-2. {yields} MG63 cells were incubated with BMP-2 and HA for various time periods. {yields} Phosphorylation of Smad 1/5/8, p38, and ERK proteins was determined by western blot analysis. To elucidate the nuclear translocation of phosphorylated Smad 1/5/8, stimulated cells were subjected to immunofluorescence microscopy. {yields} HA enhanced BMP-2 induces osteoblastic differentiation in MG63 cells via down-regulation of BMP-2 antagonists and ERK phosphorylation. -- Abstract: Objectives: Bone morphogenetic protein-2 (BMP-2) is expected to be utilized to fill bone defects and promote healing of fractures. However, it is unable to generate an adequate clinical response for use in bone regeneration. Recently, it was reported that glycosaminoglycans, including heparin, heparan sulfate, keratan sulfate, dermatan sulfate, chondroitin-4-sulfate, chondroitin-6-sulfate, and hyaluronic acid (HA), regulate BMP-2 activity, though the mechanism by which HA regulates osteogenic activities has not been fully elucidated. The aim of this study was to investigate the effects of HA on osteoblast differentiation induced by BMP-2. Materials and methods: Monolayer cultures of osteoblastic lineage MG63 cells were incubated with BMP-2 and HA for various time periods. To determine osteoblastic differentiation, alkaline phosphatase (ALP) activity in the cell lysates was quantified. Phosphorylation of Smad 1/5/8, p38, and ERK proteins was determined by Western blot analysis. To elucidate the nuclear translocation of phosphorylated Smad 1/5/8, stimulated cells were subjected to immunofluorescence microscopy. To further elucidate the role of HA in enhancement of BMP-2-induced Smad signaling, mRNA expressions of the BMP-2 receptor antagonists noggin and follistatin were detected using real-time RT-PCR. Results: BMP-2-induced ALP activation, Smad 1/5/8 phosphorylation, and

  8. Indirect interactions among tropical tree species through shared rodent seed predators: a novel mechanism of tree species coexistence.

    PubMed

    Garzon-Lopez, Carol X; Ballesteros-Mejia, Liliana; Ordoñez, Alejandro; Bohlman, Stephanie A; Olff, Han; Jansen, Patrick A

    2015-08-01

    The coexistence of numerous tree species in tropical forests is commonly explained by negative dependence of recruitment on the conspecific seed and tree density due to specialist natural enemies that attack seeds and seedlings ('Janzen-Connell' effects). Less known is whether guilds of shared seed predators can induce a negative dependence of recruitment on the density of different species of the same plant functional group. We studied 54 plots in tropical forest on Barro Colorado Island, Panama, with contrasting mature tree densities of three coexisting large seeded tree species with shared seed predators. Levels of seed predation were far better explained by incorporating seed densities of all three focal species than by conspecific seed density alone. Both positive and negative density dependencies were observed for different species combinations. Thus, indirect interactions via shared seed predators can either promote or reduce the coexistence of different plant functional groups in tropical forest.

  9. Mechanism(S) Involved in the Colon-Specific Expression of the Thiamine Pyrophosphate (Tpp) Transporter.

    PubMed

    Nabokina, Svetlana M; Ramos, Mel Brendan; Said, Hamid M

    2016-01-01

    Microbiota of the large intestine synthesizes considerable amount of vitamin B1 (thiamine) in the form of thiamine pyrophosphate (TPP). We have recently demonstrated the existence of an efficient and specific carrier-mediated uptake process for TPP in human colonocytes, identified the TPP transporter (TPPT) involved (product of the SLC44A4 gene), and shown that expression of TPPT along the gastrointestinal (GI) tract is restricted to the colon. Our aim in this study was to determine the molecular basis of the colon-specific expression of TPPT focusing on a possible epigenetic mechanism. Our results showed that the CpG island predicted in the SLC44A4 promoter is non-methylated in the human colonic epithelial NCM460 cells, but is hyper-methylated in the human duodenal epithelial HuTu80 cells (as well as in the human retinal pigment epithelial ARPE19 cells). In the mouse (where TPPT expression in the GI tract is also restricted to the colon), the CpG island predicted in the Slc44a4 promoter is non-methylated in both the jejunum and colon, thus arguing against possible contribution of DNA methylation in the colon-specific expression of TPPT. A role for histone modifications in the tissue-specific pattern of Slc44a4 expression, however, was suggested by the findings that in mouse colon, histone H3 in the 5'-regulatory region of Slc44a4 is tri-methylated at lysine 4 and acetylated at lysine 9, whereas the tri-methylation at lysine 27 modification was negligible. In contrast, in the mouse jejunum, histone H3 is hyper-trimethylated at lysine 27 (repressor mark). Similarly, possible involvement of miRNA(s) in the tissue-specific expression of TPPT was also suggested by the findings that the 3'-UTR of SLC44A4 is targeted by specific miRNAs/RNA binding proteins in non-colonic, but not in colonic, epithelial cells. These studies show, for the first time, epigenetic mechanisms (histone modifications) play a role in determining the tissue-specific pattern of expression of TPPT

  10. Indirect inversions

    NASA Astrophysics Data System (ADS)

    Sergienko, Olga

    2013-04-01

    Since Doug MacAyeal's pioneering studies of the ice-stream basal traction optimizations by control methods, inversions for unknown parameters (e.g., basal traction, accumulation patterns, etc) have become a hallmark of the present-day ice-sheet modeling. The common feature of such inversion exercises is a direct relationship between optimized parameters and observations used in the optimization procedure. For instance, in the standard optimization for basal traction by the control method, ice-stream surface velocities constitute the control data. The optimized basal traction parameters explicitly appear in the momentum equations for the ice-stream velocities (compared to the control data). The inversion for basal traction is carried out by minimization of the cost (or objective, misfit) function that includes the momentum equations facilitated by the Lagrange multipliers. Here, we build upon this idea, and demonstrate how to optimize for parameters indirectly related to observed data using a suite of nested constraints (like Russian dolls) with additional sets of Lagrange multipliers in the cost function. This method opens the opportunity to use data from a variety of sources and types (e.g., velocities, radar layers, surface elevation changes, etc.) in the same optimization process.

  11. Alteration of sequence specificity of the type II restriction endonuclease HincII through an indirect readout mechanism.

    PubMed

    Joshi, Hemant K; Etzkorn, Christopher; Chatwell, Lorentz; Bitinaite, Jurate; Horton, Nancy C

    2006-08-18

    The functional and structural consequences of a mutation of the DNA intercalating residue of HincII, Q138F, are presented. Modeling has suggested that the DNA intercalation by Gln-138 results in DNA distortions potentially used by HincII in indirect readout of its cognate DNA, GTYRAC (Y = C or T, R = A or G) (Horton, N. C., Dorner, L. F., and Perona, J. J. (2002) Nat. Struct. Biol. 9, 42-47). Kinetic data presented here indicate that the mutation of glutamine 138 to phenylalanine (Q138F) results in a change in sequence specificity at the center two base pairs of the cognate recognition site. We show that the preference of HincII for cutting, but not binding, the three cognate sites differing in the center two base pairs has been altered by the mutation Q138F. Five new crystal structures are presented including Q138F HincII bound to GTTAAC and GTCGAC both with and without Ca2+ as well as the structure of wild type HincII bound to GTTAAC. The Q138F HincII/DNA structures show conformational changes in the protein, bound DNA, and at the protein-DNA interface, consistent with the formation of adaptive complexes. Analysis of these structures and the effect of Ca2+ binding on the protein-DNA interface illuminates the origin of the altered specificity by the mutation Q138F in the HincII enzyme.

  12. Altered Disrupted-in-Schizophrenia-1 Function Affects the Development of Cortical Parvalbumin Interneurons by an Indirect Mechanism

    PubMed Central

    Millar, J. Kirsty; Price, David J.

    2016-01-01

    Disrupted-in-Schizophrenia-1 (DISC1) gene has been linked to schizophrenia and related major mental illness. Mouse Disc1 has been implicated in brain development, mainly in the proliferation, differentiation, lamination, neurite outgrowth and synapse formation and maintenance of cortical excitatory neurons. Here, the effects of two loss-of-function point mutations in the mouse Disc1 sequence (Q31L and L100P) on cortical inhibitory interneurons were investigated. None of the mutations affected the overall number of interneurons. However, the 100P, but not the 31L, mutation resulted in a significant decrease in the numbers of interneurons expressing parvalbumin mRNA and protein across the sensory cortex. To investigate role of Disc1 in regulation of parvalbumin expression, mouse wild-type Disc-1 or the 100P mutant form were electroporated in utero into cortical excitatory neurons. Overexpression of wild-type Disc1 in these cells caused increased densities of parvalbumin-expressing interneurons in the electroporated area and in areas connected with it, whereas expression of Disc1-100P did not. We conclude that the 100P mutation prevents expression of parvalbumin by a normally sized cohort of interneurons and that altering Disc1 function in cortical excitatory neurons indirectly affects parvalbumin expression by cortical interneurons, perhaps as a result of altered functional input from the excitatory neurons. PMID:27244370

  13. IR spectral density of weak H-bonds involving indirect damping. I. A new approach using non-Hermitean effective Hamiltonians

    NASA Astrophysics Data System (ADS)

    Belharaya, Khedidja; Blaise, Paul; Henri-Rousseau, Olivier

    2003-08-01

    A new approach of the combined effects of quantum direct and indirect dampings (within the adiabatic approximation) on the infrared lineshapes of the νX-H stretching mode of simple and single weak H-bonds is proposed. The approach is based on our precedent model dealing only with bare weak H-bonds [B. Boulil, O. Henri-Rousseau , P. Blaise Chem. Phys. 126 (1988) 263; B. Boulil, J.-L. Déjardin, N. El-Ghandour, O. Henri-Rousseau, J. Mol. Struct. (Theochem) 314 (1994) 83]. As in this initial model, the indirect relaxation of the H-bond bridge is described by the aid of the driven damped quantum harmonic oscillator model [W. Louisell, L. Walker, Phys. Rev. 137 (1965) 204]. It is shown that the Hamiltonian characterizing the driven damped quantum harmonic oscillator may be obtained in a non-Hermitean reduced form, allowing, contrarily to the initial approach, the possibility of generalizations to more complex situations than those of bare H-bonds.

  14. Optimized basis sets for the calculation of indirect nuclear spin-spin coupling constants involving the atoms B, Al, Si, P, and Cl.

    PubMed

    Provasi, Patricio F; Sauer, Stephan P A

    2010-08-07

    The aug-cc-pVTZ-J series of basis sets for indirect nuclear spin-spin coupling constants has been extended to the atoms B, Al, Si, P, and Cl. The basis sets were obtained according to the scheme previously described by Provasi et al. [J. Chem. Phys. 115, 1324 (2001)]. First, the completely uncontracted correlation consistent aug-cc-pVTZ basis sets were extended with four tight s and three tight d functions. Second, the s and p basis functions were contracted with the molecular orbital coefficients of self-consistent-field calculations performed with the uncontracted basis sets on the simplest hydrides of each atom. As a first illustration, we have calculated the one-bond indirect spin-spin coupling constants in BH(4)(-), BF, AlH, AlF, SiH(4), SiF(4), PH(3), PF(3), H(2)S, SF(6), HCl, and ClF at the level of density functional theory using the Becke three parameter Lee-Yang-Parr and the second order polarization propagator approximation with coupled cluster singles and doubles amplitudes.

  15. Direct and Indirect Psychosocial Outcomes for Children with Autism Spectrum Disorder and their Parents Following a Parent-involved Social Skills Group Intervention.

    PubMed

    Weiss, Jonathan A; Viecili, Michelle A; Sloman, Leon; Lunsky, Yona

    2013-11-01

    This study examined the direct and indirect outcomes of a social skills group intervention for children with high functioning autism spectrum disorders and their parents. Thirty-five children and their parents participated in the program evaluation. Children and parents completed measures of child social skills and problem behaviors. Children reported on their self-concept, and parents reported on their psychological acceptance and empowerment. Results indicate significant increases in overall child social skills according to parent and child report, in child general self-worth, and in parent service empowerment and psychological acceptance. While past program evaluations of social skills groups highlight changes in social competence, taking a broader perspective on the types of positive outcomes suggests potential benefits for both child and parent.

  16. Indirect Effects of the Fast Track Intervention on Conduct Disorder Symptoms and Callous-Unemotional Traits: Distinct Pathways Involving Discipline and Warmth

    PubMed Central

    Pasalich, Dave S.; Witkiewitz, Katie; McMahon, Robert J.; Pinderhughes, Ellen E.

    2016-01-01

    Little is known about intervening processes that explain how prevention programs improve particular youth antisocial outcomes. We examined whether parental harsh discipline and warmth in childhood differentially account for Fast Track intervention effects on conduct disorder (CD) symptoms and callous-unemotional (CU) traits in early adolescence. Participants included 891 high-risk kindergarteners (69% male; 51% African American) from urban and rural United States communities who were randomized into either the Fast Track intervention (n = 445) or non-intervention control (n = 446) groups. The 10-year intervention included parent management training and other services (e.g., social skills training, universal classroom curriculum) targeting various risk factors for the development of conduct problems. Harsh discipline (Grades 1 through 3) and warmth (Grades 1 and 2) were measured using parent responses to vignettes and direct observations of parent-child interaction, respectively. Parents reported on children’s CD symptoms in Grade 6 and CU traits in Grade 7. Results demonstrated indirect effects of the Fast Track intervention on reducing risk for youth antisocial outcomes. That is, Fast Track was associated with lower scores on harsh discipline, which in turn predicted decreased levels of CD symptoms. In addition, Fast Track was associated with higher scores on warmth, which in turn predicted reduced levels of CU traits. Our findings inform developmental and intervention models of youth antisocial behavior by providing evidence for the differential role of harsh discipline and warmth in accounting for indirect effects of Fast Track on CD symptoms versus CU traits, respectively. PMID:26242993

  17. Indirect Effects of the Fast Track Intervention on Conduct Disorder Symptoms and Callous-Unemotional Traits: Distinct Pathways Involving Discipline and Warmth.

    PubMed

    Pasalich, Dave S; Witkiewitz, Katie; McMahon, Robert J; Pinderhughes, Ellen E

    2016-04-01

    Little is known about intervening processes that explain how prevention programs improve particular youth antisocial outcomes. We examined whether parental harsh discipline and warmth in childhood differentially account for Fast Track intervention effects on conduct disorder (CD) symptoms and callous-unemotional (CU) traits in early adolescence. Participants included 891 high-risk kindergarteners (69% male; 51% African American) from urban and rural United States communities who were randomized into either the Fast Track intervention (n = 445) or non-intervention control (n = 446) groups. The 10-year intervention included parent management training and other services (e.g., social skills training, universal classroom curriculum) targeting various risk factors for the development of conduct problems. Harsh discipline (Grades 1 to 3) and warmth (Grades 1 and 2) were measured using parent responses to vignettes and direct observations of parent-child interaction, respectively. Parents reported on children's CD symptoms in Grade 6 and CU traits in Grade 7. Results demonstrated indirect effects of the Fast Track intervention on reducing risk for youth antisocial outcomes. That is, Fast Track was associated with lower scores on harsh discipline, which in turn predicted decreased levels of CD symptoms. In addition, Fast Track was associated with higher scores on warmth, which in turn predicted reduced levels of CU traits. Our findings inform developmental and intervention models of youth antisocial behavior by providing evidence for the differential role of harsh discipline and warmth in accounting for indirect effects of Fast Track on CD symptoms versus CU traits, respectively.

  18. Basolateral to apical transcytosis in polarized cells is indirect and involves BFA and trimeric G protein sensitive passage through the apical endosome

    PubMed Central

    1994-01-01

    We have used temperature and nocodazole blocks in an in vivo basolateral to apical transcytosis assay to dissociate the early transcytotic steps occurring during the formation of transcytotic vesicles and their microtubule-dependent translocation into the apical region, from the late steps when transcytotic cargo is delivered into the apical media. We found that polarized MDCK cells transfected with rabbit polymeric IgA receptor (pIgA-R) internalize basolaterally added pIgA-R ligand ([Fab]2 fragment of IgG against the receptor's ectodomain) at 17 degrees C but do not deliver it to the apical PM. Instead, the ligand accumulates in an apically localized transcytotic compartment, distal to the basolateral endosome and the microtubule- requiring translocation step. We have characterized this compartment and show that it is distinct from basolateral transferrin recycling endosomes, basolateral early endosomes or late endosomes or lysosomes. The apical transcytotic compartment colocalizes with the compartment containing apically recycling membrane markers (ricin and apically internalized pIgA-R ligand) but is distinct from the compartment receiving apically internalized fluid phase marker (BSA). This compartment is an intermediate station of the overall pathway since transcytotic ligand can exit the compartment and be released into the apical medium when cells preloaded at 17 degrees C are subsequently incubated at 37 degrees C. We have used this system to examine the effect of Brefeldin A (BFA) and the involvement of trimeric GTPases in the late (post apical transcytotic compartment) steps of the transcytotic pathway. We found that addition of BFA or cholera toxin, a known activator of Gs alpha, to cells preloaded with transcytotic ligand at 17 degrees C significantly inhibits the exit of ligand from the apical transcytotic compartment. General structure and function of the apical endosome are not affected since neither BFA nor cholera toxin inhibit the recycling of

  19. Systems Biology Reveals Cigarette Smoke-Induced Concentration-Dependent Direct and Indirect Mechanisms That Promote Monocyte-Endothelial Cell Adhesion.

    PubMed

    Poussin, Carine; Laurent, Alexandra; Peitsch, Manuel C; Hoeng, Julia; De Leon, Hector

    2015-10-01

    Cigarette smoke (CS) affects the adhesion of monocytes to endothelial cells, a critical step in atherogenesis. Using an in vitro adhesion assay together with innovative computational systems biology approaches to analyze omics data, our study aimed at investigating CS-induced mechanisms by which monocyte-endothelial cell adhesion is promoted. Primary human coronary artery endothelial cells (HCAECs) were treated for 4 h with (1) conditioned media of human monocytic Mono Mac-6 (MM6) cells preincubated with low or high concentrations of aqueous CS extract (sbPBS) from reference cigarette 3R4F for 2 h (indirect treatment, I), (2) unconditioned media similarly prepared without MM6 cells (direct treatment, D), or (3) freshly generated sbPBS (fresh direct treatment, FD). sbPBS promoted MM6 cells-HCAECs adhesion following I and FD, but not D. In I, the effect was mediated at a low concentration through activation of vascular inflammation processes promoted in HCAECs by a paracrine effect of the soluble mediators secreted by sbPBS-treated MM6 cells. Tumor necrosis factor α (TNFα), a major inducer, was actually shed by unstable CS compound-activated TNFα-converting enzyme. In FD, the effect was triggered at a high concentration that also induced some toxicity. This effect was mediated through an yet unknown mechanism associated with a stress damage response promoted in HCAECs by unstable CS compounds present in freshly generated sbPBS, which had decayed in D unconditioned media. Aqueous CS extract directly and indirectly promotes monocytic cell-endothelial cell adhesion in vitro via distinct concentration-dependent mechanisms.

  20. Multi-parametric MRI as an indirect evaluation tool of the mechanical properties of in-vitro cardiac tissues.

    PubMed

    Périé, Delphine; Dahdah, Nagib; Foudis, Anthony; Curnier, Daniel

    2013-03-27

    Early detection of heart failure is essential to effectively reduce related mortality. The quantification of the mechanical properties of the myocardium, a primordial indicator of the viability of the cardiac tissue, is a key element in patient's care. Despite an incremental utilization of multi-parametric magnetic resonance imaging (MRI) for cardiac tissue characteristics and function, the link between multi-parametric MRI and the mechanical properties of the heart has not been established. We sought to determine the parametric relationship between the myocardial mechanical properties and the MR parameters. The specific aim was to develop a reproducible evaluative quantitative tool of the mechanical properties of cardiac tissue using multi-parametric MRI associated to principal component analysis. Samples from porcine hearts were submitted to a multi-parametric MRI acquisition followed by a uniaxial tensile test. Multi linear regressions were performed between dependent (Young's modulus E) and independent (relaxation times T1, T2 and T2*, magnetization transfer ratio MTR, apparent diffusion coefficient ADC and fractional anisotropy FA) variables. A principal component analysis was used to convert the set of possibly correlated variables into a set of linearly uncorrelated variables. Values of 46.1 ± 12.7 MPa for E, 729 ± 21 ms for T1, 61 ± 6 ms for T2, 26 ± 7 for T2*, 35 ± 5% for MTR x 100, 33.8 ± 4.7 for FA x 10⁻², and 5.85 ± 0.21 mm²/s for ADC x 10⁻⁴ were measured. Multi linear regressions showed that only 45% of E can be explained by the MRI parameters. The principal component analysis reduced our seven variables to two principal components with a cumulative variability of 63%, which increased to 80% when considering the third principal component. The proposed multi-parametric MRI protocol associated to principal component analysis is a promising tool for the evaluation of mechanical properties within the left ventricle in the in vitro porcine

  1. Multi-parametric MRI as an indirect evaluation tool of the mechanical properties of in-vitro cardiac tissues

    PubMed Central

    2013-01-01

    Background Early detection of heart failure is essential to effectively reduce related mortality. The quantification of the mechanical properties of the myocardium, a primordial indicator of the viability of the cardiac tissue, is a key element in patient’s care. Despite an incremental utilization of multi-parametric magnetic resonance imaging (MRI) for cardiac tissue characteristics and function, the link between multi-parametric MRI and the mechanical properties of the heart has not been established. We sought to determine the parametric relationship between the myocardial mechanical properties and the MR parameters. The specific aim was to develop a reproducible evaluative quantitative tool of the mechanical properties of cardiac tissue using multi-parametric MRI associated to principal component analysis. Methods Samples from porcine hearts were submitted to a multi-parametric MRI acquisition followed by a uniaxial tensile test. Multi linear regressions were performed between dependent (Young’s modulus E) and independent (relaxation times T1, T2 and T2*, magnetization transfer ratio MTR, apparent diffusion coefficient ADC and fractional anisotropy FA) variables. A principal component analysis was used to convert the set of possibly correlated variables into a set of linearly uncorrelated variables. Results Values of 46.1±12.7 MPa for E, 729±21 ms for T1, 61±6 ms for T2, 26±7 for T2*, 35±5% for MTRx100, 33.8±4.7 for FAx10-2, and 5.85±0.21 mm2/s for ADCx10-4 were measured. Multi linear regressions showed that only 45% of E can be explained by the MRI parameters. The principal component analysis reduced our seven variables to two principal components with a cumulative variability of 63%, which increased to 80% when considering the third principal component. Conclusions The proposed multi-parametric MRI protocol associated to principal component analysis is a promising tool for the evaluation of mechanical properties within the left ventricle in the

  2. Comparison of direct and indirect bronchoprovocation testing using ventilator-acquired pulmonary mechanics in healthy cats and cats with experimental allergic asthma.

    PubMed

    Chang, C-H; Dodam, J R; Cohn, L A; Reinero, C R

    2013-11-01

    Airway hyperresponsiveness (AHR) is a key feature of asthma and can be measured using bronchoprovocation. Direct (methacholine, MCh) or indirect (adenosine-5-monophosphate, AMP; or mannitol) bronchoprovocants are used in human patients, the latter inducing AHR only with pre-existing airway inflammation. The present study compared the responses to direct (MCh) and indirect (mannitol, AMP) bronchoprovocation in healthy and asthmatic cats (n=6/group). The order of bronchoprovocant was randomized using a published table of random numbers and there was a 1-month washout before crossover to the next treatment. Pulmonary mechanics were measured in anesthetized and mechanically ventilated cats using a critical care ventilator. Saline at baseline and increasing doses of each bronchoprovocant were aerosolized for 30 s, followed by 4 min of data collection between doses. The endpoint for each bronchoprovocant was reached when airway resistance exceeded 200% of baseline values (EC200Raw). There was a significant difference (P<0.001) in the airway response of asthmatic vs. healthy cats over the range of MCh concentrations, despite there being no significant difference in the EC200Raw between the groups. Response to MCh was significantly greater (P<0.05) in asthmatic than in healthy cats at MCh concentrations as low as 0.0625 mg/mL. For AMP, a small subset of asthmatics (n=2/6) responded at low concentrations; four asthmatic cats and all healthy cats failed to respond even to the highest concentrations of AMP. One asthmatic cat but no healthy cats responded to mannitol. In conclusion, MCh discriminated asthmatic from healthy cats but neither AMP nor mannitol was an effective bronchoprovocant in this model. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Transcriptional regulation of the Clostridium cellulolyticum cip-cel operon: a complex mechanism involving a catabolite-responsive element.

    PubMed

    Abdou, Laetitia; Boileau, Céline; de Philip, Pascale; Pagès, Sandrine; Fiérobe, Henri-Pierre; Tardif, Chantal

    2008-03-01

    The cip-cel cluster of genes plays an important role in the catabolism of the substrate cellulose by Clostridium cellulolyticum. It encodes several key components of the cellulosomes, including the scaffolding protein CipC and the major cellulase Cel48F. All the genes of this cluster display linked transcription, focusing attention on the promoter upstream from the first gene, cipC. We analyzed the regulation of the cipC promoter using a transcriptional fusion approach. A single promoter is located between nucleotides -671 and -643 with respect to the ATG start codon, and the large mRNA leader sequence is processed at position -194. A catabolite-responsive element (CRE) 414 nucleotides downstream from the transcriptional start site has been shown to be involved in regulating this operon by a carbon catabolite repression mechanism. This CRE is thought to bind a CcpA-like regulator complexed with a P-Ser-Crh-like protein. Sequences surrounding the promoter sequence may also be involved in direct (sequence-dependent DNA curvature) or indirect (unknown regulator binding) regulation.

  4. Relative contributions of direct and indirect mechanisms mediating endothelin-induced contraction of guinea-pig trachea.

    PubMed Central

    Hay, D. W.; Hubbard, W. C.; Undem, B. J.

    1993-01-01

    1. The present study was undertaken to determine the mechanism of action of endothelin-1 (ET-1)-induced contraction of the guinea-pig isolated trachea. 2. ET-1 (1 nM-0.3 microM) produces a concentration-dependent contraction of guinea-pig trachea with an EC50 of approximately 25 nM. The combination of the peptidoleukotriene receptor antagonist, SK&F 104353 (10 microM) and the H1-histamine receptor antagonist, mepyramine (10 microM), which abolishes antigen-induced contraction in guinea-pig trachea, was without effect on ET-1 concentration-response curves. Furthermore, the platelet-activating factor (PAF) receptor antagonist, WEB 2086, (1 or 10 microM) did not inhibit ET-induced contraction. 3. ET-1 (0.3 microM) did not stimulate histamine or immunoreactive peptidoleukotriene release from guinea-pig isolated trachea. 4. The release of various prostanoids from guinea-pig trachea was increased significantly by ET-1 (0.3 microM); the profile of release was prostaglandin D2 (PGD2) = PGE2 = 6-keto PGF1 alpha (PGI2 metabolite) > thromboxane B2 = PGF2 alpha >> 9 alpha, 11 beta PGF2 (PGD2 metabolite). ET-1-induced release of prostaglandins, which was about 30% of that elicited by antigen in sensitized tissues, was not affected by epithelium removal and was observed in tissues from which the smooth muscle had been removed. Previous studies in our laboratory indicated that indomethacin potentiated contraction produced by high concentrations of ET-1, whereas a thromboxane receptor antagonist was without appreciable effect on ET-1 concentration-response curves. 5. Pretreatment of tissues for 1 h with capsaicin (10 microM), which depletes different sensory neurones, produced a small, but significant, inhibitory effect on ET-1 concentration-response curves in the presence but not the absence of the epithelium.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7507780

  5. Dual antiplasmodial activity of vitamin D3 and its analog, 22-oxacalcitriol, by direct and indirect mechanisms.

    PubMed

    Yamamoto, Kiichi; Iwagami, Moritoshi; Seki, Takenori; Kano, Shigeyuki; Ota, Nobuo; Ato, Manabu

    2017-04-01

    Recent evidence suggests that 1α,25-dihydroxyvitamin D3 (calcitriol, VD3), the active form of vitamin D (VD), can inhibit the proliferation of microorganisms. In the present study, we conducted in vitro experiments and utilized in vivo murine models to investigate the antimalarial activity of VD3 and its analog, 22-oxacalcitriol (22-OCT), which was designed to cause less hypercalcemia than VD3. VD3 and 22-OCT treatments effectively resolved a Plasmodium chabaudi (Pc) infection in wild-type mice. Reduced parasitemia was observed during the acute phase of infection in the presence of VD3 and 22-OCT, followed by a delayed peak during the chronic stage of infection. Some anti-Pc activity was observed in VD receptor knockout (KO) mice. VD3 and 22-OCT also completely inhibited the proliferation of P. falciparum (Pf) in human red blood cells in vitro. Plasma levels of interferon (IFN)-γ in VD3-treated B10 and B6 mice were lower than those in vehicle-treated animals, and VD3 resolved a Pc infection in IFN-γ-KO mice, which greatly improved survival. These data suggest that the protective effects of VD3 are elicited through an IFN-γ-independent mechanism. Effective antiplasmodial doses of VD3 and 22-OCT resulted in a loss of body weight in mice. This loss in body weight occurred concomitantly with the development of hypercalcemia. Zoledronic acid partially attenuated VD3-induced hypercalcemia and abrogated the antiparasitic effects of VD3. This study highlights a potential therapeutic role for VD3 in the treatment of malarial infections and shows that hypercalcemia is excellent indicator of the antiplasmodial activity of VD3.

  6. Mechanism(s) involved in opioid drug abuse modulation of HAND.

    PubMed

    Dutta, Raini; Roy, Sabita

    2012-07-01

    Drug abuse and HIV infection are interlinked. From the onset of the HIV/AIDS epidemic, the impact of illicit drug use on HIV disease progression has been a focus of many investigations. Both laboratory-based and epidemiological studies strongly indicate that drug abuse may exacerbate HIV disease progression and increase mortality and morbidity in these patients. Increase susceptibility to opportunistic infection has been implicated as one of the major causes for this detriment. Furthermore, opioids are known to elicit prevalence of neurodegenerative disorders in HIV-infected patients. Numerous authors have delineated various molecular as well as cellular mechanisms associated with neurological complications in these patients. This review gives an overview of these findings. Understanding the mechanisms will allow for the development of targeted therapies aimed at reducing the progression of neurocognitive decline in the drug abusing HIV infected individuals.

  7. Peripheral and central mechanisms involved in the control of food intake by dietary amino acids and proteins.

    PubMed

    Fromentin, Gilles; Darcel, Nicolas; Chaumontet, Catherine; Marsset-Baglieri, Agnes; Nadkarni, Nachiket; Tomé, Daniel

    2012-06-01

    The present review summarises current knowledge and recent findings on the modulation of appetite by dietary protein, via both peripheral and central mechanisms. Of the three macronutrients, proteins are recognised as the strongest inhibitor of food intake. The well-recognised poor palatability of proteins is not the principal mechanism explaining the decrease in high-protein (HP) diet intake. Consumption of a HP diet does not induce conditioned food aversion, but rather experience-enhanced satiety. Amino acid consumption is detected by multiple and redundant mechanisms originating from visceral (during digestion) and metabolic (inter-prandial period) sources, recorded both directly and indirectly (mainly vagus-mediated) by the central nervous system (CNS). Peripherally, the satiating effect of dietary proteins appears to be mediated by anorexigenic gut peptides, principally cholecystokinin, glucagon-like peptide-1 and peptide YY. In the CNS, HP diets trigger the activation of noradrenergic and adrenergic neurons in the nucleus of the solitary tract and melanocortin neurons in the arcuate nucleus. Additionally, there is evidence that circulating leucine levels may modulate food intake. Leucine is associated with neural mechanisms involving mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), energy sensors active in the control of energy intake, at least in the arcuate nucleus of the hypothalamus. In addition, HP diets inhibit the activation of opioid and GABAergic neurons in the nucleus accumbens, and thus inhibit food intake by reducing the hedonic response to food, presumably because of their low palatability. Future studies should concentrate on studying the adaptation of different neural circuits following the ingestion of protein diets.

  8. Mechanisms involved in regulation of osteoclastic differentiation by mechanical stress-loaded osteoblasts

    SciTech Connect

    Kaneuji, Takeshi; Ariyoshi, Wataru; Okinaga, Toshinori; Toshinaga, Akihiro; Takahashi, Tetsu; Nishihara, Tatsuji

    2011-04-29

    Highlights: {yields} Effect of compressive force on osteoblasts were examined. {yields} Compressive force induced OPG expression and suppressed osteoclastogenesis. {yields} This enhancement of OPG is dependent on Wnt/Ca2+ signal pathway. -- Abstract: Mechanical stress is known to be important for regulation of bone turnover, though the detailed mechanisms are not fully understood. In the present study, we examined the effect of mechanical stress on osteoblasts using a novel compression model. Mouse osteoblastic MC3T3-E1 cells were embedded in three-dimensional (3D) gels and cultured with continuous compressive force (0-10.0 g/cm{sup 2}) for 48 h, and the conditioned medium were collected. RAW264.7 cells were then incubated with the conditioned medium for various times in the presence of receptor activator of nuclear factor-{kappa}B ligand (RANKL). Conditioned medium was found to inhibit the differentiation of RAW264.7 cells into osteoclasts induced by RANKL via down-regulation of the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of I{kappa}B{alpha}, and nuclear translocation of p50 and p65. Interestingly, the conditioned medium also had a high level of binding activity to RANKL and blocked the binding of RANK to RANKL. Furthermore, the binding activity of conditioned medium to RANKL was reduced when the 3D gel was supplemented with KN-93, an inhibitor of non-canonical Wnt/Ca{sup 2+} pathway. In addition, expression level of osteoprotegerin (OPG) mRNA was increased in time- and force-dependent manners, and remarkably suppressed by KN-93. These results indicate that osteoblastic cells subjected to mechanical stress produce OPG, which binds to RANKL. Furthermore, this binding activity strongly inhibited osteoclastogenesis through suppression of TRAF6 and the nuclear factor-kappa B (NF-{kappa}B) signaling pathway, suggesting that enhancement of OPG expression induced by mechanical stress is dependent on non-canonical Wnt

  9. Indirect rapid prototyping of sol-gel hybrid glass scaffolds for bone regeneration - Effects of organic crosslinker valence, content and molecular weight on mechanical properties.

    PubMed

    Hendrikx, Stephan; Kascholke, Christian; Flath, Tobias; Schumann, Dirk; Gressenbuch, Mathias; Schulze, F Peter; Hacker, Michael C; Schulz-Siegmund, Michaela

    2016-04-15

    We present a series of organic/inorganic hybrid sol-gel derived glasses, made from a tetraethoxysilane-derived silica sol (100% SiO2) and oligovalent organic crosslinkers functionalized with 3-isocyanatopropyltriethoxysilane. The material was susceptible to heat sterilization. The hybrids were processed into pore-interconnected scaffolds by an indirect rapid prototyping method, described here for the first time for sol-gel glass materials. A large panel of polyethylene oxide-derived 2- to 4-armed crosslinkers of molecular weights ranging between 170 and 8000Da were incorporated and their effect on scaffold mechanical properties was investigated. By multiple linear regression, 'organic content' and the 'content of ethylene oxide units in the hybrid' were identified as the main factors that determined compressive strength and modulus, respectively. In general, 3- and 4-armed crosslinkers performed better than linear molecules. Compression tests and cell culture experiments with osteoblast-like SaOS-2 cells showed that macroporous scaffolds can be produced with compressive strengths of up to 33±2MPa and with a pore structure that allows cells to grow deep into the scaffolds and form mineral deposits. Compressive moduli between 27±7MPa and 568±98MPa were obtained depending on the hybrid composition and problems associated with the inherent brittleness of sol-gel glass materials could be overcome. SaOS-2 cells showed cytocompatibility on hybrid glass scaffolds and mineral accumulation started as early as day 7. On day 14, we also found mineral accumulation on control hybrid glass scaffolds without cells, indicating a positive effect of the hybrid glass on mineral accumulation. We produced a hybrid sol-gel glass material with significantly improved mechanical properties towards an application in bone regeneration and processed the material into macroporous scaffolds of controlled architecture by indirect rapid prototyping. We were able to produce macroporous materials

  10. First example of a high-level correlated calculation of the indirect spin-spin coupling constants involving tellurium: tellurophene and divinyl telluride.

    PubMed

    Rusakov, Yury Yu; Krivdin, Leonid B; Østerstrøm, Freja F; Sauer, Stephan P A; Potapov, Vladimir A; Amosova, Svetlana V

    2013-08-21

    This paper documents the very first example of a high-level correlated calculation of spin-spin coupling constants involving tellurium taking into account relativistic effects, vibrational corrections and solvent effects for medium sized organotellurium molecules. The (125)Te-(1)H spin-spin coupling constants of tellurophene and divinyl telluride were calculated at the SOPPA and DFT levels, in good agreement with experimental data. A new full-electron basis set, av3z-J, for tellurium derived from the "relativistic" Dyall's basis set, dyall.av3z, and specifically optimized for the correlated calculations of spin-spin coupling constants involving tellurium was developed. The SOPPA method shows a much better performance compared to DFT, if relativistic effects calculated within the ZORA scheme are taken into account. Vibrational and solvent corrections are next to negligible, while conformational averaging is of prime importance in the calculation of (125)Te-(1)H spin-spin couplings. Based on the performed calculations at the SOPPA(CCSD) level, a marked stereospecificity of geminal and vicinal (125)Te-(1)H spin-spin coupling constants originating in the orientational lone pair effect of tellurium has been established, which opens a new guideline in organotellurium stereochemistry.

  11. Direct and Indirect Regulation of the ycnKJI Operon Involved in Copper Uptake through Two Transcriptional Repressors, YcnK and CsoR, in Bacillus subtilis

    PubMed Central

    Edahiro, Takayosh; Kimura, Kosuke; Fujita, Yasutaro

    2012-01-01

    Northern blot and primer extension analyses revealed that the ycnKJI operon and the ycnL gene of Bacillus subtilis are transcribed from adjacent promoters that are divergently oriented. The ycnK and ycnJ genes encode a DeoR-type transcriptional regulator and a membrane protein involved in copper uptake, respectively. DNA binding experiments showed that the YcnK protein specifically binds to the ycnK-ycnL intergenic region, including a 16-bp direct repeat that is essential for the high binding affinity of YcnK, and that a copper-specific chelator significantly inhibits YcnK's DNA binding. lacZ reporter analysis showed that the ycnK promoter is induced by copper limitation or ycnK disruption. These results are consistent with YcnK functioning as a copper-responsive repressor that derepresses ycnKJI expression under copper limitation. On the other hand, the ycnL promoter was hardly induced by copper limitation, but ycnK disruption resulted in a slight induction of the ycnL promoter, suggesting that YcnK also represses ycnL weakly. Moreover, while the CsoR protein did not bind to the ycnK-ycnL intergenic region, lacZ reporter analysis demonstrated that csoR disruption induces the ycnK promoter only in the presence of intact ycnK and copZA genes. Since the copZA operon is involved in copper export and repressed by CsoR, it appears that the constitutive copZA expression brought by csoR disruption causes intracellular copper depletion, which releases the repression of the ycnKJI operon by YcnK. PMID:22904286

  12. Mechanical behavior of bulk direct composite versus block composite and lithium disilicate indirect Class II restorations by CAD-FEM modeling.

    PubMed

    Ausiello, Pietro; Ciaramella, Stefano; Fabianelli, Andrea; Gloria, Antonio; Martorelli, Massimo; Lanzotti, Antonio; Watts, David C

    2017-06-01

    To study the influence of resin based and lithium disilicate materials on the stress and strain distributions in adhesive class II mesio-occlusal-distal (MOD) restorations using numerical finite element analysis (FEA). To investigate the materials combinations in the restored teeth during mastication and their ability to relieve stresses. One 3D model of a sound lower molar and three 3D class II MOD cavity models with 95° cavity-margin-angle shapes were modelled. Different material combinations were simulated: model A, with a 10μm thick resin bonding layer and a resin composite bulk filling material; model B, with a 70μm resin cement with an indirect CAD-CAM resin composite inlay; model C, with a 70μm thick resin cement with an indirect lithium disilicate machinable inlay. To simulate polymerization shrinkage effects in the adhesive layers and bulk fill composite, the thermal expansion approach was used. Shell elements were employed for representing the adhesive layers. 3D solid CTETRA elements with four grid points were employed for modelling the food bolus and tooth. Slide-type contact elements were used between the tooth surface and food. A vertical occlusal load of 600 N was applied, and nodal displacements on the bottom cutting surfaces were constrained in all directions. All the materials were assumed to be isotropic and elastic and a static linear analysis was performed. Displacements were different in models A, B and C. Polymerization shrinkage hardly affected model A and mastication only partially affected mechanical behavior. Shrinkage stress peaks were mainly located marginally along the enamel-restoration interface at occlusal and mesio-distal sites. However, at the internal dentinal walls, stress distributions were critical with the highest maximum stresses concentrated in the proximal boxes. In models B and C, shrinkage stress was only produced by the 70μm thick resin layer, but the magnitudes depended on the Young's modulus (E) of the inlay

  13. Molecular Mechanisms Mediating Involvement of Glial Cells in Brain Plastic Remodeling in Epilepsy.

    PubMed

    Khaspekov, L G; Frumkina, L E

    2017-03-01

    In this review we summarize published data on the involvement of glial cells in molecular mechanisms underlying brain plastic reorganization in epilepsy. The role of astrocytes as glial elements in pathological plasticity in epilepsy is discussed. Data on the involvement of aquaporin-4 in epileptogenic plastic changes and on participation of microglia and extracellular matrix in dysregulation of synaptic transmission and plastic remodeling in epileptic brain tissue are reviewed.

  14. [THE ROLE OF MATERNAL DIET IN METABOLIC AND BEHAVIOURAL PROGRAMMING: REVIEW OF BIOLOGIC MECHANISMS INVOLVED].

    PubMed

    Ramírez-López, María Teresa; Vázquez Berrios, Mariam; Arco González, Rocío; Blanco Velilla, Rosario Noemí; Decara Del Olmo, Juan; Suárez Pérez, Juan; Rodríguez de Fonseca, Fernando; Gómez de Heras, Raquel

    2015-12-01

    Over the last few years, a considerable amount of studies have focused on the effect of undernutrition and overnutrition during critical periods of offspring development and their risk of developing metabolic diseases later in life. Additionally, inadequate maternal diets have been involved in the malprogramming of brain functions and some behaviours. Several mechanisms have been associated with the process of malprogramming such as epigenetics modifications, excessive oxidative stress or hypothalamic alterations. This evidence supports the idea that nutritional prevention strategies must be considered for offspring during early development stages that include the preconceptional period. Additionally, studying involved mechanisms could be particularly useful in the search of efficient therapies against malprogramming.

  15. Mechanism of an indirect effect of aqueous cigarette smoke extract on the adhesion of monocytic cells to endothelial cells in an in vitro assay revealed by transcriptomics analysis.

    PubMed

    Poussin, Carine; Gallitz, Inka; Schlage, Walter K; Steffen, Yvonne; Stolle, Katrin; Lebrun, Stefan; Hoeng, Julia; Peitsch, Manual C; Lietz, Michael

    2014-08-01

    The adhesion of monocytic cells to the "dysfunctional" endothelium constitutes a critical step in the initiation of atherosclerosis. Cigarette smoke (CS) has been shown to contribute to this process, the complex mechanism of which still needs to be unraveled. We developed an in vitro adhesion assay to investigate the CS-induced adhesion of monocytic MM6 cells to human umbilical vein endothelial cells (HUVECs) following exposure to an aqueous CS extract (smoke-bubbled phosphate buffered saline: sbPBS), reasoning that in vivo monocytes and endothelial cells are exposed primarily to soluble constituents from inhaled CS absorbed through the lung alveolar wall. MM6 cell adhesion was increased exclusively by the conditioned medium from sbPBS-exposed MM6 cells, not by direct sbPBS exposure of the HUVECs within a range of sbPBS doses. Using a transcriptomics approach followed by confirmation experiments, we identified different exposure effects on both cell types and a key mechanism by which sbPBS promoted the adhesion of MM6 cells to HUVECs. While sbPBS provoked a strong oxidative stress response in both cell types, the expression of E-selectin, VCAM-1 and ICAM-1, responsible for the adhesion of MM6 cells to HUVECs, was induced in the latter through a proinflammatory paracrine effect. We confirmed that this effect was driven mainly by TNFα produced by MM6 cells exposed to sbPBS. In conclusion, we have elucidated an indirect mechanism by which sbPBS increases the adhesion of monocytic cells to endothelial cells in this in vitro assay that was designed for tobacco product risk assessment while mimicking the in vivo exposure conditions as closely as possible.

  16. Mechanisms involved in the transport of mercuric ions in target tissues.

    PubMed

    Bridges, Christy C; Zalups, Rudolfs K

    2017-01-01

    Mercury exists in the environment in various forms, all of which pose a risk to human health. Despite guidelines regulating the industrial release of mercury into the environment, humans continue to be exposed regularly to various forms of this metal via inhalation or ingestion. Following exposure, mercuric ions are taken up by and accumulate in numerous organs, including brain, intestine, kidney, liver, and placenta. In order to understand the toxicological effects of exposure to mercury, a thorough understanding of the mechanisms that facilitate entry of mercuric ions into target cells must first be obtained. A number of mechanisms for the transport of mercuric ions into target cells and organs have been proposed in recent years. However, the ability of these mechanisms to transport mercuric ions and the regulatory features of these carriers have not been characterized completely. The purpose of this review is to summarize the current findings related to the mechanisms that may be involved in the transport of inorganic and organic forms of mercury in target tissues and organs. This review will describe mechanisms known to be involved in the transport of mercury and will also propose additional mechanisms that may potentially be involved in the transport of mercuric ions into target cells.

  17. Mechanism and comparison of needle-type non-thermal direct and indirect atmospheric pressure plasma jets on the degradation of dyes

    NASA Astrophysics Data System (ADS)

    Attri, Pankaj; Yusupov, Maksudbek; Park, Ji Hoon; Lingamdinne, Lakshmi Prasanna; Koduru, Janardhan Reddy; Shiratani, Masaharu; Choi, Eun Ha; Bogaerts, Annemie

    2016-10-01

    Purified water supply for human use, agriculture and industry is the major global priority nowadays. The advanced oxidation process based on atmospheric pressure non-thermal plasma (NTP) has been used for purification of wastewater, although the underlying mechanisms of degradation of organic pollutants are still unknown. In this study we employ two needle-type atmospheric pressure non-thermal plasma jets, i.e., indirect (ID-APPJ) and direct (D-APPJ) jets operating at Ar feed gas, for the treatment of methylene blue, methyl orange and congo red dyes, for two different times (i.e., 20 min and 30 min). Specifically, we study the decolorization/degradation of all three dyes using the above mentioned plasma sources, by means of UV-Vis spectroscopy, HPLC and a density meter. We also employ mass spectroscopy to verify whether only decolorization or also degradation takes place after treatment of the dyes by the NTP jets. Additionally, we analyze the interaction of OH radicals with all three dyes using reactive molecular dynamics simulations, based on the density functional-tight binding method. This investigation represents the first report on the degradation of these three different dyes by two types of NTP setups, analyzed by various methods, and based on both experimental and computational studies.

  18. Mechanism and comparison of needle-type non-thermal direct and indirect atmospheric pressure plasma jets on the degradation of dyes

    PubMed Central

    Attri, Pankaj; Yusupov, Maksudbek; Park, Ji Hoon; Lingamdinne, Lakshmi Prasanna; Koduru, Janardhan Reddy; Shiratani, Masaharu; Choi, Eun Ha; Bogaerts, Annemie

    2016-01-01

    Purified water supply for human use, agriculture and industry is the major global priority nowadays. The advanced oxidation process based on atmospheric pressure non-thermal plasma (NTP) has been used for purification of wastewater, although the underlying mechanisms of degradation of organic pollutants are still unknown. In this study we employ two needle-type atmospheric pressure non-thermal plasma jets, i.e., indirect (ID-APPJ) and direct (D-APPJ) jets operating at Ar feed gas, for the treatment of methylene blue, methyl orange and congo red dyes, for two different times (i.e., 20 min and 30 min). Specifically, we study the decolorization/degradation of all three dyes using the above mentioned plasma sources, by means of UV-Vis spectroscopy, HPLC and a density meter. We also employ mass spectroscopy to verify whether only decolorization or also degradation takes place after treatment of the dyes by the NTP jets. Additionally, we analyze the interaction of OH radicals with all three dyes using reactive molecular dynamics simulations, based on the density functional-tight binding method. This investigation represents the first report on the degradation of these three different dyes by two types of NTP setups, analyzed by various methods, and based on both experimental and computational studies. PMID:27708352

  19. Mechanism and comparison of needle-type non-thermal direct and indirect atmospheric pressure plasma jets on the degradation of dyes.

    PubMed

    Attri, Pankaj; Yusupov, Maksudbek; Park, Ji Hoon; Lingamdinne, Lakshmi Prasanna; Koduru, Janardhan Reddy; Shiratani, Masaharu; Choi, Eun Ha; Bogaerts, Annemie

    2016-10-06

    Purified water supply for human use, agriculture and industry is the major global priority nowadays. The advanced oxidation process based on atmospheric pressure non-thermal plasma (NTP) has been used for purification of wastewater, although the underlying mechanisms of degradation of organic pollutants are still unknown. In this study we employ two needle-type atmospheric pressure non-thermal plasma jets, i.e., indirect (ID-APPJ) and direct (D-APPJ) jets operating at Ar feed gas, for the treatment of methylene blue, methyl orange and congo red dyes, for two different times (i.e., 20 min and 30 min). Specifically, we study the decolorization/degradation of all three dyes using the above mentioned plasma sources, by means of UV-Vis spectroscopy, HPLC and a density meter. We also employ mass spectroscopy to verify whether only decolorization or also degradation takes place after treatment of the dyes by the NTP jets. Additionally, we analyze the interaction of OH radicals with all three dyes using reactive molecular dynamics simulations, based on the density functional-tight binding method. This investigation represents the first report on the degradation of these three different dyes by two types of NTP setups, analyzed by various methods, and based on both experimental and computational studies.

  20. Cooperation under Indirect Reciprocity and Imitative Trust

    PubMed Central

    Saavedra, Serguei; Smith, David; Reed-Tsochas, Felix

    2010-01-01

    Indirect reciprocity, a key concept in behavioral experiments and evolutionary game theory, provides a mechanism that allows reciprocal altruism to emerge in a population of self-regarding individuals even when repeated interactions between pairs of actors are unlikely. Recent empirical evidence show that humans typically follow complex assessment strategies involving both reciprocity and social imitation when making cooperative decisions. However, currently, we have no systematic understanding of how imitation, a mechanism that may also generate negative effects via a process of cumulative advantage, affects cooperation when repeated interactions are unlikely or information about a recipient's reputation is unavailable. Here we extend existing evolutionary models, which use an image score for reputation to track how individuals cooperate by contributing resources, by introducing a new imitative-trust score, which tracks whether actors have been the recipients of cooperation in the past. We show that imitative trust can co-exist with indirect reciprocity mechanisms up to a threshold and then cooperation reverses -revealing the elusive nature of cooperation. Moreover, we find that when information about a recipient's reputation is limited, trusting the action of third parties towards her (i.e. imitating) does favor a higher collective cooperation compared to random-trusting and share-alike mechanisms. We believe these results shed new light on the factors favoring social imitation as an adaptive mechanism in populations of cooperating social actors. PMID:21048950

  1. A theoretical study of the molecular mechanism of the GAPDH Trypanosoma cruzi enzyme involving iodoacetate inhibitor

    NASA Astrophysics Data System (ADS)

    Carneiro, Agnaldo Silva; Lameira, Jerônimo; Alves, Cláudio Nahum

    2011-10-01

    The glyceraldehyde-3-phosphate dehydrogenase enzyme (GAPDH) is an important biological target for the development of new chemotherapeutic agents against Chagas disease. In this Letter, the inhibition mechanism of GAPDH involving iodoacetate (IAA) inhibitor was studied using the hybrid quantum mechanical/molecular mechanical (QM/MM) approach and molecular dynamic simulations. Analysis of the potential energy surface and potential of mean force show that the covalent attachment of IAA inhibitor to the active site of the enzyme occurs as a concerted process. In addition, the energy terms decomposition shows that NAD+ plays an important role in stabilization of the reagents and transition state.

  2. On reaction mechanisms involved in the deuteron–induced surrogate reactions

    SciTech Connect

    Avrigeanu, M.; Avrigeanu, V.; Mănăilescu, C.

    2015-02-24

    An extended analysis of the nuclear reaction mechanisms involved within deuteron interaction with nuclei, namely the breakup, stripping, pick-up, pre-equilibrium emission, and evaporation from fully equilibrated compound nucleus, is presented in order to highlight the importance of the direct mechanisms still neglected in the analysis of deuteron-induced surrogate reactions. Particularly, the dominance of the breakup mechanism at low energies around the Coulomb barrier should be considered in the case of (d,x) surrogate reactions on actinide target nuclei.

  3. Evaluation of autophagy as a mechanism involved in air pollutant-induced pulmonary injury

    EPA Science Inventory

    Evaluation of autophagy as a mechanism involved in air pollutant-induced pulmonary injuryHenriquez, A.1, Snow, S.2, Miller, D1.,Schladweiler, M.2 and Kodavanti, U2.1 Curriculum in Toxicology, UNC, Chapel Hill, NC. 2 EPHD/NHEERL, US EPA, RTP, Durham, NC. ...

  4. Involvement of the Central Cognitive Mechanism in Word Production in Adults Who Stutter

    ERIC Educational Resources Information Center

    Tsai, Pei-Tzu; Bernstein Ratner, Nan

    2016-01-01

    Purpose: The study examined whether semantic and phonological encoding processes were capacity demanding, involving the central cognitive mechanism, in adults who do and do not stutter (AWS and NS) to better understand the role of cognitive demand in linguistic processing and stuttering. We asked (a) whether the two linguistic processes in AWS are…

  5. Evaluation of autophagy as a mechanism involved in air pollutant-induced pulmonary injury

    EPA Science Inventory

    Evaluation of autophagy as a mechanism involved in air pollutant-induced pulmonary injuryHenriquez, A.1, Snow, S.2, Miller, D1.,Schladweiler, M.2 and Kodavanti, U2.1 Curriculum in Toxicology, UNC, Chapel Hill, NC. 2 EPHD/NHEERL, US EPA, RTP, Durham, NC. ...

  6. Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin.

    PubMed

    Sawyer, J R; Tricot, G; Mattox, S; Jagannath, S; Barlogie, B

    1998-03-01

    Karyotypes in multiple myeloma (MM) are complex and exhibit numerous structural and numerical aberrations. The largest subset of structural chromosome anomalies in clinical specimens and cell lines involves aberrations of chromosome 1. Unbalanced translocations and duplications involving all or part of the whole long arm of chromosome 1 presumably occur as secondary aberrations and are associated with tumor progression and advanced disease. Unfortunately, cytogenetic evidence is scarce as to how these unstable whole-arm rearrangements may take place. We report nonrandom, unbalanced whole-arm translocations of 1q in the cytogenetic evolution of patients with aggressive MM. Whole-arm or "jumping translocations" of 1q were found in 36 of 158 successive patients with abnormal karyotypes. Recurring whole-arm translocations of 1q involved chromosomes 5,8,12,14,15,16,17,19,21, and 22. A newly delineated breakpoint present in three patients involved a whole-arm translocation of 1q to band 5q15. Three recurrent translocations of 1q10 to the short arms of different acrocentric chromosomes have also been identified, including three patients with der(15)t(1;15)(q10;p10) and two patients each with der(21)t(1;21)(q10;p13) and der(22)t(1;22) (q10;p10). Whole-arm translocations of 1q10 to telomeric regions of nonacrocentric chromosomes included der(12)t(1;12) (q10;q24.3) and der(19)t(1;19)(q10;q13.4) in three and two patients, respectively. Recurrent whole-arm translocations of 1q to centromeric regions included der(16)t(1;16)(q10;q10) and der(19)t(1;19)(q10;p10). The mechanisms involved in the 1q instability in MM may be associated with highly decondensed pericentromeric heterochromatin, which may permit recombination and formation of unstable translocations of chromosome 1q. The clonal evolution of cells with extra copies of 1q suggests that this aberration directly or indirectly provides a proliferative advantage.

  7. The logic of indirect speech

    PubMed Central

    Pinker, Steven; Nowak, Martin A.; Lee, James J.

    2008-01-01

    When people speak, they often insinuate their intent indirectly rather than stating it as a bald proposition. Examples include sexual come-ons, veiled threats, polite requests, and concealed bribes. We propose a three-part theory of indirect speech, based on the idea that human communication involves a mixture of cooperation and conflict. First, indirect requests allow for plausible deniability, in which a cooperative listener can accept the request, but an uncooperative one cannot react adversarially to it. This intuition is supported by a game-theoretic model that predicts the costs and benefits to a speaker of direct and indirect requests. Second, language has two functions: to convey information and to negotiate the type of relationship holding between speaker and hearer (in particular, dominance, communality, or reciprocity). The emotional costs of a mismatch in the assumed relationship type can create a need for plausible deniability and, thereby, select for indirectness even when there are no tangible costs. Third, people perceive language as a digital medium, which allows a sentence to generate common knowledge, to propagate a message with high fidelity, and to serve as a reference point in coordination games. This feature makes an indirect request qualitatively different from a direct one even when the speaker and listener can infer each other's intentions with high confidence. PMID:18199841

  8. Cell resistance to the Cytolethal Distending Toxin involves an association of DNA repair mechanisms.

    PubMed

    Bezine, Elisabeth; Malaisé, Yann; Loeuillet, Aurore; Chevalier, Marianne; Boutet-Robinet, Elisa; Salles, Bernard; Mirey, Gladys; Vignard, Julien

    2016-10-24

    The Cytolethal Distending Toxin (CDT), produced by many bacteria, has been associated with various diseases including cancer. CDT induces DNA double-strand breaks (DSBs), leading to cell death or mutagenesis if misrepaired. At low doses of CDT, other DNA lesions precede replication-dependent DSB formation, implying that non-DSB repair mechanisms may contribute to CDT cell resistance. To address this question, we developed a proliferation assay using human cell lines specifically depleted in each of the main DNA repair pathways. Here, we validate the involvement of the two major DSB repair mechanisms, Homologous Recombination and Non Homologous End Joining, in the management of CDT-induced lesions. We show that impairment of single-strand break repair (SSBR), but not nucleotide excision repair, sensitizes cells to CDT, and we explore the interplay of SSBR with the DSB repair mechanisms. Finally, we document the role of the replicative stress response and demonstrate the involvement of the Fanconi Anemia repair pathway in response to CDT. In conclusion, our work indicates that cellular survival to CDT-induced DNA damage involves different repair pathways, in particular SSBR. This reinforces a model where CDT-related genotoxicity primarily involves SSBs rather than DSBs, underlining the importance of cell proliferation during CDT intoxication and pathogenicity.

  9. Cell resistance to the Cytolethal Distending Toxin involves an association of DNA repair mechanisms

    PubMed Central

    Bezine, Elisabeth; Malaisé, Yann; Loeuillet, Aurore; Chevalier, Marianne; Boutet-Robinet, Elisa; Salles, Bernard; Mirey, Gladys; Vignard, Julien

    2016-01-01

    The Cytolethal Distending Toxin (CDT), produced by many bacteria, has been associated with various diseases including cancer. CDT induces DNA double-strand breaks (DSBs), leading to cell death or mutagenesis if misrepaired. At low doses of CDT, other DNA lesions precede replication-dependent DSB formation, implying that non-DSB repair mechanisms may contribute to CDT cell resistance. To address this question, we developed a proliferation assay using human cell lines specifically depleted in each of the main DNA repair pathways. Here, we validate the involvement of the two major DSB repair mechanisms, Homologous Recombination and Non Homologous End Joining, in the management of CDT-induced lesions. We show that impairment of single-strand break repair (SSBR), but not nucleotide excision repair, sensitizes cells to CDT, and we explore the interplay of SSBR with the DSB repair mechanisms. Finally, we document the role of the replicative stress response and demonstrate the involvement of the Fanconi Anemia repair pathway in response to CDT. In conclusion, our work indicates that cellular survival to CDT-induced DNA damage involves different repair pathways, in particular SSBR. This reinforces a model where CDT-related genotoxicity primarily involves SSBs rather than DSBs, underlining the importance of cell proliferation during CDT intoxication and pathogenicity. PMID:27775089

  10. Cissus sicyoides: Pharmacological Mechanisms Involved in the Anti-Inflammatory and Antidiarrheal Activities

    PubMed Central

    Beserra, Fernando Pereira; de Cássia Santos, Raquel; Périco, Larissa Lucena; Rodrigues, Vinicius Peixoto; de Almeida Kiguti, Luiz Ricardo; Saldanha, Luiz Leonardo; Pupo, André Sampaio; da Rocha, Lúcia Regina Machado; Dokkedal, Anne Lígia; Vilegas, Wagner; Hiruma-Lima, Clélia Akiko

    2016-01-01

    The objective of this study was to evaluate the pharmacological mechanisms involved in anti-inflammatory and antidiarrheal actions of hydroalcoholic extract obtained from the leaves of Cissus sicyoides (HECS). The anti-inflammatory effect was evaluated by oral administration of HECS against acute model of edema induced by xylene, and the mechanisms of action were analysed by involvement of arachidonic acid (AA) and prostaglandin E2 (PGE2). The antidiarrheal effect of HECS was observed and we analyzed the motility and accumulation of intestinal fluid. We also analyzed the antidiarrheal mechanisms of action of HECS by evaluating the role of the opioid receptor, α2 adrenergic receptor, muscarinic receptor, nitric oxide (NO) and PGE2. The oral administration of HECS inhibited the edema induced by xylene and AA and was also able to significantly decrease the levels of PGE2. The extract also exhibited significant anti-diarrheal activity by reducing motility and intestinal fluid accumulation. This extract significantly reduced intestinal transit stimulated by muscarinic agonist and intestinal secretion induced by PGE2. Our data demonstrate that the mechanism of action involved in the anti-inflammatory effect of HECS is related to PGE2. The antidiarrheal effect of this extract may be mediated by inhibition of contraction by acting on the intestinal smooth muscle and/or intestinal transit. PMID:26805827

  11. Tissue transglutaminase is involved in mechanical load-induced osteogenic differentiation of human ligamentum flavum cells.

    PubMed

    Chao, Yuan-Hung; Huang, Shih-Yung; Yang, Ruei-Cheng; Sun, Jui-Sheng

    2016-07-01

    Mechanical load-induced osteogenic differentiation might be the key cellular event in the calcification and ossification of ligamentum flavum. The aim of this study was to investigate the influence of tissue transglutaminase (TGM2) on mechanical load-induced osteogenesis of ligamentum flavum cells. Human ligamentum flavum cells were obtained from 12 patients undergoing lumbar spine surgery. Osteogenic phenotypes of ligamentum flavum cells, such as alkaline phosphatase (ALP), Alizarin red-S stain, and gene expression of osteogenic makers were evaluated following the administration of mechanical load and BMP-2 treatment. The expression of TGM2 was evaluated by real-time PCR, Western blotting, and enzyme-linked immunosorbent assay (ELISA) analysis. Our results showed that mechanical load in combination with BMP-2 enhanced calcium deposition and ALP activity. Mechanical load significantly increased ALP and OC gene expression on day 3, whereas BMP-2 significantly increased ALP, OPN, and Runx2 on day 7. Mechanical load significantly induced TGM2 gene expression and enzyme activity in human ligamentum flavum cells. Exogenous TGM2 increased ALP and OC gene expression; while, inhibited TG activity significantly attenuated mechanical load-induced and TGM2-induced ALP activity. In summary, mechanical load-induced TGM2 expression and enzyme activity is involved in the progression of the calcification of ligamentum flavum.

  12. Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways.

    PubMed

    Rajsbaum, Ricardo; García-Sastre, Adolfo

    2013-08-01

    Early innate and cell-intrinsic responses are essential to protect host cells against pathogens. In turn, viruses have developed sophisticated mechanisms to establish productive infections by counteracting host innate immune responses. Increasing evidence indicates that these antiviral factors may have a dual role by directly inhibiting viral replication as well as by sensing and transmitting signals to induce antiviral cytokines. Recent studies have pointed at new, unappreciated mechanisms of viral evasion of host innate protective responses including manipulating the host ubiquitin (Ub) system. Virus-mediated inhibition of antiviral factors by Ub-dependent degradation is emerging as a crucial mechanism for evading the antiviral response. In addition, recent studies have uncovered new mechanisms by which virus-encoded proteins inhibit Ub and Ub-like (Ubl) modification of host proteins involved in innate immune signaling pathways. Here we discuss recent findings and novel strategies that viruses have developed to counteract these early innate antiviral defenses.

  13. Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation.

    PubMed

    Sharma, Manoranjan; Mohapatra, Jogeswar; Wagh, Akshaya; Patel, Hiren M; Pandey, Dheerendra; Kadam, Shekhar; Argade, Anil; Deshpande, Shrikalp S; Shah, Gourang B; Chatterjee, Abhijit; Jain, Mukul R

    2014-03-01

    TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation. Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.

  14. Glucagon increase after chronic AT1 blockade is more likely related to an indirect leptin-dependent than to a pancreatic α-cell-dependent mechanism.

    PubMed

    Mildner, Martin; Müller-Fielitz, Helge; Stölting, Ines; Jöhren, Olaf; Steckelings, Muscha; Raasch, Walter

    2017-05-01

    AT1 blockers (ARB) prevent diabetes by improving pancreatic β cell function. Less is known about whether α cells are affected although they express angiotensin II (AngII) receptors. We aimed to investigate glucagon release upon AngII stimulation. We determined glucagon release after AngII stimulation (0.01-100 μM) in α cells (InR1G9) and isolated murine islets. We determined plasma glucagon in rats that were chronically treated with AngII (9 μg/h) or the ARBs telmisartan (8 mg/kg/day) and candesartan (16 mg/kg/day) and correlated glucagon with additional hormones (e.g. leptin). Glucagon was only released from InR1G9 cells and islets at the highest AngII concentrations (>10 μM). This was not inhibited by losartan or PD123319. Ang(1-7) and AngIV were also almost ineffective. AngII did not alter glucagon secretion from islets. Plasma glucagon increased when obese Zucker rats were treated with AngII or candesartan and also when Sprague Dawley rats were treated with telmisartan in parallel to high-calorie feeding. Plasma glucagon and leptin negatively correlated in ARB-treated rats. The glucagon release from InR1G9 cells or islets after AngII, AngIV or Ang(1-7) is unspecific since it only occurs, if at all, after the highest concentrations and cannot be blocked by specific inhibitors. Thus, the AngII-dependent increase in plasma glucagon seems to be mediated by indirect mechanisms. The negative correlations between plasma leptin and glucagon confirm findings showing that leptin suppresses glucagon release, leading us to suppose that the increase in plasma glucagon is related to the decrease in leptin after ARB treatment.

  15. A Mechanism Involving Solar Ultraviolet Variations for Modulating the Interannual Climatology of the Middle Atmosphere

    NASA Technical Reports Server (NTRS)

    Hood, L. L.; Jirikowic, J. L.

    1990-01-01

    In years of low solar activity, free traveling wave modes in the upper stratosphere are dominated by atmospheric normal modes such as the 16-day wave. However, within a 4-year interval centered on the 1980 to 1981 solar maximum, cross-spectral analyses of zonal mean satellite temperature data versus the solar UV flux demonstrate significant power near 27 and 13 days, providing indirect evidence that short-term UV variations were capable of exciting traveling planetary-scale waves in the upper stratosphere. Previous theoretical and observational work has indicated that interference between traveling waves and stationary waves forced from below (and the resulting oscillating latitudinal heat transports) plays a likely role in the initiation of stratospheric warmings. Researchers therefore hypothesize that the initiation of a major stratospheric warming in the upper stratosphere and lower mesosphere may depend to some extent on the amplitude of longer-period 27-day traveling waves in the upper stratosphere. This would represent a new mechanism for solar UV effects on stratospheric climatology that may be relevant to the interpretation of some recent long-term correlative results.

  16. Neural Mechanisms Involved in Hypersensitive Hearing: Helping Children with ASD Who Are Overly Sensitive to Sounds

    PubMed Central

    Lucker, Jay R.; Doman, Alex

    2015-01-01

    Professionals working with children diagnosed with autism spectrum disorder (ASD) may find that these children are overly sensitive to sounds. These professionals are often concerned as to why children may have auditory hypersensitivities. This review article discusses the neural mechanisms identified underlying hypersensitive hearing in people. The authors focus on brain research to support the idea of the nonclassical auditory pathways being involved in connecting the auditory system with the emotional system of the brain. The authors also discuss brain mechanisms felt to be involved in auditory hypersensitivity. The authors conclude with a discussion of some treatments for hypersensitive hearing. These treatments include desensitization training and the use of listening therapies such as The Listening Program. PMID:26823983

  17. Overconsumption of dietary fat and alcohol: Mechanisms involving lipids and hypothalamic peptides

    PubMed Central

    Leibowitz, Sarah F.

    2007-01-01

    The studies described in this report provide interesting animal models for exploring some of the metabolic and neural antecedents to the over-consumption of fat and alcohol. The results provide strong support for the existence of positive feedback loops that involve a close relation between circulating lipids and orexigenic peptides in dorsal regions of the hypothalamus. The peptides involved in these circuits include galanin, enkephalin, dynorphin and orexin. These peptides are expressed in the paraventricular nucleus and perifornical lateral hypothalamus, and they have very different functions from peptides expressed in the arcuate nucleus. Through mechanisms involving circulating lipids that rise on energy-dense diets, these peptides in the dorsal hypothalamus are each increased by the consumption of fat and ethanol; these nutrients, in turn, stimulate further production of these same peptides that promote overeating and excess drinking. These mechanisms involving non-homeostatic, positive feedback circuits may be required under conditions when food supplies are scarce and periods of gorging are essential to survival. However, they have pathological and sometimes life-threatening consequences in modern society, where fat-rich foods and alcoholic drinks are abundantly available and are contributing to the marked rise over the past 25 years in obesity and diabetes in both children and adults. PMID:17481672

  18. Identification of genes involved in regulatory mechanism of pigments in broiler chickens.

    PubMed

    Tarique, T M; Yang, S; Mohsina, Z; Qiu, J; Yan, Z; Chen, G; Chen, A

    2014-09-05

    Chicken is an important model organism that unites the evolutionary gap between mammals and other vertebrates and provide major source of protein from meat and eggs for all over the world population. However, specific genes underlying the regulatory mechanism of broiler pigmentation have not yet been determined. In order to better understand the genes involved in the mechanism of pigmentation in the muscle tissues of broilers, the Affymetrix microarray hybridization experiment platform was used to identify gene expression profiles at 7 weeks of age. Broilers fed canthaxanthin, natural lutein, and orangeII pigments (100 mg/kg) were used to explore gene expression profiles). Our data showed that the 7th week of age was a very important phase with regard to gene expression profiles. We identified a number of differentially expressed genes; in canthaxanthin, natural lutein, and orangeII, there were 54 (32 upregulated and 22 downregulated), 23 (15 upregulated and 8 downregulated), and 7 (5 upregulated and 2 downregulated) known genes, respectively. Our data indicate that the numbers of differentially expressed genes were more upregulated than downregulated, and several genes showed conserved signaling to previously known functions. Thus, functional characterization of differentially expressed genes revealed several categories that are involved in important biological processes, including pigmentation, growth, molecular mechanisms, fat metabolism, cell proliferation, immune response, lipid metabolism, and protein synthesis and degradation. The results of the present study demonstrate that the genes associated with canthaxanthin, natural lutein, and orangeII are key regulatory genes that control the regulatory mechanisms of pigmentation.

  19. Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking.

    PubMed

    Kost, Gina Chun; Selvaraj, Senthil; Lee, Young Bok; Kim, Deog Joong; Ahn, Chang-Ho; Singh, Brij B

    2011-10-24

    Clavulanic acid is a CNS-modulating compound with exceptional blood-brain barrier permeability and safety profile. Clavulanic acid has been proposed to have anti-depressant activity and is currently entering Phase IIb clinical trials for the treatment of Major Depressive Disorder (MDD). Studies have also shown that clavulanic acid suppresses anxiety and enhances sexual functions in rodent and primate models by a mechanism involving central nervous system (CNS) modulation, although its detailed mechanism of action has yet to be elucidated. To further examine its potential as a CNS modulating agent as well as its mechanism of action, we investigated the effects of clavulanic acid in neuronal cells. Our results indicate that clavulanic acid enhances dopamine release in PC12 and SH-SY5Y cells without affecting dopamine synthesis. Furthermore, using affinity chromatography we were able to identify two proteins, Munc18-1 and Rab4 that potentially bind to clavulanic acid and play a critical role in neurosecretion and the vesicle trafficking process. Consistent with this result, an increase in the translocation of Munc18-1 and Rab4 from the cytoplasm to the plasma membrane was observed in clavulanic acid treated cells. Overall, these data suggest that clavulanic acid enhances dopamine release in a mechanism involving Munc18-1 and Rab4 modulation and warrants further investigation of its therapeutic use in CNS disorders, such as depression. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  20. Indirect Reciprocity; A Field Experiment.

    PubMed

    van Apeldoorn, Jacobien; Schram, Arthur

    2016-01-01

    Indirect reciprocity involves cooperative acts towards strangers, either in response to their kindness to third parties (downstream) or after receiving kindness from others oneself (upstream). It is considered to be important for the evolution of cooperative behavior amongst humans. Though it has been widely studied theoretically, the empirical evidence of indirect reciprocity has thus far been limited and based solely on behavior in laboratory experiments. We provide evidence from an online environment where members can repeatedly ask and offer services to each other, free of charge. For the purpose of this study we created several new member profiles, which differ only in terms of their serving history. We then sent out a large number of service requests to different members from all over the world. We observe that a service request is more likely to be rewarded for those with a profile history of offering the service (to third parties) in the past. This provides clear evidence of (downstream) indirect reciprocity. We find no support for upstream indirect reciprocity (in this case, rewarding the service request after having previously received the service from third parties), however. Our evidence of downstream indirect reciprocity cannot be attributed to reputational effects concerning one's trustworthiness as a service user.

  1. Indirect Reciprocity; A Field Experiment

    PubMed Central

    van Apeldoorn, Jacobien; Schram, Arthur

    2016-01-01

    Indirect reciprocity involves cooperative acts towards strangers, either in response to their kindness to third parties (downstream) or after receiving kindness from others oneself (upstream). It is considered to be important for the evolution of cooperative behavior amongst humans. Though it has been widely studied theoretically, the empirical evidence of indirect reciprocity has thus far been limited and based solely on behavior in laboratory experiments. We provide evidence from an online environment where members can repeatedly ask and offer services to each other, free of charge. For the purpose of this study we created several new member profiles, which differ only in terms of their serving history. We then sent out a large number of service requests to different members from all over the world. We observe that a service request is more likely to be rewarded for those with a profile history of offering the service (to third parties) in the past. This provides clear evidence of (downstream) indirect reciprocity. We find no support for upstream indirect reciprocity (in this case, rewarding the service request after having previously received the service from third parties), however. Our evidence of downstream indirect reciprocity cannot be attributed to reputational effects concerning one’s trustworthiness as a service user. PMID:27043712

  2. The Future of Indirect Evidence

    PubMed Central

    Efron, Bradley

    2009-01-01

    Familiar statistical tests and estimates are obtained by the direct observation of cases of interest: a clinical trial of a new drug, for instance, will compare the drug’s effects on a relevant set of patients and controls. Sometimes, though, indirect evidence may be temptingly available, perhaps the results of previous trials on closely related drugs. Very roughly speaking, the difference between direct and indirect statistical evidence marks the boundary between frequentist and Bayesian thinking. Twentieth-century statistical practice focused heavily on direct evidence, on the grounds of superior objectivity. Now, however, new scientific devices such as microarrays routinely produce enormous data sets involving thousands of related situations, where indirect evidence seems too important to ignore. Empirical Bayes methodology offers an attractive direct/indirect compromise. There is already some evidence of a shift toward a less rigid standard of statistical objectivity that allows better use of indirect evidence. This article is basically the text of a recent talk featuring some examples from current practice, with a little bit of futuristic speculation. PMID:21243111

  3. Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK-8 in the pithed rat.

    PubMed Central

    Gaw, A. J.; Hills, D. M.; Spraggs, C. F.

    1995-01-01

    1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582487

  4. Peripheral and Central Mechanisms Involved in the Hormonal Control of Male and Female Reproduction

    PubMed Central

    Rudolph, L. M.; Bentley, G. E.; Calandra, R. S.; Paredes, A. H.; Tesone, M.; Wu, T. J.; Micevych, P. E.

    2016-01-01

    Reproduction involves the integration of hormonal signals acting across multiple systems to generate a synchronised physiological output. A critical component of reproduction is the luteinising hormone (LH) surge, which is mediated by oestradiol (E2) and neuroprogesterone interacting to stimulate kisspeptin release in the rostral periventricular nucleus of the third ventricle in rats. Recent evidence indicates the involvement of both classical and membrane E2 and progesterone signalling in this pathway. A metabolite of gonadotrophin-releasing hormone (GnRH), GnRH-(1-5), has been shown to stimulate GnRH expression and secretion, and has a role in the regulation of lordosis. Additionally, gonadotrophin release-inhibitory hormone (GnIH) projects to and influences the activity of GnRH neurones in birds. Stress-induced changes in GnIH have been shown to alter breeding behaviour in birds, demonstrating another mechanism for the molecular control of reproduction. Peripherally, paracrine and autocrine actions within the gonad have been suggested as therapeutic targets for infertility in both males and females. Dysfunction of testicular prostaglandin synthesis is a possible cause of idiopathic male infertility. Indeed, local production of melatonin and corticotrophin-releasing hormone could influence spermatogenesis via immune pathways in the gonad. In females, vascular endothelial growth factor A has been implicated in an angiogenic process that mediates development of the corpus luteum and thus fertility via the Notch signalling pathway. Age-induced decreases in fertility involve ovarian kisspeptin and its regulation of ovarian sympathetic innervation. Finally, morphological changes in the arcuate nucleus of the hypothalamus influence female sexual receptivity in rats. The processes mediating these morphological changes have been shown to involve the rapid effects of E2 controlling synaptogenesis in this hypothalamic nucleus. In summary, this review highlights new

  5. Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression.

    PubMed

    Verduijn, J; Milaneschi, Y; Schoevers, R A; van Hemert, A M; Beekman, A T F; Penninx, B W J H

    2015-09-29

    Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic-pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18-65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C-reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are

  6. Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression

    PubMed Central

    Verduijn, J; Milaneschi, Y; Schoevers, R A; van Hemert, A M; Beekman, A T F; Penninx, B W J H

    2015-01-01

    Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic–pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18–65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C-reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are

  7. Indirect Reciprocity under Incomplete Observation

    PubMed Central

    Nakamura, Mitsuhiro; Masuda, Naoki

    2011-01-01

    Indirect reciprocity, in which individuals help others with a good reputation but not those with a bad reputation, is a mechanism for cooperation in social dilemma situations when individuals do not repeatedly interact with the same partners. In a relatively large society where indirect reciprocity is relevant, individuals may not know each other's reputation even indirectly. Previous studies investigated the situations where individuals playing the game have to determine the action possibly without knowing others' reputations. Nevertheless, the possibility that observers of the game, who generate the reputation of the interacting players, assign reputations without complete information about them has been neglected. Because an individual acts as an interacting player and as an observer on different occasions if indirect reciprocity is endogenously sustained in a society, the incompleteness of information may affect either role. We examine the game of indirect reciprocity when the reputations of players are not necessarily known to observers and to interacting players. We find that the trustful discriminator, which cooperates with good and unknown players and defects against bad players, realizes cooperative societies under seven social norms. Among the seven social norms, three of the four suspicious norms under which cooperation (defection) to unknown players leads to a good (bad) reputation enable cooperation down to a relatively small observation probability. In contrast, the three trustful norms under which both cooperation and defection to unknown players lead to a good reputation are relatively efficient. PMID:21829335

  8. A proposed biochemical mechanism involving hemoglobin for blast overpressure-induced injury.

    PubMed

    Elsayed, N M; Gorbunov, N V; Kagan, V E

    1997-07-25

    Blast overpressure (BOP) is the abrupt, rapid, rise in atmospheric pressure resulting from explosive detonation, firing of large-caliber weapons, and accidental occupational explosions. Exposure to incident BOP waves causes internal injuries, mostly to the hollow organs, particularly the ears, lungs and gastrointestinal tract. BOP-induced injury used to be considered of military concern because it occurred mostly in military environments during military actions or training, and to a lesser extent during civilian occupational accidents. However, in recent years with the proliferation of indiscriminate terrorist bombings worldwide involving civilians, blast injury has become a societal concern, and the need to understand the biochemical and molecular mechanism(s) of injury, and to find new and effective methods for treatment gained importance. In general, past BOP research has focused on the physiological and pathological manifestations of incapacitation, thresholds of safety, and on predictive modeling. However, we have been studying the molecular mechanism of BOP-induced injury, and recently began to have an insight into that mechanism, and recognize the role of hemoglobin released during hemorrhage in catalyzing free radical reactions leading to oxidative stress. In this report we discuss the biochemical changes observed after BOP exposure in rat blood and lung tissue, and propose a biochemical mechanism for free radical-induced oxidative stress that can potentially complicate the injury. Moreover, we observed that some antioxidants can interact with Hb oxidation products (oxy-, met- and oxoferrylHb) and act as prooxidants that can increase the damage rather than decrease it.

  9. Human axillary apocrine glands: proteins involved in the apocrine secretory mechanism.

    PubMed

    Stoeckelhuber, Mechthild; Schubert, Christoph; Kesting, Marco R; Loeffelbein, Denys J; Nieberler, Markus; Koehler, Claudia; Welsch, Ulrich

    2011-02-01

    The apocrine secretory mechanism is a mode of secretion by which the apical part of the cell cytoplasm is pinched off, which leads to the formation of an aposome. The distinct mechanism of formation and decapitation of the aposome is not well investigated. Only few proteins are known that are involved in this secretory mechanism. We studied the human axillary apocrine gland and looked at proteins associated with cytokinesis, a process that is comparable to the pinching-off mechanism of apocrine glandular cells. By immunohistochemistry, we detected actin, myosin II, cytokeratin 7 and 19, α- and β-tubulin, anillin, cofilin, syntaxin 2, vamp8/endobrevin and septin 2. In highly active glandular cells, these proteins are located at the base of the apical protrusion when the aposome is in the process of being released or are concentrated in the cap of the apical protrusion. These findings demonstrate new insights on apocrine secretory mechanisms and point to similarities to the terminal step of cytokinesis, which is regulated by a SNARE-mediated membrane fusion event.

  10. Differential gene expression in seasonal sympatry: mechanisms involved in diverging life histories

    PubMed Central

    Peterson, Mark P.; Greives, Timothy J.; Atwell, Jonathan W.; Bridge, Eli S.; Ketterson, Ellen D.

    2016-01-01

    In an era of climate change, understanding the genetic and physiological mechanisms underlying flexibility in phenology and life history has gained greater importance. These mechanisms can be elucidated by comparing closely related populations that differ in key behavioural and physiological traits such as migration and timing of reproduction. We compared gene expression in two recently diverged dark-eyed Junco ( Junco hyemalis) subspecies that live in seasonal sympatry during winter and early spring, but that differ in behaviour and physiology, despite exposure to identical environmental cues. We identified 547 genes differentially expressed in blood and pectoral muscle. Genes involved in lipid transport and metabolism were highly expressed in migrant juncos, while genes involved in reproductive processes were highly expressed in resident breeders. Seasonal differences in gene expression in closely related populations residing in the same environment provide significant insights into mechanisms underlying variation in phenology and life history, and have potential implications for the role of seasonal timing differences in gene flow and reproductive isolation. PMID:26979563

  11. Review of endocrine disorders associated with environmental toxicants and possible involved mechanisms.

    PubMed

    Maqbool, Faheem; Mostafalou, Sara; Bahadar, Haji; Abdollahi, Mohammad

    2016-01-15

    Endocrine disrupting chemicals (EDC) are released into environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDC have major risks for human by targeting different organs and systems in the body. Multiple mechanisms are involved in targeting the normal system, through estrogen receptors, nuclear receptors and steroidal receptors activation. In this review, different methods by which xenobiotics stimulate signaling pathways and genetic mutation or DNA methylation have been discussed. These methods help to understand the results of xenobiotic action on the endocrine system. Endocrine disturbances in the human body result in breast cancer, ovarian problems, thyroid eruptions, testicular carcinoma, Alzheimer disease, schizophrenia, nerve damage and obesity. EDC characterize a wide class of compounds such as organochlorinated pesticides, industrial wastes, plastics and plasticizers, fuels and numerous other elements that exist in the environment or are in high use during daily life. The interactions and mechanism of toxicity in relation to human general health problems, especially endocrine disturbances with particular reference to reproductive problems, diabetes, and breast, testicular and ovarian cancers should be deeply investigated. There should also be a focus on public awareness of these EDC risks and their use in routine life. Therefore, the aim of this review is to summarize all evidence regarding different physiological disruptions in the body and possible involved mechanisms, to prove the association between endocrine disruptions and human diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. GABA(B) receptors and opioid mechanisms involved in homotaurine-induced analgesia.

    PubMed

    Serrano, M I; Serrano, J S; Fernández, A; Asadi, I; Serrano-Martino, M C

    1998-03-01

    1. The involvement of GABA(B) receptors and opioid mechanisms in homotaurine-induced analgesia has been investigated in current models of nociception by using a GABA(B) receptor antagonist, morphine, and naloxone. CGP 35348 (50-200 mg/kg IP), a highly selective GABA(B) antagonist, was administered prior to carrying out a dose-response curve of homotaurine (22.6-445 mg/kg IP) antinociceptive effect in the abdominal constriction (mice) and tail flick (rats) tests. 2. The tail flick test was performed in animals pretreated with morphine (0.5 mg/kg SC) and naloxone (1 mg/kg), 15 min before amino acid. Animals treated with saline 10 ml/kg (mice) or 1.25 ml/kg (rats) were included as control for the vehicle used. 3. CGP 35348 antagonized the antinociceptive effect of homotaurine in both tests. The range of doses affected by the interaction depended on the test assayed, but it was coincident for the main part of the dose-response curve. 4. A subanalgesic dose of morphine potentiated the antinociceptive effect of lower doses of homotaurine in the tail flick test. Naloxone pretreatment inhibited the antinociceptive effect of homotaurine. 5. These data imply that GABA(B) receptor subpopulations and opiate mechanisms are involved in the antinociceptive effect of homotaurine. Because functional relationships have been found between GABAergic and opiate systems in analgesic effects, an interaction of the two mechanisms may be operating in the effects described for homotaurine.

  13. Differential gene expression in seasonal sympatry: mechanisms involved in diverging life histories.

    PubMed

    Fudickar, Adam M; Peterson, Mark P; Greives, Timothy J; Atwell, Jonathan W; Bridge, Eli S; Ketterson, Ellen D

    2016-03-01

    In an era of climate change, understanding the genetic and physiological mechanisms underlying flexibility in phenology and life history has gained greater importance. These mechanisms can be elucidated by comparing closely related populations that differ in key behavioural and physiological traits such as migration and timing of reproduction. We compared gene expression in two recently diverged dark-eyed Junco ( Junco hyemalis) subspecies that live in seasonal sympatry during winter and early spring, but that differ in behaviour and physiology, despite exposure to identical environmental cues. We identified 547 genes differentially expressed in blood and pectoral muscle. Genes involved in lipid transport and metabolism were highly expressed in migrant juncos, while genes involved in reproductive processes were highly expressed in resident breeders. Seasonal differences in gene expression in closely related populations residing in the same environment provide significant insights into mechanisms underlying variation in phenology and life history, and have potential implications for the role of seasonal timing differences in gene flow and reproductive isolation. © 2016 The Author(s).

  14. Absorption of Carotenoids and Mechanisms Involved in Their Health-Related Properties.

    PubMed

    Cervantes-Paz, Braulio; Victoria-Campos, Claudia I; Ornelas-Paz, José de Jesús

    Carotenoids participate in the normal metabolism and function of the human body. They are involved in the prevention of several diseases, especially those related to the inflammation syndrome. Their main mechanisms of action are associated to their potent antioxidant activity and capacity to regulate the expression of specific genes and proteins. Recent findings suggest that carotenoid metabolites may explain several processes where the participation of their parent carotenoids was unclear. The health benefits of carotenoids strongly depend on their absorption and transformation during gastrointestinal digestion. The estimation of the 'bioaccessibility' of carotenoids through in vitro models have made possible the evaluation of the effect of a large number of factors on key stages of carotenoid digestion and intestinal absorption. The bioaccessibility of these compounds allows us to have a clear idea of their potential bioavailability, a term that implicitly involves the biological activity of these compounds.

  15. Mechanisms Involved in the Pro-Apoptotic Effect of Melatonin in Cancer Cells

    PubMed Central

    Rodriguez, Carmen; Martín, Vanesa; Herrera, Federico; García-Santos, Guillermo; Rodriguez-Blanco, Jezabel; Casado-Zapico, Sara; Sánchez-Sánchez, Ana María; Suárez, Santos; Puente-Moncada, Noelia; Anítua, María José; Antolín, Isaac

    2013-01-01

    It is well established that melatonin exerts antitumoral effects in many cancer types, mostly decreasing cell proliferation at low concentrations. On the other hand, induction of apoptosis by melatonin has been described in the last few years in some particular cancer types. The cytotoxic effect occurs after its administration at high concentrations, and the molecular pathways involved have been only partially determined. Moreover, a synergistic effect has been found in several cancer types when it is administered in combination with chemotherapeutic agents. In the present review, we will summarize published work on the pro-apoptotic effect of melatonin in cancer cells and the reported mechanisms involved in such action. We will also construct a hypothesis on how different cell signaling pathways may relate each other on account for such effect. PMID:23528889

  16. Mechanisms involved in the inhibitory effect of chronic alcohol exposure on pancreatic acinar thiamin uptake.

    PubMed

    Srinivasan, Padmanabhan; Subramanian, Veedamali S; Said, Hamid M

    2014-04-01

    Pancreatic acinar cells (PAC) obtain thiamin from the circulation via a carrier-mediated process that involves thiamin transporters 1 and 2 (THTR-1 and THTR-2; products of SLC19A2 and SLC19A3, respectively). Chronic alcohol exposure of PAC inhibits thiamin uptake, and, on the basis of in vitro studies, this inhibition appears to be transcriptionally mediated. The aim of this study was to confirm the involvement of a transcriptional mechanism in mediating the chronic alcohol effect in in vivo settings and to delineate the molecular mechanisms involved. Using transgenic mice carrying full-length SLC19A2 and SLC19A3 promoters, we found that chronic alcohol feeding led to a significant reduction in the activity of SLC19A2 and SLC19A3 promoters (as well as in thiamin uptake and expression of THTR-1 and -2). Similar findings were seen in 266-6 cells chronically exposed to alcohol in vitro. In the latter studies, the alcohol inhibitory effect was found to be mediated via the minimal SLC19A2 and SLC19A3 promoters and involved the cis-regulatory elements stimulating protein 1 (SP1)/gut-enriched Kruppel-like factor and SP1-GG-box and SP1/GC, respectively. Chronic alcohol exposure of PAC also led to a significant reduction in the expression of the SP1 transcription factor, which upon correction (via expression) led to the prevention of alcohol inhibitory effects on not only the activity of SLC19A2 and SLC19A3 promoters but also on the expression of THTR-1 and -2 mRNA and thiamin uptake. These results demonstrate that the inhibitory effect of chronic alcohol exposure on physiological/molecular parameters of thiamin uptake by PAC is mediated via specific cis-regulatory elements in SLC19A2 and SLC19A3 minimal promoters.

  17. Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

    PubMed Central

    Puighermanal, Emma; Busquets-Garcia, Arnau; Maldonado, Rafael; Ozaita, Andrés

    2012-01-01

    Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system. PMID:23108544

  18. Pathogenic Mechanisms Involved in the Hematological Alterations of Arenavirus-induced Hemorrhagic Fevers

    PubMed Central

    Schattner, Mirta; Rivadeneyra, Leonardo; Pozner, Roberto G.; Gómez, Ricardo M.

    2013-01-01

    Viral hemorrhagic fevers (VHFs) caused by arenaviruses are acute diseases characterized by fever, headache, general malaise, impaired cellular immunity, eventual neurologic involvement, and hemostatic alterations that may ultimately lead to shock and death. The causes of the bleeding are still poorly understood. However, it is generally accepted that these causes are associated to some degree with impaired hemostasis, endothelial cell dysfunction and low platelet counts or function. In this article, we present the current knowledge about the hematological alterations present in VHF induced by arenaviruses, including new aspects on the underlying pathogenic mechanisms. PMID:23337384

  19. Mechanisms regulating proteostasis are involved in sympatric speciation of the blind mole rat, Spalax galili.

    PubMed

    Rodriguez, Karl A; Li, Kexin; Nevo, Eviatar; Buffenstein, Rochelle

    2016-01-01

    Genome-wide analysis demonstrates extensive genomic adaptive complexes involved in sympatric speciation between blind mole rats (Spalax galili) in abutting populations living in basalt and chalk soils. Among the gene ontology (GO) enrichment, musculature and metabolism stood out in basalt dwellers while nutrition and neurogenetics were highlighted in chalk residents. Measurements of mechanisms regulating protein homeostasis inspired by these GO terms suggest that at the proteomic level there is also a habitat/soil-type driven divergence with the basalt residents exhibiting higher proteasome activity whereas elevated levels of markers of autophagy are evident in the chalk inhabitants.

  20. Pathogenic mechanisms involved in the hematological alterations of arenavirus-induced hemorrhagic fevers.

    PubMed

    Schattner, Mirta; Rivadeneyra, Leonardo; Pozner, Roberto G; Gómez, Ricardo M

    2013-01-21

    Viral hemorrhagic fevers (VHFs) caused by arenaviruses are acute diseases characterized by fever, headache, general malaise, impaired cellular immunity, eventual neurologic involvement, and hemostatic alterations that may ultimately lead to shock and death. The causes of the bleeding are still poorly understood. However, it is generally accepted that these causes are associated to some degree with impaired hemostasis, endothelial cell dysfunction and low platelet counts or function. In this article, we present the current knowledge about the hematological alterations present in VHF induced by arenaviruses, including new aspects on the underlying pathogenic mechanisms.

  1. Mechanisms regulating proteostasis are involved in sympatric speciation of the blind mole rat, Spalax galili

    PubMed Central

    Rodriguez, Karl A.; Li, Kexin; Nevo, Eviatar; Buffenstein, Rochelle

    2016-01-01

    ABSTRACT Genome-wide analysis demonstrates extensive genomic adaptive complexes involved in sympatric speciation between blind mole rats (Spalax galili) in abutting populations living in basalt and chalk soils. Among the gene ontology (GO) enrichment, musculature and metabolism stood out in basalt dwellers while nutrition and neurogenetics were highlighted in chalk residents. Measurements of mechanisms regulating protein homeostasis inspired by these GO terms suggest that at the proteomic level there is also a habitat/soil-type driven divergence with the basalt residents exhibiting higher proteasome activity whereas elevated levels of markers of autophagy are evident in the chalk inhabitants. PMID:27050459

  2. Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

    PubMed Central

    Wang, Juan; Zhang, Hai-yan; Tang, Xi-can

    2009-01-01

    Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation. PMID:19574993

  3. A review on the molecular mechanisms involved in insulin resistance induced by organophosphorus pesticides.

    PubMed

    Lasram, Mohamed Montassar; Dhouib, Ines Bini; Annabi, Alya; El Fazaa, Saloua; Gharbi, Najoua

    2014-08-01

    There is increasing evidence reporting that organophosphorus pesticides (OPs) impair glucose homeostasis and cause insulin resistance and type 2 diabetes. Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Formation of advanced glycation end products, accumulation of lipid metabolites, activation of inflammatory pathways and oxidative stress have all been implicated in the pathogenesis of insulin resistance. Ultimately, these molecular processes activate a series of stress pathways involving a family of serine kinases, which in turn have a negative effect on insulin signaling. Experimental and clinical data suggest an association between these molecular mechanisms and OPs compounds. It was first reported that OPs induce hyperglycemia. Then a concomitant increase of blood glucose and insulin was pointed out. For some years only, we have begun to understand that OPs promote insulin resistance and increase the risk of type 2 diabetes. Overall, this review outlines various mechanisms that lead to the development of insulin resistance by OPs exposure.

  4. Reaction mechanisms involved in reduction of halogenated hydrocarbons using sulfated iron

    SciTech Connect

    Hassan, S.M.; Cipollone, M.G.; Wolfe, N.L.

    1995-12-01

    Experiments were carried out to investigate the mechanisms and pathways involved in the reduction of halogenated hydrocarbons represented by trichloroethylene (TCE) and tetrachloroethylene (PCE) with sulfated iron aqueous media. Results suggested that iron sulfide acted as the dehalogenation center. Zero-valent iron acted as a generator for molecular hydrogen through its reaction with water. Results of experiments in which iron sulfide was replaced by other transition metal sulfides and experiments in which zero-valent iron was replaced by other sources of molecular hydrogen will be reported. The main reduction product of chloroethylene derivatives was ethyne which under the catalytic reaction of zero-valent iron was reduced further to ethene and finally to ethane. Intermediate products were identified using GC-MS. Mechanisms and pathways will be presented.

  5. Transcription factor abundance controlled by an auto-regulatory mechanism involving a transcription start site switch.

    PubMed

    Ngondo, Richard Patryk; Carbon, Philippe

    2014-02-01

    A transcriptional feedback loop is the simplest and most direct means for a transcription factor to provide an increased stability of gene expression. In this work performed in human cells, we reveal a new negative auto-regulatory mechanism involving an alternative transcription start site (TSS) usage. Using the activating transcription factor ZNF143 as a model, we show that the ZNF143 low-affinity binding sites, located downstream of its canonical TSS, play the role of protein sensors to induce the up- or down-regulation of ZNF143 gene expression. We uncovered that the TSS switch that mediates this regulation implies the differential expression of two transcripts with an opposite protein production ability due to their different 5' untranslated regions. Moreover, our analysis of the ENCODE data suggests that this mechanism could be used by other transcription factors to rapidly respond to their own aberrant expression level.

  6. Luminal and basolateral mechanisms involved in the renal tubular uptake of inorganic mercury

    SciTech Connect

    Zalups, R.K.; Minor, K.H.

    1995-09-01

    The present study provides evidence for the existence of both a luminal and a basolateral mechanism involved in the renal tubular uptake of inorganic mercury. The researchers compared the disposition of inorganic mercury in groups of surgical control rats, rats that underwent a unilateral ureteral ligation, and rats that underwent a bilateral ureteral ligation that were pretreated with either normal saline or a 7.5 mmol/kg intravenous dose of PAH 5 min prior to receiving a nontoxic 0.5-{mu}mol/kg intravenous dose of mercuric chloride. The {open_quotes}stop-flow{close_quotes} conditions induced by either unilateral or bilateral ureteral ligation caused a significant reduction in the uptake and content of mercury in the kidneys (whose ureter was ligated) both at 1 h and 24 h after the intravenous injection of the nontoxic dose of mercuric chloride. This decreased renal uptake of mercury was due specifically to decreased uptake of mercury in the renal cortex and outer stripe of the outer medulla. The amount of mercury has not taken up during ureteral ligation represents the portion of mercury that is presumably taken up by a luminal mechanism. Pretreatment with PAH also caused a significant reduction in the renal uptake of mercury in the cortex and outer stripe of the outer medulla. When either unilateral or bilateral ureteral ligation was combined with PAH pretreatment, an additive inhibitory effect occurred with respect to the renal uptake of mercury. In fact, the renal uptake of mercury was reduced by approximately 85% at 1 h after the injection of mercuric chloride. Since the luminal uptake of mercury was blocked by ureteral ligation, the effect of PAH on the renal uptake of mercury must have occurred at the basolateral membrane. Two distinct mechanisms are involved in mercury uptake, with one mechanism located on the luminal membrane and another located on the basolateral membrane. 22 refs., 11 figs., 2 tabs.

  7. Are calcium oxalate crystals involved in the mechanism of acute renal failure in ethylene glycol poisoning?

    PubMed

    McMartin, Kenneth

    2009-11-01

    Ethylene glycol (EG) poisoning often results in acute renal failure, particularly if treatment with fomepizole or ethanol is delayed because of late presentation or diagnosis. The mechanism has not been established but is thought to result from the production of a toxic metabolite. A literature review utilizing PubMed identified papers dealing with renal toxicity and EG or oxalate. The list of papers was culled to those relevant to the mechanism and treatment of the renal toxicity associated with either compound. ROLE OF METABOLITES: Although the "aldehyde" metabolites of EG, glycolaldehyde, and glyoxalate, have been suggested as the metabolites responsible, recent studies have shown definitively that the accumulation of calcium oxalate monohydrate (COM) crystals in kidney tissue produces renal tubular necrosis that leads to kidney failure. In vivo studies in EG-dosed rats have correlated the severity of renal damage with the total accumulation of COM crystals in kidney tissue. Studies in cultured kidney cells, including human proximal tubule (HPT) cells, have demonstrated that only COM crystals, not the oxalate ion, glycolaldehyde, or glyoxylate, produce a necrotic cell death at toxicologically relevant concentrations. COM CRYSTAL ACCUMULATION: In EG poisoning, COM crystals accumulate to high concentrations in the kidney through a process involving adherence to tubular cell membranes, followed by internalization of the crystals. MECHANISM OF TOXICITY: COM crystals have been shown to alter membrane structure and function, to increase reactive oxygen species and to produce mitochondrial dysfunction. These processes are likely to be involved in the mechanism of cell death. Accumulation of COM crystals in the kidney is responsible for producing the renal toxicity associated with EG poisoning. The development of a pharmacological approach to reduce COM crystal adherence to tubular cells and its cellular interactions would be valuable as this would decrease the renal

  8. The mechanism of sperm-egg interaction and the involvement of IZUMO1 in fusion.

    PubMed

    Inoue, Naokazu; Ikawa, Masahito; Okabe, Masaru

    2011-01-01

    An average human ejaculate contains over 100 million sperm, but only a few succeed in accomplishing the journey to an egg by migration through the female reproductive tract. Among these few sperm, only one participates in fertilization. There might be an ingenious molecular mechanism to ensure that the very best sperm fertilize an egg. However, recent gene disruption experiments in mice have revealed that many factors previously described as important for fertilization are largely dispensable. One could argue that the fertilization mechanism is made robust against gene disruptions. However, this is not likely, as there are already six different gene-disrupted mouse lines (Calmegin, Adam1a, Adam2, Adam3, Ace and Pgap1), all of which result in male sterility. The sperm from these animals are known to have defective zona-binding ability and at the same time lose oviduct-migrating ability. Concerning sperm-zona binding, the widely accepted involvement of sugar moiety on zona pellucida 3 (ZP3) is indicated to be dispensable by gene disruption experiments. Thus, the landscape of the mechanism of fertilization is revolving considerably. In the sperm-egg fusion process, CD9 on egg and IZUMO1 on sperm have emerged as essential factors. This review focuses on the mechanism of fertilization elucidated by gene-manipulated animals.

  9. Resistance to spiramycin in Streptomyces ambofaciens, the producer organism, involves at least two different mechanisms.

    PubMed

    Pernodet, J L; Alegre, M T; Blondelet-Rouault, M H; Guérineau, M

    1993-05-01

    During its stationary phase, Streptomyces ambofaciens produces the macrolide antibiotic spiramycin, and has to protect itself against this antibiotic. Young mycelia, not yet producing spiramycin, are sensitive to it, but they become fully resistant when production begins. In a sensitive mycelium, resistance could be induced by exposure to sub-inhibitory concentrations of spiramycin, and these induced mycelia, like producing mycelia were resistant not only to spiramycin but also to several other macrolide antibiotics. Ribosomes extracted from these resistant mycelia were shown in vitro to be more resistant to spiramycin than ribosomes extracted from sensitive mycelium, indicating that S. ambofaciens possesses a spiramycin-inducible ribosomal resistance to spiramycin and to macrolide antibiotics. Studies with spiramycin non-producing mutants showed that, in these mutants, resistance to spiramycin also varies during cultivation, in that an old culture was much more resistant than a young one. But with these non-producing mutants, the spectrum of resistance was narrower, and in vitro data showed that resistance was not due to ribosomal modification. These results suggest that S. ambofaciens presents at least two distinct mechanisms for spiramycin resistance; a spiramycin-inducible ribosomal resistance, and a second resistance mechanism which might be temporally regulated and which could involve decreased permeability to, or export of, the antibiotic. The two mechanisms are probably at work simultaneously in the producing mycelium, the spiramycin-inducible resistance being induced by endogenous spiramycin. In non-producing mutants, in the absence of self-induction by spiramycin, only the second mechanism is observed.

  10. Epigenetic mechanisms in the development of memory and their involvement in certain neurological diseases.

    PubMed

    Rosales-Reynoso, M A; Ochoa-Hernández, A B; Juárez-Vázquez, C I; Barros-Núñez, P

    Today, scientists accept that the central nervous system of an adult possesses considerable morphological and functional flexibility, allowing it to perform structural remodelling processes even after the individual is fully developed and mature. In addition to the vast number of genes participating in the development of memory, different known epigenetic mechanisms are involved in normal and pathological modifications to neurons and therefore also affect the mechanisms of memory development. This study entailed a systematic review of biomedical article databases in search of genetic and epigenetic factors that participate in synaptic function and memory. The activation of gene expression in response to external stimuli also occurs in differentiated nerve cells. Neural activity induces specific forms of synaptic plasticity that permit the creation and storage of long-term memory. Epigenetic mechanisms play a key role in synaptic modification processes and in the creation and development of memory. Changes in these mechanisms result in the cognitive and memory impairment seen in neurodegenerative diseases (Alzheimer disease, Huntington disease) and in neurodevelopmental disorders (Rett syndrome, fragile X, and schizophrenia). Nevertheless, results obtained from different models are promising and point to potential treatments for some of these diseases. Copyright © 2013 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Viral fitness: relation to drug resistance mutations and mechanisms involved: nucleoside reverse transcriptase inhibitor mutations.

    PubMed

    Weber, Jan; Henry, Kenneth R; Arts, Eric J; Quiñones-Mateu, Miguel E

    2007-03-01

    Nucleoside and nucleotide reverse transcriptase inhibitors constitute the backbone of highly active antiretroviral therapy in the treatment of HIV-1 infection. One of the major obstacles in achieving the long-term efficacy of anti-HIV-1 therapy is the development of resistance. The advent of resistance mutations is usually accompanied by a change in viral replicative fitness. This review focuses on the most common nucleoside reverse transcriptase inhibitor-associated mutations and their effects on HIV-1 replicative fitness. Recent studies have explained the two main mechanisms of resistance to nucleoside reverse transcriptase inhibitors and their role in HIV-1 replicative fitness. The first involves mutations directly interfering with binding or incorporation and seems to impact replicative fitness more adversely than the second mechanism, which involves enhanced excision of the newly incorporated analogue. Further studies have helped explain the antagonistic effects between amino acid substitutions, K65R, L74V, M184V, and thymidine analogue mutations, showing how viral replicative fitness influences the evolution of thymidine analogue resistance pathways. Nucleoside reverse transcriptase inhibitor resistance mutations impact HIV-1 replicative fitness to a lesser extent than protease resistance mutations. The monitoring of viral replicative fitness may help in the management of HIV-1 infection in highly antiretroviral-experienced individuals.

  12. Soil biochar amendment as a climate change mitigation tool: Key parameters and mechanisms involved.

    PubMed

    Brassard, Patrick; Godbout, Stéphane; Raghavan, Vijaya

    2016-10-01

    Biochar, a solid porous material obtained from the carbonization of biomass under low or no oxygen conditions, has been proposed as a climate change mitigation tool because it is expected to sequester carbon (C) for centuries and to reduce greenhouse gas (GHG) emissions from soils. This review aimed to identify key biochar properties and production parameters that have an effect on these specific applications of the biochar. Moreover, mechanisms involved in interactions between biochar and soils were highlighted. Following a compilation and comparison of the characteristics of 76 biochars from 40 research studies, biochars with a lower N content, and consequently a higher C/N ratio (>30), were found to be more suitable for mitigation of N2O emissions from soils. Moreover, biochars produced at a higher pyrolysis temperature, and with O/C ratio <0.2, H/Corg ratio <0.4 and volatile matter below 80% may have high C sequestration potential. Based on these observations, biochar production and application to the field can be used as a tool to mitigate climate change. However, it is important to determine the pyrolysis conditions and feedstock needed to produce a biochar with the desired properties for a specific application. More research studies are needed to identify the exact mechanisms involved following biochar amendment to soil.

  13. Integrated Innate Mechanisms Involved in Airway Allergic Inflammation to the Serine Protease Subtilisin

    PubMed Central

    Florsheim, Esther; Yu, Shuang; Bragatto, Ivan; Faustino, Lucas; Gomes, Eliane; Ramos, Rodrigo N.; Barbuto, José Alexandre M.; Medzhitov, Ruslan; Russo, Momtchilo

    2015-01-01

    Proteases are recognized environmental allergens, but little is known about the mechanisms responsible for sensing enzyme activity and initiating the development of allergic inflammation. Because usage of the serine protease subtilisin in the detergent industry resulted in an outbreak of occupational asthma in workers, we sought to develop an experimental model of allergic lung inflammation to subtilisin and to determine the immunological mechanisms involved in type 2 responses. By using a mouse model of allergic airway disease, we have defined here that subcutaneous or intranasal sensitization followed by airway challenge to subtilisin induces prototypic allergic lung inflammation, characterized by airway eosinophilia, type 2 cytokines release, mucus production, high levels of serum IgE, and airway reactivity. These allergic responses were dependent on subtilisin protease activity, protease-activated receptor (PAR)-2, IL-33 receptor ST2, and MyD88 signaling. Also, subtilisin stimulated the expression of the pro-allergic cytokines IL-1α, IL-33, TSLP, and the growth factor amphiregulin in a human bronchial epithelial cell line. Notably, acute administration of subtilisin into the airways increased lung IL-5-producing type 2 innate lymphoid cells, which required PAR-2 expression. Finally, subtilisin activity acted as a Th2 adjuvant to an unrelated airborne antigen promoting allergic inflammation to inhaled OVA. Therefore, we established a murine model of occupational asthma to a serine protease and characterized the main molecular pathways involved in allergic sensitization to subtilisin that potentially contribute to initiate allergic airway disease. PMID:25876764

  14. Mechanism involved in phagocytosis and killing of Listeria monocytogenes by Acanthamoeba polyphaga.

    PubMed

    Akya, Alisha; Pointon, Andrew; Thomas, Connor

    2009-10-01

    Intra-cellular pathogen, Listeria monocytogenes, is capable of invasion and survival within mammalian cells. However, Acanthamoeba polyphaga trophozoites phagocytose and rapidly degrade Listeria cells. In order to provide more information on amoeba phagocytosis and killing mechanisms, this study used several inhibitor agents known to affect the phagocytosis and killing of bacteria by eukaryotes. Amoebae were pre-treated with mannose, cytochalasin D, wortmannin, suramin, ammonium chloride, bafilomycin A and monensin followed by co-culture with bacteria. Phagocytosis and killing of bacterial cells by amoeba trophozoites was assessed using plate counting methods and microscopy. The data presented indicates that actin polymerisation and cytoskeletal rearrangement are involved in phagocytosis of L. monocytogenes cells by A. polyphaga trophozoites. Further, both phagosomal acidification and phagosome-lysosome fusion are involved in killing and degradation of L. monocytogenes cells by A. polyphaga. However, the mannose-binding protein receptor does not play an important role in uptake of bacteria by amoeba trophozoites. In conclusion, this data reveals the similar principles of molecular mechanisms used by different types of eukaryotes in uptake and killing of bacteria.

  15. Antinociceptive Activity of Methanol Extract of Muntingia calabura Leaves and the Mechanisms of Action Involved

    PubMed Central

    Sani, M. H. Mohd.; Zakaria, Z. A.; Balan, T.; Teh, L. K.; Salleh, M. Z.

    2012-01-01

    Muntingia calabura L. (family Elaeocarpaceae) has been traditionally used to relieve various pain-related ailments. The present study aimed to determine the antinociceptive activity of methanol extract of M. calabura leaves (MEMC) and to elucidate the possible mechanism of antinociception involved. The in vivo chemicals (acetic acid-induced abdominal constriction and formalin-, capsaicin-, glutamate-, serotonin-induced paw licking test) and thermal (hot plate test) models of nociception were used to evaluate the extract antinociceptive activity. The extract (100, 250, and 500 mg/kg) was administered orally 60 min prior to subjection to the respective test. The results obtained demonstrated that MEMC produced significant (P < 0.05) antinociceptive response in all the chemical- and thermal-induced nociception models, which was reversed after pretreatment with 5 mg/kg naloxone, a non-selective opioid antagonist. Furthermore, pretreatment with L-arginine (a nitric oxide (NO) donor), NG-nitro-L-arginine methyl esters (L-NAME; an inhibitor of NO synthase (NOS)), methylene blue (MB; an inhibitor of cyclic-guanosine monophosphate (cGMP) pathway), or their combination also caused significant (P < 0.05) change in the intensity of the MEMC antinociception. In conclusion, the MEMC antinociceptive activity involves activation of the peripheral and central mechanisms, and modulation via, partly, the opioid receptors and NO/cGMP pathway. PMID:22611437

  16. Mechanisms involved in reduction of ochratoxin A produced by Aspergillus westerdijkiae using Debaryomyces hansenii CYC 1244.

    PubMed

    Gil-Serna, Jéssica; Patiño, Belén; Cortés, Laura; González-Jaén, María Teresa; Vázquez, Covadonga

    2011-11-15

    Aspergillus westerdijkiae is one of the most relevant ochratoxin A (OTA) producing species within the Section Circumdati contaminating a number of agroproducts. The yeast Debaryomyces hansenii CYC 1244 was previously reported to be able to reduce growth and extracellular OTA produced by A. westerdijkiae. In this work, we examined several mechanisms possibly involved in this OTA reduction in in vitro experiments. OTA biosynthesis was evaluated by quantitation of expression levels of pks (polyketide synthase) and p450-B03 (cytochrome p450 monooxygenase) genes using newly developed and specific real time RT-PCR protocols. Both genes showed significant lower levels in presence of D. hansenii CYC 1244 suggesting an effect on regulation of OTA biosynthesis at transcriptional level. High levels of removal of extracellular OTA were observed by adsorption to yeast cell walls, particularly at low pH (98% at pH 3). On the contrary, no evidences were obtained of absorption of OTA into yeast cells or the production of constitutively expressed enzymes that degrade OTA by D. hansenii CYC 1244. These results described the potential of this yeast strain as a safe and efficient biocontrol agent to decrease OTA in A. westerdijkiae and two important mechanisms involved which may permit its application at different points of the food chain. Copyright © 2011. Published by Elsevier B.V.

  17. The Possible Mechanisms Involved in Degradation of Patulin by Pichia caribbica

    PubMed Central

    Zheng, Xiangfeng; Yang, Qiya; Zhang, Hongyin; Cao, Jing; Zhang, Xiaoyun; Apaliya, Maurice Tibiru

    2016-01-01

    In this work, we examined the mechanisms involved in the degradation of patulin by Pichia caribbica. Our results indicate that cell-free filtrate of P. caribbica reduced patutlin content. The heat-killed cells could not degrade patulin. However, the live cells significantly reduced the concentration of the patulin. In furtherance to this, it was observed that patulin was not detected in the broken yeast cells and cell wall. The addition of cycloheximide to the P. caribbica cells decreased the capacity of degradation of patulin. Proteomics analyses revealed that patulin treatment resulted in an upregulated protein which was involved in metabolism and stress response processes. Our results suggested that the mechanism of degradation of patulin by P. caribbica was not absorption; the presence of patulin can induce P. caribbica to produce associated intracellular and extracellular enzymes, both of which have the ability to degrade patulin. The result provides a new possible method that used the enzymes produced by yeast to detoxify patulin in food and feed. PMID:27735830

  18. Dietary restriction involves NAD⁺ -dependent mechanisms and a shift toward oxidative metabolism.

    PubMed

    Moroz, Natalie; Carmona, Juan J; Anderson, Edward; Hart, Anne C; Sinclair, David A; Blackwell, T Keith

    2014-12-01

    Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD⁺ -dependent deacylases known as sirtuins, and increases in NAD⁺ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol. DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD⁺ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption. We conclude that stress response and NAD⁺ -dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD⁺ salvage. Under DR conditions, NAD⁺ -dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.

  19. Mechanisms and neuronal networks involved in reactive and proactive cognitive control of interference in working memory.

    PubMed

    Irlbacher, Kerstin; Kraft, Antje; Kehrer, Stefanie; Brandt, Stephan A

    2014-10-01

    Cognitive control can be reactive or proactive in nature. Reactive control mechanisms, which support the resolution of interference, start after its onset. Conversely, proactive control involves the anticipation and prevention of interference prior to its occurrence. The interrelation of both types of cognitive control is currently under debate: Are they mediated by different neuronal networks? Or are there neuronal structures that have the potential to act in a proactive as well as in a reactive manner? This review illustrates the way in which integrating knowledge gathered from behavioral studies, functional imaging, and human electroencephalography proves useful in answering these questions. We focus on studies that investigate interference resolution at the level of working memory representations. In summary, different mechanisms are instrumental in supporting reactive and proactive control. Distinct neuronal networks are involved, though some brain regions, especially pre-SMA, possess functions that are relevant to both control modes. Therefore, activation of these brain areas could be observed in reactive, as well as proactive control, but at different times during information processing.

  20. Molecular and Cellular Mechanisms Involved in the Trypanosoma cruzi/Host Cell Interplay

    PubMed Central

    Romano, Patricia Silvia; Cueto, Juan Agustín; Casassa, Ana Florencia; Vanrell, María Cristina; Gottlieb, Roberta A.; Colombo, María Isabel

    2013-01-01

    Summary The protozoan parasite Trypanosoma cruzi has a complex bi-ological cycle that involves vertebrate and invertebrate hosts. In mammals, the infective trypomastigote form of this parasite can invade several cell types by exploiting phagocytic-like or non-phagocytic mechanisms depending on the class of cell involved. Morphological studies showed that when trypomastigotes contact macrophages, they induce the formation of plasma membrane protrusions that differ from the canonical phagocytosis that occurs in the case of noninfective epimastigotes. In contrast, when trypomastigotes infect epithelial or muscle cells, the cell surface is minimally modified, suggesting the induction of a different class of process. Lysosomal-dependent or -independent T. cruzi invasion of host cells are two different models that describe the molecular and cellular events activated during parasite entry into nonphagocytic cells. In this context, we have previously shown that induction of autophagy in host cells before infection favors T. cruzi invasion. Furthermore, we demonstrate that autophagosomes and the autophagosomal protein LC3 are recruited to the T. cruzi entry sites and that the newly formed T. cruzi parasitophorous vacuole has characteristics of an autophagolysosome. This review summarizes the current knowledge of the molecular and cellular mechanisms of T. cruzi invasion in nonphagocytic cells. Based on our findings, we propose a new model in which T. cruzi takes advantage of the up-regulation of autophagy during starvation to increase its successful colonization of host cells. PMID:22454195

  1. Molecular and cellular mechanisms involved in the Trypanosoma cruzi/host cell interplay.

    PubMed

    Romano, Patricia Silvia; Cueto, Juan Agustín; Casassa, Ana Florencia; Vanrell, María Cristina; Gottlieb, Roberta A; Colombo, María Isabel

    2012-05-01

    The protozoan parasite Trypanosoma cruzi has a complex biological cycle that involves vertebrate and invertebrate hosts. In mammals, the infective trypomastigote form of this parasite can invade several cell types by exploiting phagocytic-like or nonphagocytic mechanisms depending on the class of cell involved. Morphological studies showed that when trypomastigotes contact macrophages, they induce the formation of plasma membrane protrusions that differ from the canonical phagocytosis that occurs in the case of noninfective epimastigotes. In contrast, when trypomastigotes infect epithelial or muscle cells, the cell surface is minimally modified, suggesting the induction of a different class of process. Lysosomal-dependent or -independent T. cruzi invasion of host cells are two different models that describe the molecular and cellular events activated during parasite entry into nonphagocytic cells. In this context, we have previously shown that induction of autophagy in host cells before infection favors T. cruzi invasion. Furthermore, we demonstrate that autophagosomes and the autophagosomal protein LC3 are recruited to the T. cruzi entry sites and that the newly formed T. cruzi parasitophorous vacuole has characteristics of an autophagolysosome. This review summarizes the current knowledge of the molecular and cellular mechanisms of T. cruzi invasion in nonphagocytic cells. Based on our findings, we propose a new model in which T. cruzi takes advantage of the upregulation of autophagy during starvation to increase its successful colonization of host cells. Copyright © 2012 Wiley Periodicals, Inc.

  2. Estradiol decreases cortical reactive astrogliosis after brain injury by a mechanism involving cannabinoid receptors.

    PubMed

    López Rodríguez, Ana Belén; Mateos Vicente, Beatriz; Romero-Zerbo, Silvana Y; Rodriguez-Rodriguez, Noé; Bellini, María José; Rodriguez de Fonseca, Fernando; Bermudez-Silva, Francisco Javier; Azcoitia, Iñigo; Garcia-Segura, Luis M; Viveros, María-Paz

    2011-09-01

    The neuroactive steroid estradiol reduces reactive astroglia after brain injury by mechanisms similar to those involved in the regulation of reactive gliosis by endocannabinoids. In this study, we have explored whether cannabinoid receptors are involved in the effects of estradiol on reactive astroglia. To test this hypothesis, the effects of estradiol, the cannabinoid CB1 antagonist/inverse agonist AM251, and the cannabinoid CB2 antagonist/inverse agonist AM630 were assessed in the cerebral cortex of male rats after a stab wound brain injury. Estradiol reduced the number of vimentin immunoreactive astrocytes and the number of glial fibrillary acidic protein immunoreactive astrocytes in the proximity of the wound. The effect of estradiol was significantly inhibited by the administration of either CB1 or CB2 receptor antagonists. The effect of estradiol may be in part mediated by alterations in endocannabinoid signaling because the hormone increased in the injured cerebral cortex the messenger RNA levels of CB2 receptors and of some of the enzymes involved in the synthesis and metabolism of endocannabinoids. These findings suggest that estradiol may decrease reactive astroglia in the injured brain by regulating the activity of the endocannabinoid system.

  3. Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor.

    PubMed

    Bariani, María Victoria; Domínguez Rubio, Ana Paula; Cella, Maximiliano; Burdet, Juliana; Franchi, Ana María; Aisemberg, Julieta

    2015-12-01

    Prematurity is the leading cause of perinatal morbidity and mortality worldwide. There is a strong causal relationship between infection and preterm births. Intrauterine infection elicits an immune response involving the release of inflammatory mediators like cytokines and prostaglandins (PG) that trigger uterine contractions and parturition events. Anandamide (AEA) is an endogenous ligand for the cannabinoid receptors CB1 and CB2. Similarly to PG, endocannabinoids are implicated in different aspects of reproduction, such as maintenance of pregnancy and parturition. Little is known about the involvement of endocannabinoids on the onset of labor in an infectious milieu. Here, using a mouse model of preterm labor induced by lipopolysaccharide (LPS), we explored changes on the expression of components of endocannabinoid system (ECS). We have also determined whether AEA and CB antagonists alter PG production that induces labor. We observed an increase in uterine N-acylphosphatidylethanolamine-specific phospholipase D expression (NAPE-PLD, the enzyme that synthesizes AEA) upon LPS treatment. Activity of catabolic enzyme fatty acid amide hydrolase (FAAH) did not change significantly. In addition, we also found that LPS modulated uterine cannabinoid receptors expression by downregulating Cb2 mRNA levels and upregulating CB1 protein expression. Furthermore, LPS and AEA induced PGF2a augmentation, and this was reversed by antagonizing CB1 receptor. Collectively, our results suggest that ECS may be involved in the mechanism by which infection causes preterm birth. © 2015 Society for Reproduction and Fertility.

  4. Epigenetic mechanisms are involved in the regulation of ethanol consumption in mice.

    PubMed

    Qiang, Mei; Li, Ji G; Denny, Ashley D; Yao, Jie-Min; Lieu, Mai; Zhang, Kerang; Carreon, Stephanie

    2014-10-31

    Repeated alcohol exposure is known to increase subsequent ethanol consumption in mice. However, the underlying mechanisms have not been fully elucidated. One postulated mechanism involves epigenetic modifications, including histone modifications and DNA methylation of relevant genes such as NR2B or BDNF. To investigate the role of epigenetic mechanisms in the development of alcohol drinking behavior, an established chronic intermittent ethanol exposure reinforced ethanol drinking mouse model with vapor inhalation over two 9-day treatment regimens was used. The DNA methyltransferase inhibitor, 5-azacytidine or the histone deacetylase inhibitor, Trichostatin A was administered (intraperitoneally) to C57BL/6 mice 30 min before daily exposure to chronic intermittent ethanol. Changes in ethanol consumption were measured using the 2-bottle choice test. The results indicated that systemic administration of Trichostatin A (2.5 µg/g) facilitated chronic intermittent ethanol-induced ethanol drinking, but systemic administration of 5-azacytidine (2 µg/g) did not cause the same effect. However, when 5-azacytidine was administered by intracerebroventricular injection, it facilitated chronic intermittent ethanol-induced ethanol drinking. Furthermore, the increased drinking caused by chronic intermittent ethanol was prevented by injection of a methyl donor, S-adenosyl-L-methionine. To provide evidence that chronic intermittent ethanol- or Trichostatin A-induced DNA demethylation and histone modifications of the NR2B promoter may underlie the altered ethanol consumption, we examined epigenetic modifications and NR2B expression in the prefrontal cortex of these mice. Chronic intermittent ethanol or Trichostatin A decreased DNA methylation and increased histone acetylation in the NR2B gene promoter, as well as mRNA levels of NR2B in these mice. Taken together, these results indicate that epigenetic modifications are involved in regulating ethanol drinking behavior, partially

  5. Epigenetic Mechanisms Are Involved in the Regulation of Ethanol Consumption in Mice

    PubMed Central

    Li, Ji G.; Denny, Ashley D.; Yao, Jie-min; Lieu, Mai; Zhang, Kerang; Carreon, Stephanie

    2015-01-01

    Background: Repeated alcohol exposure is known to increase subsequent ethanol consumption in mice. However, the underlying mechanisms have not been fully elucidated. One postulated mechanism involves epigenetic modifications, including histone modifications and DNA methylation of relevant genes such as NR2B or BDNF. Methods: To investigate the role of epigenetic mechanisms in the development of alcohol drinking behavior, an established chronic intermittent ethanol exposure reinforced ethanol drinking mouse model with vapor inhalation over two 9-day treatment regimens was used. The DNA methyltransferase inhibitor, 5-azacytidine or the histone deacetylase inhibitor, Trichostatin A was administered (intraperitoneally) to C57BL/6 mice 30min before daily exposure to chronic intermittent ethanol. Changes in ethanol consumption were measured using the 2-bottle choice test. Results: The results indicated that systemic administration of Trichostatin A (2.5 µg/g) facilitated chronic intermittent ethanol-induced ethanol drinking, but systemic administration of 5-azacytidine (2 µg/g) did not cause the same effect. However, when 5-azacytidine was administered by intracerebroventricular injection, it facilitated chronic intermittent ethanol-induced ethanol drinking. Furthermore, the increased drinking caused by chronic intermittent ethanol was prevented by injection of a methyl donor, S-adenosyl-L-methionine. To provide evidence that chronic intermittent ethanol- or Trichostatin A-induced DNA demethylation and histone modifications of the NR2B promoter may underlie the altered ethanol consumption, we examined epigenetic modifications and NR2B expression in the prefrontal cortex of these mice. Chronic intermittent ethanol or Trichostatin A decreased DNA methylation and increased histone acetylation in the NR2B gene promoter, as well as mRNA levels of NR2B in these mice. Conclusions: Taken together, these results indicate that epigenetic modifications are involved in regulating

  6. Mitochondrial DNA replication proceeds via a ‘bootlace’ mechanism involving the incorporation of processed transcripts

    PubMed Central

    Reyes, Aurelio; Kazak, Lawrence; Wood, Stuart R.; Yasukawa, Takehiro; Jacobs, Howard T.; Holt, Ian J.

    2013-01-01

    The observation that long tracts of RNA are associated with replicating molecules of mitochondrial DNA (mtDNA) suggests that the mitochondrial genome of mammals is copied by an unorthodox mechanism. Here we show that these RNA-containing species are present in living cells and tissue, based on interstrand cross-linking. Using DNA synthesis in organello, we demonstrate that isolated mitochondria incorporate radiolabeled RNA precursors, as well as DNA precursors, into replicating DNA molecules. RNA-containing replication intermediates are chased into mature mtDNA, to which they are thus in precursor–product relationship. While a DNA chain terminator rapidly blocks the labeling of mitochondrial replication intermediates, an RNA chain terminator does not. Furthermore, processed L-strand transcripts can be recovered from gel-extracted mtDNA replication intermediates. Therefore, instead of concurrent DNA and RNA synthesis, respectively, on the leading and lagging strands, preformed processed RNA is incorporated as a provisional lagging strand during mtDNA replication. These findings indicate that RITOLS is a physiological mechanism of mtDNA replication, and that it involves a ‘bootlace' mechanism, in which processed transcripts are successively hybridized to the lagging-strand template, as the replication fork advances. PMID:23595151

  7. An overview of potential molecular mechanisms involved in VSMC phenotypic modulation.

    PubMed

    Zhang, Ming-Jie; Zhou, Yi; Chen, Lei; Wang, Yan-Qin; Wang, Xu; Pi, Yan; Gao, Chang-Yue; Li, Jing-Cheng; Zhang, Li-Li

    2016-02-01

    The fully differentiated medial vascular smooth muscle cells (VSMCs) of mature vessels keep quiescent and contractile. However, VSMC can exhibit the plasticity in phenotype switching from a differentiated and contractile phenotype to a dedifferentiated state in response to alterations in local environmental cues, which is called phenotypic modulation or switching. Distinguishing from its differentiated state expressing more smooth muscle (SM)-specific/selective proteins, the phenotypic modulation in VSMC is characterized by an increased rate of proliferation, migration, synthesis of extracellular matrix proteins and decreased expression of SM contractile proteins. Although it has been well demonstrated that phenotypic modulation of VSMC contributes to the occurrence and progression of many proliferative vascular diseases, little is known about the details of the molecular mechanisms of VSMC phenotypic modulation. Growing evidence suggests that variety of molecules including microRNAs, cytokines and biochemical factors, membrane receptors, ion channels, cytoskeleton and extracellular matrix play important roles in controlling VSMC phenotype. The focus of the present review is to provide an overview of potential molecular mechanisms involved in VSMC phenotypic modulation in recent years. To clarify VSMC differentiation and phenotypic modulation mechanisms will contribute to producing cell-based therapeutic interventions for aberrant VSMC differentiation-related diseases.

  8. Genes and mechanisms involved in beta-amyloid generation and Alzheimer's disease.

    PubMed

    Steiner, H; Capell, A; Leimer, U; Haass, C

    1999-01-01

    Alzheimer's disease is characterized by the invariable accumulation of senile plaques that are predominantly composed of amyloid beta-peptide (Abeta). Abeta is generated by proteolytic processing of the beta-amyloid precursor protein (betaAPP) involving the combined action of beta- and gamma-secretase. Cleavage within the Abeta domain by alpha-secretase prevents Abeta generation. In some very rare cases of familial AD (FAD), mutations have been identified within the betaAPP gene. These mutations are located close to or at the cleavage sites of the secretases and pathologically effect betaAPP processing by increasing Abeta production, specifically its highly amyloidogenic 42 amino acid variant (Abeta42). Most of the mutations associated with FAD have been identified in the two presenilin (PS) genes, particularly the PS1 gene. Like the mutations identified within the betaAPP gene, mutations in PS1 and PS2 cause the increased generation of Abeta42. PS1 has been shown to be functionally involved in Notch signaling, a key process in cellular differentation, and in betaAPP processing. A gene knock out of PS1 in mice leads to an embryonic lethal phenotype similar to that of mice lacking Notch. In addition, absence of PS1 results in reduced gamma-secretase cleavage and leads to an accumulation of betaAPP C-terminal fragments and decreased amounts of Abeta. Recent work may suggest that PS1 could be the gamma-secretase itself, exhibiting the properties of a novel aspartyl protease. Mutagenesis of either of two highly conserved intramembraneous aspartate residues of PS1 leads to reduced Abeta production as observed in the PS1 knockout. A corresponding mutation in PS2 interfered with betaAPP processing and Notch signaling suggesting a functional redundancy of both presenilins. In this issue, some of the recent work on the molecular mechanisms involved in Alzheimer's disease (AD) as well as novel diagnostic approaches and risk factors for AD will be discussed. In the first

  9. Indirect reciprocity with optional interactions.

    PubMed

    Ghang, Whan; Nowak, Martin A

    2015-01-21

    Indirect reciprocity is a mechanism for the evolution of cooperation that is relevant for prosocial behavior among humans. Indirect reciprocity means that my behavior towards you also depends on what you have done to others. Indirect reciprocity is associated with the evolution of social intelligence and human language. Most approaches to indirect reciprocity assume obligatory interactions, but here we explore optional interactions. In any one round a game between two players is offered. A cooperator accepts a game unless the reputation of the other player indicates a defector. For a game to take place, both players must accept. In a game between a cooperator and a defector, the reputation of the defector is revealed to all players with probability Q. After a sufficiently large number of rounds the identity of all defectors is known and cooperators are no longer exploited. The crucial condition for evolution of cooperation can be written as hQB>1, where h is the average number of rounds per person and B=(b/c)-1 specifies the benefit-to-cost ratio. We analyze both stochastic and deterministic evolutionary game dynamics. We study two extensions that deal with uncertainty: hesitation and malicious gossip. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Peptide Bond Synthesis by a Mechanism Involving an Enzymatic Reaction and a Subsequent Chemical Reaction.

    PubMed

    Abe, Tomoko; Hashimoto, Yoshiteru; Zhuang, Ye; Ge, Yin; Kumano, Takuto; Kobayashi, Michihiko

    2016-01-22

    We recently reported that an amide bond is unexpectedly formed by an acyl-CoA synthetase (which catalyzes the formation of a carbon-sulfur bond) when a suitable acid and l-cysteine are used as substrates. DltA, which is homologous to the adenylation domain of nonribosomal peptide synthetase, belongs to the same superfamily of adenylate-forming enzymes, which includes many kinds of enzymes, including the acyl-CoA synthetases. Here, we demonstrate that DltA synthesizes not only N-(d-alanyl)-l-cysteine (a dipeptide) but also various oligopeptides. We propose that this enzyme catalyzes peptide synthesis by the following unprecedented mechanism: (i) the formation of S-acyl-l-cysteine as an intermediate via its "enzymatic activity" and (ii) subsequent "chemical" S → N acyl transfer in the intermediate, resulting in peptide formation. Step ii is identical to the corresponding reaction in native chemical ligation, a method of chemical peptide synthesis, whereas step i is not. To the best of our knowledge, our discovery of this peptide synthesis mechanism involving an enzymatic reaction and a subsequent chemical reaction is the first such one to be reported. This new process yields peptides without the use of a thioesterified fragment, which is required in native chemical ligation. Together with these findings, the same mechanism-dependent formation of N-acyl compounds by other members of the above-mentioned superfamily demonstrated that all members most likely form peptide/amide compounds by using this novel mechanism. Each member enzyme acts on a specific substrate; thus, not only the corresponding peptides but also new types of amide compounds can be formed. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Coral bleaching under thermal stress: putative involvement of host/symbiont recognition mechanisms

    PubMed Central

    Vidal-Dupiol, Jeremie; Adjeroud, Mehdi; Roger, Emmanuel; Foure, Laurent; Duval, David; Mone, Yves; Ferrier-Pages, Christine; Tambutte, Eric; Tambutte, Sylvie; Zoccola, Didier; Allemand, Denis; Mitta, Guillaume

    2009-01-01

    Background Coral bleaching can be defined as the loss of symbiotic zooxanthellae and/or their photosynthetic pigments from their cnidarian host. This major disturbance of reef ecosystems is principally induced by increases in water temperature. Since the beginning of the 1980s and the onset of global climate change, this phenomenon has been occurring at increasing rates and scales, and with increasing severity. Several studies have been undertaken in the last few years to better understand the cellular and molecular mechanisms of coral bleaching but the jigsaw puzzle is far from being complete, especially concerning the early events leading to symbiosis breakdown. The aim of the present study was to find molecular actors involved early in the mechanism leading to symbiosis collapse. Results In our experimental procedure, one set of Pocillopora damicornis nubbins was subjected to a gradual increase of water temperature from 28°C to 32°C over 15 days. A second control set kept at constant temperature (28°C). The differentially expressed mRNA between the stressed states (sampled just before the onset of bleaching) and the non stressed states (control) were isolated by Suppression Subtractive Hybridization. Transcription rates of the most interesting genes (considering their putative function) were quantified by Q-RT-PCR, which revealed a significant decrease in transcription of two candidates six days before bleaching. RACE-PCR experiments showed that one of them (PdC-Lectin) contained a C-Type-Lectin domain specific for mannose. Immunolocalisation demonstrated that this host gene mediates molecular interactions between the host and the symbionts suggesting a putative role in zooxanthellae acquisition and/or sequestration. The second gene corresponds to a gene putatively involved in calcification processes (Pdcyst-rich). Its down-regulation could reflect a trade-off mechanism leading to the arrest of the mineralization process under stress. Conclusion Under thermal

  12. Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation.

    PubMed

    Colussi, Gian Luca; Di Fabio, Alessandro; Catena, Cristiana; Chiuch, Alessandra; Sechi, Leonardo A

    2011-08-01

    Benzodiazepine (BDZ) infusion has been shown to reduce blood pressure in both humans and animals. Although the inhibitory effects of BDZ on the central nervous system have been well documented, less is known about the direct effects of BDZ on the vascular bed. The aims of this study were to assess the effects of the BDZ midazolam on the vascular system in C57/BL6 mouse aortic rings and to investigate the mechanisms of its direct vascular action. We found that midazolam induced reversible, dose-dependent vasodilation in potassium- and phenylephrine-precontracted rings. In rings that were precontracted with potassium or phenylephrine, treatment with 10 μmol l(-1) midazolam increased vasodilation by 15 and 60%, respectively, compared with baseline. Vasodilation increased by 80 and 87%, respectively, after treatment with 50 μmol l(-1) midazolam. Only the low concentration of midazolam (10 μmol l(-1)) induced endothelium-dependent vasodilation in phenylephrine-precontracted rings. Vasodilation increased by 60% in rings with endothelium and by 20% in rings without endothelium. Conversely, only the high concentration of midazolam (50 μmol l(-1)) reduced the CaCl(2)-induced vasoconstriction of aortic rings with EC(50) (the concentration giving 50% of the maximal effect) values of 1 and 6 mmol l(-1) for vehicle- and midazolam-treated rings, respectively. Furthermore, the incubation of phenylephrine-precontracted rings with an inhibitor of the nitric oxide synthase (NOS) NG-nitro-L-arginine methyl ester or the inhibitors of central or peripheral type BDZ receptors (flumazenil or PK 11195, respectively) produced no change in midazolam-induced vasodilation. Thus, low concentrations of midazolam induce vasodilation via an endothelium-dependent mechanism that does not involve NO production. In contrast, high concentrations of midazolam induce vasodilation via an endothelium-independent mechanism that implies reduced sensitivity of aortic rings to calcium ions. Additionally

  13. One mechanism of glucocorticoid action in asthma may involve the inhibition of IL-25 expression

    PubMed Central

    Lu, Wei; Lu, Chao; Zhang, Chengming; Zhang, Chenghao

    2017-01-01

    While the mechanism of action of classic cytokines in asthma has received increased attention from researchers, certain non-classical cytokines, such as IL-25, also participate in this mechanism. The present study was performed to investigate the changes in IL-25 (IL-17E) mRNA and protein in bronchial asthma and to further characterize the mechanism underlying the action of glucocorticoids in asthma. A total of 96 specific pathogen-free BALB/c male mice were randomly divided into three normal groups (after the first allergization, after the second allergization and after excitation), three asthma groups (with the same three subgroups), a dexamethasone group and a budesonide group (n=12/group). An asthma model was established via the ovalbumin-sensitized excitation method. Mice in the dexamethasone group received intraperitoneal injections of dexamethasone 1 h prior to each excitation, the budesonide group received a budesonide suspension via inhalation 2 h before and after each provocation, and the normal group was sensitized and challenged with isotonic saline. IL-25 protein expression levels in the bronchoalveolar lavage fluid were measured by ELISA, and the relative IL-25 mRNA content in lung tissue was determined by reverse transcription-quantitative polymerase chain reaction. Compared with the normal groups, both the protein and mRNA levels of IL-25 were significantly increased (P<0.05) in the asthma groups. Dexamethasone and budesonide groups exhibited significant protein and mRNA reductions in IL-25, as compared with the asthma group after excitation (P<0.05), whereas these two groups significantly increased levels compared with the normal group after excitation (P<0.05). No significant differences in IL-25 mRNA expression levels were detected in the dexamethasone and budesonide groups when compared with the normal group after excitation. Therefore, we conclude that IL-25 is involved throughout the process of inflammation and inflammatory immune pathogenesis

  14. Coral bleaching under thermal stress: putative involvement of host/symbiont recognition mechanisms.

    PubMed

    Vidal-Dupiol, Jeremie; Adjeroud, Mehdi; Roger, Emmanuel; Foure, Laurent; Duval, David; Mone, Yves; Ferrier-Pages, Christine; Tambutte, Eric; Tambutte, Sylvie; Zoccola, Didier; Allemand, Denis; Mitta, Guillaume

    2009-08-04

    Coral bleaching can be defined as the loss of symbiotic zooxanthellae and/or their photosynthetic pigments from their cnidarian host. This major disturbance of reef ecosystems is principally induced by increases in water temperature. Since the beginning of the 1980s and the onset of global climate change, this phenomenon has been occurring at increasing rates and scales, and with increasing severity. Several studies have been undertaken in the last few years to better understand the cellular and molecular mechanisms of coral bleaching but the jigsaw puzzle is far from being complete, especially concerning the early events leading to symbiosis breakdown. The aim of the present study was to find molecular actors involved early in the mechanism leading to symbiosis collapse. In our experimental procedure, one set of Pocillopora damicornis nubbins was subjected to a gradual increase of water temperature from 28 degrees C to 32 degrees C over 15 days. A second control set kept at constant temperature (28 degrees C). The differentially expressed mRNA between the stressed states (sampled just before the onset of bleaching) and the non stressed states (control) were isolated by Suppression Subtractive Hybridization. Transcription rates of the most interesting genes (considering their putative function) were quantified by Q-RT-PCR, which revealed a significant decrease in transcription of two candidates six days before bleaching. RACE-PCR experiments showed that one of them (PdC-Lectin) contained a C-Type-Lectin domain specific for mannose. Immunolocalisation demonstrated that this host gene mediates molecular interactions between the host and the symbionts suggesting a putative role in zooxanthellae acquisition and/or sequestration. The second gene corresponds to a gene putatively involved in calcification processes (Pdcyst-rich). Its down-regulation could reflect a trade-off mechanism leading to the arrest of the mineralization process under stress. Under thermal stress

  15. Mechanism involved in Danshen-induced fluid secretion in salivary glands

    PubMed Central

    Wei, Fei; Wei, Mu-Xin; Murakami, Masataka

    2015-01-01

    AIM: Danshen’s capability to induce salivary fluid secretion and its mechanisms were studied to determine if it could improve xerostomia. METHODS: Submandibular glands were isolated from male Wistar rats under systemic anesthesia with pentobarbital sodium. The artery was cannulated and vascularly perfused at a constant rate. The excretory duct was also cannulated and the secreted saliva was weighed in a cup on an electronic balance. The weight of the accumulated saliva was measured every 3 s and the salivary flow rate was calculated. In addition, the arterio-venous difference in the partial oxygen pressure was measured as an indicator of oxygen consumption. In order to assess the mechanism involved in Danshen-induced fluid secretion, either ouabain (an inhibitor of Na+/K+ ATPase) or bumetanide (an inhibitor of NKCC1) was additionally applied during the Danshen stimulation. In order to examine the involvement of the main membrane receptors, atropine was added to block the M3 muscarinic receptors, or phentolamine was added to block the α1 adrenergic receptors. In order to examine the requirement for extracellular Ca2+, Danshen was applied during the perfusion with nominal Ca2+ free solution. RESULTS: Although Danshen induced salivary fluid secretion, 88.7 ± 12.8 μL/g-min, n = 9, (the highest value around 20 min from start of DS perfusion was significantly high vs 32.5 ± 5.3 μL/g-min by carbamylcholine, P = 0.00093 by t-test) in the submandibular glands, the time course of that secretion differed from that induced by carbamylcholine. There was a latency associated with the fluid secretion induced by Danshen, followed by a gradual increase in the secretion to its highest value, which was in turn followed by a slow decline to a near zero level. The application of either ouabain or bumetanide inhibited the fluid secretion by 85% or 93%, and suppressed the oxygen consumption by 49% or 66%, respectively. These results indicated that Danshen activates Na+/K+ ATPase

  16. Afferent control mechanisms involved in the development of soleus fiber alterations in simulated hypogravity

    NASA Astrophysics Data System (ADS)

    Shenkman, B. S.; Nemirovskaya, T. L.; Shapovalova, K. B.; Podlubnaya, Z. A.; Vikhliantsev, I. M.; Moukhina, A. M.; Kozlovskaya, I. B.

    2007-02-01

    It was recently established that support withdrawal (withdrawal of support reaction force) in microgravity provokes a sequence of functional shifts in the activity of motor units (inactivation of slow ones) and peripheral muscle apparatus which lead to the decline of postural muscle contractility and alterations in fiber characteristics. However, mechanisms involved in inactivation of the slow motor units and appropriate slow-twitch muscle fiber disuse under the supportless conditions remained unknown. We show here that artificial inactivation of muscles-antagonists (which are known to be hyperactive during unloading) counteracts some of the unloading-induced events in the rat soleus (fiber size reduction, slow-to-fast fiber-type transition and decline of titin and nebulin content). It was also demonstrated that direct activation of the muscarinic receptors of the neostriatum neurons prevented slow-to-fast fiber-type transformation in soleus of hindlimb suspended rats.

  17. Understanding The Neural Mechanisms Involved In Sensory Control Of Voice Production

    PubMed Central

    Parkinson, Amy L.; Flagmeier, Sabina G.; Manes, Jordan L.; Larson, Charles R.; Rogers, Bill; Robin, Donald A.

    2012-01-01

    Auditory feedback is important for the control of voice fundamental frequency (F0). In the present study we used neuroimaging to identify regions of the brain responsible for sensory control of the voice. We used a pitch-shift paradigm where subjects respond to an alteration, or shift, of voice pitch auditory feedback with a reflexive change in F0. To determine the neural substrates involved in these audio-vocal responses, subjects underwent fMRI scanning while vocalizing with or without pitch-shifted feedback. The comparison of shifted and unshifted vocalization revealed activation bilaterally in the superior temporal gyrus (STG) in response to the pitch shifted feedback. We hypothesize that the STG activity is related to error detection by auditory error cells located in the superior temporal cortex and efference copy mechanisms whereby this region is responsible for the coding of a mismatch between actual and predicted voice F0. PMID:22406500

  18. MicroRNA: biogenetic and functional mechanisms and involvements in cell differentiation and cancer.

    PubMed

    Tsuchiya, Soken; Okuno, Yasushi; Tsujimoto, Gozoh

    2006-08-01

    MicroRNAs (miRNAs) are endogenous small noncoding RNAs (20-23 nucleotides) that negatively regulate the gene expressions at the posttranscriptional level by base pairing to the 3' untranslated region of target messenger RNAs. Hundreds of miRNAs have been identified in humans and evolutionarily conserved from plants to animals. It is revealed that miRNAs regulate various physiological and pathological pathways such as cell differentiation, cell proliferation, and tumoriogenesis. By the computational analysis, it is predicted that 30% of protein-encoding genes are regulated by miRNAs. In this review, we discuss recent remarkable advances in the miRNA biogenetic and functional mechanisms and the involvements of miRNAs in cell differentiation, especially in hematopoietic lineages, and cancer. These evidences offer the possibility that miRNAs would be potentially useful for drug discovery.

  19. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    PubMed Central

    Massi, Paola; Valenti, Marta; Solinas, Marta; Parolaro, Daniela

    2010-01-01

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells. PMID:24281104

  20. Mechanisms Involved in Glucocorticoid Induction of Pituitary GH Expression During Embryonic Development

    PubMed Central

    Ellestad, Laura E.; Puckett, Stefanie A.

    2015-01-01

    Glucocorticoid hormones are involved in functional differentiation of GH-producing somatotrophs. Glucocorticoid treatment prematurely induces GH expression in mammals and birds in a process requiring protein synthesis and Rat sarcoma (Ras) signaling. The objective of this study was to investigate mechanisms through which glucocorticoids initiate GH expression during embryogenesis, taking advantage of the unique properties of chicken embryos as a developmental model. We determined that stimulation of GH expression occurred through transcriptional activation of GH, rather than enhancement of mRNA stability, and this process requires histone deacetylase activity. Through pharmacological inhibition, we identified the ERK1/2 pathway as a likely downstream Ras effector necessary for glucocorticoid stimulation of GH. However, we also found that chronic activation of ERK1/2 activity with a constitutively active mutant or stimulatory ligand reduced initiation of GH expression by glucocorticoid treatment. Corticosterone treatment of cultured embryonic pituitary cells increased ERK1/2 activity in an apparent cyclical manner, with a rapid increase within 5 minutes, followed by a reduction to near-basal levels at 3 hours, and a subsequent increase again at 6 hours. Therefore, we conclude that ERK1/2 signaling must be strictly controlled for maximal glucocorticoid induction of GH to occur. These results are the first in any species to demonstrate that Ras- and ERK1/2-mediated transcriptional events requiring histone deacetylase activity are involved in glucocorticoid induction of pituitary GH during embryonic development. This report increases our understanding of the molecular mechanisms underlying glucocorticoid recruitment of somatotrophs during embryogenesis and should provide insight into glucocorticoid-induced developmental changes in other tissues and cell types. PMID:25560830

  1. Cellular mechanisms involved in CO(2) and acid signaling in chemosensitive neurons.

    PubMed

    Putnam, Robert W; Filosa, Jessica A; Ritucci, Nicola A

    2004-12-01

    An increase in CO(2)/H(+) is a major stimulus for increased ventilation and is sensed by specialized brain stem neurons called central chemosensitive neurons. These neurons appear to be spread among numerous brain stem regions, and neurons from different regions have different levels of chemosensitivity. Early studies implicated changes of pH as playing a role in chemosensitive signaling, most likely by inhibiting a K(+) channel, depolarizing chemosensitive neurons, and thereby increasing their firing rate. Considerable progress has been made over the past decade in understanding the cellular mechanisms of chemosensitive signaling using reduced preparations. Recent evidence has pointed to an important role of changes of intracellular pH in the response of central chemosensitive neurons to increased CO(2)/H(+) levels. The signaling mechanisms for chemosensitivity may also involve changes of extracellular pH, intracellular Ca(2+), gap junctions, oxidative stress, glial cells, bicarbonate, CO(2), and neurotransmitters. The normal target for these signals is generally believed to be a K(+) channel, although it is likely that many K(+) channels as well as Ca(2+) channels are involved as targets of chemosensitive signals. The results of studies of cellular signaling in central chemosensitive neurons are compared with results in other CO(2)- and/or H(+)-sensitive cells, including peripheral chemoreceptors (carotid body glomus cells), invertebrate central chemoreceptors, avian intrapulmonary chemoreceptors, acid-sensitive taste receptor cells on the tongue, and pain-sensitive nociceptors. A multiple factors model is proposed for central chemosensitive neurons in which multiple signals that affect multiple ion channel targets result in the final neuronal response to changes in CO(2)/H(+).

  2. GABAB receptors modulate catecholamine secretion in chromaffin cells by a mechanism involving cyclic AMP formation.

    PubMed

    Oset-Gasque, M J; Parramón, M; González, M P

    1993-12-01

    1. The function of gamma-aminobutyric acidB (GABAB) receptors in modulation of catecholamine secretion by chromaffin cells and the possible mechanism involved in this action have been examined. 2. The GABAB agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) were found to induce a dose-dependent increase of basal catecholamine secretion. The EC50s were 151 +/- 35 microM and 225 +/- 58 microM for baclofen and 3-APPA, respectively. This stimulatory effect was specific since it could be blocked by 0.5 mM of the specific GABAB antagonist CGP-35348. 3. In contrast, preincubation of chromaffin cells with the GABAB agonists was found to inhibit, in a dose-dependent manner, the catecholamine secretion evoked by 10 microM nicotine and 200 microM muscimol. 4. The effects of GABAB agonists on both basal and evoked catecholamine secretion were found to be accompanied by parallel changes in intracellular calcium concentration ([Ca2+]i). GABAB agonists produced a dose-dependent increase in [Ca2+]i which was partially blocked by CGP 35348, but they produced a strong inhibition of the [Ca2+]i increase induced by nicotine and muscimol. 5. The GABAB agonists also produced a dose-dependent increase in intracellular cyclic AMP levels, there being a direct correlation between both increase in catecholamine secretion and in intracellular cyclic AMP levels. 6. The pretreatment of chromaffin cells with pertussis toxin doubled the catecholamine secretion and increased by four times the intracellular cyclic AMP levels evoked by GABAB agonists. 7. The possible involvement of adenylate cyclase in the mechanism of GABAA receptor modulation of catecholamine secretion is discussed.

  3. Myeloma cells resistance to NK cell lysis mainly involves an HLA class I-dependent mechanism.

    PubMed

    Gao, Minjie; Gao, Lu; Yang, Guang; Tao, Yi; Hou, Jun; Xu, Hongwei; Hu, Xiaojing; Han, Ying; Zhang, Qianqiao; Zhan, Fenghuang; Wu, Xiaosong; Shi, Jumei

    2014-07-01

    The anti-multiple myeloma (MM) potential of natural killer (NK) cells has been of rising interest in recent years. However, the molecular mechanism of NK cell cytotoxicity to myeloma cells remains unclear. In the present study, we investigated the expressions of human leukocyte antigen (HLA) class I and HLA-G in patient myeloma cells, and determined their relevance in patient tumor-cell susceptibility to NK cell cytotoxicity. Our results showed that patient myeloma cells (n = 12) were relatively resistant to NK-92 cell lysis, compared with myeloma cell lines (n = 7, P < 0.01). Gene expression profiling and flow cytometry analysis showed that both mRNA and protein of HLA class I were highly expressed in 12 patient myeloma cells. Interestingly, no or low HLA-G surface expression was detected, although multiple HLA-G transcripts were detected in these myeloma cells. NK cell function assay showed that down-regulating HLA class I expression on patient cells by acid treatment significantly increased the susceptibility of MM cells to NK-mediated lysis. Furthermore, we found that the blocking of membrane-bound HLA class I rather than HLA-G using antibodies on myeloma samples markedly increased their susceptibility to NK-mediated killing. These results demonstrated that the resistance of patient MM cells to NK lysis mainly involves an HLA class I-dependent mechanism, suggesting that HLA class I may be involved in protecting MM cells from NK-mediated attack and contribute to their immune escape in vivo.

  4. GABAB receptors modulate catecholamine secretion in chromaffin cells by a mechanism involving cyclic AMP formation.

    PubMed Central

    Oset-Gasque, M. J.; Parramón, M.; González, M. P.

    1993-01-01

    1. The function of gamma-aminobutyric acidB (GABAB) receptors in modulation of catecholamine secretion by chromaffin cells and the possible mechanism involved in this action have been examined. 2. The GABAB agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) were found to induce a dose-dependent increase of basal catecholamine secretion. The EC50s were 151 +/- 35 microM and 225 +/- 58 microM for baclofen and 3-APPA, respectively. This stimulatory effect was specific since it could be blocked by 0.5 mM of the specific GABAB antagonist CGP-35348. 3. In contrast, preincubation of chromaffin cells with the GABAB agonists was found to inhibit, in a dose-dependent manner, the catecholamine secretion evoked by 10 microM nicotine and 200 microM muscimol. 4. The effects of GABAB agonists on both basal and evoked catecholamine secretion were found to be accompanied by parallel changes in intracellular calcium concentration ([Ca2+]i). GABAB agonists produced a dose-dependent increase in [Ca2+]i which was partially blocked by CGP 35348, but they produced a strong inhibition of the [Ca2+]i increase induced by nicotine and muscimol. 5. The GABAB agonists also produced a dose-dependent increase in intracellular cyclic AMP levels, there being a direct correlation between both increase in catecholamine secretion and in intracellular cyclic AMP levels. 6. The pretreatment of chromaffin cells with pertussis toxin doubled the catecholamine secretion and increased by four times the intracellular cyclic AMP levels evoked by GABAB agonists. 7. The possible involvement of adenylate cyclase in the mechanism of GABAA receptor modulation of catecholamine secretion is discussed. PMID:8306105

  5. Post-ictal analgesia: involvement of opioid, serotoninergic and cholinergic mechanisms.

    PubMed

    Coimbra, N C; Castro-Souza, C; Segato, E N; Nora, J E; Herrero, C F; Tedeschi-Filho, W; Garcia-Cairasco, N

    2001-01-12

    The neural mechanisms involved in post-ictal analgesia remain to be elucidated. Pentylenetetrazol (PTZ) is used experimentally to induce seizure in animal subjects. This non-competitive antagonist blocks GABA-mediated Cl(-) flux. The aim of this work is to study the neurochemical basis of the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test, in eight rats per group. Convulsions were followed by significant increase in the tail-flick latencies (TFL), at least for 30 min of the post-ictal period. Peripheral administration of naloxone (5 mg/kg and 10 mg/kg), atropine (1 mg/kg and 5 mg/kg), methysergide (1 mg/kg and 5 mg/kg) and ketanserine (1 mg/kg and 2 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls. However, while naloxone antagonized analgesia 15 and 25 min post convulsions, the other drugs caused a blockade of the post-ictal analgesia in a relatively greater period of time. These results indicate that endogenous opioids, serotonin and acetylcholine may be involved in post-ictal analgesia.

  6. Key diffusion mechanisms involved in regulating bidirectional water permeation across E. coli outer membrane lectin

    PubMed Central

    Sachdeva, Shivangi; Kolimi, Narendar; Nair, Sanjana Anilkumar; Rathinavelan, Thenmalarchelvi

    2016-01-01

    Capsular polysaccharides (CPSs) are major bacterial virulent determinants that facilitate host immune evasion. E. coli group1 K30CPS is noncovalently attached to bacterial surface by Wzi, a lectin. Intriguingly, structure based phylogenetic analysis indicates that Wzi falls into porin superfamily. Molecular dynamics (MD) simulations further shed light on dual role of Wzi as it also functions as a bidirectional passive water specific porin. Such a functional role of Wzi was not realized earlier, due to the occluded pore. While five water specific entry points distributed across extracellular & periplasmic faces regulate the water diffusion involving different mechanisms, a luminal hydrophobic plug governs water permeation across the channel. Coincidently, MD observed open state structure of “YQF” triad is seen in sugar-binding site of sodium-galactose cotransporters, implicating its involvement in K30CPS surface anchorage. Importance of Loop 5 (L5) in membrane insertion is yet another highlight. Change in water diffusion pattern of periplasmic substitution mutants suggests Wzi’s role in osmoregulation by aiding in K30CPS hydration, corroborating earlier functional studies. Water molecules located inside β-barrel of Wzi crystal structure further strengthens the role of Wzi in osmoregulation. Thus, interrupting water diffusion or L5 insertion may reduce bacterial virulence. PMID:27320406

  7. Neural mechanisms involved in the comprehension of metaphoric and literal sentences: an fMRI study.

    PubMed

    Shibata, Midori; Abe, Jun-Ichi; Terao, Atsushi; Miyamoto, Tamaki

    2007-08-29

    In this study, we investigated the neural substrate involved in the comprehension of novel metaphoric sentences by comparing the findings to those obtained with literal and anomalous sentences using event-related functional magnetic resonance imaging (fMRI). Stimuli consisted of 63 copula sentences ("An A is a B") in Japanese with metaphorical, literal, or anomalous meanings. Thirteen normal participants read these sentences silently and responded as to whether or not they could understand the meaning of each sentence. When participants read metaphoric sentences in contrast to literal sentences, higher activation was seen in the left medial frontal cortex (MeFC: Brodmann's area (BA) 9/10), the left superior frontal cortex (SFC: BA 9), and the left inferior frontal cortex (IFC: BA 45). The opposite contrast (literal sentences in contrast to metaphoric sentences) gave higher activation in the precuneus (BA 7) and the right middle and SFC (BA 8/9). These findings suggest that metaphor comprehension is involved in specific neural mechanisms of semantic and pragmatic processing which differ from those in literal comprehension. Especially, our results suggest that activation in the left IFC reflects the semantic processing and that activation in the MeFC reflects the process of inference for metaphorical interpretation to establish semantic coherence.

  8. Depletion of bovine pituitary prolactin by cysteamine involves a thiol:disulfide mechanism

    SciTech Connect

    Lorenson, M.Y.; Jacobs, L.S.

    1984-10-01

    Cysteamine (2-aminoethanethiol (CySH)) reduces measurable PRL concentrations in vivo and in vitro. Since secretion is also inhibited, CySH may block conversion from a poorly assayable hormone storage form(s) to readily assayable, releasable PRL. This would represent a previously unrecognized mechanism for secretory regulation. We undertook the present study to identify the sites involved in the loss of measurable PRL (depletion) induced by cysteamine. The disulfide cystamine was ineffective on secretory granules unless combined with reduced glutathione, indicating the generation of the active CySH-thiol form. Pretreatment of granules with thiol-blocking agents resulted in dose-dependent enhancement of CySH inhibition, achieving nearly complete inhibition with 5 mM iodoacetamide. In contrast, pretreatment with reduced glutathione or dithiothreitol, respectively, impaired or abolished the CySH effect. These data suggest that the mechanism by which CySH causes PRL depletion is mediated by granule disulfides and the -SH of CySH. The regulation of thiol:disulfide equilibria appears to be an important determinant of the detectability of PRL storage forms and of their secretion.

  9. Exploring the temporal mechanism involved in the pitch of unresolved harmonics.

    PubMed

    Kaernbach, C; Bering, C

    2001-08-01

    This paper continues a line of research initiated by Kaernbach and Demany [J. Acoust. Soc. Am. 104, 2298-2306 (1998)], who employed filtered click sequences to explore the temporal mechanism involved in the pitch of unresolved harmonics. In a first experiment, the just noticeable difference (jnd) for the fundamental frequency (F0) of high-pass filtered and low-pass masked click trains was measured, with F0 (100 to 250 Hz) and the cut frequency (0.5 to 6 kHz) being varied orthogonally. The data confirm the result of Houtsma and Smurzynski [J. Acoust. Soc. Am. 87, 304-310 (1990)] that a pitch mechanism working on the temporal structure of the signal is responsible for analyzing frequencies higher than ten times the fundamental. Using high-pass filtered click trains, however, the jnd for the temporal analysis is at 1.2% as compared to 2%-3% found in studies using band-pass filtered stimuli. Two further experiments provide evidence that the pitch of this stimulus can convey musical information. A fourth experiment replicates the finding of Kaernbach and Demany on first- and second-order regularities with a cut frequency of 2 kHz and extends the paradigm to binaural aperiodic click sequences. The result suggests that listeners can detect first-order temporal regularities in monaural click streams as well as in binaurally fused click streams.

  10. Anti-inflammatory effect of certain dihydroxy flavones and the mechanisms involved.

    PubMed

    Vidyalakshmi, K; Kamalakannan, P; Viswanathan, S; Ramaswamy, S

    2012-01-01

    This study was designed to evaluate the anti-inflammatory action of four dihydroxy flavone derivatives; 3,3'- dihydroxy flavone, 5,6-dihydroxy flavone, 3,7-dihydroxy flavone and 6,3'-dihydroxy flavone and to further investigate the multiple cellular mechanisms underlying the anti-inflammatory effect of these compounds. The effect of dihydroxy flavones on acute inflammation was studied in rats employing carrageenan induced hind paw edema method. Further, the role of proinflammatory cytokines like TNF-α and IL-1β, cyclooxygenases (COX-1 and COX-2), and free radicals in the action of flavone derivatives was investigated using in vitro assays. All the four dihydroxy flavone derivatives exhibited time and dose dependent inhibition of carrageenan induced paw edema. In addition, the investigated compounds inhibited both the isoforms of cyclooxygenase and cytokines in a concentration dependent manner and also suppressed the release of reactive oxygen species. The anti-inflammatory effect of dihydroxy flavones may be through mechanisms that involve an interaction with cyclooxygenases, cytokines and reactive oxygen species.

  11. Bovine glycomacropeptide ameliorates experimental rat ileitis by mechanisms involving downregulation of interleukin 17

    PubMed Central

    Requena, P; Daddaoua, A; Martínez-Plata, E; González, M; Zarzuelo, A; Suárez, M D; Sánchez de Medina, F; Martínez-Augustin, O

    2008-01-01

    Background and purpose: Bovine glycomacropeptide (BGMP) is an inexpensive, non-toxic milk peptide with anti-inflammatory effects in rat experimental colitis but its mechanism of action is unclear. It is also unknown whether BGMP can ameliorate inflammation in proximal regions of the intestine. Our aim was therefore two-fold: first, to determine the anti-inflammatory activity of BGMP in the ileum; second, to characterise its mechanism of action. Experimental approach: We used a model of ileitis induced by trinitrobenzenesulphonic acid in rats. Rats were treated orally with BGMP and its efficacy compared with that of oral 5-aminosalicylic acid or vehicle, starting 2 days before ileitis induction. Key results: BGMP pretreatment (500 mg kg−1 day−1) resulted in marked reduction of inflammatory injury, as assessed by lower extension of necrosis and damage score, myeloperoxidase, alkaline phosphatase, inducible nitric oxide synthase, interleukin 1β, tumour necrosis factor and interleukin 17. These effects were generally comparable to those of 5-aminosalicylic acid (200 mg kg−1 day−1). Neither compound affected the production of interferon γ, tumour necrosis factor and interleukin 2 by mesenteric lymph node cells isolated from animals with ileitis. The expression of Foxp3 was increased in ileitis and not reduced significantly by BGMP or aminosalicylate treatment. Conclusions and implications: These results demonstrate that BGMP has anti-inflammatory activity in the ileum with similar efficacy to 5-aminosalicylic acid. The mechanism of action may involve Th17 and regulatory T cells and perhaps macrophages but probably not Th1 lymphocytes. Patients with Crohn's ileitis may benefit from treatment with BGMP. PMID:18536735

  12. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.

    PubMed

    Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

    2012-12-05

    Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.

  13. Crosstalk of Signaling Mechanisms Involved in Host Defense and Symbiosis Against Microorganisms in Rice

    PubMed Central

    Akamatsu, Akira; Shimamoto, Ko; Kawano, Yoji

    2016-01-01

    Rice is one of the most important food crops, feeding about half population in the world. Rice pathogens cause enormous damage to rice production worldwide. In plant immunity research, considerable progress has recently been made in our understanding of the molecular mechanisms underlying microbe-associated molecular pattern (MAMP)-triggered immunity. Using genome sequencing and molecular techniques, a number of new MAMPs and their receptors have been identified in the past two decades. Notably, the mechanisms for chitin perception via the lysine motif (LysM) domain-containing receptor OsCERK1, as well as the mechanisms for bacterial MAMP (e.g. flg22, elf18) perception via the leucine-rich repeat (LRR) domain-containing receptors FLS2 and EFR, have been clarified in rice and Arabidopsis, respectively. In chitin signaling in rice, two direct substrates of OsCERK1, Rac/ROP GTPase guanine nucleotide exchange factor OsRacGEF1 and receptor-like cytoplasmic kinase OsRLCK185, have been identified as components of the OsCERK1 complex and are rapidly phosphorylated by OsCERK1 in response to chitin. Interestingly, OsCERK1 also participates in symbiosis with arbuscular mycorrhizal fungi (AMF) in rice and plays a role in the recognition of short-chitin molecules (CO4/5), which are symbiotic signatures included in AMF germinated spore exudates and induced by synthetic strigolactone. Thus, OsCERK1 contributes to both immunity and symbiotic responses. In this review, we describe recent studies on pathways involved in rice immunity and symbiotic signaling triggered by interactions with microorganisms. In addition, we describe recent advances in genetic engineering by using plant immune receptors and symbiotic microorganisms to enhance disease resistance of rice. PMID:27499679

  14. Memantine, a Low-Affinity NMDA Receptor Antagonist, Protects against Methylmercury-Induced Cytotoxicity of Rat Primary Cultured Cortical Neurons, Involvement of Ca(2+) Dyshomeostasis Antagonism, and Indirect Antioxidation Effects.

    PubMed

    Liu, Wei; Xu, Zhaofa; Yang, Tianyao; Xu, Bin; Deng, Yu; Feng, Shu

    2017-09-01

    Methylmercury (MeHg) is an extremely dangerous environmental pollutant that induces severe toxic effects in the central nervous system. Neuronal damage plays critical roles mediating MeHg-induced loss of brain function and neurotoxicity. The molecular mechanisms of MeHg neurotoxicity are incompletely understood. The objective of the study is to explore mechanisms that contribute to MeHg-induced neurocyte injuries focusing on neuronal Ca(2+) dyshomeostasis and alteration of N-methyl-D-aspartate receptors (NMDARs) expression, as well as oxidative stress in primary cultured cortical neurons. In addition, the neuroprotective effects of memantine against MeHg cytotoxicity were also investigated. The cortical neurons were exposed to 0, 0.01, 0.1, 1, or 2 μM methylmercury chloride (MeHgCl) for 0.5-12 h, or pre-treated with 2.5, 5, 10, or 20 μM memantine for 0.5-6 h, respectively; cell viability and LDH release were then quantified. For further experiments, 2.5, 5, and 10 μM of memantine pre-treatment for 3 h followed by 1 μM MeHgCl for 6 h were performed for evaluation of neuronal injuries, specifically addressing apoptosis; intracellular free Ca(2+) concentrations; ATPase activities; calpain activities; expressions of NMDAR subunits (NR1, NR2A, NR2B); NPSH levels; and ROS formation. Exposure of MeHgCl resulted in toxicity of cortical neurons, which were shown as a loss of cell viability, high levels of LDH release, morphological changes, and cell apoptosis. Moreover, intracellular Ca(2+) dyshomeostasis, ATPase activities inhibition, calpain activities, and NMDARs expression alteration were observed with 1 μM MeHgCl administration. Last but not least, NPSH depletion and reactive oxygen species (ROS) overproduction showed an obvious oxidative stress in neurons. However, memantine pre-treatment dose-dependently antagonized MeHg-induced neuronal toxic effects, apoptosis, Ca(2+) dyshomeostasis, NMDARs expression alteration, and oxidative stress. In conclusion

  15. Epidemiological and genetic clues for molecular mechanisms involved in uterine leiomyoma development and growth

    PubMed Central

    Commandeur, Arno E.; Styer, Aaron K.; Teixeira, Jose M.

    2015-01-01

    BACKGROUND Uterine leiomyomas (fibroids) are highly prevalent benign smooth muscle tumors of the uterus. In the USA, the lifetime risk for women developing uterine leiomyomas is estimated as up to 75%. Except for hysterectomy, most therapies or treatments often provide only partial or temporary relief and are not successful in every patient. There is a clear racial disparity in the disease; African-American women are estimated to be three times more likely to develop uterine leiomyomas and generally develop more severe symptoms. There is also familial clustering between first-degree relatives and twins, and multiple inherited syndromes in which fibroid development occurs. Leiomyomas have been described as clonal and hormonally regulated, but despite the healthcare burden imposed by the disease, the etiology of uterine leiomyomas remains largely unknown. The mechanisms involved in their growth are also essentially unknown, which has contributed to the slow progress in development of effective treatment options. METHODS A comprehensive PubMed search for and critical assessment of articles related to the epidemiological, biological and genetic clues for uterine leiomyoma development was performed. The individual functions of some of the best candidate genes are explained to provide more insight into their biological function and to interconnect and organize genes and pathways in one overarching figure that represents the current state of knowledge about uterine leiomyoma development and growth. RESULTS In this review, the widely recognized roles of estrogen and progesterone in uterine leiomyoma pathobiology on the basis of clinical and experimental data are presented. This is followed by fundamental aspects and concepts including the possible cellular origin of uterine fibroids. The central themes in the subsequent parts are cytogenetic aberrations in leiomyomas and the racial/ethnic disparities in uterine fibroid biology. Then, the attributes of various in vitro and

  16. Insights into reference point indentation involving human cortical bone: sensitivity to tissue anisotropy and mechanical behavior.

    PubMed

    Granke, Mathilde; Coulmier, Aurélie; Uppuganti, Sasidhar; Gaddy, Jennifer A; Does, Mark D; Nyman, Jeffry S

    2014-09-01

    Reference point indentation (RPI) is a microindentation technique involving 20 cycles of loading in "force-control" that can directly assess a patient׳s bone tissue properties. Even though preliminary clinical studies indicate a capability for fracture discrimination, little is known about what mechanical behavior the various RPI properties characterize and how these properties relate to traditional mechanical properties of bone. To address this, the present study investigated the sensitivity of RPI properties to anatomical location and tissue organization as well as examined to what extent RPI measurements explain the intrinsic mechanical properties of human cortical bone. Multiple indents with a target force of 10N were done in 2 orthogonal directions (longitudinal and transverse) per quadrant (anterior, medial, posterior, and lateral) of the femoral mid-shaft acquired from 26 donors (25-101 years old). Additional RPI measurements were acquired for 3 orthogonal directions (medial only). Independent of age, most RPI properties did not vary among these locations, but they did exhibit transverse isotropy such that resistance to indentation is greater in the longitudinal (axial) direction than in the transverse direction (radial or circumferential). Next, beam specimens (~2mm×5mm×40mm) were extracted from the medial cortex of femoral mid-shafts, acquired from 34 donors (21-99 years old). After monotonically loading the specimens in three-point bending to failure, RPI properties were acquired from an adjacent region outside the span. Indent direction was orthogonal to the bending axis. A significant inverse relationship was found between resistance to indentation and the apparent-level mechanical properties. Indentation distance increase (IDI) and a linear combination of IDI and the loading slope, averaged over cycles 3 through 20, provided the best explanation of the variance in ultimate stress (r(2)=0.25, p=0.003) and toughness (r(2)=0.35, p=0.004), respectively

  17. Zuclopenthixol facilitates memory retrieval in rats: possible involvement of noradrenergic and serotonergic mechanisms.

    PubMed

    Khalifa, Amani E

    2003-07-01

    Although disturbed memory function often coexists with psychosis, the cognitive effects of antipsychotic medications with diverse pharmacodynamic properties are rarely investigated. The neurocognitive profile of zuclopenthixol, a thioxanthene dopaminergic antagonist and a conventional neuroleptic agent, has yet to be investigated despite the effect of the drug on a variety of neurotransmitter systems involved in mediation of learning and memory processes. In this study, the effect of zuclopenthixol was tested on memory retrieval 24 h after training using an inhibitory avoidance task in rats. Acute administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) before retrieval testing increased step-through latency during the test session. The same doses of zuclopenthixol did not affect the ambulatory activity of rats in the openfield test and therefore the facilitatory effect of the drug on memory function could not be confounded with any motoric properties. This study also investigated the effect of zuclopenthixol on cortical and hippocampal monoaminergic neurotransmitters' levels together with acetylcholinesterase enzyme (AChE) activity, both of which are known to be important in control of cognitive function. Administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) neither affected dopamine (DA) level nor AChE activity in rat cortex and hippocampus. On the other hand, the lower dose of zuclopenthixol elevated cortical norepinephrine (NE) level, while the higher dose elevated both cortical and hippocampal NE level together with hippocampal serotonin (5-HT) level. These results may suggest the involvement of adrenergic and serotonergic mechanisms in the facilitatory effect of zuclopenthixol on retrieval memory. Zuclopenthixol may therefore be a better alternative than other commonly used antipsychotic medications reported to impair cognitive function of schizophrenic patients.

  18. Molecular Mechanisms Involved in the Interaction Effects of Alcohol and Hepatitis C Virus in Liver Cirrhosis

    PubMed Central

    Mas, Valeria R; Fassnacht, Ryan; Archer, Kellie J; Maluf, Daniel

    2010-01-01

    The mechanisms by which alcohol consumption accelerates liver disease in patients with chronic hepatitis C virus (HCV) are not well understood. To identify the characteristics of molecular pathways affected by alcohol in HCV patients, we fit probe-set level linear models that included the additive effects as well as the interaction between alcohol and HCV. The study included liver tissue samples from 78 patients, 23 (29.5%) with HCV-cirrhosis, 13 (16.7%) with alcohol-cirrhosis, 23 (29.5%) with HCV/alcohol cirrhosis and 19 (24.4%) with no liver disease (no HCV/no alcohol group). We performed gene-expression profiling by using microarrays. Probe-set expression summaries were calculated by using the robust multiarray average. Probe-set level linear models were fit where probe-set expression was modeled by HCV status, alcohol status, and the interaction between HCV and alcohol. We found that 2172 probe sets (1895 genes) were differentially expressed between HCV cirrhosis versus alcoholic cirrhosis groups. Genes involved in the virus response and the immune response were the more important upregulated genes in HCV cirrhosis. Genes involved in apoptosis regulation were also overexpressed in HCV cirrhosis. Genes of the cytochrome P450 superfamily of enzymes were upregulated in alcoholic cirrhosis, and 1230 probe sets (1051 genes) had a significant interaction estimate. Cell death and cellular growth and proliferation were affected by the interaction between HCV and alcohol. Immune response and response to the virus genes were downregulated in HCV-alcohol interaction (interaction term alcohol*HCV). Alcohol*HCV in the cirrhotic tissues resulted in a strong negative regulation of the apoptosis pattern with concomitant positive regulation of cellular division and proliferation. PMID:20386865

  19. Development of neurodevelopmental disorders: a regulatory mechanism involving bromodomain-containing proteins.

    PubMed

    Li, Junlin; Zhao, Guifang; Gao, Xiaocai

    2013-02-20

    Neurodevelopmental disorders are classified as diseases that cause abnormal functions of the brain or central nervous system. Children with neurodevelopmental disorders show impaired language and speech abilities, learning and memory damage, and poor motor skills. However, we still know very little about the molecular etiology of these disorders. Recent evidence implicates the bromodomain-containing proteins (BCPs) in the initiation and development of neurodevelopmental disorders. BCPs have a particular domain, the bromodomain (Brd), which was originally identified as specifically binding acetyl-lysine residues at the N-terminus of histone proteins in vitro and in vivo. Other domains of BCPs are responsible for binding partner proteins to form regulatory complexes. Once these complexes are assembled, BCPs alter chromosomal states and regulate gene expression. Some BCP complexes bind nucleosomes, are involved in basal transcription regulation, and influence the transcription of many genes. However, most BCPs are involved in targeting. For example, some BCPs function as a recruitment platform or scaffold through their Brds-binding targeting sites. Others are recruited to form a complex to bind the targeting sites of their partners. The regulation mediated by these proteins is especially critical during normal and abnormal development. Mutant BCPs or dysfunctional BCP-containing complexes are implicated in the initiation and development of neurodevelopmental disorders. However, the pathogenic molecular mechanisms are not fully understood. In this review, we focus on the roles of regulatory BCPs associated with neurodevelopmental disorders, including mental retardation, Fragile X syndrome (FRX), Williams syndrome (WS), Rett syndrome and Rubinstein-Taybi syndrome (RTS). A better understanding of the molecular pathogenesis, based upon the roles of BCPs, will lead to screening of targets for the treatment of neurodevelopmental disorders.

  20. Lysine 2,3-aminomutase. Support for a mechanism of hydrogen transfer involving S-adenosylmethionine.

    PubMed

    Baraniak, J; Moss, M L; Frey, P A

    1989-01-25

    The conversion of L-lysine to L-beta-lysine is catalyzed by lysine 2,3-aminomutase. The reaction involves the interchange of the 2-amino group of lysine with a hydrogen at carbon 3. As such the reaction is formally analogous to adenosylcobalamin-dependent rearrangements. However, the enzyme does not contain and is not activated by this coenzyme. Instead it contains iron and pyridoxal phosphate and is activated by S-adenosylmethionine. Earlier experiments implicated adenosyl-C-5' of S-adenosylmethionine in the hydrogen transfer mechanism, apparently in a role similar or analogous to that of adenosyl moiety of adenosylcobalamin in the B12-dependent rearrangements. The question of whether both hydrogens or only one hydrogen at adenosyl-C-5' participate in the hydrogen-transfer process has been addressed by carrying out the lysine 2,3-aminomutase reaction with S-[5'-3H] adenosylmethionine in the presence of 10 times its molar concentration of enzyme. Under these conditions all of the tritium appeared in lysine and beta-lysine, showing that C-5'-hydrogens participate. To determine whether hydrogen transfer is compulsorily intermolecular and intramolecular, various molar ratios of [3,3-2H2]lysine and unlabeled lysine were submitted to the action of lysine 2,3-aminomutase under conditions in which 10-15% conversion to beta-lysine occurred. Mass spectral analysis of the beta-lysine for monodeutero and dideutero species showed conclusively that hydrogen transfer is both intramolecular and intermolecular. The results quantitatively support our postulate that activation of the enzyme involves a transformation of S-adenosylmethionine into a form that promotes the generation of an adenosyl-5' free radical, which abstracts hydrogen from lysine to form 5'-deoxyadenosine as an intermediate.

  1. Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease

    PubMed Central

    Wang, Zhigang; Yao, Tong; Song, Zhenyuan

    2010-01-01

    The mechanisms involved in the development of alcoholic liver disease (ALD) are not well established. We investigated the involvement of acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) upregulation in mediating hepatic fat accumulation induced by chronic alcohol consumption. Chronic alcohol feeding caused fatty liver and increased hepatic DGAT2 gene and protein expression, concomitant with a significant suppression of hepatic MAPK/ERK kinase/extracellular regulated kinase 1/2 (MEK/ERK1/2) activation. In vitro studies demonstrated that specific inhibitors of the MEK/ERK1/2 pathway increased DGAT2 gene expression and triglyceride (TG) contents in HepG2 cells, whereas epidermal growth factor, a strong ERK1/2 activator, had the opposite effect. Moreover, chronic alcohol feeding decreased hepatic S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio, an indicator of disrupted transmethylation reactions. Mechanistic investigations revealed that N-acetyl-S-farnesyl-l-cysteine, a potent inhibitor of isoprenylcysteine carboxyl methyltransferase, suppressed ERK1/2 activation, followed by an enhanced DGAT2 expression and an elevated TG content in HepG2 cells. Lastly, we demonstrated that the beneficial effects of betaine supplementation in ALD were associated with improved SAM/SAH ratio, alleviated ERK1/2 inhibition, and attenuated DGAT2 upregulation. In conclusion, our data suggest that upregulation of DGAT2 plays an important role in the pathogenesis of ALD, and that abnormal methionine metabolism contributes, at least partially, to DGAT2 upregulation via suppression of MEK/ERK1/2 activation. PMID:20739640

  2. Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease.

    PubMed

    Wang, Zhigang; Yao, Tong; Song, Zhenyuan

    2010-11-01

    The mechanisms involved in the development of alcoholic liver disease (ALD) are not well established. We investigated the involvement of acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) upregulation in mediating hepatic fat accumulation induced by chronic alcohol consumption. Chronic alcohol feeding caused fatty liver and increased hepatic DGAT2 gene and protein expression, concomitant with a significant suppression of hepatic MAPK/ERK kinase/extracellular regulated kinase 1/2 (MEK/ERK1/2) activation. In vitro studies demonstrated that specific inhibitors of the MEK/ERK1/2 pathway increased DGAT2 gene expression and triglyceride (TG) contents in HepG2 cells, whereas epidermal growth factor, a strong ERK1/2 activator, had the opposite effect. Moreover, chronic alcohol feeding decreased hepatic S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio, an indicator of disrupted transmethylation reactions. Mechanistic investigations revealed that N-acetyl-S-farnesyl-L-cysteine, a potent inhibitor of isoprenylcysteine carboxyl methyltransferase, suppressed ERK1/2 activation, followed by an enhanced DGAT2 expression and an elevated TG content in HepG2 cells. Lastly, we demonstrated that the beneficial effects of betaine supplementation in ALD were associated with improved SAM/SAH ratio, alleviated ERK1/2 inhibition, and attenuated DGAT2 upregulation. In conclusion, our data suggest that upregulation of DGAT2 plays an important role in the pathogenesis of ALD, and that abnormal methionine metabolism contributes, at least partially, to DGAT2 upregulation via suppression of MEK/ERK1/2 activation.

  3. Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms

    PubMed Central

    Srinivasan, Padmanabhan; Kapadia, Rubina; Biswas, Arundhati

    2014-01-01

    Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5′-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na+ dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms. PMID:25214397

  4. Toxic effects of expanded ataxin-1 involve mechanical instability of the nuclear membrane.

    PubMed

    Mapelli, Lisa; Canale, Claudio; Pesci, Daniela; Averaimo, Stefania; Guizzardi, Fabiana; Fortunati, Valentina; Falasca, Laura; Piacentini, Mauro; Gliozzi, Alessandra; Relini, Annalisa; Mazzanti, Michele; Jodice, Carla

    2012-06-01

    Ataxin 1 (ATXN1) is the protein involved in spinocerebellar ataxia type 1, one of nine dominantly inherited neurodegenerative diseases triggered by polyglutamine expansion. One of the isolated polyglutamine tracts properties is to interact with lipid bilayers. Here we used a multidisciplinary approach to test whether one of the mechanisms responsible for neuronal degeneration involves the destabilization of the nuclear membrane. We thus analyzed the interaction between ATXN1 and lipid membranes, both on cellular models and on artificial lipid bilayers, comparing pathological expanded polyglutamine and histidine interrupted non-harmful polyglutamine tracts of the same length. The toxicity of the different constructs was tested in transiently transfected COS1 cells. Cells expressing pathological ATXN1 presented a significantly higher frequency of anomalous nuclei with respect to those expressing non-harmful ATXN1. Immunofluorescence and electron microscopy showed severe damage in the nuclear membrane of cells expressing the pathological protein. Atomic force microscopy on artificial membranes containing interrupted and non-interrupted partial ATXN1 peptides revealed a different arrangement of the peptides within the lipid bilayer. Force-distance measurements indicated that membrane fragility increases with the lengthening of the uninterrupted glutamine. Transmembrane electrical measurements were performed on artificial bilayers and on the inner nuclear membrane of ATXN1 full length transfected cells. Both artificial lipid bilayers and cellular models demonstrated the dynamic appearance of ionic pathways. Uninterrupted polyglutamines showed not only a larger ionic flow, but also an increase in the single event conductance. Collectively, our results suggest that expanded ATXN1 may induce unregulated ionic pathways in the nuclear membrane, causing severe damage to the cell.

  5. Development of neurodevelopmental disorders: a regulatory mechanism involving bromodomain-containing proteins

    PubMed Central

    2013-01-01

    Neurodevelopmental disorders are classified as diseases that cause abnormal functions of the brain or central nervous system. Children with neurodevelopmental disorders show impaired language and speech abilities, learning and memory damage, and poor motor skills. However, we still know very little about the molecular etiology of these disorders. Recent evidence implicates the bromodomain-containing proteins (BCPs) in the initiation and development of neurodevelopmental disorders. BCPs have a particular domain, the bromodomain (Brd), which was originally identified as specifically binding acetyl-lysine residues at the N-terminus of histone proteins in vitro and in vivo. Other domains of BCPs are responsible for binding partner proteins to form regulatory complexes. Once these complexes are assembled, BCPs alter chromosomal states and regulate gene expression. Some BCP complexes bind nucleosomes, are involved in basal transcription regulation, and influence the transcription of many genes. However, most BCPs are involved in targeting. For example, some BCPs function as a recruitment platform or scaffold through their Brds-binding targeting sites. Others are recruited to form a complex to bind the targeting sites of their partners. The regulation mediated by these proteins is especially critical during normal and abnormal development. Mutant BCPs or dysfunctional BCP-containing complexes are implicated in the initiation and development of neurodevelopmental disorders. However, the pathogenic molecular mechanisms are not fully understood. In this review, we focus on the roles of regulatory BCPs associated with neurodevelopmental disorders, including mental retardation, Fragile X syndrome (FRX), Williams syndrome (WS), Rett syndrome and Rubinstein-Taybi syndrome (RTS). A better understanding of the molecular pathogenesis, based upon the roles of BCPs, will lead to screening of targets for the treatment of neurodevelopmental disorders. PMID:23425632

  6. Distinct cognitive mechanisms involved in the processing of single objects and object ensembles

    PubMed Central

    Cant, Jonathan S.; Sun, Sol Z.; Xu, Yaoda

    2015-01-01

    Behavioral research has demonstrated that the shape and texture of single objects can be processed independently. Similarly, neuroimaging results have shown that an object's shape and texture are processed in distinct brain regions with shape in the lateral occipital area and texture in parahippocampal cortex. Meanwhile, objects are not always seen in isolation and are often grouped together as an ensemble. We recently showed that the processing of ensembles also involves parahippocampal cortex and that the shape and texture of ensemble elements are processed together within this region. These neural data suggest that the independence seen between shape and texture in single-object perception would not be observed in object-ensemble perception. Here we tested this prediction by examining whether observers could attend to the shape of ensemble elements while ignoring changes in an unattended texture feature and vice versa. Across six behavioral experiments, we replicated previous findings of independence between shape and texture in single-object perception. In contrast, we observed that changes in an unattended ensemble feature negatively impacted the processing of an attended ensemble feature only when ensemble features were attended globally. When they were attended locally, thereby making ensemble processing similar to single-object processing, interference was abolished. Overall, these findings confirm previous neuroimaging results and suggest that distinct cognitive mechanisms may be involved in single-object and object-ensemble perception. Additionally, they show that the scope of visual attention plays a critical role in determining which type of object processing (ensemble or single object) is engaged by the visual system. PMID:26360156

  7. Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms.

    PubMed

    Srinivasan, Padmanabhan; Kapadia, Rubina; Biswas, Arundhati; Said, Hamid M

    2014-11-01

    Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5'-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na(+) dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms. Copyright © 2014 the American Physiological Society.

  8. Two Mechanisms Involved in Trigeminal CGRP Release: Implications for Migraine Treatment

    PubMed Central

    Durham, Paul L.; Masterson, Caleb G.

    2012-01-01

    Objective The goal of this study was to better understand the cellular mechanisms involved in proton stimulation of calcitonin gene-related peptide (CGRP) secretion from cultured trigeminal neurons by investigating the effects of two anti-migraine therapies, onabotulinumtoxin A and rizatriptan. Background Stimulated CGRP release from peripheral and central terminating processes of trigeminal ganglia neurons is implicated in migraine pathology by promoting inflammation and nociception. Based on models of migraine pathology, several inflammatory molecules including protons are thought to facilitate sensitization and activation of trigeminal nociceptive neurons and stimulate CGRP secretion. Despite the reported efficacy of triptans and onabotulinumtoxinA to treat acute and chronic migraine, respectively, a substantial number of migraneurs do not get adequate relief with these therapies. A possible explanation is that triptans and onabutulinumtoxinA are not able to block proton mediated CGRP secretion. Methods CGRP secretion from cultured primary trigeminal ganglia neurons was quantitated by radioimmunoassay while intracellular calcium and sodium levels were measured in neurons via live cell imaging using Fura2-AM and SBFI-AM, respectively. The expression of ASIC3 was determined by immunocytochemistry and western blot analysis. In addition, the involvement of ASICs in mediating proton stimulation of CGRP was investigated using the potent and selective ASIC3 inhibitor APETx2. Results While KCl caused a significant increase in CGRP secretion that was significantly repressed by treatment with EGTA, onabotulinumtoxinA, and rizatriptan, the stimulatory effect of protons (pH 5.5) was not suppressed by EGTA, onabotulinumtoxinA, or rizatriptan. In addition, while KCl caused a transient increase in intracellular calcium levels that was blocked by EGTA, no appreciable change in calcium levels was observed with proton treatment. However, protons did significantly increase the

  9. Targeting GLI by GANT61 involves mechanisms dependent on inhibition of both transcription and DNA licensing

    PubMed Central

    Zhang, Ruowen; Wu, Jiahui; Ferrandon, Sylvain; Glowacki, Katie J.; Houghton, Janet A.

    2016-01-01

    The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter. Pretreatment of HT29 cells with α-amanitin reduced GANT61-induced γH2AX foci. Co-localization of GLI1 and BrdU foci, inhibited by GANT61, indicated GLI1 and DNA replication to be linked. By co-immunoprecipitation and confocal microscopy, GLI1 co-localized with the DNA licensing factors ORC4, CDT1, and MCM2. Significant co-localization of GLI1 and ORC4 was inhibited by GANT61, and enrichment of ORC4 occurred at the GLI binding site in the FOXM1 promoter. CDT1 was found to be a transcription target of GLI1. Overexpression of CDT1 in HT29 and SW480 cells reduced GANT61-induced cell death, gH2AX foci, and cleavage of caspase-3. Data demonstrate involvement of transcription and of DNA replication licensing factors by non-transcriptional and transcriptional mechanisms in the GLI-dependent mechanism of action of GANT61. PMID:27863397

  10. The involvement and possible mechanism of NR4A1 in chondrocyte apoptosis during osteoarthritis

    PubMed Central

    Shi, Xinge; Ye, Hui; Yao, Xuedong; Gao, Yanzheng

    2017-01-01

    Osteoarthritis (OA) is a joint disease caused by the breakdown of joint cartilage and underlying bone, and places great burdens to daily life of patients. Nuclear orphan receptor nuclear receptor subfamily 4, group A, member 1 (NR4A1) is vital for cell apoptosis, but little is known about its role in OA. This study aims to reveal the expression and function of NR4A1 during OA chondrocyte apoptosis. NR4A1 expression by qRT-PCR and western blot, and chondrocyte apoptosis by TUNEL assay were detected in normal and OA joint cartilage. NR4A1 was located in cartilage sections by immunohistofluorescence. Chondrocytes from normal joint cartilage were cultured in vitro for interleukin 6 (IL6) or tumor necrosis factor (TNF) treatment and si-NR4A1 transfection, after which the possible mechanism involving NR4A1 was analyzed. Results showed that NR4A1 expression and chondrocyte apoptosis were significantly elevated in OA cartilage (P < 0.05 and P < 0.01). NR4A1 was located in nuclei of normal cartilage chondrocytes, but was translocated to mitochondria and co-located with B-cell lymphoma 2 in OA chondrocytes. NR4A1 expression in cultured chondrocytes could be promoted by both IL6 and TNF treatment. si-NR4A1 partly reduced TNF-induced cell apoptosis. Inhibiting p38 by SB203580 could decrease TNF-induced NR4A1 to some extent, while inhibiting JNK could not. So NR4A1 is likely to facilitate OA chondrocyte apoptosis, which is associated with p38 MAPK and mitochondrial apoptosis pathway. This study provides a potential therapeutic target for OA treatment and offers information for regulatory mechanisms in OA. PMID:28337303

  11. Neural Correlates of Successful and Unsuccessful Strategical Mechanisms Involved in Uncertain Decision-Making.

    PubMed

    Giustiniani, Julie; Gabriel, Damien; Nicolier, Magali; Monnin, Julie; Haffen, Emmanuel

    2015-01-01

    The ability to develop successful long-term strategies in uncertain situations relies on complex neural mechanisms. Although lesion studies have shown some of the mechanisms involved, it is still unknown why some healthy subjects are able to make the right decision whereas others are not. The aim of our study was to investigate neurophysiological differences underlying this ability to develop a successful strategy in a group of healthy subjects playing a monetary card game called the Iowa Gambling Task (IGT). In this task, subjects have to win and earn money by choosing between four decks of cards, two were advantageous in the long term and two disadvantageous. Twenty healthy right-handed subjects performed the IGT while their cerebral activity was recorded by electroencephalography. Based on their behavioral performances, two groups of subjects could clearly be distinguished: one who selected the good decks and thus succeeded in developing a Favorable strategy (9 subjects) and one who remained Undecided (11 subjects). No neural difference was found between each group before the selection of a deck, but in both groups a greater negativity was found emerging from the right superior frontal gyrus 600 ms before a disadvantageous selection. During the processing of the feedback, an attenuation of the P200 and P300 waveforms was found for the Undecided group, and a P300 originating from the medial frontal gyrus was found in response to a loss only in the Favorable group. Our results suggest that undecided subjects are hyposensitive to the valence of the cards during gambling, which affects the feedback processing.

  12. Neural Correlates of Successful and Unsuccessful Strategical Mechanisms Involved in Uncertain Decision-Making

    PubMed Central

    Giustiniani, Julie; Gabriel, Damien; Nicolier, Magali; Monnin, Julie; Haffen, Emmanuel

    2015-01-01

    The ability to develop successful long-term strategies in uncertain situations relies on complex neural mechanisms. Although lesion studies have shown some of the mechanisms involved, it is still unknown why some healthy subjects are able to make the right decision whereas others are not. The aim of our study was to investigate neurophysiological differences underlying this ability to develop a successful strategy in a group of healthy subjects playing a monetary card game called the Iowa Gambling Task (IGT). In this task, subjects have to win and earn money by choosing between four decks of cards, two were advantageous in the long term and two disadvantageous. Twenty healthy right-handed subjects performed the IGT while their cerebral activity was recorded by electroencephalography. Based on their behavioral performances, two groups of subjects could clearly be distinguished: one who selected the good decks and thus succeeded in developing a Favorable strategy (9 subjects) and one who remained Undecided (11 subjects). No neural difference was found between each group before the selection of a deck, but in both groups a greater negativity was found emerging from the right superior frontal gyrus 600 ms before a disadvantageous selection. During the processing of the feedback, an attenuation of the P200 and P300 waveforms was found for the Undecided group, and a P300 originating from the medial frontal gyrus was found in response to a loss only in the Favorable group. Our results suggest that undecided subjects are hyposensitive to the valence of the cards during gambling, which affects the feedback processing. PMID:26086196

  13. Semiquinone Intermediates are involved in the Energy Coupling Mechanism of E. coli Complex I

    PubMed Central

    Narayanan, Madhavan; Leung, Steven A.; Inaba, Yuta; Elguindy, Mahmoud M.; Nakamaru-Ogiso, Eiko

    2015-01-01

    Complex I (NADH:quinone oxidoreductase) is central to cellular aerobic energy metabolism, and its deficiency is involved in many human mitochondrial diseases. Complex I translocates protons across the membrane using electron transfer energy. Semiquinone (SQ) intermediates appearing during catalysis are suggested to be key for the coupling mechanism in complex I. However, the existence of SQ has remained controversial due to the extreme difficulty in detecting unstable and low intensity SQ signals. Here, for the first time with E. coli complex I reconstituted in proteoliposomes, we successfully resolved and characterized three distinct SQ species by EPR. These species include: fast-relaxing SQ (SQNf) with P1/2 (half-saturation power level) > 50 mW and a wider linewidth (12.8 G); slow-relaxing SQ (SQNs) with P1/2 = 2–3 mW and a 10 G linewidth; and very slow-relaxing SQ (SQNvs) with P1/2 = ~ 0.1 mW and a 7.5 G linewidth. The SQNf signals completely disappeared in the presence of the uncoupler gramicidin D or squamotacin, a potent E. coli complex I inhibitor. The pH dependency of the SQNf signals correlated with the proton-pumping activities of complex I. The SQNs signals were insensitive to gramicidin D, but sensitive to squamotacin. The SQNvs signals were insensitive to both gramicidin D and squamotacin. Our deuterium exchange experiments suggested that SQNf is neutral, while SQNs and SQNvs are anion radicals. The SQNs signals were lost in the ΔNuoL mutant missing transporter module subunits NuoL and NuoM. The roles and relationships of the SQ intermediates in the coupling mechanism are discussed. PMID:25868873

  14. Involvement of metabolites in early defense mechanism of oil palm (Elaeis guineensis Jacq.) against Ganoderma disease.

    PubMed

    Nusaibah, S A; Siti Nor Akmar, A; Idris, A S; Sariah, M; Mohamad Pauzi, Z

    2016-12-01

    Understanding the mechanism of interaction between the oil palm and its key pathogen, Ganoderma spp. is crucial as the disease caused by this fungal pathogen leads to a major loss of revenue in leading palm oil producing countries in Southeast Asia. Here in this study, we assess the morphological and biochemical changes in Ganoderma disease infected oil palm seedling roots in both resistant and susceptible progenies. Rubber woodblocks fully colonized by G. boninense were applied as a source of inoculum to artificially infect the roots of resistant and susceptible oil palm progenies. Gas chromatography-mass spectrometry was used to measure an array of plant metabolites in 100 resistant and susceptible oil palm seedling roots treated with pathogenic Ganoderma boninense fungus. Statistical effects, univariate and multivariate analyses were used to identify key-Ganoderma disease associated metabolic agitations in both resistant and susceptible oil palm root tissues. Ganoderma disease related defense shifts were characterized based on (i) increased antifungal activity in crude extracts, (ii) increased lipid levels, beta- and gamma-sitosterol particularly in the resistant progeny, (iii) detection of heterocyclic aromatic organic compounds, benzo [h] quinoline, pyridine, pyrimidine (iv) elevation in antioxidants, alpha- and beta-tocopherol (iv) degraded cortical cell wall layers, possibly resulting from fungal hydrolytic enzyme activity needed for initial penetration. The present study suggested that plant metabolites mainly lipids and heterocyclic aromatic organic metabolites could be potentially involved in early oil palm defense mechanism against G. boninense infection, which may also highlight biomarkers for disease detection, treatment, development of resistant variety and monitoring.

  15. Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

    SciTech Connect

    Wang, Jun; Cao, Hui; Wang, Hongjie; Yin, Guoxiao; Du, Jiao; Xia, Fei; Lu, Jingli; Xiang, Ming

    2015-06-15

    Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation.

  16. Three-way interaction model to trace the mechanisms involved in Alzheimer's disease transgenic mice.

    PubMed

    Khayer, Nasibeh; Marashi, Sayed-Amir; Mirzaie, Mehdi; Goshadrou, Fatemeh

    2017-01-01

    Alzheimer's disease (AD) is the most common cause for dementia in human. Currently, more than 46 million people in the world suffer from AD and it is estimated that by 2050 this number increases to more than 131 million. AD is considered as a complex disease. Therefore, understanding the mechanism of AD is a universal challenge. Nowadays, a huge number of disease-related high-throughput "omics" datasets are freely available. Such datasets contain valuable information about disease-related pathways and their corresponding gene interactions. In the present work, a three-way interaction model is used as a novel approach to understand AD-related mechanisms. This model can trace the dynamic nature of co-expression relationship between two genes by introducing their link to a third gene. Apparently, such relationships cannot be traced by the classical two-way interaction model. Liquid association method was applied to capture the statistically significant triplets which are involved in three-way interaction. Subsequently, gene set enrichment analysis (GSEA) and gene regulatory network (GRN) inference were applied to analyze the biological relevance of the statistically significant triplets. The results of this study suggest that the innate immunity processes are important in AD. Specifically, our results suggest that H2-Ob as the switching gene and the gene pair {Csf1r, Milr1} form a statistically significant and biologically relevant triplet, which may play an important role in AD. We propose that the homeostasis-related link between mast cells and microglia is presumably controlled with H2-Ob expression levels as a switching gene.

  17. The central anorexigenic mechanism of adrenocorticotropic hormone involves the caudal hypothalamus in chicks.

    PubMed

    Shipp, Steven L; Yi, Jiaqing; Dridi, Sami; Gilbert, Elizabeth R; Cline, Mark A

    2015-10-01

    Adrenocorticotropic hormone (ACTH), consisting of 39 amino acids, is most well-known for its involvement in an organism's response to stress. It also participates in satiety, as exogenous ACTH causes decreased food intake in rats. However, its anorexigenic mechanism is not well understood in any species and its effect on appetite is not reported in the avian class. Thus, the present study was designed to evaluate central ACTH's effect on food intake and to elucidate the mechanism mediating this response using broiler chicks. Chicks that received intracerebroventricular (ICV) injection of 1, 2, or 4 nmol of ACTH reduced food intake, under both ad libitum and 180 min fasted conditions. Water intake was also reduced in ACTH-injected chicks under both feeding conditions, but when measured without access to feed it was not affected. Blood glucose was not affected in either feeding condition. Following ACTH injection, c-Fos immunoreactivity was quantified in key appetite-associated hypothalamic nuclei including the ventromedial hypothalamus (VMH), dorsomedial hypothalamus, lateral hypothalamus (LH), arcuate nucleus (ARC) and the parvo- and magno-cellular portions of the paraventricular nucleus. ACTH-injected chicks had increased c-Fos immunoreactivity in the VMH, LH, and ARC. Hypothalamus was collected at 1h post-injection, and real-time PCR performed to measure mRNA abundance of some appetite-associated factors. Neuropeptide Y, pro-opiomelanocortin, glutamate decarboxylase 1, melanocortin receptors 2-5, and urocortin 3 mRNA abundance was not affected by ACTH treatment. However, expression of corticotropin releasing factor (CRF), urotensin 2 (UT), agouti-related peptide (AgRP), and orexin (ORX), and melanocortin receptor 1 (MC1R) mRNA decreased in the hypothalamus of ACTH-injected chicks. In conclusion, ICV ACTH causes decreased food intake in chicks, and is associated with VMH, LH, and ARC activation, and a decrease in hypothalamic mRNA abundance of CRF, UT, AgRP, ORX

  18. Structure and Mechanism of Enzymes Involved in Biosynthesis and Breakdown of the Phosphonates Fosfomycin, Dehydrophos, and Phosphinothricin

    PubMed Central

    Nair, Satish K.; van der Donk, Wilfred A.

    2011-01-01

    Recent years have seen a rapid increase in the mechanistic and structural information on enzymes that are involved in the biosynthesis and breakdown of naturally occurring phosphonates. This review focuses on these recent developments with an emphasis on those enzymes that have been characterized crystallographically in the past five years, including proteins involved in the biosynthesis of phosphinothricin, fosfomycin, and dehydrophos and proteins involved in resistance mechanisms. PMID:20854789

  19. Noradrenergic mechanism involved in the nociceptive modulation of hippocampal CA3 region of normal rats.

    PubMed

    Jin, Hua; Teng, Yueqiu; Zhang, Xuexin; Yang, Chunxiao; Xu, Manying; Yang, Lizhuang

    2014-06-27

    Norepinephrine (NE) is an important neurotransmitter in the brain, and regulates antinociception. However, the mechanism of action of NE on pain-related neurons in the hippocampal CA3 region is not clear. This study examines the effects of NE, phentolamine on the electrical activities of pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal CA3 region of rats. Trains of electric impulses applied to the right sciatic nerve were used as noxious stimulation. The electrical activities of PENs or PINs in the hippocampal CA3 region were recorded by using a glass microelectrode. Our results revealed that, in the hippocampal CA3 region, the intra-CA3 region microinjection of NE decreased the pain-evoked discharged frequency and prolonged the discharged latency of PEN, and increased the pain-evoked discharged frequency and shortened discharged inhibitory duration (ID) of PIN, exhibiting the specific analgesic effect of NE. While intra-CA3 region microinjection of phentolamine produced the opposite response. It implies that phentolamine can block the effect of endogenous NE to cause the enhanced response of PEN and PIN to noxious stimulation. On the basis of above findings we can deduce that NE, phentolamine and alpha-adrenoceptor are involved in the modulation of nociceptive information transmission in the hippocampal CA3 region.

  20. Strict control of auricin production in Streptomyces aureofaciens CCM 3239 involves a feedback mechanism.

    PubMed

    Kutas, Peter; Feckova, Lubomira; Rehakova, Alena; Novakova, Renata; Homerova, Dagmar; Mingyar, Erik; Rezuchova, Bronislava; Sevcikova, Beatrica; Kormanec, Jan

    2013-03-01

    The polyketide gene cluster aur1 is responsible for the production of the angucycline antibiotic auricin in Streptomyces aureofaciens CCM 3239. Auricin production is regulated in a complex manner involving several regulators, including a key pathway-specific positive regulator Aur1P that belongs to the family of 'atypical' response regulators. Production of auricin is induced after entry into stationary phase. However, auricin was produced in only a short time interval of several hours. We found that the decrease of auricin production was due to a strict regulation of auricin biosynthetic genes at the transcriptional level by a feedback mechanism; auricin and/or its intermediate(s) inhibited binding of Aur1P to its cognate biosynthetic promoter aur1Ap and consequently stopped its activation. In addition, we also determined that synthesised auricin is unstable during growth of S. aureofaciens CCM3239 in the production medium even though purified auricin is stable for days in various organic solvents. The critical parameter affecting its stability was pH. Auricin is stable at acid pH and unstable at neutral and alkaline pH. The drop in auricin concentration was due to an increase of pH shortly after induction of auricin production during cultivation of S. aureofaciens CCM3239.

  1. A novel mechanism for regulating hepatic glycogen synthesis involving serotonin and cyclin-dependent kinase-5.

    PubMed

    Tudhope, Susan J; Wang, Chung-Chi; Petrie, John L; Potts, Lloyd; Malcomson, Fiona; Kieswich, Julius; Yaqoob, Muhammad M; Arden, Catherine; Hampson, Laura J; Agius, Loranne

    2012-01-01

    Hepatic autonomic nerves regulate postprandial hepatic glucose uptake, but the signaling pathways remain unknown. We tested the hypothesis that serotonin (5-hydroxytryptamine [5-HT]) exerts stimulatory and inhibitory effects on hepatic glucose disposal. Ligands of diverse 5-HT receptors were used to identify signaling pathway(s) regulating glucose metabolism in hepatocytes. 5-HT had stimulatory and inhibitory effects on glycogen synthesis in hepatocytes mediated by 5-HT1/2A and 5-HT2B receptors, respectively. Agonists of 5-HT1/2A receptors lowered blood glucose and increased hepatic glycogen after oral glucose loading and also stimulated glycogen synthesis in freshly isolated hepatocytes with greater efficacy than 5-HT. This effect was blocked by olanzapine, an antagonist of 5-HT1/2A receptors. It was mediated by activation of phosphorylase phosphatase, inactivation of glycogen phosphorylase, and activation of glycogen synthase. Unlike insulin action, it was not associated with stimulation of glycolysis and was counteracted by cyclin-dependent kinase (cdk) inhibitors. A role for cdk5 was supported by adaptive changes in the coactivator protein p35 and by elevated glycogen synthesis during overexpression of p35/cdk5. These results support a novel mechanism for serotonin stimulation of hepatic glycogenesis involving cdk5. The opposing effects of serotonin, mediated by distinct 5-HT receptors, could explain why drugs targeting serotonin function can cause either diabetes or hypoglycemia in humans.

  2. New insight into the mechanism of Lonomia obliqua envenoming: toxin involvement and molecular approach.

    PubMed

    Alvarez Flores, M P; Zannin, M; Chudzinski-Tavassi, A M

    2010-01-01

    Despite the nearly worldwide distribution of Lepidoptera, there are few species with clear documentation of adverse reactions in humans. Most syndromes caused by Lepidoptera are consequences of direct contact with the hairs or setae of caterpillars. In most instances, the adverse effects caused by moth and caterpillars are self-limited and the treatment is based on the removal of hairs, application of topical antipruritics and, in some cases, the use of oral antihistamines. However, in the case of envenoming by South American Lonomiaobliqua caterpillars, the antilonomic serum produced at Instituto Butantan in Brazil is the only effective treatment to re-establish the physiological coagulation parameters in poisoned patients and to abolish the complications seen in severe cases (e.g. consumptive coagulopathy, intracerebral hemorrhage, and acute renal failure). Many studies have been carried out to understand the pathophysiological mechanism of envenoming by L. obliqua. Several toxic principles were found in bristle extract and the hemolymph, probably related to the envenoming. An interesting fact is that some toxins from the venom usually have more than one function. With the advent of molecular biology techniques it has become possible to analyze these processes at a molecular level, thus giving rise to hypotheses on the molecular basis of envenomation. This review contributes to enhance our understanding of the dramatic alterations that hemorrhagic syndrome causes in patients, current treatment, and the diversity of the molecules involved in this pathology. Copyright © 2010 S. Karger AG, Basel.

  3. Molecular mechanisms involved in the response to desiccation stress and persistence in Acinetobacter baumannii.

    PubMed

    Gayoso, Carmen M; Mateos, Jesús; Méndez, José A; Fernández-Puente, Patricia; Rumbo, Carlos; Tomás, María; Martínez de Ilarduya, Oskar; Bou, Germán

    2014-02-07

    Desiccation tolerance contributes to the maintenance of bacterial populations in hospital settings and may partly explain its propensity to cause outbreaks. Identification and relative quantitation of proteins involved in bacterial desiccation tolerance was made using label-free quantitation and iTRAQ labeling. Under desiccating conditions, the population of the Acinetobacter baumannii clinical strain AbH12O-A2 decreased in the first week, and thereafter, a stable population of 0.5% of the original population was maintained. Using label-free quantitation and iTRAQ labeling, 727 and 765 proteins, respectively, were detected; 584 of them by both methods. Proteins overexpressed under desiccation included membrane and periplasmic proteins. Proteins associated with antimicrobial resistance, efflux pumps, and quorum quenching were overexpressed in the samples subjected to desiccation stress. Electron microscopy revealed clear morphological differences between desiccated and control bacteria. We conclude that A. baumannii is able to survive long periods of desiccation through the presence of cells in a dormant state, via mechanisms affecting control of cell cycling, DNA coiling, transcriptional and translational regulation, protein stabilization, antimicrobial resistance, and toxin synthesis, and that a few surviving cells embedded in a biofilm matrix are able to resume growth and restore the original population in appropriate environmental conditions following a "bust-and-boom" strategy.

  4. Evidence for the involvement of central serotonin in mechanism of domestication of silver foxes.

    PubMed

    Popova, N K; Voitenko, N N; Kulikov, A V; Avgustinovich, D F

    1991-12-01

    Silver foxes selected for more than 30 years for tame behavior and displaying no defensive reaction to human contact were shown to have a higher serotonin level in midbrain and hypothalamus, and a higher 5-hydroxyindole acetic acid (5-HIAA) content in midbrain, hypothalamus and hippocampus in comparison to nonselected wild silver foxes bred in captivity over the same time span. Tryptophan hydroxylase (TPH) activity in midbrain and hypothalamus in domesticated foxes was increased as compared with their aggressive/defensive counterparts. Monoamine oxidase type A (MAO A) activity was was decreased with an increased Km and unchanged Vmax in domesticated foxes. No changes in specific [3H]ketanserin or [3H]8-OH-DPAT binding in frontal cortex was revealed. A reduced density (Bmax) of 5HT1A receptors in hypothalamic membranes in domesticated foxes was shown. It is suggested that the brain serotonergic system is involved in the mechanism of domestication converting wild aggressive/defensive animals into tame ones.

  5. Mechanisms involved in Escherichia coli and Serratia marcescens removal during activated sludge wastewater treatment

    PubMed Central

    Orruño, Maite; Garaizabal, Idoia; Bravo, Zaloa; Parada, Claudia; Barcina, Isabel; Arana, Inés

    2014-01-01

    Wastewater treatment reduces environmental contamination by removing gross solids and mitigating the effects of pollution. Treatment also reduces the number of indicator organisms and pathogens. In this work, the fates of two coliform bacteria, Escherichia coli and Serratia marcescens, were analyzed in an activated sludge process to determine the main mechanisms involved in the reduction of pathogenic microorganisms during wastewater treatment. These bacteria, modified to express green fluorescent protein, were inoculated in an activated sludge unit and in batch systems containing wastewater. The results suggested that, among the different biological factors implied in bacterial removal, bacterivorous protozoa play a key role. Moreover, a representative number of bacteria persisted in the system as free-living or embedded cells, but their distribution into liquid or solid fractions varied depending on the bacterium tested, questioning the real value of bacterial indicators for the control of wastewater treatment process. Additionally, viable but nonculturable cells constituted an important part of the bacterial population adhered to solid fractions, what can be derived from the competition relationships with native bacteria, present in high densities in this environment. These facts, taken together, emphasize the need for reliable quantitative and qualitative analysis tools for the evaluation of pathogenic microbial composition in sludge, which could represent an undefined risk to public health and ecosystem functions when considering its recycling. PMID:25044599

  6. Molecular mechanisms involved in the pathogenesis of alphavirus-induced arthritis.

    PubMed

    Assunção-Miranda, Iranaia; Cruz-Oliveira, Christine; Da Poian, Andrea T

    2013-01-01

    Arthritogenic alphaviruses, including Ross River virus (RRV), Chikungunya virus (CHIKV), Sindbis virus (SINV), Mayaro virus (MAYV), O'nyong-nyong virus (ONNV), and Barmah Forest virus (BFV), cause incapacitating and long lasting articular disease/myalgia. Outbreaks of viral arthritis and the global distribution of these diseases point to the emergence of arthritogenic alphaviruses as an important public health problem. This review discusses the molecular mechanisms involved in alphavirus-induced arthritis, exploring the recent data obtained with in vitro systems and in vivo studies using animal models and samples from patients. The factors associated to the extension and persistence of symptoms are highlighted, focusing on (a) virus replication in target cells, and tissues, including macrophages and muscle cells; (b) the inflammatory and immune responses with recruitment and activation of macrophage, NK cells and T lymphocytes to the lesion focus and the increase of inflammatory mediators levels; and (c) the persistence of virus or viral products in joint and muscle tissues. We also discuss the importance of the establishment of novel animal models to test new molecular targets and to develop more efficient and selective drugs to treat these diseases.

  7. The Mechanism of L-Arginine Modulates Signal Proteins Involved in Glucose and Lipid Metabolic Imbalance.

    PubMed

    Hu, Shengdi; Han, Meng; Rezaei, Arash; Li, Defa; Guoyao, W; Ma, Xi

    2016-06-26

    Type 2 diabetes has become a global public health problem affecting approximately 380 million people throughout the world. It can cause many complications and lead to greater mortality. At present, there is no available medicine for effectively preventing diabetes. L-arginine, a functional amino acid, the precursor of nitric oxide, plays a crucial role in maintenance, reproduction, growth, anti-aging and immunity in animals. Growing clinical evidence indicates that dietary L-arginine supplementation can reduce obesity, decrease arterial blood pressure, resist oxidation and normalize endothelial dysfunction to cause remission of type 2 diabetes. The potential molecular mechanism may play a role in modulating glucose homeostasis, promoting lipolysis, maintaining hormone level, ameliorating insulin resistance, and fetal programing in early stage. The possible signaling pathway of the beneficial effects of L-arginine likely involves L-arginine-nitric oxide pathway through which cell signal protein can be activated. Accumulating studies have indicated that L-arginine may have potential to prevent and/or relieve type 2 diabetes via restoring insulin sensitivity in vivo.

  8. Indirect decentralized learning control

    NASA Technical Reports Server (NTRS)

    Longman, Richard W.; Lee, Soo C.; Phan, M.

    1992-01-01

    The new field of learning control develops controllers that learn to improve their performance at executing a given task, based on experience performing this specific task. In a previous work, the authors presented a theory of indirect learning control based on use of indirect adaptive control concepts employing simultaneous identification and control. This paper develops improved indirect learning control algorithms, and studies the use of such controllers in decentralized systems. The original motivation of the learning control field was learning in robots doing repetitive tasks such as on an assembly line. This paper starts with decentralized discrete time systems, and progresses to the robot application, modeling the robot as a time varying linear system in the neighborhood of the nominal trajectory, and using the usual robot controllers that are decentralized, treating each link as if it is independent of any coupling with other links. The basic result of the paper is to show that stability of the indirect learning controllers for all subsystems when the coupling between subsystems is turned off, assures convergence to zero tracking error of the decentralized indirect learning control of the coupled system, provided that the sample time in the digital learning controller is sufficiently short.

  9. Mechanism involved in trichloroethylene-induced liver cancer: Importance to environmental cleanup. 1998 annual progress report

    SciTech Connect

    Bull, R.J.; Thrall, B.D.; Sasser, L.B.; Miller, J.H.; Schultz, I.R.

    1998-06-01

    'The objective of this project is to develop critical data for changing risk-based clean-up standards for trichloroethylene (TCE). The project is organized around two interrelated tasks: Task 1 addresses the tumorigenic and dosimetry issues for the metabolites of TCE that produce liver cancer in mice, dichloroacetate (DCA) and trichloroacetate (TCA). Early work had suggested that TCA was primarily responsible for TCE-induced liver tumors, but several, more mechanistic observations suggest that DCA may play a prominent role. This task is aimed at determining the basis for the selection hypothesis and seeks to prove that this mode of action is responsible for TCE-induced tumors. This project will supply the basic dose-response data from which low-dose extrapolations would be made. Task 2 seeks specific evidence that TCA and DCA are capable of promoting the growth of spontaneously initiated cells from mouse liver, in vitro. The data provide the clearest evidence that both metabolites act by a mechanism of selection rather than mutation. These data are necessary to select between a linear (i.e. no threshold) and non-linear low-dose extrapolation model. As of May of 1998, this research has identified two plausible modes of action by which TCE produces liver tumors in mice. These modes of action do not require the compounds to be mutagenic. The bulk of the experimental evidence suggests that neither TCE nor the two hepatocarcinogenic metabolites of TCE are mutagenic. The results from the colony formation assay clearly establish that both of these metabolites cause colony growth from initiated cells that occur spontaneously in the liver of B 6 C 3 F 1 mice, although the phenotypes of the colonies differ in the same manner as tumors differ, in vivo. In the case of DCA, a second mechanism may occur at a lower dose involving the release of insulin. This observation is timely as it was recently reported that occupational exposures to trichloroethylene results in 2 to 4-fold

  10. The effects of cavity-margin-angles and bolus stiffness on the mechanical behavior of indirect resin composite class II restorations.

    PubMed

    Ausiello, Pietro; Ciaramella, Stefano; Garcia-Godoy, Franklin; Gloria, Antonio; Lanzotti, Antonio; Maietta, Saverio; Martorelli, Massimo

    2017-01-01

    To study the influence of the different class II mesio-occlusal-distal (MOD) cavity shape on the stress and strain distributions in adhesive indirect restorations, using numerical finite element analysis (FEA). To investigate the relationship between restored teeth failure and stiffness of food, three values of Young's modulus were used for the food. A 3D model of a sound lower molar and three class II MOD cavities with different shape were created. Slide-type contact elements were used between tooth surface and food. An adhesive resin-based cement, modeled with fixed-type contact elements, and a single restorative filling materials were considered. To simulate polymerization shrinkage effect, which is basically restricted to the thin composite cement layer, shell elements were employed and the thermal expansion approach was used. A vertical occlusal load of 600N was applied, while assigning fixed zero-displacements on the cutting surfaces below the crevices. All the materials were assumed to be isotropic and elastic. A static linear analysis was carried out. In the lingual cusp, the displacements increased as the values of the stiffness food increased. In the restored teeth, the stress near the restoration-tooth interface was strongly dependent on the MOD cavity shape. The stress peaks were mainly located along the enamel-dentin interface at the lingual side; wedge-shaped MOD cavity with a low angle, in combination with the lowest food stiffness provided the best results. A more complex load application on the occlusal surfaces was introduced. Food stiffness slightly affected the stress distribution of the restored and sound teeth. Teeth with adhesive class II MOD indirect resin composite restorations were potentially more susceptible to damage if the class II MOD cavity-margin-angle was higher than 95°. Restored teeth with a higher cavity-margin-angle led to considerable stress concentration in the lingual cusp along the enamel-dentin interface. These models

  11. Direct and indirect effects in causal networks

    NASA Astrophysics Data System (ADS)

    Krämer, Andreas

    2013-03-01

    Literature-derived networks of biomolecular interactions representing cause-effect relationships generally contain many indirect relationships where the actually observed causal effect results from a sequence of events represented in the same network. A statistical method is developed, based on an Ising-like spin model operating on the edges of the network, to distinguish between direct and indirect effects using only the network structure itself. This allows to identify paths representing likely causation mechanisms.

  12. Social cognition of indirect speech: Evidence from Parkinson's Disease.

    PubMed

    McNamara, Patrick; Holtgraves, Thomas; Durso, Raymon; Harris, Erica

    2010-03-01

    We examined potential neurocognitive mechanisms of indirect speech in support of face management in 28 patients with Parkinson's disease (PD) and 32 elderly controls with chronic disease. In experiment 1, we demonstrated automatic activation of indirect meanings of particularized implicatures in controls but not in PD patients. Failure to automatically engage comprehension of indirect meanings of indirect speech acts in PD patients was correlated with a measure of prefrontal dysfunction. In experiment 2, we showed that while PD patients and controls offered similar interpretations of indirect speech acts, PD participants were overly confident in their interpretations and unaware of errors of interpretation. Efficient reputational adjustment mechanisms apparently require intact striatal-prefrontal networks.

  13. Study of the Genes and Mechanism Involved in the Radioadaptive Response

    NASA Technical Reports Server (NTRS)

    Dasgupta, Pushan R.

    2009-01-01

    The radioadaptive response is a phenomenon where exposure to a prior low dose of radiation reduces the level of damage induced by a subsequent high radiation dose. The molecular mechanism behind this is still not well understood. Learning more about the radioadaptive response is critical for long duration spaceflight since astronauts are exposed to low levels of cosmic radiation. The micronucleus assay was used to measure the level of damage caused by radiation. Although cells which were not washed with phosphate buffered saline (PBS) after a low priming dose of 5cGy did not show adaptation to the challenge dose, washing the cells with PBS and giving the cells fresh media after the low dose did allow radioadaptation to occur. This is consistent with the results of a previous publication by another research group. In the present study, genes involved in DNA damage signaling and the oxidative stress response were studied using RT PCR techniques in order to look at changes in expression level after the low dose with or without washing. Our preliminary results indicate that upregulation of oxidative stress response genes ANGPTL7, NCF2, TTN, and SRXN1 may be involved in the radioadaptive response. The low dose of radiation alone was found to activate the oxidative stress response genes GPR156 and MTL5, whereas, washing the cells alone caused relatively robust upregulation of the oxidative stress response genes DUSP1 and PTGS2. Washing after the priming dose showed some changes in the expression level of several DNA damage signaling genes. In addition, we studied whether washing the cells after the priming dose has an effect on the level of nitric oxide in both the media and cells, since nitric oxide levels are known to increase in the media of the cells after a high dose of radiation only if the cells were already exposed to a low priming dose. Based on this preliminary study, we propose that washing the cells after priming exposure actually eliminates some factor

  14. Mammary blood flow and metabolic activity are linked by a feedback mechanism involving nitric oxide synthesis.

    PubMed

    Cieslar, S R L; Madsen, T G; Purdie, N G; Trout, D R; Osborne, V R; Cant, J P

    2014-01-01

    To test which, if any, of the major milk precursors can elicit a rapid change in the rate of mammary blood flow (MBF) and to define the time course and magnitude of such changes, 4 lactating cows were infused with glucose, amino acids, or triacylglycerol into the external iliac artery feeding one udder half while iliac plasma flow (IPF) was monitored continuously by dye dilution. Adenosine and saline were infused as positive and negative controls, respectively, and insulin was infused to characterize the response to a centrally produced anabolic hormone. To test the roles of cyclooxygenase, NO synthase and ATP-sensitive K (KATP) channels in nutrient-mediated changes in blood flow, their respective inhibitors-indomethacin, Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), and glibenclamide-were infused simultaneously with glucose. Each day, 1 infusate was given twice to each cow, over a 20-min period each time, separated by a 20-min washout period. In addition, each treatment protocol was administered on 2 separate days. A 73% increase in IPF during adenosine infusion showed that the mammary vasodilatory response was quadratic in time, with most changes occurring in the first 5min. Glucose infusion decreased IPF by 9% in a quadratic manner, most rapidly in the first 5min, indicating that a feedback mechanism of local blood flow control, likely through adenosine release, was operative in the mammary vasculature. Amino acid infusion increased IPF 9% in a linear manner, suggesting that mammary ATP utilization was stimulated more than ATP production. This could reflect a stimulation of protein synthesis. Triacylglycerol only tended to decrease IPF and insulin did not affect IPF. A lack of IPF response to glibenclamide indicates that KATP channels are not involved in MBF regulation. Indomethacin and L-NAME both depressed IPF. In the presence of indomethacin, glucose infusion caused a quadratic 9% increase in IPF. Indomethacin is an inhibitor of mitochondrial

  15. Study of the Genes and Mechanism Involved in the Radioadaptive Response

    NASA Technical Reports Server (NTRS)

    Dasgupta, Pushan R.

    2009-01-01

    The radioadaptive response is a phenomenon where exposure to a prior low dose of radiation reduces the level of damage induced by a subsequent high radiation dose. The molecular mechanism behind this is still not well understood. Learning more about the radioadaptive response is critical for long duration spaceflight since astronauts are exposed to low levels of cosmic radiation. The micronucleus assay was used to measure the level of damage caused by radiation. Although cells which were not washed with phosphate buffered saline (PBS) after a low priming dose of 5cGy did not show adaptation to the challenge dose, washing the cells with PBS and giving the cells fresh media after the low dose did allow radioadaptation to occur. This is consistent with the results of a previous publication by another research group. In the present study, genes involved in DNA damage signaling and the oxidative stress response were studied using RT PCR techniques in order to look at changes in expression level after the low dose with or without washing. Our preliminary results indicate that upregulation of oxidative stress response genes ANGPTL7, NCF2, TTN, and SRXN1 may be involved in the radioadaptive response. The low dose of radiation alone was found to activate the oxidative stress response genes GPR156 and MTL5, whereas, washing the cells alone caused relatively robust upregulation of the oxidative stress response genes DUSP1 and PTGS2. Washing after the priming dose showed some changes in the expression level of several DNA damage signaling genes. In addition, we studied whether washing the cells after the priming dose has an effect on the level of nitric oxide in both the media and cells, since nitric oxide levels are known to increase in the media of the cells after a high dose of radiation only if the cells were already exposed to a low priming dose. Based on this preliminary study, we propose that washing the cells after priming exposure actually eliminates some factor

  16. Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets

    PubMed Central

    Higuera-de la Tijera, Fátima; Servín-Caamaño, Alfredo I

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as non-alcoholic fatty liver (NAFL) or simple steatosis, and non-alcoholic steatohepatitis (NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms, such as, insulin resistance (IR), lipotoxicity, inflammation, oxidative stress, and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1 (GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion, inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted, GLP-1 is quickly degraded by dipeptidyl peptidase-4 (DPP-4). Therefore, DPP-4 inhibitors are able to extend the activity of GLP-1. Currently, GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors, such as the farsenoid X receptor, also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid with immunomodulatory, anti-inflammatory, antiapoptotic, antioxidant and anti-fibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as, TGR5, farnesoid X receptor-α, or the small heterodimeric partner. Finally, pharmacologic modulation of the gut microbiota could have a role in the therapy of

  17. Evidence for direct and indirect mechanisms in the potent modulatory action of interleukin-2 on the release of acetylcholine in rat hippocampal slices

    PubMed Central

    Seto, David; Kar, Satyabrata; Quirion, Rémi

    1997-01-01

    The biphasic nature of the potent modulatory action of interleukin-2 (IL-2) on hippocampal acetylcholine (ACh) release was investigated by use of brain slice superfusion.Both the potentiating (10−13 M) and inhibitory (10−9 M) effects of IL-2 on hippocampal ACh release were stimulation-dependent and were blocked by a neutralizing IL-2 receptor antibody, suggesting the activation of typical IL-2 receptors in both cases.Tetrodotoxin (TTX; 10 μM) failed to block the potentiation of ACh release induced by a very low concentration of IL-2 (10−13M) suggesting a direct effect on cholinergic nerve terminals.In contrast, the inhibitory effect seen at a higher concentration (10−9 M) was TTX-sensitive, and hence indicative of an indirect action.To establish the nature of this intermediate mediator, blockers of nitric oxide synthesis, and of opioid and γ-aminobutyric acid (GABA) receptors were used. Only GABAA and GABAB receptor antagonists altered the inhibitory action of IL-2, suggesting the participation of GABA as mediator.Taken together, these results provide further evidence for the potent role of IL-2 in the modulation of cholinergic function in the rat hippocampus. PMID:9134229

  18. The crystal structure of the tandem-PAS sensing domain of Campylobacter jejuni chemoreceptor Tlp1 suggests indirect mechanism of ligand recognition.

    PubMed

    Machuca, Mayra A; Liu, Yu C; Beckham, Simone A; Gunzburg, Menachem J; Roujeinikova, Anna

    2016-05-01

    Chemotaxis and motility play an important role in the colonisation of avian and human hosts by Campylobacter jejuni. Chemotactic recognition of extracellular signals is mediated by the periplasmic sensing domain of methyl-accepting chemotactic proteins (membrane-embedded receptors). In this work, we report a high-resolution structure of the periplasmic sensing domain of transducer-like protein 1 (Tlp1), an aspartate receptor of C. jejuni. Crystallographic analysis revealed that it contains two Per-Arnt-Sim (PAS) subdomains. An acetate and chloride ions (both from the crystallisation buffer) were observed bound to the membrane-proximal and membrane-distal PAS subdomains, respectively. Surprisingly, despite being crystallised in the presence of aspartate, the structure did not show any electron density corresponding to this amino acid. Furthermore, no binding between the sensing domain of Tlp1 and aspartate was detected by microcalorimetric experiments. These structural and biophysical data suggest that Tlp1 does not sense aspartate directly; instead, ligand recognition is likely to occur indirectly via an as yet unidentified periplasmic binding protein.

  19. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

    PubMed

    Sagai, Masaru; Bocci, Velio

    2011-12-20

    stress. Recently these concepts have become widely accepted. The versatility of ozone in treating vascular and degenerative diseases as well as skin lesions, hernial disc and primary root carious lesions in children is emphasized. Further researches able to elucidate whether the mechanisms of action of ozone therapy involve nuclear transcription factors, such as Nrf2, NFAT, AP-1, and HIF-1α are warranted.

  20. Molecular mechanisms involved in the hormonal prevention of aging in the rat.

    PubMed

    Tresguerres, Jesús A F; Kireev, Roman; Tresguerres, Ana F; Borras, Consuelo; Vara, Elena; Ariznavarreta, Carmen

    2008-02-01

    Previous data from our group have provided support for the role of GH, melatonin and estrogens in the prevention of aging of several physiological parameters from bone, liver metabolism, vascular activity, the central nervous system (CNS), the immune system and the skin. In the present work data on the molecular mechanisms involved are presented. A total of 140 male and female rats have been submitted to different treatments over 10 weeks, between 22 and 24 months of age. Males have been treated with GH and melatonin. Females were divided in two groups: intact and castrated at 12 months of age. The first group was treated with GH and melatonin and the second with the two latter compounds and additionally with estradiol and Phytosoya. Aging was associated with a reduction in the number of neurons of the hylus of the dentate gyrus of the hippocampus and with a reduction of neurogenesis. GH treatment increased the number of neurons but did not increase neurogenesis thus suggesting a reduction of apoptosis. This was supported by the reduction in nucleosomes and the increase in Bcl2 observed in cerebral homogenates together with an increase in sirtuin2 and a reduction of caspases 9 and 3. Melatonin, estrogen and Phytosoya treatments increased neurogenesis but did not enhance the total number of neurons. Aging induced a significant increase in mitochondrial nitric oxide in the hepatocytes, together with a reduction in the mitochondrial fraction content in cytochrome C and an increase of this compound in the cytosolic fraction. Reductions of glutathione peroxidase and glutathione S-transferase were also detected, thus indicating oxidative stress and possibly apoptosis. Treatment for 2.5 months of old rats with GH and melatonin were able to significantly and favourably affect age-induced deteriorations, thus reducing oxidative damage. Keratinocytes obtained from old rats in primary culture showed an increase in lipoperoxides, caspases 8 and 3 as well as a reduction in Bcl2

  1. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

    PubMed Central

    2011-01-01

    oxidative stress. Recently these concepts have become widely accepted. The versatility of ozone in treating vascular and degenerative diseases as well as skin lesions, hernial disc and primary root carious lesions in children is emphasized. Further researches able to elucidate whether the mechanisms of action of ozone therapy involve nuclear transcription factors, such as Nrf2, NFAT, AP-1, and HIF-1α are warranted. PMID:22185664

  2. Potential mechanisms involved in the absorptive transport of cadmium in isolated perfused rabbit renal proximal tubules.

    PubMed

    Wang, Yanhua; Zalups, Rudolfs K; Barfuss, Delon W

    2010-03-01

    Lumen-to-cell transport, cellular accumulation, and toxicity of cadmium as ionic cadmium (Cd(2+)) or as the L-cysteine (Cys) or D,L-homocysteine (Hcy) S-conjugate of cadmium (Cys-S-Cd-S-Cys, Hcy-S-Cd-S-Hcy) were studied in isolated, perfused rabbit proximal tubular segments. When Cd(2+) (0.73 microM) or Cys-S-Cd-S-Cys (0.73 microM) was perfused through the lumen of S(2) segments of the proximal tubule, no visual evidence of cellular pathological changes was detected during 30 min of study. Cd(2+)-transport was temperature-dependent and was inhibited by Fe(2+), Zn(2+), and elevated concentrations of Ca(2+). Luminal uptake of Cys-S-Cd-S-Cys was also temperature-dependent and was inhibited by the amino acids L-cystine and L-arginine, while stimulated by L-methionine. Neither L-aspartate, L-glutamate, the synthetic dipeptide, Gly-Sar nor Zn(2+) had any effect on the rate of Cys-S-Cd-S-Cys transport. When delivered to the luminal compartment, Cd(2+) appears to be capable of utilizing certain transporter(s) of Zn(2+) and some transport systems sensitive to Ca(2+) and Fe(2+). In addition, Cys-S-Cd-S-Cys and Hcy-S-Cd-S-Hcy appear to be transportable substrates of one or more amino acid transporters participating in luminal absorption of the amino acid L-cystine (such as system b(0,+)). These findings indicate that multiple mechanisms could be involved in the luminal absorption of cadmium (Cd) in proximal tubular segments depending on its form. These findings provide a focus for future studies of Cd absorption in the proximal tubule. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  3. POTENTIAL MECHANISMS INVOLVED IN THE ABSORPTIVE TRANSPORT OF CADMIUM IN ISOLATED PERFUSED RABBIT RENAL PROXIMAL TUBULES

    PubMed Central

    Wang, Yanhua; Zalups, Rudolfs K.; Barfuss, Delon W.

    2009-01-01

    Lumen-to-cell transport, cellular accumulation, and toxicity of cadmium as ionic cadmium (Cd2+) or as the L-cysteine (Cys) or D,L-homocysteine (Hcy) S-conjugate of cadmium (Cys-S-Cd-S-Cys, Hcy-S-Cd-S-Hcy) were studied in isolated, perfused rabbit proximal tubular segments. When Cd2+ (0.73μM) or Cys-S-Cd-S-Cys (0.73μM) was perfused through the lumen of S2 segments of the proximal tubule, no visual evidence of cellular pathological changes was detected during 30 min of study. Cd2+-transport was temperature-dependent and was inhibited by Fe2+, Zn2+, and elevated concentrations of Ca2+. Luminal uptake of Cys-S-Cd-S-Cys was also temperature-dependent and was inhibited by the amino acids L-cystine and L-arginine, while stimulated by L-methionine. Neither L-aspartate, L-glutamate, the synthetic dipeptide, Gly-Sar nor Zn2+ had any effect on the rate of Cys-S-Cd-S-Cys transport. Conclusions: When delivered to the luminal compartment, Cd2+ appears to be capable of utilizing certain transporter(s) of Zn2+ and some transport systems sensitive to Ca2+ and Fe2+. In addition, Cys-S-Cd-S-Cys and Hcy-S-Cd-S-Hcy appear to be transportable substrates of one or more amino acid transporters participating in luminal absorption of the amino acid L-cystine (such as system b0,+). These findings indicate that multiple mechanisms could be involved in the luminal absorption of cadmium (Cd) in proximal tubular segments depending on its form. These findings provide a focus for future studies of Cd absorption in the proximal tubule. PMID:20018233

  4. Protooncogene c-fos Involvement in the Molecular Mechanism of Rat Brain Sexual Differentiation.

    PubMed

    Giannakopoulou, M; Bozas, E; Philippidis, H; Stylianopoulou, F

    2001-06-01

    Brain sexual differentiation is mediated through testosterone, which acts during the perinatal period in the form of both 5alpha-dihydrotestosterone and estradiol. In order to gain insight into the molecular mechanisms involved, we studied induction of c-fos, an index of functional neuronal activation, in the 2-day-old female rat brain after injection of a masculinizing dose of testosterone. Administration of testosterone resulted in induction of c-fos gene expression in the hypothalamus, as determined by Northern analysis. Following immunocytochemistry, we demonstrated an increase in the number of Fos-positive nuclei in the median and medial preoptic nucleus, the medial preoptic area extending to the lateral preoptic area, and the peri- and paraventricular area. In an effort to see whether testosterone acted as 5alpha-dihydrotestosterone or as estradiol, we injected either steroid and looked at fos induction. Estradiol mimicked the effect of testosterone, while 5alpha-dihydrotestosterone was without effect. Furthermore, injection of an estrogen receptor blocker, clomiphene, together with testosterone, abolished the testosterone-induced increase in Fos-positive nuclei, thus confirming the finding that testosterone induces c-fos by acting through estrogen receptors. Electrophoretic mobility shift assays showed that nuclear extracts from 2-day-old female hypothalamus contain a protein, most probably the estrogen receptor, which binds specifically to oligodeoxynucleotides with the sequence of either vitERE, the consensus estrogen-responsive element (ERE) found in the vittelogenin gene, or fosERE, the ERE found in the 3'-untranslated region of the mouse c-fos gene. This suggests that the effect of testosterone-derived estradiol on c-fos expression is a direct one, mediated by binding of estrogen receptors to an ERE in the c-fos gene-regulatory regions.

  5. Achyranthes aspera Attenuates epilepsy in experimental animals: possible involvement of GABAergic mechanism.

    PubMed

    Viswanatha, Gollapalle Lakshminarayanashastry; Venkataranganna, Marikunte V; Prasad, Nunna Bheema Lingeswara; Godavarthi, Ashok

    2017-03-06

    The present study was aimed to examine the possible anticonvulsant property of aerial parts of Achyranthes aspera using various experimental models of epilepsy in mice. Petroleum ether extract of aerial parts of A. aspera (PeAA), methanolic eAA (MeAA) and aqueous eAA (AeAA) was initially evaluated against six-hertz seizure model in mice, based on the outcomes the effective extract was further evaluated against maximal electroshock (MES) and pentylenetetrazole (PTZ) models in mice. In addition, the potent extract was evaluated against the PTZ model by co-administering with flumazenil (FMZ), and also evaluated for its effect on GABA levels in brain and NMDA-induced lethality in mice. Furthermore, the probable locomotor deficit-inducing property of the extract was evaluated by actophotometer test in mice. In results, only MeAA showed protection against six-hertz-induced seizures in mice, based on these outcomes only MeAA was evaluated in MES and PTZ models. Notably, the MeAA (200, 400 and 800 mg/kg) has offered mild and dose dependent protection against MES and PTZ-induced seizures in mice. Alongside, the MeAA (400 mg/kg) showed a significant increase in GABA levels in the brain compared to control, and in line with these findings the anti-PTZ effect of MeAA (400 mg/kg, p.o.) was blocked when co-administered with flumazenil (5 mg/kg, i.p.). However, the MeAA has not shown significant protection against NMDA-induced mortality and also did not cause significant change in locomotor activity compared to before treatment. These findings suggest that MeAA possess mild anticonvulsant activity and the outcomes further confirmed the involvement of GABAergic mechanism behind the anticonvulsant activity of MeAA.

  6. Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages

    PubMed Central

    Donnelly, Sheila; Stack, Colin M.; O'Neill, Sandra M.; Sayed, Ahmed A.; Williams, David L.; Dalton, John P.

    2008-01-01

    During helminth infections, alternatively activated macrophages (AAMacs) are key to promoting Th2 responses and suppressing Th1-driven inflammatory pathology. Th2 cytokines IL-4 and/or IL-13 are believed to be important in the induction and activation of AAMacs. Using murine models for the helminth infections caused by Fasciola hepatica (Fh) and Schistosoma mansoni (Sm), we show that a secreted antioxidant, peroxiredoxin (Prx), induces alternative activation of macrophages. These activated, Ym1-expressing macrophages enhanced the secretion of IL-4, IL-5, and IL-13 from naive CD4+ T cells. Administration of recombinant FhPrx and SmPrx to wild-type and IL-4−/− and IL-13−/− mice induced the production of AAMacs. In addition, Prx stimulated the expression of markers of AAMacs (particularly, Ym1) in vitro, and therefore can act independently of IL-4/IL-13 signaling. The immunomodulatory property of Prx is not due to its antioxidant activity, as an inactive recombinant variant with active site Cys residues replaced by Gly could also induce AAMacs and Th2 responses. Immunization of mice with recombinant Prx or passive transfer of anti-Prx antibodies prior to infection with Fh not only blocked the induction of AAMacs but also the development of parasite-specific Th2 responses. We propose that Prx activates macrophages as an initial step in the induction of Th2 responses by helminth parasites and is thereby a novel pathogen-associated molecular pattern.—Donnelly, S., Stack, C. M., O'Neill, S. M., Sayed, A. A., Williams, D. L., Dalton, J. P. Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages. PMID:18708590

  7. Ventrolateral medulla mechanisms involved in cardiorespiratory responses to central chemoreceptor activation in rats.

    PubMed

    Takakura, Ana C; Colombari, Eduardo; Menani, José V; Moreira, Thiago S

    2011-02-01

    A rise in arterial Pco(2) stimulates breathing and sympathetic activity to the heart and blood vessels. In the present study, we investigated the involvement of the retrotrapezoid nucleus (RTN) and glutamatergic mechanisms in the Bötzinger/C1 region (Bötz/C1) in these responses. Splanchnic sympathetic nerve discharge (sSND) and phrenic nerve discharge (PND) were recorded in urethane-anesthetized, sino-aortic-denervated, vagotomized, and artificially ventilated rats subjected to hypercapnia (end-expiratory CO(2) from 5% to 10%). Phrenic activity was absent at end-expiratory CO(2) of 4%, and strongly increased when end-expiratory CO(2) reached 10%. Hypercapnia also increased sSND by 103 ± 7%. Bilateral injections of the GABA-A agonist muscimol (2 mM) into the RTN eliminated the PND and blunted the sSND activation (Δ = +56 ± 8%) elicited by hypercapnia. Injections of NMDA receptor antagonist AP-5 (100 mM), non-NMDA receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (DNQX; 100 mM) or metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG; 100 mM) bilaterally into the Bötz/C1 reduced PND (Δ = +43 ± 7%, +52 ± 6% or +56 ± 11%, respectively). MCPG also reduced sSND (Δ = +41 ± 7%), whereas AP-5 and DNQX had no effect. In conclusion, the increase in sSND caused by hypercapnia depends on increased activity of the RTN and on metabotropic receptors in the Bötz/C1, whereas PND depends on increased RTN activity and both ionotropic and metabotropic receptors in the Bötz/C1.

  8. Ghrelin prevents tumour- and cisplatin-induced muscle wasting: characterization of multiple mechanisms involved

    PubMed Central

    Chen, Ji-an; Splenser, Andres; Guillory, Bobby; Luo, Jiaohua; Mendiratta, Meenal; Belinova, Blaga; Halder, Tripti; Zhang, Guohua; Li, Yi-Ping; Garcia, Jose M

    2015-01-01

    Background Cachexia and muscle atrophy are common consequences of cancer and chemotherapy administration. The novel hormone ghrelin has been proposed as a treatment for this condition. Increases in food intake and direct effects on muscle proteolysis and protein synthesis are likely to mediate these effects, but the pathways leading to these events are not well understood. Methods We characterized molecular pathways involved in muscle atrophy induced by Lewis lung carcinoma (LLC) tumour implantation in c57/bl6 adult male mice and by administration of the chemotherapeutic agent cisplatin in mice and in C2C12 myotubes. The effects of exogenous ghrelin administration and its mechanisms of action were examined in these settings. Results Tumour implantation and cisplatin induced muscle atrophy by activating pro-inflammatory cytokines, p38-C/EBP-β, and myostatin, and by down-regulating Akt, myoD, and myogenin, leading to activation of ubiquitin-proteasome-mediated proteolysis and muscle weakness. Tumour implantation also increased mortality. In vitro, cisplatin up-regulated myostatin and atrogin-1 by activating C/EBP-β and FoxO1/3. Ghrelin prevented these changes in vivo and in vitro, significantly increasing muscle mass (P < 0.05 for LLC and P < 0.01 for cisplatin models) and grip strength (P = 0.038 for LLC and P = 0.001 for cisplatin models) and improving survival (P = 0.021 for LLC model). Conclusion Ghrelin prevents muscle atrophy by down-regulating inflammation, p38/C/EBP-β/myostatin, and activating Akt, myogenin, and myoD. These changes appear, at least in part, to target muscle cells directly. Ghrelin administration in this setting is associated with improved muscle strength and survival. PMID:26136189

  9. Indirect microbial detection

    NASA Technical Reports Server (NTRS)

    Wilkins, J. R.

    1980-01-01

    Indirect method for detection of microbial growth utilizes flow of charged particles across barrier that physically separated growing cells from electrodes and measures resulting difference in potential between two platinum electrodes. Technique allows simplified noncontact monitoring of all growth in highly infectious cultures or in critical biochemical studies.

  10. Indirect decentralized repetitive control

    NASA Technical Reports Server (NTRS)

    Lee, Soo Cheol; Longman, Richard W.

    1993-01-01

    Learning control refers to controllers that learn to improve their performance at executing a given task, based on experience performing this specific task. In a previous work, the authors presented a theory of indirect decentralized learning control based on use of indirect adaptive control concepts employing simultaneous identification and control. This paper extends these results to apply to the indirect repetitive control problem in which a periodic (i.e., repetitive) command is given to a control system. Decentralized indirect repetitive control algorithms are presented that have guaranteed convergence to zero tracking error under very general conditions. The original motivation of the repetitive control and learning control fields was learning in robots doing repetitive tasks such as on an assembly line. This paper starts with decentralized discrete time systems, and progresses to the robot application, modeling the robot as a time varying linear system in the neighborhood of the desired trajectory. Decentralized repetitive control is natural for this application because the feedback control for link rotations is normally implemented in a decentralized manner, treating each link as if it is independent of the other links.

  11. Adult criminal involvement: A cross-sectional inquiry into correlates and mechanisms over the life course

    PubMed Central

    DePadilla, Lara; Perkins, Molly M.; Elifson, Kirk W.; Sterk, Claire E.

    2013-01-01

    In this paper, we examine the relative contribution of four domains of predictors that have been linked to adult criminal involvement: (1) socio-demographic characteristics, (2) family-of-origin factors, (3) proximal processes developed during adolescence, and (4) current lifestyle and situational factors. Cross-sectional data were collected through face-to-face interviews with 242 community-recruited adults. Data analysis involved negative binomial regression. Being male, family size, juvenile delinquency, aggression, living with someone involved in illegal activity and recent violent victimization were independently associated with non-violent criminal involvement. Aggression, association with deviant peers, and recent violent victimization were independently associated with violent criminal involvement. Juvenile delinquency and aggression mediated the affect of multiple family-of-origin characteristics on non-violent criminal involvement and aggression mediated the effect of childhood physical abuse on violent criminal involvement. The results emphasize the importance of investigating both antecedents and proximal risk factors predictive of different types of criminal involvement, which, in turn, will assist in developing risk-focused prevention and intervention programs. PMID:24307752

  12. Mechanisms involved in the psychological distress of Black Caribbeans in the United States

    NASA Astrophysics Data System (ADS)

    Govia, Ishtar O.

    The mental health of ethnic minorities in the United States is of urgent concern. The accelerated growth of groups of ethnic minorities and immigrants in the United States and the stressors to which they are exposed, implores academic researchers to investigate more deeply health disparities and the factors that exacerbate or minimize such inequalities. This dissertation attended to that concern. It used data from the National Survey of American Life (NSAL), the first survey with a national representative sample of Black Caribbeans, to explore mechanisms that involved in the psychological distress of Black Caribbeans in the United States. In a series of three studies, the dissertation investigated the role and consequence of (1) chronic discrimination, immigration factors, and closeness to ethnic and racial groups; (2) personal control and social support; and (3) family relations and social roles in the psychological distress of Black Caribbeans. Study 1 examined how the associations between discrimination and psychological distress were buffered or exacerbated by closeness to ethnic group and closeness to racial group. It also examined how these associations differed depending on immigration factors. Results indicated that the buffering or exacerbating effect of ethnic and racial group closeness varied according to the type of discrimination (subtle or severe) and were more pronounced among those born in the United States. Using the stress process framework, Study 2 tested moderation and mediation models of the effects of social support and personal control in the association between discrimination and distress. Results from a series of analyses on 579 respondents suggested that personal control served as a mediator in this relationship and that emotional support exerted a direct distress deterring function. Study 3 investigated sex differences in the associations between social roles, intergenerational family relationship perceptions and distress. Results

  13. Involvement of purinergic signalling in central mechanisms of body temperature regulation in rats

    PubMed Central

    Gourine, Alexander V; Melenchuk, Ekaterina V; Poputnikov, Dmitry M; Gourine, Valery N; Spyer, K Michael

    2002-01-01

    P2 purinoreceptors are present in hypothalamic and brainstem nuclei that are involved in the regulation of body temperature (Tb). The role of ATP acting on these P2 receptors in thermoregulation was investigated by studying the effects of the stable ATP analogue α,β-methyleneATP (α,β-meATP) and P2 receptor antagonists suramin and pyridoxal-5′-phosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS) on Tb when injected intracerebroventricularly (i.c.v.) via a pre-implanted cannula in conscious rats at various ambient temperatures and during lipopolysaccharide (LPS)-induced fever.Depending on ambient temperature, α,β-meATP (0.2 μmol, i.c.v.) induced a fall in Tb (−3.3°C, P<0.05), no changes in Tb when compared to pre-injection levels, or an increase in Tb (∼1.0°C, P<0.05) in rats maintained at 10°C, 25°C and 30°C ambient temperature, respectively.Suramin (7 nmol, i.c.v.) induced a lasting (up to 6 h) increase in Tb (on average 1.2°C, P<0.05) in rats kept at 25°C or 30°C, but failed to induce any rise in Tb in rats at 10°C ambient temperature. An increase in Tb was also observed in rats (25°C ambient temperature) treated with PPADS (0.2 μmol, i.c.v.).α,β-meATP (0.2 μmol) injected i.c.v. or directly into the anterior hypothalamus caused a profound fall in Tb (by 0.9°C and 1.0°C, respectively; P<0.05) during LPS (E.coli; 50 μg kg−1)-induced fever in rats at 25°C ambient temperature. Fever was initiated more rapidly in rats treated with suramin (7 nmol) or PPADS (70 nmol), however its late phase was unaffected. Suramin (7 nmol) and PPADS (70 nmol) injected at the time when fever was already developed (2.5 h after LPS injections) did not alter febrile Tb.These data indicate that purinergic signalling may play a significant role in central mechanisms of Tb regulation at various ambient temperatures and during fever. PMID:11959809

  14. The mechanism of binding staphylococcal protein A to immunoglobin G does not involve helix unwinding.

    PubMed

    Jendeberg, L; Tashiro, M; Tejero, R; Lyons, B A; Uhlén, M; Montelione, G T; Nilsson, B

    1996-01-09

    maintains its three-helical bundle structure in the Z-Fc complex, though there may be a small structural change involved in the binding mechanism.

  15. Mangiferin, a natural xanthone, accelerates gastrointestinal transit in mice involving cholinergic mechanism

    PubMed Central

    Morais, Talita Cavalcante; Lopes, Synara Cavalcante; Carvalho, Karine Maria Martins Bezerra; Arruda, Bruno Rodrigues; de Souza, Francisco Thiago Correia; Trevisan, Maria Teresa Salles; Rao, Vietla Satyanarayana; Santos, Flávia Almeida

    2012-01-01

    AIM: To investigate the effects of mangiferin on gastrointestinal transit (GIT) in normal and constipated mice, together with the possible mechanism. METHODS: Intragastrically-administered charcoal meal was used to measure GIT in overnight starved Swiss mice. In the first experiments, mangiferin (3 mg/kg, 10 mg/kg, 30 mg/kg, and 100 mg/kg, po) or tegaserod (1 mg/kg, ip) were administered 30 min before the charcoal meal to study their effects on normal transit. In the second series, mangiferin (30 mg/kg) was tested on delayed GIT induced by several different pharmacological agonists (morphine, clonidine, capsaicin) or antagonists (ondansetron, verapamil, and atropine) whereas in the third series, mangiferin (30 mg/kg, 100 mg/kg and 300 mg/kg) or tegaserod (1 mg/kg) were tested on 6 h fecal pellets outputted by freely fed mice. The ratio of wet to dry weight was calculated and used as a marker of fecal water content. RESULTS: Mangiferin administered orally significantly (P < 0.05) accelerated GIT at 30 mg/kg and 100 mg/kg (89% and 93%, respectively), similarly to 5-hydroxytryptamine4 (5-HT4) agonist tegaserod (81%) when compared to vehicle-treated control (63%). Co-administered mangiferin (30 mg/kg) totally reversed the inhibitory effect of opioid agonist morphine, 5-HT3-receptor antagonist ondansetron and transient receptor potential vanilloid-1 receptor agonist capsaicin on GIT, but only to a partial extent with the GIT-delay induced by α2-adrenoceptor agonist clonidine, and calcium antagonist verapamil. However, co-administered atropine completely blocked the stimulant effect of mangiferin on GIT, suggesting the involvement of muscarinic acetylcholine receptor activation. Although mangiferin significantly enhanced the 6 h fecal output at higher doses (245.5 ± 10.43 mg vs 161.9 ± 10.82 mg and 227.1 ± 20.11 mg vs 161.9 ± 10.82 mg of vehicle-treated control, at 30 and 100 mg/kg, P < 0.05, respectively), the effect of tegaserod was more potent (297.4 ± 7.42 mg

  16. Indirect Ultraviolet-Reactivation of Phage λ

    PubMed Central

    George, Jacqueline; Devoret, Raymond; Radman, Miroslav

    1974-01-01

    When an F- recipient Escherichia coli K12 bacterium receives Hfr or F-lac+ DNA from an ultraviolet-irradiated donor, its capacity to promote DNA repair and mutagenesis of ultraviolet-damaged phage λ is substantially increased. We call this phenomenon indirect ultraviolet-reactivation, since its features are essentially the same as those of ultraviolet-reactivation; this repair process occurs in pyrimidine dimer excision-deficient strains and produces clear plaque mutations of the restored phage. Moreover, this process is similar to indirect ultraviolet-induction of prophage λ, since it is promoted by conjugation. However, contrarily to indirect induction, it is produced by Hfr donors and occurs in recipients restricting the incoming ultraviolet-damaged donor DNA. The occurrence of indirect ultraviolet-reactivation provides evidence for the existence in E. coli of an inducible error-prone mechanism for the repair of DNA. PMID:4589889

  17. Indirect resin composites

    PubMed Central

    Nandini, Suresh

    2010-01-01

    Aesthetic dentistry continues to evolve through innovations in bonding agents, restorative materials, and conservative preparation techniques. The use of direct composite restoration in posterior teeth is limited to relatively small cavities due to polymerization stresses. Indirect composites offer an esthetic alternative to ceramics for posterior teeth. This review article focuses on the material aspect of the newer generation of composites. This review was based on a PubMed database search which we limited to peer-reviewed articles in English that were published between 1990 and 2010 in dental journals. The key words used were ‘indirect resin composites,’ composite inlays,’ and ‘fiber-reinforced composites.’ PMID:21217945

  18. Another look at the mechanism involving trimeric dUTPases in Staphylococcus aureus pathogenicity island induction involves novel players in the party

    PubMed Central

    Maiques, Elisa; Quiles-Puchalt, Nuria; Donderis, Jorge; Ciges-Tomas, J. Rafael; Alite, Christian; Bowring, Janine Z.; Humphrey, Suzanne; Penadés, José R.

    2016-01-01

    Abstract We have recently proposed that the trimeric staphylococcal phage encoded dUTPases (Duts) are signaling molecules that act analogously to eukaryotic G-proteins, using dUTP as a second messenger. To perform this regulatory role, the Duts require their characteristic extra motif VI, present in all the staphylococcal phage coded trimeric Duts, as well as the strongly conserved Dut motif V. Recently, however, an alternative model involving Duts in the transfer of the staphylococcal islands (SaPIs) has been suggested, questioning the implication of motifs V and VI. Here, using state-of the-art techniques, we have revisited the proposed models. Our results confirm that the mechanism by which the Duts derepress the SaPI cycle depends on dUTP and involves both motifs V and VI, as we have previously proposed. Surprisingly, the conserved Dut motif IV is also implicated in SaPI derepression. However, and in agreement with the proposed alternative model, the dUTP inhibits rather than inducing the process, as we had initially proposed. In summary, our results clarify, validate and establish the mechanism by which the Duts perform regulatory functions. PMID:27112567

  19. Another look at the mechanism involving trimeric dUTPases in Staphylococcus aureus pathogenicity island induction involves novel players in the party.

    PubMed

    Maiques, Elisa; Quiles-Puchalt, Nuria; Donderis, Jorge; Ciges-Tomas, J Rafael; Alite, Christian; Bowring, Janine Z; Humphrey, Suzanne; Penadés, José R; Marina, Alberto

    2016-06-20

    We have recently proposed that the trimeric staphylococcal phage encoded dUTPases (Duts) are signaling molecules that act analogously to eukaryotic G-proteins, using dUTP as a second messenger. To perform this regulatory role, the Duts require their characteristic extra motif VI, present in all the staphylococcal phage coded trimeric Duts, as well as the strongly conserved Dut motif V. Recently, however, an alternative model involving Duts in the transfer of the staphylococcal islands (SaPIs) has been suggested, questioning the implication of motifs V and VI. Here, using state-of the-art techniques, we have revisited the proposed models. Our results confirm that the mechanism by which the Duts derepress the SaPI cycle depends on dUTP and involves both motifs V and VI, as we have previously proposed. Surprisingly, the conserved Dut motif IV is also implicated in SaPI derepression. However, and in agreement with the proposed alternative model, the dUTP inhibits rather than inducing the process, as we had initially proposed. In summary, our results clarify, validate and establish the mechanism by which the Duts perform regulatory functions.

  20. Molecular mechanisms involved in gamete interaction: evidence for the participation of cysteine-rich secretory proteins (CRISP) in sperm-egg fusion.

    PubMed

    Da Ros, V; Busso, D; Cohen, D J; Maldera, J; Goldweic, N; Cuasnicu, P S

    2007-01-01

    Epididymal protein DE and testicular protein Tpx-1 are two cysteine-rich secretory proteins also known as CRISP-1 and CRISP-2, respectively. DE/ CRISP-1 is localised on the equatorial segment of acrosome-reacted sperm and participates in rat gamete fusion through its binding to egg-complementary sites. Recent results using bacterially-expressed recombinant fragments of DE as well as synthetic peptides revealed that the ability of DE to bind to the egg surface and inhibit gamete fusion resides in a region of 12 amino acids corresponding to an evolutionary conserved motif of the CRISP family (Signature 2). Given the high degree of homology between DE/CRISP-1 and Tpx-1/CRISP-2, we also explored the potential participation of the testicular intra-acrosomal protein in gamete fusion. Results showing the ability of recombinant Tpx-1 to bind to the surface of rat eggs (evaluated by indirect immunofluorescence) and to significantly inhibit zona-free egg penetration, support the participation of this protein in gamete fusion through its interaction with egg-binding sites. Interestingly, rat Tpx-1 exhibits only two substitutions in Signature 2 when compared to this region in DE. Together, these results provide evidence for the involvement of both epididymal DE/CRISP-1 and testicular Tpx-1/CRISP-2 in gamete fusion suggesting the existence of a functional cooperation between homologue molecules as a mechanism to ensure the success of fertilisation.

  1. Combined Quantum Mechanical and Molecular Mechanics Studies of the Electron-Transfer Reactions Involving Carbon Tetrachloride in Solution

    SciTech Connect

    Valiev, Marat; Bylaska, Eric J.; Dupuis, Michel; Tratnyek, Paul G.

    2008-03-27

    The reductive dechlorination of carbon tetrachloride, CC₄, was investigated using combined high level quantum mechanical and molecular mechanics (QM/MM) approach. The first electron transfer process was assumed to proceed by a concerted electron transfer-bond breaking mechanism, and reaction barriers for the first electron reduction were estimated by using the crossing point of the free energy profiles of CCl₃-Cl and CCl₃-Cl•- as a function of the CCl₃-Cl distance. The results of these calculations showed that the activation barriers for this reaction are reachable under a wide range of reduction potentials. In the gas-phase, the barrier to reduction varied from 0.8 kcal/mol for reducing agent with a -5 kcal/mol work function to 24.7 kcal/mol for a reducing agent with a 40 kcal/mol work function at the CCSD(T)/aug-cc-pVDZ level. In the aqueous phase, QM/MM calculations at the CCSD(T)/aug-cc-pVDZ level predicted that the barrier to reduction varied from 0.7 kcal/mol to 35.2 kcal/mol for -2.32 V and 0.93 V reduction potentials respectively. COSMO continuum solvation calculations were also performed for comparison. For strong reducing agents (EH < -1.5V) very little difference was seen between the QM/MM and COSMO activation barriers. For weak reducing agents (EH > 0V) the activation barriers differed by as much as 6 kcal/mol between the QM/MM and COSMO calculations. These results demonstrate that ab initio electronic structure methods coupled with explicit molecular mechanics representation of the aqueous environment offer an efficient and accurate way to calculate the free energy reaction barriers for dissociative electron transfer reactions of organochlorine compounds to identify the potentially important environmental degradation processes.

  2. Involvement of a glibenclamide-sensitive mechanism in the nitrergic neurotransmission of the pig intravesical ureter

    PubMed Central

    Hernández, Medardo; Prieto, Dolores; Orensanz, Luis M; Barahona, María Victoria; Jiménez-Cidre, Miguel; Rivera, Luis; García-Sacristán, Albino; Simonsen, Ulf

    1997-01-01

    The present study was designed to investigate whether potassium (K+) channels are involved in the relaxations to nitric oxide (NO) of pig intravesical ureteral preparations suspended in organ baths for isometric tension recordings. In ureteral strips treated with guanethidine (10−5 M) and atropine (10−7 M) to block adrenergic neurotransmission and muscarinic receptors, respectively, NO was either released from nitrergic nerves by electrical field stimulation (EFS, 0.5–10 Hz, 1 ms duration, 20 s trains), or exogenously-applied as an acidified solution of sodium nitrite (NaNO2, 10−6–10−3 M).Incubation with an inhibitor of guanylate cyclase activation by NO, methylene blue (10−5 M) did not change the basal tension of intravesical ureteral strips but inhibited the relaxation induced by EFS or exogenous NO on ureteral preparations contracted with the thromboxane analogue U46619 (10−7 M).Incubation with charybdotoxin (3×10−8 M) and apamin (5×10−7 M), which are inhibitors of large and small conductance calcium (Ca2+)-activated K+ channels, respectively, did not modify basal tension or the relaxations induced by EFS and exogenous NO. Treatment with charybdotoxin or apamin plus methylene blue (10−5 M) significantly reduced the relaxations to EFS and exogenous NO. However, in both cases the reductions were similar to the inhibition evoked by methylene blue alone. The combined addition of charybdotoxin plus apamin did not change the relaxations to EFS or exogenously added NO of the porcine intravesical ureter.Cromakalim (10−8–3×10−6 M), an opener of ATP-sensitive K+ channels, evoked a dose-dependent relaxation with a pD2 of 7.3±0.2 and maximum relaxant effect of a 71.8±4.2% of the contraction induced by U46619 in the pig intravesical ureter. The blocker of ATP-sensitive K+ channels, glibenclamide (10−6 M), inhibited markedly the relaxations to cromakalim.Glibenclamide (10−6 M) had no effect on the basal tone of

  3. Swarming mechanisms in the yellow fever mosquito: aggregation pheromones involved in the mating behavior of Aedes aegypti

    USDA-ARS?s Scientific Manuscript database

    Mosquitoes of various species mate in swarms comprised of tens to thousands flying males. Yet little information is known about mosquito swarming mechanism. Discovering chemical cues involved in mosquito biology leads to better adaptation of disease control interventions. In this study, we aimed ...

  4. Sodium tungstate activates glycogen synthesis through a non-canonical mechanism involving G-proteins.

    PubMed

    Zafra, Delia; Nocito, Laura; Domínguez, Jorge; Guinovart, Joan J

    2013-01-31

    Tungstate treatment ameliorates experimental diabetes by increasing liver glycogen deposition through an as yet unidentified mechanism. The signalling mechanism of tungstate was studied in CHOIR cells and primary cultured hepatocytes. This compound exerted its pro-glycogenic effects through a new G-protein-dependent and Tyr-Kinase Receptor-independent mechanism. Chemical or genetic disruption of G-protein signalling prevented the activation of the Ras/ERK cascade and the downstream induction of glycogen synthesis caused by tungstate. Thus, these findings unveil a novel non-canonical signalling pathway that leads to the activation of glycogen synthesis and that could be exploited as an approach to treat diabetes.

  5. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect.

    PubMed

    Shen, Yuh-Chiang; Chen, Chieh-Fu; Chiou, Wen-Fei

    2002-01-01

    We have reported that andrographolide (ANDRO), an active component of Andrographis paniculata, inhibits inflammatory responses by rat neutrophils. To further elucidate the possible mechanism(s) underlying the ANDRO's effect, N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced adhesion and transmigration of isolated peripheral human neutrophils were studied. Pretreatment with ANDRO (0.1 - 10 microM) concentration-dependently prevented fMLP-induced neutrophil adhesion and transmigration. We further examined the up-expression of surface Mac-1 (CD11b/CD18), an essential integrin mediated in neutrophil adhesion and transmigration. ANDRO pretreatment significantly decreased fMLP-induced up-expression of both CD11b and CD18. Accumulation of reactive oxygen species (ROS) as well as quick intracellular calcium ([Ca(++)](i)) mobilization induced by fMLP displays two important signalling pathways in regulating the up-expression of Mac-1 by neutrophils. That ANDRO pretreatment diminished fMLP-induced production of H(2)O(2) and O(2)*(-), but failed to block that of [Ca(++)](i) mobilization suggested that the ROS but not [Ca(++)](i) signalling could be modulated by ANDRO. To clarify whether ROS production impeded by ANDRO could be an antagonism of fMLP binding, phorbol-12-myristate-13-acetate (PMA), a direct protein kinase C (PKC) activator, was introduced to activate ROS production. PMA triggered remarkable ROS production and adhesion, and were partially reversed by ANDRO. This indicated that a PKC-dependent mechanism might be interfered by ANDRO. We conclude that the prevention of ROS production through, at least in part, modulation of PKC-dependent pathway could confer ANDRO the ability to down-regulate Mac-1 up-expression that is essential for neutrophil adhesion and transmigration.

  6. Effect of Mas-related gene (Mrg) receptors on hyperalgesia in rats with CFA-induced inflammation via direct and indirect mechanisms.

    PubMed

    Jiang, Jianping; Wang, Dongmei; Zhou, Xiaolong; Huo, Yuping; Chen, Tingjun; Hu, Fenjuan; Quirion, Rémi; Hong, Yanguo

    2013-11-01

    Mas oncogene-related gene (Mrg) receptors are exclusively distributed in small-sized neurons in trigeminal and dorsal root ganglia (DRG). We investigated the effects of MrgC receptor activation on inflammatory hyperalgesia and its mechanisms. A selective MrgC receptor agonist, bovine adrenal medulla peptide 8-22 (BAM8-22) or melanocyte-stimulating hormone (MSH) or the μ-opioid receptor (MOR) antagonist CTAP was administered intrathecally (i.t.) in rats injected with complete Freund's adjuvant (CFA) in one hindpaw. Thermal and mechanical nociceptive responses were assessed. Neurochemicals were measured by immunocytochemistry, Western blot, ELISA and RT-PCR. CFA injection increased mRNA for MrgC receptors in lumbar DRG. BAM8-22 or MSH, given i.t., generated instant short and delayed long-lasting attenuations of CFA-induced thermal hyperalgesia, but not mechanical allodynia. These effects were associated with decreased up-regulation of neuronal NOS (nNOS), CGRP and c-Fos expression in the spinal dorsal horn and/or DRG. However, i.t. administration of CTAP blocked the induction by BAM8-22 of delayed anti-hyperalgesia and inhibition of nNOS and CGRP expression in DRG. BAM8-22 also increased mRNA for MORs and pro-opiomelanocortin, along with β-endorphin content in the lumbar spinal cord and/or DRG. MrgC receptors and nNOS were co-localized in DRG neurons. Activation of MrgC receptors suppressed up-regulation of pronociceptive mediators and consequently inhibited inflammatory pain, because of the activation of up-regulated MrgC receptors and subsequent endogenous activity at MORs. The uniquely distributed MrgC receptors could be a novel target for relieving inflammatory pain. © 2013 The British Pharmacological Society.

  7. Effect of Mas-related gene (Mrg) receptors on hyperalgesia in rats with CFA-induced inflammation via direct and indirect mechanisms

    PubMed Central

    Jiang, Jianping; Wang, Dongmei; Zhou, Xiaolong; Huo, Yuping; Chen, Tingjun; Hu, Fenjuan; Quirion, Rémi; Hong, Yanguo

    2013-01-01

    Background and Purpose Mas oncogene-related gene (Mrg) receptors are exclusively distributed in small-sized neurons in trigeminal and dorsal root ganglia (DRG). We investigated the effects of MrgC receptor activation on inflammatory hyperalgesia and its mechanisms. Experimental Approach A selective MrgC receptor agonist, bovine adrenal medulla peptide 8-22 (BAM8-22) or melanocyte-stimulating hormone (MSH) or the μ-opioid receptor (MOR) antagonist CTAP was administered intrathecally (i.t.) in rats injected with complete Freund's adjuvant (CFA) in one hindpaw. Thermal and mechanical nociceptive responses were assessed. Neurochemicals were measured by immunocytochemistry, Western blot, ELISA and RT-PCR. Key Results CFA injection increased mRNA for MrgC receptors in lumbar DRG. BAM8-22 or MSH, given i.t., generated instant short and delayed long-lasting attenuations of CFA-induced thermal hyperalgesia, but not mechanical allodynia. These effects were associated with decreased up-regulation of neuronal NOS (nNOS), CGRP and c-Fos expression in the spinal dorsal horn and/or DRG. However, i.t. administration of CTAP blocked the induction by BAM8-22 of delayed anti-hyperalgesia and inhibition of nNOS and CGRP expression in DRG. BAM8-22 also increased mRNA for MORs and pro-opiomelanocortin, along with β-endorphin content in the lumbar spinal cord and/or DRG. MrgC receptors and nNOS were co-localized in DRG neurons. Conclusions and Implications Activation of MrgC receptors suppressed up-regulation of pronociceptive mediators and consequently inhibited inflammatory pain, because of the activation of up-regulated MrgC receptors and subsequent endogenous activity at MORs. The uniquely distributed MrgC receptors could be a novel target for relieving inflammatory pain. PMID:23909597

  8. Regulation of local host-mediated anti-tumor mechanisms by cytokines: direct and indirect effects on leukocyte recruitment and angiogenesis.

    PubMed Central

    Watanabe, M.; McCormick, K. L.; Volker, K.; Ortaldo, J. R.; Wigginton, J. M.; Brunda, M. J.; Wiltrout, R. H.; Fogler, W. E.

    1997-01-01

    The regulation of tumor growth by cytokine-induced alterations in host effector cell recruitment and activation is intimately associated with leukocyte adhesion and angiogenic modulation. In the present study, we have developed a novel tumor model to investigate this complex series of events in response to cytokine administration. Gelatin sponges containing recombinant human basic fibroblast growth factor (rhFGFb) and B16F10 melanoma cells were implanted onto the serosal surface of the left lateral hepatic lobe in syngeneic C57BL/6 mice. The tumor model was characterized by progressive tumor growth initially localized within the sponge and the subsequent development of peritoneal carcinomatosis. Microscopic examination of the sponge matrix revealed well developed tumor-associated vascular structures and areas of endothelial cell activation as evidenced by leukocyte margination. Treatment of mice 3 days after sponge implantation with a therapeutic regimen consisting of pulse recombinant human interleukin-2 (rhIL-2) combined with recombinant murine interleukin-12 (rmIL-12) resulted in a marked hepatic mononuclear infiltrate and inhibition of tumor growth. In contrast to the control group, sponges from mice treated with rhIL-2/rmIL-12 demonstrated an overall lack of cellularity and vascular structure. The regimen of rhIL-2 in combination with rmIL-12 was equally effective against gelatin sponge implants of rhFGFb/B16F10 melanoma in SCID mice treated with anti-asialo-GM1 in the absence of a mononuclear infiltration, suggesting that T, B, and/or NK cells were not the principal mediators of the anti-tumor response in this tumor model. The absence of vascularity within the sponge after treatment suggests that a potential mechanism of rhIL-2/rmIL-12 anti-tumor activity is the inhibition of neovascular growth associated with the establishment of tumor lesions. This potential mechanism could be dissociated from the known activities of these two cytokines to induce the

  9. A Mechanism for Land-Atmosphere Feedback Involving Planetary Wave Structures

    NASA Technical Reports Server (NTRS)

    Koster, Randal D.; Chang, Yehui; Schubert, Siegfried D.

    2014-01-01

    While the ability of land surface conditions to influence the atmosphere has been demonstrated in various modeling and observational studies, the precise mechanisms by which land-atmosphere feedback occurs are still largely unknown particularly the mechanisms that allow land moisture state in one region to affect atmospheric conditions in another. Such remote impacts are examined here in the context of atmospheric general circulation model (AGCM) simulations, leading to the identification of one potential mechanism: the phase-locking and amplification of a planetary wave through the imposition of a spatial pattern of soil moisture at the land surface. This mechanism, shown here to be relevant in the AGCM, apparently also operates in nature, as suggested by supporting evidence found in reanalysis data.

  10. Molecules and mechanisms involved in the generation and migration of cortical interneurons.

    PubMed

    Hernández-Miranda, Luis R; Parnavelas, John G; Chiara, Francesca

    2010-03-31

    The GABA (γ-aminobutyric acid)-containing interneurons of the neocortex are largely derived from the ganglionic eminences in the subpallium. Numerous studies have previously defined the migratory paths travelled by these neurons from their origins to their destinations in the cortex. We review here results of studies that have identified many of the genes expressed in the subpallium that are involved in the specification of the subtypes of cortical interneurons, and the numerous transcription factors, motogenic factors and guidance molecules that are involved in their migration.

  11. Molecules and mechanisms involved in the generation and migration of cortical interneurons

    PubMed Central

    Hernández-Miranda, Luis R; Parnavelas, John G; Chiara, Francesca

    2010-01-01

    The GABA (γ-aminobutyric acid)-containing interneurons of the neocortex are largely derived from the ganglionic eminences in the subpallium. Numerous studies have previously defined the migratory paths travelled by these neurons from their origins to their destinations in the cortex. We review here results of studies that have identified many of the genes expressed in the subpallium that are involved in the specification of the subtypes of cortical interneurons, and the numerous transcription factors, motogenic factors and guidance molecules that are involved in their migration. PMID:20360946

  12. Indirect Comparisons and Network Meta-Analyses.

    PubMed

    Kiefer, Corinna; Sturtz, Sibylle; Bender, Ralf

    2015-11-20

    Systematic reviews provide a structured summary of the results of trials that have been carried out on any particular subject. If the data from multiple trials are sufficiently homogenous, a meta-analysis can be performed to calculate pooled effect estimates. Traditional meta-analysis involves groups of trials that compare the same two interventions directly (head to head). Lately, however, indirect comparisons and network metaanalyses have become increasingly common. Various methods of indirect comparison and network meta-analysis are presented and discussed on the basis of a selective review of the literature. The main assumptions and requirements of these methods are described, and a checklist is provided as an aid to the evaluation of published indirect comparisons and network meta-analyses. When no head-to-head trials of two interventions are available, indirect comparisons and network metaanalyses enable the estimation of effects as well as the simultaneous analysis of networks involving more than two interventions. Network meta-analyses and indirect comparisons can only be useful if the trial or patient characteristics are similar and the observed effects are sufficiently homogeneous. Moreover, there should be no major discrepancy between the direct and indirect evidence. If trials are available that compare each of two treatments against a third one, but not against each other, then the third intervention can be used as a common comparator to enable a comparison of the other two. Indirect comparisons and network metaanalyses are an important further development of traditional meta-analysis. Clear and detailed documentation is needed so that findings obtained by these new methods can be reliably judged.

  13. In vitro reassortment between Infectious Pancreatic Necrosis Virus (IPNV) strains: The mechanisms involved and its effect on virulence.

    PubMed

    Lago, María; Bandín, Isabel; Olveira, José G; Dopazo, Carlos P

    2017-01-15

    Reassortment is one of the main mechanisms of evolution in dsRNA viruses with segmented genomes. It contributes to generate genetic diversity and plays an important role in the emergence and spread of new strains with altered virulence. Natural reassorment has been demonstrated among infectious pancreatic necrosis-like viruses (genus Aquabirnavirus, Birnaviridae). In the present study, coinfections between different viral strains, and genome sequencing by the Sanger and Illumina methods were applied to analyze the frequency of reassortment of this virus in vitro, the possible mechanisms involved, and its effect on virulence. Results have demonstrated that reassortment is a cell-dependent and non-random process, probably through differential expression of the different mRNA classes in the ribosomes of a specific cell, and by specific associations between the components to construct the ribonucleoprotein (RNP) complexes and/or RNP cross-inhibition. However, the precise mechanisms involved, known in other viruses, still remain to be demonstrated in birnaviruses.

  14. Cumulative asbestos exposure for US automobile mechanics involved in brake repair (circa 1950s-2000).

    PubMed

    Finley, Brent L; Richter, Richard O; Mowat, Fionna S; Mlynarek, Steve; Paustenbach, Dennis J; Warmerdam, John M; Sheehan, Patrick J

    2007-11-01

    We analyzed cumulative lifetime exposure to chrysotile asbestos experienced by brake mechanics in the US during the period 1950-2000. Using Monte Carlo methods, cumulative exposures were calculated using the distribution of 8-h time-weighted average exposure concentrations for brake mechanics and the distribution of job tenure data for automobile mechanics. The median estimated cumulative exposures for these mechanics, as predicted by three probabilistic models, ranged from 0.16 to 0.41 fibers per cubic centimeter (f/cm(3)) year for facilities with no dust-control procedures (1970s), and from 0.010 to 0.012 f/cm(3) year for those employing engineering controls (1980s). Upper-bound (95%) estimates for the 1970s and 1980s were 1.96 to 2.79 and 0.07-0.10 f/cm(3) year, respectively. These estimates for US brake mechanics are consistent with, but generally slightly lower than, those reported for European mechanics. The values are all substantially lower than the cumulative exposure of 4.5 f/cm(3) year associated with occupational exposure to 0.1 f/cm(3) of asbestos for 45 years that is currently permitted under the current occupational exposure limits in the US. Cumulative exposures were usually about 100- to 1,000-fold less than those of other occupational groups with asbestos exposure for similar time periods. The cumulative lifetime exposure estimates presented here, combined with the negative epidemiology data for brake mechanics, could be used to refine the risk assessments for chrysotile-exposed populations.

  15. Dysregulation of apoptosis is a major mechanism in the lymph node involvement in colorectal carcinoma.

    PubMed

    Bandres, Eva; Catalan, Victoria; Sola, Iosu; Honorato, Beatriz; Cubedo, Elena; Cordeu, Lucia; Andion, Esther; Escalada, Alvaro; Zarate, Ruth; Salgado, Esteban; Zabalegui, Natalia; García, Fermin; Garcia-Foncillas, Jesus

    2004-08-01

    The purpose of this study was to define gene expression profile changes in colorectal tumors in order to identify target genes involved in neoplastic progression. cDNA microarray analysis was used to detect differences in gene expression profiles between colon tumor samples obtained from 20 patients in different tumor stages. Genes included in the cDNA microarray were selected according to their role in the cell cycle, apoptosis process, drug resistance and transcription factor regulation. Cluster analysis showed 2 well differentiated gene expression profiles between colorectal tumors with or without lymph node involvement. Some of these genes are important regulators of apoptotic pathways (DAD1, APO3, DRAK1 or BIK), suggesting that this process could be associated with node involvement. Subsequent analysis of certain genes identified in the microarray analysis were confirmed by quantitative real-time PCR. Our data suggest that microarray technology could discriminate between the involvement of regional lymph node in colon cancer where apoptosis-related genes would be implied. This preliminary analysis also suggests that the gene expression profile may be useful in improving risk-group stratification.

  16. Sensitizing Children to the Social and Emotional Mechanisms Involved in Racism: A Program Evaluation

    ERIC Educational Resources Information Center

    Triliva, Sofia; Anagnostopoulou, Tanya; Vleioras, Georgios

    2014-01-01

    This paper describes and discusses the results of an intervention aiming to sensitize children to the social and emotional processes involved in racism. The intervention was applied and evaluated in 10 Greek elementary schools. The goals and the intervention methods of the program modules are briefly outlined and the results of the program…

  17. Activated spinal astrocytes are involved in the maintenance of chronic widespread mechanical hyperalgesia after cast immobilization

    PubMed Central

    2014-01-01

    Background In the present study, we examined spinal glial cell activation as a central nervous system mechanism of widespread mechanical hyperalgesia in rats that experienced chronic post-cast pain (CPCP) 2 weeks after cast immobilization. Activated spinal microglia and astrocytes were investigated immunohistologically in lumbar and coccygeal spinal cord segments 1 day, 5 weeks, and 13 weeks following cast removal. Results In the lumbar cord, astrocytes were activated after microglia. Astrocytes also were activated after microglia in the coccygeal cord, but with a delay that was longer than that observed in the lumbar cord. This activation pattern paralleled the observation that mechanical hyperalgesia occurred in the hindleg or the hindpaw before the tail. The activating transcription factor 3 (ATF3) immune response in dorsal root ganglia (DRG) on the last day of cast immobilization suggested that nerve damage might not occur in CPCP rats. The neural activation assessed by the phosphorylated extracellular signal-regulated kinase (pERK) immune response in DRG arose 1 day after cast removal. In addition, L-α-aminoadipate (L-α-AA), an inhibitor of astrocyte activation administered intrathecally 5 weeks after cast removal, inhibited mechanical hyperalgesia in several body parts including the lower leg skin and muscles bilaterally, hindpaws, and tail. Conclusions These findings suggest that activation of lumbar cord astrocytes is an important factor in widespread mechanical hyperalgesia in CPCP. PMID:24456903

  18. Indirect reciprocity with trinary reputations.

    PubMed

    Tanabe, Shoma; Suzuki, Hideyuki; Masuda, Naoki

    2013-01-21

    Indirect reciprocity is a reputation-based mechanism for cooperation in social dilemma situations when individuals do not repeatedly meet. The conditions under which cooperation based on indirect reciprocity occurs have been examined in great details. Most previous theoretical analysis assumed for mathematical tractability that an individual possesses a binary reputation value, i.e., good or bad, which depends on their past actions and other factors. However, in real situations, reputations of individuals may be multiple valued. Another puzzling discrepancy between the theory and experiments is the status of the so-called image scoring, in which cooperation and defection are judged to be good and bad, respectively, independent of other factors. Such an assessment rule is found in behavioral experiments, whereas it is known to be unstable in theory. In the present study, we fill both gaps by analyzing a trinary reputation model. By an exhaustive search, we identify all the cooperative and stable equilibria composed of a homogeneous population or a heterogeneous population containing two types of players. Some results derived for the trinary reputation model are direct extensions of those for the binary model. However, we find that the trinary model allows cooperation under image scoring under some mild conditions.

  19. The Role and Mechanisms of Action of Glucocorticoid Involvement in Memory Storage

    PubMed Central

    Sandi, Carmen

    1998-01-01

    Adrenal steroid hormones modulate learning and memory processes by interacting with specific glucocorticoid receptors at different brain areas. In this article, certain components of the physiological response to stress elicited by learning situations are proposed to form an integral aspect of the neurobiological mechanism underlying memory formation. By reviewing the work carried out in different learning models in chicks (passive avoidance learning) and rats (spatial orientation in the Morris water maze and contextual fear conditioning), a role for brain corticosterone action through the glucocorticoid receptor type on the mechanisms of memory consolidation is hypothesized. Evidence is also presented to relate post-training corticosterone levels to the strength of memory storage. Finally, the possible molecular mechanisms that might mediate the influences of glucocorticoids in synaptic plasticity subserving long-term memory formation are considered, mainly by focusing on studies implicating a steroid action through (i) glutamatergic transmission and (ii) cell adhesion molecules. PMID:9920681

  20. [Biological effects of arsenic and diseases: The mechanisms involved in arsenic-induced carcinogenesis].

    PubMed

    Suzuki, Takehiro; Takumi, Shota; Okamura, Kazuyuki; Nohara, Keiko

    2016-07-01

    Chronic arsenic exposure is associated with many diseases, including cancers. Our study using in vivo assay in gpt-delta transgenic mice showed that arsenic particularly induces G : C to T : A transversions, a mutation type induced through oxidative-stress-induced 8-OHdG formation. Gestational arsenic exposure of C3H mice was reported to increase hepatic tumor incidence. We showed that gestational arsenic exposure increased hepatic tumors having activated oncogene Ha-ras by C to A mutation. We also showed that DNA methylation status of Fosb region is implicated in tumor augmentation by gestational arsenic exposure. We further showed that long-term arsenic exposure induces premature senescence. Recent studies reported that senescence is involved in not only tumor suppression, but also tumorgenesis. All these effects of arsenic might be involved in arsenic-induced carcinogenesis.

  1. Pragma- und textilinguistische Untersuchungsmethoden zur indirekten Rede im Englischen (Pragmatic and Text-Linguistic Research Methods on Indirect Discourse in English)

    ERIC Educational Resources Information Center

    Ziegesar, Detlef von

    1976-01-01

    Examines the mechanisms involved in changing from direct to indirect discourse, taking as a starting point research findings in linguistic pragmatics, which involve the practical application of speech symbol use between speaker and hearer. (Text is in German.) (IFS/WGA)

  2. Pragma- und textilinguistische Untersuchungsmethoden zur indirekten Rede im Englischen (Pragmatic and Text-Linguistic Research Methods on Indirect Discourse in English)

    ERIC Educational Resources Information Center

    Ziegesar, Detlef von

    1976-01-01

    Examines the mechanisms involved in changing from direct to indirect discourse, taking as a starting point research findings in linguistic pragmatics, which involve the practical application of speech symbol use between speaker and hearer. (Text is in German.) (IFS/WGA)

  3. "Coding" and "Decoding": hypothesis for the regulatory mechanism involved in heparan sulfate biosynthesis.

    PubMed

    Zhang, Xu; Wang, Fengshan; Sheng, Juzheng

    2016-06-16

    Heparan sulfate (HS) is widely distributed in mammalian tissues in the form of HS proteoglycans, which play essential roles in various physiological and pathological processes. In contrast to the template-guided processes involved in the synthesis of DNA and proteins, HS biosynthesis is not believed to involve a template. However, it appears that the final structure of HS chains was strictly regulated. Herein, we report research based hypothesis that two major steps, namely "coding" and "decoding" steps, are involved in the biosynthesis of HS, which strictly regulate its chemical structure and biological activity. The "coding" process in this context is based on the distribution of sulfate moieties on the amino groups of the glucosamine residues in the HS chains. The sulfation of these amine groups is catalyzed by N-deacetylase/N-sulfotransferase, which has four isozymes. The composition and distribution of sulfate groups and iduronic acid residues on the glycan chains of HS are determined by several other modification enzymes, which can recognize these coding sequences (i.e., the "decoding" process). The degree and pattern of the sulfation and epimerization in the HS chains determines the extent of their interactions with several different protein factors, which further influences their biological activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Bioechnology of indirect liquefaction

    SciTech Connect

    Datta, R.; Jain, M.K.; Worden, R.M.; Grethlein, A.J.; Soni, B.; Zeikus, J.G.; Grethlein, H.

    1990-05-07

    The project on biotechnology of indirect liquefaction was focused on conversion of coal derived synthesis gas to liquid fuels using a two-stage, acidogenic and solventogenic, anaerobic bioconversion process. The acidogenic fermentation used a novel and versatile organism, Butyribacterium methylotrophicum, which was fully capable of using CO as the sole carbon and energy source for organic acid production. In extended batch CO fermentations the organism was induced to produce butyrate at the expense of acetate at low pH values. Long-term, steady-state operation was achieved during continuous CO fermentations with this organism, and at low pH values (a pH of 6.0 or less) minor amounts of butanol and ethanol were produced. During continuous, steady-state fermentations of CO with cell recycle, concentrations of mixed acids and alcohols were achieved (approximately 12 g/l and 2 g/l, respectively) which are high enough for efficient conversion in stage two of the indirect liquefaction process. The metabolic pathway to produce 4-carbon alcohols from CO was a novel discovery and is believed to be unique to our CO strain of B. methylotrophicum. In the solventogenic phase, the parent strain ATCC 4259 of Clostridium acetobutylicum was mutagenized using nitrosoguanidine and ethyl methane sulfonate. The E-604 mutant strain of Clostridium acetobutylicum showed improved characteristics as compared to parent strain ATCC 4259 in batch fermentation of carbohydrates.

  5. siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms.

    PubMed

    Morgan-Warren, Peter J; O'Neill, Jenna; de Cogan, Felicity; Spivak, Igor; Ashush, Hagit; Kalinski, Hagar; Ahmed, Zubair; Berry, Martin; Feinstein, Elena; Scott, Robert A H; Logan, Ann

    2016-02-01

    To investigate, using in vivo and in vitro models, retinal ganglion cell (RGC) neuroprotective and axon regenerative effects and underlying mechanisms of siRTP801, a translatable small-interfering RNA (siRNA) targeting the mTOR negative regulator RTP801. Adult rats underwent optic nerve (ON) crush (ONC) followed by intravitreal siRTP801 or control siRNA (siEGFP) every 8 days, with Brn3a+ RGC survival, GFAP+ reactive gliosis, and GAP43+ regenerating axons analyzed immunohistochemically 24 days after injury. Retinal cultures, prepared from uninjured animals or 5 days after ONC to activate retinal glia, were treated with siRTP801/controls in the presence/absence of rapamycin and subsequently assessed for RGC survival and neurite outgrowth, RTP801 expression, glial responses, and mTOR activity. Conditioned medium was analyzed for neurotrophin titers by ELISA. Intravitreal siRTP801 enabled 82% RGC survival compared to 45% with siEGFP 24 days after ONC, correlated with greater GAP43+ axon regeneration at 400 to 1200 μm beyond the ONC site, and potentiated the reactive GFAP+ Müller glial response. In culture, siRTP801 had a direct RGC neuroprotective effect, but required GFAP+ activated glia to stimulate neurite elongation. The siRTP801-induced neuroprotection was significantly reduced, but not abolished, by rapamycin. The siRTP801 potentiated the production and release of neurotrophins NGF, NT-3, and BDNF, and prevented downregulation of RGC mTOR activity. The RTP801 knockdown promoted RGC survival and axon elongation after ONC, without increasing de novo regenerative sprouting. The neuroprotection was predominantly direct, with mTORC1-dependent and -independent components. Enhanced neurite/axon elongation by siRTP801 required the presence of activated retinal glia and was mediated by potentiated secretion of neurotrophic factors.

  6. Are immunological mechanisms involved in colon cancer and are they possible markers for biotherapy improvement?

    PubMed

    Berghella, Anna Maria; Contasta, Ida; Pellegrini, Patrizia; Del Beato, Tiziana; Adorno, Domenico

    2006-10-01

    This paper focuses on our data on colon cancer patients. Our overall results lead us to believe that the suppressive effect of specific cytokines in colon cancer patients alters the functionality of TH1 and TH2 subsets of CD4+ T-cells, with an expansion of TH2 cells and a malfunctioning of TH1 cells. This immunological disregulation appears to increase with stage progression, suggesting a direct role in the mechanisms that allow the tumour to locate and expand within the host. It is also clear that in order to identify disease markers and generate an in vivo immune response that corrects the imbalance between TH1 and TH2 cells, we need to understand how tumour mechanisms cause this imbalance to begin with.

  7. Motivational concordance: an important mechanism in self-help therapeutic rituals involving inert (placebo) substances.

    PubMed

    Hyland, Michael E; Whalley, Ben

    2008-11-01

    We tested the contribution of two mechanisms, response expectancy and motivational concordance, to reported psychological benefit from a popular, biologically inactive, self-help, complementary therapy (a placebo). Flower essences were taken by 251 people for self-selected symptoms and were randomized to receive three different kinds of information. When the flower essence was presented as a spiritual therapy, then baseline spirituality (beta=.35, P=.01) and expectancy (beta=.25, P=.03) independently predicted outcome. When flower essences were presented as an affirmation (i.e., nonspiritual) therapy, then spirituality negatively (beta=-.27, P=.03) and expectancy (beta=.33, P=.01) predicted outcome. For both groups, expectancy predicted outcome after controlling for spirituality and compliance, but did not after controlling for ease of task completion. Expectancy failed to predict outcome in the nonenhanced ritual group. The results suggest that motivational concordance is an important therapeutic mechanism for real-life placebos.

  8. Molecular mechanisms involved in the bidirectional relationship between diabetes mellitus and periodontal disease

    PubMed Central

    Grover, Harpreet Singh; Luthra, Shailly

    2013-01-01

    Both diabetes and periodontitis are chronic diseases. Diabetes has many adverse effects on the periodontium, and conversely periodontitis may have deleterious effects further aggravating the condition in diabetics. The potential common pathophysiologic pathways include those associated with inflammation, altered host responses, altered tissue homeostasis, and insulin resistance. This review examines the relationship that exists between periodontal diseases and diabetes mellitus with a focus on potential common pathophysiologic mechanisms. PMID:24049328

  9. Molecular mechanisms involved in the bidirectional relationship between diabetes mellitus and periodontal disease.

    PubMed

    Grover, Harpreet Singh; Luthra, Shailly

    2013-05-01

    Both diabetes and periodontitis are chronic diseases. Diabetes has many adverse effects on the periodontium, and conversely periodontitis may have deleterious effects further aggravating the condition in diabetics. The potential common pathophysiologic pathways include those associated with inflammation, altered host responses, altered tissue homeostasis, and insulin resistance. This review examines the relationship that exists between periodontal diseases and diabetes mellitus with a focus on potential common pathophysiologic mechanisms.

  10. Mechanisms involved in hearing disorders of thyroid ontogeny: a literature review.

    PubMed

    Andrade, Caio Leônidas Oliveira de; Machado, Gabriela Carvalho; Fernandes, Luciene da Cruz; Albuquerque, Jamile Morais de; Casais-E-Silva, Luciana Lyra; Ramos, Helton Estrela; Alves, Crésio de Aragão Dantas

    2017-09-18

    Endocochlear, retrocochlear and/or central origin hearing damage may be related to the absence of appropriate levels of thyroid hormone during morphogenesis and/or auditory system development. Hearing disorders related to the thyroid are not well studied, despite speculation on the pathophysiological mechanisms. The objective of this review was to characterize the main pathophysiological mechanisms of congenital hypothyroidism and to evaluate the relationship with central and peripheral hearing disorders. We conducted a literature review using the databases MedLine, LILACS, Cochrane Library, SciELO, Institute for Scientific Information (ISI), Embase, and Science Direct between July and September on 2016. We identified the studies that address hearing disorder mechanisms on the congenital hypothyroidism. Congenital hypothyroidism may have clinical and subclinical manifestations that affect the auditory system and may be a potential risk factor for hearing impairment. Hearing impairment can severely impact quality-of-life, which emphasizes the importance of monitoring and evaluating hearing during the clinical routine of these patients.

  11. Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and -independent mechanisms

    PubMed Central

    Ali, A; Bluteau, O; Messaoudi, K; Palazzo, A; Boukour, S; Lordier, L; Lecluse, Y; Rameau, P; Kraus-Berthier, L; Jacquet-Bescond, A; Lelièvre, H; Depil, S; Dessen, P; Solary, E; Raslova, H; Vainchenker, W; Plo, I; Debili, N

    2013-01-01

    Abexinostat is a pan histone deacetylase inhibitor (HDACi) that demonstrates efficacy in malignancy treatment. Like other HDACi, this drug induces a profound thrombocytopenia whose mechanism is only partially understood. We have analyzed its effect at doses reached in patient plasma on in vitro megakaryopoiesis derived from human CD34+ cells. When added at day 0 in culture, abexinostat inhibited CFU-MK growth, megakaryocyte (MK) proliferation and differentiation. These effects required only a short incubation period. Decreased proliferation was due to induction of apoptosis and was not related to a defect in TPO/MPL/JAK2/STAT signaling. When added later (day 8), the compound induced a dose-dependent decrease (up to 10-fold) in proplatelet (PPT) formation. Gene profiling from MK revealed a silencing in the expression of DNA repair genes with a marked RAD51 decrease at protein level. DNA double-strand breaks were increased as attested by elevated γH2AX phosphorylation level. Moreover, ATM was phosphorylated leading to p53 stabilization and increased BAX and p21 expression. The use of a p53 shRNA rescued apoptosis, and only partially the defect in PPT formation. These results suggest that HDACi induces a thrombocytopenia by a p53-dependent mechanism along MK differentiation and a p53-dependent and -independent mechanism for PPT formation. PMID:23887629

  12. Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system

    PubMed Central

    Berrendero, Fernando; Robledo, Patricia; Trigo, José Manuel; Martín-García, Elena; Maldonado, Rafael

    2010-01-01

    Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An upregulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the downregulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain subpopulations of smokers. PMID:20170672

  13. Chicken hemogen homolog is involved in the chicken-specific sex-determining mechanism

    PubMed Central

    Nakata, Tomohiro; Ishiguro, Manabu; Aduma, Nana; Izumi, Hiroe; Kuroiwa, Asato

    2013-01-01

    Using a comprehensive transcriptome analysis, a Z chromosome-linked chicken homolog of hemogen (cHEMGN) was identified and shown to be specifically involved in testis differentiation in early chicken embryos. Hemogen [Hemgn in mice, EDAG (erythroid differentiation-associated gene protein) in humans] was recently characterized as a hematopoietic tissue-specific gene encoding a transcription factor that regulates the proliferation and differentiation of hematopoietic cells in mammals. In chicken, cHEMGN was expressed not only in hematopoietic tissues but also in the early embryonic gonad of male chickens. The male-specific expression was identified in the nucleus of (pre)Sertoli cells after the sex determination period and before the expression of SOX9 (SRY-box 9). The expression of cHEMGN was induced in ZW embryonic gonads that were masculinized by aromatase inhibitor treatment. ZW embryos overexpressing cHEMGN, generated by infection with retrovirus carrying cHEMGN, showed masculinized gonads. These findings suggest that cHEMGN is a transcription factor specifically involved in chicken sex determination. PMID:23401550

  14. Cerebral mechanisms involved in word reading in dyslexic children: a magnetic source imaging approach.

    PubMed

    Simos, P G; Breier, J I; Fletcher, J M; Bergman, E; Papanicolaou, A C

    2000-08-01

    The purpose of the present investigation was to describe spatiotemporal brain activation profiles during word reading using magnetic source imaging (MSI). Ten right-handed dyslexic children with severe phonological decoding problems and eight age-matched non-impaired readers were tested in two recognition tasks, one involving spoken and the other printed words. Dyslexic children's activation profiles during the printed word recognition task consistently featured activation of the left basal temporal cortices followed by activation of the right temporoparietal areas (including the angular gyrus). Non-impaired readers showed predominant activation of left basal followed by left temporoparietal activation. In addition, we were able to rule out the hypothesis that hypoactivation of left temporoparietal areas in dyslexics was due to a more general cerebral dysfunction in these areas. Rather, it seems likely that reading difficulties in developmental dyslexia are associated with an aberrant pattern of functional connectivity between brain areas normally involved in reading, namely ventral visual association cortex and temporoparietal areas in the left hemisphere. The interindividual consistency of activation profiles characteristic of children with dyslexia underlines the potential utility of this technique for examining neurophysiological changes in response to specific educational intervention approaches.

  15. Regulatory Mechanisms Involved in the Expression of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor

    DTIC Science & Technology

    1996-03-01

    of Philosophy, 1996 Dissertation Advisor: Gregory P. Mueller, PhD. Associate Professor Department of Physiology Brain-derived neurotrophic factor ( BDNF ...postsynaptic effects of BDNF and GDNF, very few have addressed the regulatory mechanisms involved in the expression of these factors. In phase 1 of the project...five alternate first exons contained in the rat BDNF gene, including a novel one termed exon la, were isolated and found to be individually spliced to

  16. On a Class of Laplace Inverses Involving Doubly-Nested Square Roots and their Applications in Continuum Mechanics

    DTIC Science & Technology

    2010-01-01

    Micropolar fluids Dipolar fluids a b s t r a c t The exact inverses of a class of Laplace transforms involving doubly-nested square roots and two branch...mechanics, for a micropolar fluid is determined. Published by Elsevier Ltd. 1. Introduction and problem formulation Using the Laplace transform, we...to the case of micropolar fluids, the theory of which was formulated by Eringen (1966). In doing so, we also extend the re- sults of Jordan et al

  17. Potential Molecular Mechanisms Involved in 5-Aminolevulinic Acid-Based Photodynamic Therapy against Human Hypertrophic Scars.

    PubMed

    Chang, Mengling; Ma, Xiaorong; Ouyang, Tianxiang; Lin, Jun; Liu, Jun; Xiao, Yan; Chen, Huiping; Yu, Jie; Huang, Yingying; Xu, Miao

    2015-10-01

    Hypertrophic scars are manifestations of an abnormal process of tissue repair. Although photodynamic therapy is a promising treatment, details of the mechanisms underlying its inhibitory effects remain to be elucidated. Fibroblasts were isolated from human hypertrophic scar specimens and subjected to photodynamic therapy; 5-aminolevulinic acid was used as a photosensitizer. The accumulation of 5-aminolevulinic acid-derived protoporphyrin IX was detected under fluorescence microscopy. The potential cytotoxicity of 5-aminolevulinic acid alone and with photodynamic therapy was measured by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide. Hoechst 33258 staining and flow cytometry were conducted to search for clues to apoptosis. Protein and/or mRNA expression levels of apoptosis-related pathways and other hypertrophic scar pathogenesis-associated signaling were investigated by Western blot analysis and/or real-time polymerase chain reaction. Protoporphyrin IX accumulation peak was achieved at 1.0 mM 5-aminolevulinic acid. 5-Aminolevulinic acid ranging from 0 to 1.0 mM was demonstrated to be noncytotoxic but reduced cell viabilities in a dose-dependent manner with acid-based photodynamic therapy were demonstrated. Reduction of cell viability was attributed mainly to cell apoptosis and probably to mechanisms such as up-regulation of p53/p21, Bax/Bcl-2 ratio, and cleaved caspase-3. Concurrently, deregulation of transforming growth factor-β1-mediated signaling, serving as another putative mechanism underlying hypertrophic scar formation, was found to be reversely modulated in response to acid-based photodynamic therapy. The p53-related apoptosis pathway and transforming growth factor-β1-mediated signaling may be important factors used to predict and evaluate the treatment outcomes of 5-aminolevulinic acid-based photodynamic therapy used in hypertrophic scar patients. Therapeutic, V.

  18. The principal motions involved in the coupling mechanism of the recovery stroke of the myosin motor.

    PubMed

    Mesentean, Sidonia; Koppole, Sampath; Smith, Jeremy C; Fischer, Stefan

    2007-03-23

    Muscle contraction is driven by a cycle of conformational changes in the myosin II head. After myosin binds ATP and releases from the actin fibril, myosin prepares for the next power stroke by rotating back the converter domain that carries the lever arm by 60 degrees . This recovery stroke is coupled to the activation of myosin ATPase by a mechanism that is essential for an efficient motor cycle. The mechanics of this coupling have been proposed to occur via two distinct and successive motions of the two helices that hold the converter domain: in a first phase a seesaw motion of the relay helix, followed by a piston-like motion of the SH1 helix in a second phase. To test this model, we have determined the principal motions of these structural elements during equilibrium molecular dynamics simulations of the crystallographic end states of the recovery-stroke by using principal component analysis. This reveals that the only principal motions of these two helices that make a large-amplitude contribution towards the conformational change of the recovery stroke are indeed the predicted seesaw and piston motions. Moreover, the results demonstrate that the seesaw motion of the relay helix dominates in the dynamics of the pre-recovery stroke structure, but not in the dynamics of the post-recovery stroke structure, and vice versa for the piston motion of the SH1 helix. This is consistent with the order of the proposed two-phase model for the coupling mechanism of the recovery stroke. Molecular movies of these principal motions are available at http://www.iwr.uni-heidelberg.de/groups/biocomp/fischer.

  19. Rejection triggers liver transplant tolerance: Involvement of mesenchyme-mediated immune control mechanisms in mice.

    PubMed

    Morita, Miwa; Joyce, Daniel; Miller, Charles; Fung, John J; Lu, Lina; Qian, Shiguang

    2015-09-01

    Liver tolerance was initially recognized by the spontaneous acceptance of liver allografts in many species. The underlying mechanisms are not completely understood. However, liver transplant (LT) tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigated the rejection of liver allografts deficient in the IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effector (Tef) cell-derived IFN-γ that drives expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in LT tolerance. Comparable elevations of T-regulatory cells and myeloid-derived suppressor cells were observed in both rejection and tolerance groups and were not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, given that spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity. MMIC may represent an important homeostatic mechanism that supports peripheral tolerance and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is an active participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers. © 2015 by the American Association for the Study of Liver Diseases.

  20. Rejection Triggers Liver Transplant Tolerance: Involvements of Mesenchyme-Mediated Immune Control Mechanisms

    PubMed Central

    Morita, Miwa; Joyce, Daniel; Miller, Charles; Fung, John J.; Lu, Lina; Qian, Shiguang

    2015-01-01

    Liver tolerance was initially recognized by the spontaneous acceptance of liver allograft in many species. The underlying mechanisms are not completely understood. We have been inspired by an unexpected phenomenon that the liver transplant tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigate the rejection of liver allografts deficient in IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effectors (Tef) cell-derived IFN-γ to drive the expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in liver transplant tolerance. Comparable elevations of T regulatory cells and myeloid-derived suppressor cells are seen in both rejection and tolerance groups, and are not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, as spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity. MMCI may represent an important homeostatic mechanism that supports peripheral tolerance, and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is actively participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers. PMID:25998530

  1. Involvement of three mechanisms in the alteration of cytokine responses by sodium methyldithiocarbamate

    SciTech Connect

    Pruett, Stephen B. . E-mail: spruet@LSUHSC.edu; Fan, Ruping; Zheng, Qiang

    2006-06-01

    Sodium methyldithiocarbamate (SMD) is the third most abundantly used conventional pesticide in the U.S. We recently reported that it alters the induction of cytokine production mediated though Toll-like receptor (TLR) 4 at relevant dosages in mice. Its chemical properties and evidence from the literature suggest thee potential mechanisms of action for this compound. It could either act as a free radical scavenger (by means of its free S{sup -}group) or promote oxidation by breaking down to form methylisothiocyanate, which can deplete glutathione. It is a potent copper chelator and may affect the availability of copper to a number of copper-dependent enzymes (including some signaling molecules). SMD induces a classical neuroendocrine stress response characterized by elevated serum corticosterone concentrations, which could affect cytokine production. Although each of these mechanisms could potentially contribute to altered cytokine responses, direct evidence is lacking. The present study was conducted to obtain such evidence. The role of redox balance was investigated by pretreating mice with N-acetyl cysteine (NAC), which increases cellular glutathione concentrations, before administration of SMD. NAC exacerbated the SMD-induced suppression of IL-12 and the SMD-induced enhancement of IL-10 in the serum. The role of copper chelation was investigated by comparing the effects of SMD with an equimolar dose to SMD that was administered in the form of a copper chelation complex. Addition of copper significantly decreased the action of SMD on IL-12 production but not on IL-10 production. The role of the stress response was investigated by pretreating mice with antagonists of corticosterone and catecholamines. This treatment partially prevented the action of SMD on IL-10 and IL-12 in the peritoneal fluid. The results suggest that all of the proposed mechanisms have some role in the alteration of cytokine production by SMD.

  2. The principal motions involved in the coupling mechanism of the recovery stroke of the myosin motor.

    SciTech Connect

    Mesentean, Sidonia; Koppole, Sampath; Smith, Jeremy C; Fischer, S.

    2007-03-01

    Muscle contraction is driven by a cycle of conformational changes in the myosin II head. After myosin binds ATP and releases from the actin fibril, myosin prepares for the next power stroke by rotating back the converter domain that carries the lever arm by 60{sup o}. This recovery stroke is coupled to the activation of myosin ATPase by a mechanism that is essential for an efficient motor cycle. The mechanics of this coupling have been proposed to occur via two distinct and successive motions of the two helices that hold the converter domain: in a first phase a seesaw motion of the relay helix, followed by a piston-like motion of the SH1 helix in a second phase. To test this model, we have determined the principal motions of these structural elements during equilibrium molecular dynamics simulations of the crystallographic end states of the recovery-stroke by using principal component analysis. This reveals that the only principal motions of these two helices that make a large-amplitude contribution towards the conformational change of the recovery stroke are indeed the predicted seesaw and piston motions. Moreover, the results demonstrate that the seesaw motion of the relay helix dominates in the dynamics of the pre-recovery stroke structure, but not in the dynamics of the post-recovery stroke structure, and vice versa for the piston motion of the SH1 helix. This is consistent with the order of the proposed two-phase model for the coupling mechanism of the recovery stroke. Molecular movies of these principal motions are available at http://www.iwr.uni-heidelberg.de/groups/biocomp/fischer.

  3. GR-127935-sensitive mechanism mediating hypotension in anesthetized rats: are 5-HT5B receptors involved?

    PubMed

    Sánchez-Maldonado, Carolina; López-Sánchez, Pedro; Anguiano-Robledo, Liliana; Leopoldo, Marcello; Lacivita, Enza; Terrón, José A

    2015-04-01

    The 5-HT1B/1D receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 receptor agonist, and 5-HT5A/5B receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D receptor antagonists. Also, expression of 5-HT5A and 5-HT5B receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 μg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5-HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 receptors. This mechanism, however, resembles putative 5-HT5B receptors.

  4. A novel mechanism involved in the coupling of mitochondrial biogenesis to oxidative phosphorylation

    PubMed Central

    Ostojić, Jelena; Rago, Jean-Paul; Dujardin, Geneviève

    2014-01-01

    Mitochondria are essential organelles that are central to a multitude of cellular processes, including oxidative phosphorylation (OXPHOS), which produces most of the ATP in animal cells. Thus it is important to understand not only the mechanisms and biogenesis of this energy production machinery but also how it is regulated in both physiological and pathological contexts. A recent study by Ostojić et al. [Cell Metabolism (2013) 18, 567-577] has uncovered a regulatory loop by which the biogenesis of a major enzyme of the OXPHOS pathway, the respiratory complex III, is coupled to the energy producing activity of the mitochondria. PMID:28357209

  5. Impact of conjugated linoleic acid on bone physiology: proposed mechanism involving inhibition of adipogenesis

    PubMed Central

    Ing, Steven W; Belury, Martha A

    2013-01-01

    Conjugated linoleic acid (CLA) supplementation decreases adipose mass and increases bone mass in mice. Recent clinical studies demonstrate a beneficial effect of CLA on reducing weight and adipose mass in humans. This article reviews possible biological mechanisms of action of CLA on bone metabolism, focusing on modulation of nuclear receptor peroxisome proliferator-activated receptor gamma activity to steer mesenchymal stem cell differentiation toward an adipose and away from an osteoblast lineage. Clinical studies of the effects of CLA on bone mass and clinical implications of the effects of CLA on bone health in humans are summarized and discussed. PMID:21348876

  6. Sorcin, a calcium binding protein involved in the multidrug resistance mechanisms in cancer cells.

    PubMed

    Colotti, Gianni; Poser, Elena; Fiorillo, Annarita; Genovese, Ilaria; Chiarini, Valerio; Ilari, Andrea

    2014-09-05

    Sorcin is a penta-EF hand calcium binding protein, which participates in the regulation of calcium homeostasis in cells. Sorcin regulates calcium channels and exchangers located at the plasma membrane and at the endo/sarcoplasmic reticulum (ER/SR), and allows high levels of calcium in the ER to be maintained, preventing ER stress and possibly, the unfolded protein response. Sorcin is highly expressed in the heart and in the brain, and overexpressed in many cancer cells. Sorcin gene is in the same amplicon as other genes involved in the resistance to chemotherapeutics in cancer cells (multi-drug resistance, MDR) such as ABCB4 and ABCB1; its overexpression results in increased drug resistance to a number of chemotherapeutic agents, and inhibition of sorcin expression by sorcin-targeting RNA interference leads to reversal of drug resistance. Sorcin is increasingly considered a useful marker of MDR and may represent a therapeutic target for reversing tumor multidrug resistance.

  7. Mechanism of silver staining of histones: evidence for involvement of clustered lysine residues.

    PubMed

    Kurosaki, T; Tsutsui, K; Tsutsui, K; Aoyama, K; Oda, T

    1984-09-17

    Pretreatment of histones with formaldehyde markedly enhances the formation of metalic silver from ammoniacal silver ion. The rate of silver reduction was determined with different histones by spectrophotometric measurement of colloidal silver stabilized in solution, and the apparent reactivity thus determined was found to be in the decreasing order of H1 greater than H2B greater than H2A greater than H3 greater than H4. Involvement of lysine residues was suggested since this order coincides with that of lysine content of these histones. However, the exceptionally high reactivity of histone H1 can be explained only when greater contribution of clustered lysine residues is assumed. Amino group modification and tryptic digestion studies of H1 corroborated this assumption.

  8. Mechanisms of Prescription Drug Diversion Among Drug-Involved Club- and Street-Based Populations

    PubMed Central

    Inciardi, James A.; Surratt, Hilary L.; Kurtz, Steven P.; Cicero, Theodore J.

    2010-01-01

    Objective Prescription drug diversion involves the unlawful channeling of regulated pharmaceuticals from legal sources to the illicit marketplace, and can occur along all points in the drug delivery process, from the original manufacturing site to the wholesale distributor, the physician's office, the retail pharmacy, or the patient. However, empirical data on diversion are limited. Method In an attempt to develop a better understanding of how specific drug-using populations are diverting prescription opioids and other medications, or obtaining controlled drugs that have already been diverted, qualitative interviews and focus group data were collected on four separate populations of prescription drug abusers in Miami, Florida—club drug users, street-based illicit drug users, methadone maintenance patients, and HIV positive individuals who abuse and/or divert drugs. Results Sources of abused prescription drugs cited by focus group participants were extremely diverse, including their physicians and pharmacists; parents and relatives; “doctor shopping”; leftover supplies following an illness or injury; personal visits to Mexico, South America and the Caribbean; prescriptions intended for the treatment of mental illness; direct sales on the street and in nightclubs; pharmacy and hospital theft; through friends or acquaintances; under-the-door apartment flyers advertising telephone numbers to call; and “stealing from grandma's medicine cabinet.” Conclusion While doctor shoppers, physicians and the Internet receive much of the attention regarding diversion, the data reported in this paper suggest that there are numerous active street markets involving patients, Medicaid recipients and pharmacies as well. In addition, there are other data which suggest that the contributions of residential burglaries, pharmacy robberies and thefts, and “sneak thefts” to the diversion problem may be understated. PMID:17305688

  9. Modulation of a voltage-gated Na+ channel by sevoflurane involves multiple sites and distinct mechanisms.

    PubMed

    Barber, Annika F; Carnevale, Vincenzo; Klein, Michael L; Eckenhoff, Roderic G; Covarrubias, Manuel

    2014-05-06

    Halogenated inhaled general anesthetic agents modulate voltage-gated ion channels, but the underlying molecular mechanisms are not understood. Many general anesthetic agents regulate voltage-gated Na(+) (NaV) channels, including the commonly used drug sevoflurane. Here, we investigated the putative binding sites and molecular mechanisms of sevoflurane action on the bacterial NaV channel NaChBac by using a combination of molecular dynamics simulation, electrophysiology, and kinetic analysis. Structural modeling revealed multiple sevoflurane interaction sites possibly associated with NaChBac modulation. Electrophysiologically, sevoflurane favors activation and inactivation at low concentrations (0.2 mM), and additionally accelerates current decay at high concentrations (2 mM). Explaining these observations, kinetic modeling suggests concurrent destabilization of closed states and low-affinity open channel block. We propose that the multiple effects of sevoflurane on NaChBac result from simultaneous interactions at multiple sites with distinct affinities. This multiple-site, multiple-mode hypothesis offers a framework to study the structural basis of general anesthetic action.

  10. Control of telomere length by a trimming mechanism that involves generation of t-circles

    PubMed Central

    Pickett, Hilda A; Cesare, Anthony J; Johnston, Rebecca L; Neumann, Axel A; Reddel, Roger R

    2009-01-01

    Telomere lengths are maintained in many cancer cells by the ribonucleoprotein enzyme telomerase but can be further elongated by increasing telomerase activity through the overexpression of telomerase components. We report here that increased telomerase activity results in increased telomere length that eventually reaches a plateau, accompanied by the generation of telomere length heterogeneity and the accumulation of extrachromosomal telomeric repeat DNA, principally in the form of telomeric circles (t-circles). Telomeric DNA was observed in promyelocytic leukemia bodies, but no intertelomeric copying or telomere exchange events were identified, and there was no increase in telomere dysfunction-induced foci. These data indicate that human cells possess a mechanism to negatively regulate telomere length by trimming telomeric DNA from the chromosome ends, most likely by t-loop resolution to form t-circles. Additionally, these results indicate that some phenotypic characteristics attributed to alternative lengthening of telomeres (ALT) result from increased mean telomere length, rather than from the ALT mechanism itself. PMID:19214183

  11. Inhibition of adrenomedullary catecholamine release by propranolol isomers and clonidine involving mechanisms unrelated to adrenoceptors.

    PubMed Central

    Orts, A.; Orellana, C.; Cantó, T.; Ceña, V.; González-García, C.; García, A. G.

    1987-01-01

    1 Transmural electrical stimulation (10 Hz, 40 V, 1 ms for 60s) increased total catecholamine secretion from perfused cat adrenal glands; this response was enhanced by neostigmine and inhibited by mecamylamine, suggesting that release of acetylcholine from splanchnic nerve terminals was stimulating nicotinic receptors and enhancing catecholamine secretion. 2 Isoprenaline, (-)-propranolol and (+)-propranolol (10(-7)-10(-5)M) inhibited the electrically-evoked secretory response by 40-70%; similar reductions were obtained with clonidine and yohimbine. Neither, (+)-propranolol nor (-)-propranolol inhibited K-evoked secretion from cat adrenals; in contrast, nimodipine potently inhibited it (IC50 = 24 nM). 3 Either, racemic propranolol or the (+)- or (-)-isomers (1-10 microM) equally inhibited [3H]-noradrenaline release evoked by nicotine or acetylcholine from cultured bovine adrenal chromaffin cells; clonidine (10 microM) inhibited secretion by 50% and yohimbine or isoprenaline did not affect it. 4 The results indicate that adrenomedullary catecholamine release evoked by splanchnic nerve stimulation is not modulated by alpha- or beta-adrenoceptors and suggest that propranolol may inhibit secretion by blocking ion fluxes through the acetylcholine receptor ionophore. Clonidine may inhibit secretion by this same mechanism, and/or by interfering with some intracellular event in the secretory mechanism. PMID:2827826

  12. Mechanical Properties Involved in the Micro-forming of Ultra-thin Stainless Steel Sheets

    NASA Astrophysics Data System (ADS)

    Pham, Cong-Hanh; Thuillier, Sandrine; Manach, Pierre-Yves

    2015-08-01

    The objective of this paper is to characterize the mechanical behavior of an ultra-thin stainless steel, of 0.15-mm thickness, that is commonly used in the manufacturing of miniature connectors. The main focus is the relationship between some microstructural features, like grain size and surface roughness, and the macroscopic mechanical behavior investigated in uniaxial tension and simple shear. In tension, adaptations to the very small sheet thickness, in order to hold the specimen under the grips, are presented. Yield stress, initial elastic modulus, and evolution of the loading-unloading slope with plastic deformation were evaluated. Moreover, the kinematic contribution to the hardening was characterized by monotonic and cyclic simple shear test and reproduced by a mixed hardening law implemented in Abaqus finite element code. Then, the evolution of surface roughness with plastic strain, both in tension and simple shear, was analyzed. It was shown that in the case of an ultra-thin sheet, the stress levels, calculated either from an average thickness or when considering the effect of the surface roughness, exhibit a significant difference. Finally, the influence of surface roughness on the fracture of a tensile specimen was also investigated.

  13. Microglial cell migration stimulated by ATP and C5a involve distinct molecular mechanisms

    PubMed Central

    Miller, Aaron M.; Stella, Nephi

    2009-01-01

    Microglial cells, the macrophages of the brain, play an essential role in the propagation of neuroinflammation. Increased microglial cell migration in response to specific chemoattractants has been documented, but less is known about the differences between these stimuli and the signal transduction pathways that mediate their effects. Current methods to measure cell migration are often labor-intensive and rely on the manual counting of cell number, so more efficient and objective methods are needed. Here we present an improved and higher-throughput Boyden Chamber technique that measures microglial cell migration by using DRAQ5, a nuclear dye that emits in the near-infrared. Out of a panel of chemoattractants tested, we found that ATP and C5a potently stimulate the migration of mouse primary microglial cells. The stimulatory effects of ATP and C5a displayed significant additivity, suggesting that each chemoattractant stimulated migration through independent molecular mechanisms. Accordingly, we found key differences in these responses: ATP stimulated a combination of both chemokinesis and chemotaxis, and this response was mediated by the ROCK signaling pathway; whereas C5a stimulated only chemotaxis and this response was mediated by the Rac1 signaling pathway. Finally, we found that functional PI3-kinase is only required for random basal microglial cell migration. Thus, our results show that distinct non-overlapping signal transduction pathways control different modes of microglial cell migration and suggest that the targeting of these distinct molecular mechanisms should modulate different aspects of neuroinflammation propagation. PMID:19053059

  14. Mechanisms involved in developmental programming of hypertension and renal diseases. Gender differences.

    PubMed

    Tomat, Analia Lorena; Salazar, Francisco Javier

    2014-05-01

    A substantial body of epidemiological and experimental evidence suggests that a poor fetal and neonatal environment may "program" susceptibility in the offspring to later development of cardiovascular, renal and metabolic diseases. This review focuses on current knowledge from the available literature regarding the mechanisms linking an adverse developmental environment with an increased risk for cardiovascular, renal and metabolic diseases in adult life. Moreover, this review highlights important sex-dependent differences in the adaptation to developmental insults. Developmental programming of several diseases is secondary to changes in different mechanisms inducing important alterations in the normal development of several organs that lead to significant changes in birth weight. The different diseases occurring as a consequence of an adverse environment during development are secondary to morphological and functional cardiovascular and renal changes, to epigenetic changes and to an activation of several hormonal and regulatory systems, such as angiotensin II, sympathetic activity, nitric oxide, COX2-derived metabolites, oxidative stress and inflammation. The important sex-dependent differences in the developmental programming of diseases seem to be partly secondary to the effects of sex hormones. Recent studies have shown that the progression of these diseases is accelerated during aging in both sexes. The cardiovascular, renal and metabolic diseases during adult life that occur as a consequence of several insults during fetal and postnatal periods are secondary to multiple structural and functional changes. Future studies are needed in order to prevent the origin and reduce the incidence and consequences of developmental programmed diseases.

  15. Modulation of a voltage-gated Na+ channel by sevoflurane involves multiple sites and distinct mechanisms

    PubMed Central

    Barber, Annika F.; Carnevale, Vincenzo; Klein, Michael L.; Eckenhoff, Roderic G.; Covarrubias, Manuel

    2014-01-01

    Halogenated inhaled general anesthetic agents modulate voltage-gated ion channels, but the underlying molecular mechanisms are not understood. Many general anesthetic agents regulate voltage-gated Na+ (NaV) channels, including the commonly used drug sevoflurane. Here, we investigated the putative binding sites and molecular mechanisms of sevoflurane action on the bacterial NaV channel NaChBac by using a combination of molecular dynamics simulation, electrophysiology, and kinetic analysis. Structural modeling revealed multiple sevoflurane interaction sites possibly associated with NaChBac modulation. Electrophysiologically, sevoflurane favors activation and inactivation at low concentrations (0.2 mM), and additionally accelerates current decay at high concentrations (2 mM). Explaining these observations, kinetic modeling suggests concurrent destabilization of closed states and low-affinity open channel block. We propose that the multiple effects of sevoflurane on NaChBac result from simultaneous interactions at multiple sites with distinct affinities. This multiple-site, multiple-mode hypothesis offers a framework to study the structural basis of general anesthetic action. PMID:24753583

  16. Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis

    PubMed Central

    Wei, Shi-Yao; Wang, Yu-Xiao; Zhang, Qing-Fang; Zhao, Shi-Lei; Diao, Tian-Tian; Li, Jian-Si; Qi, Wen-Rui; He, Yi-Xin; Guo, Xin-Yu; Zhang, Man-Zhu; Chen, Jian-Yu; Wang, Xiao-Ting; Wei, Qiu-Ju; Wang, Yu; Li, Bing

    2017-01-01

    Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH + HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/β-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/β-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension. PMID:28383024

  17. Mechanism of action of methylmercury on in vivo striatal dopamine release. Possible involvement of dopamine transporter.

    PubMed

    Faro, L R F; do Nascimento, J L M; Alfonso, M; Durán, R

    2002-04-01

    Methylmercury (MeHg) produces significant increases in the spontaneous output of dopamine (DA) from rat striatal tissue. The mechanism through MeHg produces such increase in the extracellular DA levels could be due to increased DA release or decreased DA uptake into DA terminals. One of the aims of this study was to investigate the role of DA transporter (DAT) in the MeHg-induced DA release. Coinfusion of 400 microM MeHg and nomifensine (50 microM) or amphetamine (50 microM) produced increases in the release of DA similar to those produced by nomifensine and amphetamine alone. In the same way, MeHg-induced DA release was not attenuated under Ca(2+)-free conditions or after pretreatment with reserpine (10 mg/kg i.p.) or tetrodotoxin (TTX), suggesting that the DA release was independent of calcium and vesicular stores, as well as it was not affected by the blockade of voltage sensitive sodium channels. Thus, to investigate whether depolarization of dopaminergic terminal was able to affect MeHg-induced DA release, we infused 75 mM KCl through the dialysis membrane. Our results clearly showed a decrease induced by MeHg in the KCl-evoked DA release. Taken together, these results suggest that MeHg induces release of DA via transporter-dependent, calcium- and vesicular-independent mechanism and it decreases the KCl-evoked DA release.

  18. Intersections of pathways involving biotin and iron relative to therapeutic mechanisms for progressive multiple sclerosis.

    PubMed

    Heidker, Rebecca M; Emerson, Mitchell R; LeVine, Steven M

    2016-12-01

    While there are a variety of therapies for relapsing remitting multiple sclerosis (MS), there is a lack of treatments for progressive MS. An early study indicated that high dose biotin therapy has beneficial effects in approximately 12-15% of patients with progressive MS. The mechanisms behind the putative improvements seen with biotin therapy are not well understood, but have been postulated to include: 1) improving mitochondrial function which is impaired in MS, 2) increasing synthesis of lipids and cholesterol to facilitate remyelination, and 3) affecting gene expression. We suggest one reason that a greater percentage of patients with MS didn't respond to biotin therapy is the inaccessibility or lack of other nutrients, such as iron. In addition to biotin, iron (or heme) is necessary for energy production, biosynthesis of cholesterol and lipids, and for some protective mechanisms. Both biotin and iron are required for myelination during development, and by inference, remyelination. However, iron can also play a role in the pathology of MS. Increased deposition of iron can occur in some CNS structures possibly promoting oxidative damage while low iron levels can occur in other areas. Thus, the potential, detrimental effects of iron need to be considered together with the need for iron to support metabolic demands associated with repair and/or protective processes. We propose the optimal utilization of iron may be necessary to maximize the beneficial effects of biotin. This review will examine the interactions between biotin and iron in pathways that may have therapeutic or pathogenic implications for MS.

  19. Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK.

    PubMed

    Jeon, Tae-Il; Seo, Young-Kyo; Osborne, Timothy F

    2011-08-15

    T2Rs (bitter taste-sensing type 2 receptors) are expressed in the oral cavity to prevent ingestion of dietary toxins through taste avoidance. They are also expressed in other cell types, including gut enteroendocrine cells, where their physiological role is enigmatic. Previously, we proposed that T2R-dependent CCK (cholecystokinin) secretion from enteroendocrine cells limits absorption of dietary toxins, but an active mechanism was lacking. In the present study we show that T2R signalling activates ABCB1 (ATP-binding cassette B1) in intestinal cells through a CCK signalling mechanism. PTC (phenylthiocarbamide), an agonist for the T2R38 bitter receptor, increased ABCB1 expression in both intestinal cells and mouse intestine. PTC induction of ABCB1 was decreased by either T2R38 siRNA (small interfering RNA) or treatment with YM022, a gastrin receptor antagonist. Thus gut ABCB1 is regulated through signalling by CCK/gastrin released in response to PTC stimulation of T2R38 on enteroendocrine cells. We also show that PTC increases the efflux activity of ABCB1, suggesting that T2R signalling limits the absorption of bitter tasting/toxic substances through modulation of gut efflux membrane transporters.

  20. Mechanisms involved in the antinociception induced by spinal administration of inosine or guanine in mice.

    PubMed

    de Oliveira, Enderson D; Schallenberger, Cristhine; Böhmer, Ana Elisa; Hansel, Gisele; Fagundes, Aécio C; Milman, Michael; Silva, Marcos D P; Oses, Jean P; Porciúncula, Lisiane O; Portela, Luís V; Elisabetsky, Elaine; Souza, Diogo O; Schmidt, André P

    2016-02-05

    It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that guanine-based purines may produce some antinociceptive effects against chemical and thermal pain in mice. The present study was designed to investigate the antinociceptive effects of intrathecal (i.t.) administration of inosine or guanine in mice. Additionally, investigation into the mechanisms of action of these purines, their general toxicity and measurements of CSF purine levels were performed. Animals received an i.t. injection of vehicle (30mN NaOH), inosine or guanine (up to 600nmol) and submitted to several pain models and behavioural paradigms. Guanine and inosine produced dose-dependent antinociceptive effects in the tail-flick, hot-plate, intraplantar (i.pl.) glutamate, i.pl. capsaicin and acetic acid pain models. Additionally, i.t. inosine inhibited the biting behaviour induced by spinal injection of capsaicin and i.t. guanine reduced the biting behaviour induced by spinal injection of glutamate or AMPA. Intrathecal administration of inosine (200nmol) induced an approximately 115-fold increase on CSF inosine levels. This study provides new evidence on the mechanism of action of extracellular guanine and inosine presenting antinociceptive effects following spinal administration. These effects seem to be related, at least partially, to the modulation of A1 adenosine receptors.

  1. A Cell-Regulatory Mechanism Involving Feedback between Contraction and Tissue Formation Guides Wound Healing Progression

    PubMed Central

    Valero, Clara; Javierre, Etelvina; García-Aznar, José Manuel; Gómez-Benito, María José

    2014-01-01

    Wound healing is a process driven by cells. The ability of cells to sense mechanical stimuli from the extracellular matrix that surrounds them is used to regulate the forces that cells exert on the tissue. Stresses exerted by cells play a central role in wound contraction and have been broadly modelled. Traditionally, these stresses are assumed to be dependent on variables such as the extracellular matrix and cell or collagen densities. However, we postulate that cells are able to regulate the healing process through a mechanosensing mechanism regulated by the contraction that they exert. We propose that cells adjust the contraction level to determine the tissue functions regulating all main activities, such as proliferation, differentiation and matrix production. Hence, a closed-regulatory feedback loop is proposed between contraction and tissue formation. The model consists of a system of partial differential equations that simulates the evolution of fibroblasts, myofibroblasts, collagen and a generic growth factor, as well as the deformation of the extracellular matrix. This model is able to predict the wound healing outcome without requiring the addition of phenomenological laws to describe the time-dependent contraction evolution. We have reproduced two in vivo experiments to evaluate the predictive capacity of the model, and we conclude that there is feedback between the level of cell contraction and the tissue regenerated in the wound. PMID:24681636

  2. Evaluation of the analgesic effect of alkaloid extract of Peganum harmala L.: possible mechanisms involved.

    PubMed

    Farouk, Loubna; Laroubi, Amine; Aboufatima, Rachida; Benharref, Ahmed; Chait, Abderrahman

    2008-02-12

    The seeds of Peganum harmala L. (Pgh) (Zygophyllaceae) have been used in Moroccan traditional medicine for treatment of a various diseases and to relieve dolorous process. The major objective of this paper was to investigate the mechanism of the analgesia induced by alkaloid extract of Peganum harmala. In the present work, the antinociceptive action was assayed in several experimental models in mice: writhing, formalin, and hot plate tests. The alkaloid extract (12.5 and 25mg/kg) and in a dose-dependent manner significantly reduced the nociception by acetic acid intraperitoneal injection (p<0.001). In the formalin test, the extract also significantly reduced the painful stimulus in both phases of the test (p<0.001). Treatment with the extract when given by (i.p. or i.c.v.) or with morphine (10mg/kg, i.p.) produced a significant increase of the reaction time in hot plate test. These result showed that the alkaloid extract of Pgh contains active analgesic principles acting both centrally and peripherally. Furthermore, this antinociceptive effect has been avoided by naloxone at a dose of 1mg/kg in the first phase of formalin and hot plate tests indicating that this extract act partly through an opioid-mediated mechanism. In conclusion, the alkaloid extract of Peganum harmala seems to have both central and peripheral antinociceptive activities which may be mediated by opioid receptors.

  3. The principal motions involved in the coupling mechanism of the recovery stroke of the myosin motor

    SciTech Connect

    Mesentean, Sidonia; Koppole, Sampath; Smith, Jeremy C; Fischer, S.

    2006-12-01

    Muscle contraction is driven by a cycle of conformational changes in the myosin II head. After myosin binds ATP and releases from the actin fibril, myosin prepares for the next power stroke by rotating back the converter domain that carries the lever arm by {approx}60 degrees. This recovery stroke is coupled to the activation of myosin's ATPase by a mechanism that is essential for an efficient motor cycle. The mechanics of this coupling have been proposed to occur via two distinct and successive motions of the two helices that hold the converter domain: in a first phase a see-saw motion of the relay helix, followed by a piston/seesaw motion of the SH1 helix in a second phase. To test this model, we have determined the principal motions of these structural elements during equilibrium molecular dynamics simulations of the crystallographic end states of the recovery stroke by using Principal Component Analysis. This reveals that the only principal motions of these two helices that make a large amplitude contribution towards the conformational change of the recovery stroke are indeed the predicted seesaw and piston motions.

  4. Comprehension of Indirect Meaning in Spanish as a Foreign Language

    ERIC Educational Resources Information Center

    Taguchi, Naoko; Gomez-Laich, Maria Pia; Arrufat-Marques, Maria-Jose

    2016-01-01

    This study investigated comprehension of indirect meaning among learners of L2 Spanish via an original computer-delivered multimedia listening test. The comprehension of implied speaker intention is a type of indirect communication that involves the ability to understand implied intention by using linguistic knowledge, contextual cues, and the…

  5. Comprehension of Indirect Meaning in Spanish as a Foreign Language

    ERIC Educational Resources Information Center

    Taguchi, Naoko; Gomez-Laich, Maria Pia; Arrufat-Marques, Maria-Jose

    2016-01-01

    This study investigated comprehension of indirect meaning among learners of L2 Spanish via an original computer-delivered multimedia listening test. The comprehension of implied speaker intention is a type of indirect communication that involves the ability to understand implied intention by using linguistic knowledge, contextual cues, and the…

  6. Modeling of glycerol-3-phosphate transporter suggests a potential 'tilt' mechanism involved in its function.

    PubMed

    Tsigelny, Igor F; Greenberg, Jerry; Kouznetsova, Valentina; Nigam, Sanjay K

    2008-10-01

    Many major facilitator superfamily (MFS) transporters have similar 12-transmembrane alpha-helical topologies with two six-helix halves connected by a long loop. In humans, these transporters participate in key physiological processes and are also, as in the case of members of the organic anion transporter (OAT) family, of pharmaceutical interest. Recently, crystal structures of two bacterial representatives of the MFS family--the glycerol-3-phosphate transporter (GlpT) and lac-permease (LacY)--have been solved and, because of assumptions regarding the high structural conservation of this family, there is hope that the results can be applied to mammalian transporters as well. Based on crystallography, it has been suggested that a major conformational "switching" mechanism accounts for ligand transport by MFS proteins. This conformational switch would then allow periodic changes in the overall transporter configuration, resulting in its cyclic opening to the periplasm or cytoplasm. Following this lead, we have modeled a possible "switch" mechanism in GlpT, using the concept of rotation of protein domains as in the DynDom program17 and membranephilic constraints predicted by the MAPAS program.(23) We found that the minima of energies of intersubunit interactions support two alternate positions consistent with their transport properties. Thus, for GlpT, a "tilt" of 9 degrees -10 degrees rotation had the most favorable energetics of electrostatic interaction between the two halves of the transporter; moreover, this confirmation was sufficient to suggest transport of the ligand across the membrane. We conducted steered molecular dynamics simulations of the GlpT-ligand system to explore how glycerol-3-phosphate would be handled by the "tilted" structure, and obtained results generally consistent with experimental mutagenesis data. While biochemical data remain most consistent with a single-site alternating access model, our results raise the possibility that, while the

  7. Identification of mechanisms involved in the acute airway toxicity induced by parathion.

    PubMed

    Segura, P; Chávez, J; Montaño, L M; Vargas, M H; Delaunois, A; Carbajal, V; Gustin, P

    1999-12-01

    Organophosphates are still widely used worldwide and cause thousands of intoxications every year. In this work we investigated the mechanisms of parathion (Pth) airway toxicity, using biochemical and functional approaches. A plethysmographic technique for unrestrained guinea pigs was used to analyze Pth-induced modifications of airway mechanics and responsiveness to acetylcholine (ACh: 0.1-3.2 mg/ml, 2-min inhalation each dose). The isolated perfused rabbit lung preparation was used to study the acute effects of Pth on airway responsiveness to ACh (10(-8)-10(-3) M), histamine (10(-8)-10(-3) M) and substance P (10(-10)-10(-6) M), pulmonary acetylcholinesterase inhibition and cytochrome P450 (P450) activity, and their modifications with previous administration of Pth (1 mg/kg s.c. daily, 7 days). We found that: (1) In guinea pigs Pth (3.2-17 mg/kg i.p.) produced a dose-dependent increase in a lung resistance index (iRL), which was greatly reverted (approximately 50%) by salbutamol (2 mg/ml, 2-min inhalation, or 10 microg/kg i.p.). This salbutamol effect was transient (5-10 min), suggesting that this bronchodilator triggered additional obstructive mechanisms. (2) Pth increased the water content in lung parenchyma samples, but not in trachea or bronchi, and augmented the respiratory secretions measured through monosaccharide content in bronchoalveolar lavage. (3) The increase in iRL was greater in female animals, probably due to a higher P450 basal activity, and completely blocked by pharmacological inhibition of P450 with piperonyl butoxide (500 mg/kg i.p.). (4) In male guinea pigs a subclinical dose of Pth (10 mg/kg i.p.) induced airway hyperresponsiveness to ACh. In isolated perfused rabbit lung Pth (10(-6) M) produced airway hyperresponsiveness to ACh and histamine, the latter prevented by atropine (10(-5) M). (5) Repetitive exposure to subclinical doses (1 mg/kg s.c.) of Pth during 1 week caused approximately 80% inhibition of P450 activity in rabbits, which was

  8. Critical review on the physical and mechanical factors involved in tissue engineering of cartilage.

    PubMed

    Gaut, Carrie; Sugaya, Kiminobu

    2015-01-01

    Articular cartilage defects often progress to osteoarthritis, which negatively impacts quality of life for millions of people worldwide and leads to high healthcare expenditures. Tissue engineering approaches to osteoarthritis have concentrated on proliferation and differentiation of stem cells by activation and suppression of signaling pathways, and by using a variety of scaffolding techniques. Recent studies indicate a key role of environmental factors in the differentiation of mesenchymal stem cells to mature cartilage-producing chondrocytes. Therapeutic approaches that consider environmental regulation could optimize chondrogenesis protocols for regeneration of articular cartilage. This review focuses on the effect of scaffold structure and composition, mechanical stress and hypoxia in modulating mesenchymal stem cell fate and the current use of these environmental factors in tissue engineering research.

  9. Calcium ion involvement in growth inhibition of mechanically stressed soybean (Glycine max) seedlings

    NASA Technical Reports Server (NTRS)

    Jones, R. S.; Mitchell, C. A.

    1989-01-01

    A 40-50% reduction in soybean [Glycine max (L.) Merr. cv. Century 84] hypocotyl elongation occurred 24 h after application of mechanical stress. Exogenous Ca2+ at 10 mM inhibited growth by 28% if applied with the Ca2+ ionophore A23187 to the zone of maximum hypocotyl elongation. La3+ was even more inhibitory than Ca2+, especially above 5 mM. Treatment with ethyleneglycol-bis-(beta-aminoethylether)-N, N, N', N'-tetraacetic acid (EGTA) alone had no effect on growth of non-stressed seedlings at the concentrations used but negated stress-induced growth reduction by 36% at 4 mM when compared to non-treated, stressed controls. Treatment with EDTA was ineffective in negating stress-induced growth inhibition. Calmodulin antagonists calmidazolium, chlorpromazine, and 48/80 also negated stress-induced growth reduction by 23, 50, and 35%, respectively.

  10. [Cytological mechanisms involved in assimilation of n-alkanes by yeasts].

    PubMed

    Meĭsel', M N; Medvedeva, G A; Kozlova, T M

    1976-01-01

    The paper describes cytological mechanism of adaptation of yeasts to assimilation of aliphatic hydrocarbons added to a growth medium as a sole source of carbon. The process was studied by light optical and electron microscopy, employing fluorescent labelling and electron microscopy contrasting. Two types of yeasts were found, which differed by the response of the cell walls to hydrocarbons: those that formed "channels" and those that did not form them. Cytological response to hydrocarbon assimilation was detected also in the mitochondria and canals of the endoplasmic reticulum. Components of the Golgi apparatus may also participate in this process, in particular, in formation of peroxisomes (microbodies). Close contacts of the yeast cells with the hydrocarbon being assimilated is important; assimilation may start in a close vicinity of the cell walls. The rate of flavin production by Candida tropicalis 303 IBFM increases during growth on solid paraffins, beginning with C20-paraffin.

  11. A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway

    PubMed Central

    Menéndez, Javier; Pérez-Garijo, Ainhoa; Calleja, Manuel; Morata, Ginés

    2010-01-01

    Mutant larvae for the Drosophila gene lethal giant larva (lgl) develop neoplastic tumors in imaginal discs. However, lgl mutant clones do not form tumors when surrounded by wild-type tissue, suggesting the existence of a tumor-suppressing mechanism. We have investigated the tumorigenic potential of lgl mutant cells by generating wing compartments that are entirely mutant for lgl and also inducing clones of various genetic combinations of lgl− cells. We find that lgl− compartments can grow indefinitely but lgl− clones are eliminated by cell competition. lgl mutant cells may form tumors if they acquire constitutive activity of the Ras pathway (lgl− UAS-rasV12), which confers proliferation advantage through inhibition of the Hippo pathway. Yet, the majority of lgl− UAS-rasV12 clones are eliminated in spite of their high proliferation rate. The formation of a tumor requires in addition the formation of a microenvironment that allows mutant cells to evade cell competition. PMID:20679206

  12. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders

    PubMed Central

    Campos, Alline C.; Fogaça, Manoela V.; Scarante, Franciele F.; Joca, Sâmia R. L.; Sales, Amanda J.; Gomes, Felipe V.; Sonego, Andreza B.; Rodrigues, Naielly S.; Galve-Roperh, Ismael; Guimarães, Francisco S.

    2017-01-01

    Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here. PMID:28588483

  13. Increased zinc and copper availability in organic waste amended soil potentially involving distinct release mechanisms.

    PubMed

    Tella, Marie; Bravin, Matthieu N; Thuriès, Laurent; Cazevieille, Patrick; Chevassus-Rosset, Claire; Collin, Blanche; Chaurand, Perrine; Legros, Samuel; Doelsch, Emmanuel

    2016-05-01

    This study aimed at determining the fate of trace elements (TE) following soil organic waste (OW) application. We used a unique combination of X-ray absorption spectroscopy analyses, to determine TE speciation, with incubation experiments for in situ monitoring of TE availability patterns over a time course with the technique of the diffusive gradients in thin films (DGT). We showed that copper (Cu) and zinc (Zn) availability were both increased in OW-amended soil, but their release was controlled by distinct mechanisms. Zn speciation in OW was found to be dominated by an inorganic species, i.e. Zn sorbed on Fe oxides. Zn desorption from Fe oxides could explain the increase in Zn availability in OW-amended soil. Cu speciation in OW was dominated by organic species. Cu release through the mineralization of organic carbon from OW was responsible for the increase in Cu availability.

  14. Isolated plant nuclei as mechanical and thermal sensors involved in calcium signalling.

    PubMed

    Xiong, Tou Cheu; Jauneau, Alain; Ranjeva, Raoul; Mazars, Christian

    2004-10-01

    Calcium signals in the nucleus elicit downstream effects that are distinct from those of cytosolic calcium signals. In the present work, we have evaluated the ability of plant nuclei to sense stimuli directly and to convert them into calcium changes. We show that individual mechanical stimulation of isolated nuclei elicits a single calcium transient at acidic pHs, whereas a series of stimulations leads to oscillations whose frequency reflects that of the stimuli. Conversely, at alkaline pHs, nuclei respond to temperature but not to stretch. The stretch- and the temperature-activated processes differ by their sensitivity to pharmacological drugs known to affect ion channel activities in animal cells. Our data demonstrate that isolated nuclei are able to gauge physical parameters of their environment. This might have a profound influence on the functioning of calcium-dependent processes known to control a large array of molecular events in the nucleus.

  15. Calcium ion involvement in growth inhibition of mechanically stressed soybean (Glycine max) seedlings

    NASA Technical Reports Server (NTRS)

    Jones, R. S.; Mitchell, C. A.

    1989-01-01

    A 40-50% reduction in soybean [Glycine max (L.) Merr. cv. Century 84] hypocotyl elongation occurred 24 h after application of mechanical stress. Exogenous Ca2+ at 10 mM inhibited growth by 28% if applied with the Ca2+ ionophore A23187 to the zone of maximum hypocotyl elongation. La3+ was even more inhibitory than Ca2+, especially above 5 mM. Treatment with ethyleneglycol-bis-(beta-aminoethylether)-N, N, N', N'-tetraacetic acid (EGTA) alone had no effect on growth of non-stressed seedlings at the concentrations used but negated stress-induced growth reduction by 36% at 4 mM when compared to non-treated, stressed controls. Treatment with EDTA was ineffective in negating stress-induced growth inhibition. Calmodulin antagonists calmidazolium, chlorpromazine, and 48/80 also negated stress-induced growth reduction by 23, 50, and 35%, respectively.

  16. Myco-Biocontrol of Insect Pests: Factors Involved, Mechanism, and Regulation

    PubMed Central

    Sandhu, Sardul Singh; Sharma, Anil K.; Beniwal, Vikas; Goel, Gunjan; Batra, Priya; Kumar, Anil; Jaglan, Sundeep; Sharma, A. K.; Malhotra, Sonal

    2012-01-01

    The growing demand for reducing chemical inputs in agriculture and increased resistance to insecticides have provided great impetus to the development of alternative forms of insect-pest control. Myco-biocontrol offers an attractive alternative to the use of chemical pesticides. Myco-biocontrol agents are naturally occurring organisms which are perceived as less damaging to the environment. Their mode of action appears little complex which makes it highly unlikely that resistance could be developed to a biopesticide. Past research has shown some promise of the use of fungi as a selective pesticide. The current paper updates us about the recent progress in the field of myco-biocontrol of insect pests and their possible mechanism of action to further enhance our understanding about the biological control of insect pests. PMID:22567344

  17. Anticonvulsants Teratogenic Mechanism Involves Alteration of Bioelectrically-controlled Processes in the Embryo. A hypothesis

    PubMed Central

    Hernández-Díaz, Sonia; Levin, Michael

    2014-01-01

    Maternal use of anticonvulsants during the first trimester of pregnancy has been associated with an elevated risk of major congenital malformations in the offspring. Whether the increased risk is caused by the specific pharmacological mechanisms of certain anticonvulsants, the underlying epilepsy, or common genetic or environmental risk factors shared by epilepsy and malformations is controversial. We hypothesize that anticonvulsant therapies during pregnancy that attain more successful inhibition of neurotransmission might lead to both better seizure control in the mother and stronger alteration of bioelectrically-controlled processes in the embryo that result in structural malformations. If our theory were correct, development of pharmaceuticals that do not alter cell resting transmembrane voltage levels could result in safer drugs. PMID:24815983

  18. Molecular mechanisms involved in adaptive responses to radiation, UV light, and heat.

    PubMed

    Takahashi, Akihisa; Ohnishi, Takeo

    2009-09-01

    Viable organisms recognize and respond to environmental changes or stresses. When these environmental changes and their responses by organisms are extreme, they can limit viability. However, organisms can adapt to these different stresses by utilizing different possible responses via signal transduction pathways when the stress is not lethal. In particular, prior mild stresses can provide some aid to prepare organisms for subsequent more severe stresses. These adjustments or adaptations for future stresses have been called adaptive responses. These responses are present in bacteria, plants and animals. The following review covers recent research which can help describe or postulate possible mechanisms which may be active in producing adaptive responses to radiation, ultraviolet light, and heat.

  19. Dark matter dynamics and indirect detection

    SciTech Connect

    Bertone, Gianfranco; Merritt, David; /Rochester Inst. Tech.

    2005-04-01

    Non-baryonic, or ''dark'', matter is believed to be a major component of the total mass budget of the universe. We review the candidates for particle dark matter and discuss the prospects for direct detection (via interaction of dark matter particles with laboratory detectors) and indirect detection (via observations of the products of dark matter self-annihilations), focusing in particular on the Galactic center, which is among the most promising targets for indirect detection studies. The gravitational potential at the Galactic center is dominated by stars and by the supermassive black hole, and the dark matter distribution is expected to evolve on sub-parsec scales due to interaction with these components. We discuss the dominant interaction mechanisms and show how they can be used to rule out certain extreme models for the dark matter distribution, thus increasing the information that can be gleaned from indirect detection searches.

  20. Fractional gravity studies on the ISS of sensory mechanisms involved in phototropism

    NASA Astrophysics Data System (ADS)

    Kiss, John Z.; Correll, Melanie; Edelmann, Richard; Millar, Katherine

    The major goals of this research are (1) to better understand cellular mechanisms of pho-totropism in plants and (2) to determine the effects and influence of gravity on light perception in plants. Because of the interfering effect of the strong gravitropic response, microgravity conditions are needed to effectively study phototropism. Experiments performed on the In-ternational Space Station (ISS) were used to explore the mechanisms of both blue-light and red-light-induced phototropism in plants. We utilized the European Modular Cultivation Sys-tem (EMCS), which has environmental controls for plant growth as well as centrifuges for gravity treatments. TROPI-1 (for tropisms) was successfully performed on the ISS during late 2006. We obtained data on seedlings grown in microgravity and discovered a novel positive phototropic response to red light in hypocotyls of seedlings of Arabidopsis thaliana. However, one problem encoun-tered during TROPI-1 was low seed germination due to long storage periods (8 months) in flight hardware. Thus, the originally proposed fractional gravity studies were not performed. TROPI-2 provides an opportunity to regain the results from these important fractional gravity experiments. TROPI-2 experiments will provide a better understanding of how plants integrate sensory input from multiple light and gravity perception systems. This information is important for growing plants on long-term space missions as part of life support systems. The fractional gravity studies contain 0.16g (Moon) and 0.38g (Mars) treatments, so information to be obtained is relevant to exploration objectives

  1. Growth capacity and biochemical mechanisms involved in rhizobia tolerance to salinity and water deficit.

    PubMed

    Mhamdi, Rakia; Nouairi, Issam; ben Hammouda, Thouraya; Mhamdi, Ridha; Mhadhbi, Haythem

    2015-04-01

    The aim of the present study was to evaluate abiotic stress tolerance of rhizobial strains belonging to Mesorhizobium, Sinorhizobium, and Rhizobium genera, as well as to investigate specie specific stress response mechanisms. Effect of NaCl and PEG on growth capacity, protein, lipid peroxydation (MDA), membrane fatty acid composition and antioxidant enzymes were investigated. Growth capacity and viability of overall rhizobia strains decreased proportionally to the increase of NaCl and PEG levels in the medium. Sinorhizobium strains appeared the most tolerant, where 4H41strain was able to grow at 800 mM NaCl and 40% PEG. On the other hand, growth of R. gallicum and M. mediterraneum was inhibited by 200 mM NaCl. The content of MDA was unchanged in Sinorhizobium strains under both stresses. For Mesorhizobium, only PEG treatment increased the content of MDA. Amount of the C19:0 cyclo fatty-acid was increased in both Sinorhizobium and Mesorhizobium tolerant strains. NaCl stress increased Superoxide dismutase (SOD) activity of overall species; especially the most tolerant strain 4H41. Both treatments increased catalase (CAT) activity in 4H41, TII7, and 835 strains. Obtained results suggest that major response of tolerant Sinorhizobium and Mesorhizobium strains to NaCl and PEG stresses is a preferential accumulation of the C19:0 cyclo fatty acid within bacterial membrane as mechanism to reduce fluidity and maintain integrity. Cell integrity and functioning is also assured by maintaining and/or increasing activity of SOD and CAT antioxidant enzymes for tolerant strains to omit structural and functional damages related to reactive oxygen species overproduced under stressful conditions.

  2. Attentional Biases toward Attractive Alternatives and Rivals: Mechanisms Involved in Relationship Maintenance among Chinese Women

    PubMed Central

    Ma, Yidan; Zhao, Guang; Tu, Shen; Zheng, Yong

    2015-01-01

    A long-term romantic relationship can offer many benefits to committed individuals. Thus, humans possess relationship maintenance mechanisms to protect against threats from those who serve as attractive alternatives or intrasexual rivals. Many studies have indicated that romantic love can act as a commitment device to activate these mechanisms. To examine the attentional bias associated with relationship maintenance among 108 college students (49 single and 59 committed females) in China, we used a semantic priming procedure to activate mental representations associated with romantic love and then asked participants to complete a dot-probe task for the purpose of making a distinction between the engage and disengage components of attention. No significant engaging effects toward attractive faces were observed among committed females, but the following significant disengaging effects were found: when primed with romantic love, single females showed increased attention toward and difficulty in disengaging from attractive male faces, whereas females already in a committed relationship did not alter their attention, remaining as inattentive to attractive alternatives as they were in the baseline condition. In addition, committed females responded to love priming by exhibiting difficulty in disengaging from attractive rivals. The present findings provide evidence in the Chinese cultural context for the existence of early-stage attentional processes in the domain of relationship maintenance that committed Chinese females protected an ongoing relationship by not only being inattentive to attractive males who could serve as attractive alternatives, but also being more attentive to attractive females who could be potential rivals when mental representations associated with romantic love were primed. PMID:26309232

  3. Cellular mechanisms involved in the increased contraction of portal veins from Schistosoma mansoni-infected mice.

    PubMed

    Silva, C L M; Lenzi, H L; Silva, V F M; Paulo, F O; Noël, F

    2003-01-01

    We previously reported that portal veins from mice infected with male Schistosoma mansoni exhibited an increased reactivity to 5-hydroxytryptamine (5-HT). Here, we extended our observations to mice infected by both male and female worms and we further investigated another constrictor agent and the mechanism(s) responsible for the enhanced maximal contraction ( E(max)). Bisexual infection increased the E(max) of 5-HT (from 0.66+/-0.06 mN.s to 1.56+/-0.38 mN.s), in a similar way to the unisexual (male) infection. Infection with male worms increased portal vein reactivity to acetylcholine, as revealed by a higher E(max) (1.03+/-0.2 mN.s) in relation to non-infected control animals ( E(max)= 0.54+/-0.08 mN.s). Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibition with 100 nM thapsigargin reduced the E(max) of 5-HT by 35% in both tissues, discharging a deficiency of SERCA pump in infected animals. In contrast, the number of voltage-dependent Ca(2+) channels (L-type) was higher in portal veins from infected than non-infected control mice. Inhibition of Ca(2+)-activated chloride channels (Cl(Ca)) with 10 micro M niflumic acid reduced the E(max) of 5-HT in portal veins more from infected than non-infected animals (remaining tension = 60.9+/-2.2% and 70.4+/-2.3%, respectively). Histopathological analysis revealed an increased content of collagen and elastin in portal veins from male S. mansoni-infected mice, compatible with an increased intraluminal pressure. In conclusion, male S. mansoni altered portal vein physiology, increasing the E(max) of two vasoconstrictors, possibly by increasing membrane depolarisation through a more effective opening of Cl(Ca) channels, with calcium entering through L-type Ca(2+) channels.

  4. Mechanical stretch upregulates proteins involved in Ca2+ sensitization in urinary bladder smooth muscle hypertrophy.

    PubMed

    Boopathi, Ettickan; Gomes, Cristiano; Zderic, Stephen A; Malkowicz, Bruce; Chakrabarti, Ranjita; Patel, Darshan P; Wein, Alan J; Chacko, Samuel

    2014-09-15

    Partial bladder outlet obstruction (pBOO)-induced remodeling of bladder detrusor smooth muscle (DSM) is associated with the modulation of cell signals regulating contraction. We analyzed the DSM from obstructed murine urinary bladders for the temporal regulation of RhoA GTPase and Rho-activated kinase (ROCK), which are linked to Ca(2+) sensitization. In addition, the effects of equibiaxial cell stretch, a condition thought to be associated with pBOO-induced bladder wall smooth muscle hypertrophy and voiding frequency, on the expression of RhoA, ROCK, and C-kinase-activated protein phosphatase I inhibitor (CPI-17) were investigated. DSM from 1-, 3-, 7-, and 14-day obstructed male mice bladders and benign prostatic hyperplasia (BPH)-induced obstructed human bladders revealed overexpression of RhoA and ROCK-β at the mRNA and protein levels compared with control. Primary human bladder myocytes seeded onto type I collagen-coated elastic silicone membranes were subjected to cyclic equibiaxial stretch, mimicking the cellular mechanical stretch in the bladder in vivo, and analyzed for the expression of RhoA, ROCK-β, and CPI-17. Stretch caused a significant increase of RhoA, ROCKβ, and CPI-17 expression. The stretch-induced increase in CPI-17 expression occurs at the transcriptional level and is associated with CPI-17 promoter binding by GATA-6 and NF-κB, the transcription factors responsible for CPI-17 gene transcription. Cell stretch caused by bladder overdistension in pBOO is the likely mechanism for initiating overexpression of the signaling proteins regulating DSM tone.

  5. Evidence for TRPA1 involvement in central neural mechanisms in a rat model of dry eye.

    PubMed

    Katagiri, A; Thompson, R; Rahman, M; Okamoto, K; Bereiter, D A

    2015-04-02

    Dry eye (DE) disease is commonly associated with ocular surface inflammation, an unstable tear film and symptoms of irritation. However, little is known about the role of central neural mechanisms in DE. This study used a model for persistent aqueous tear deficiency, exorbital gland removal, to assess the effects of mustard oil (MO), a transient receptor potential ankyrin (TRPA1) agonist, on eyeblink and eyewipe behavior and Fos-like immunoreactivity (Fos-LI) in the trigeminal brainstem of male rats. Spontaneous tear secretion was reduced by about 50% and spontaneous eyeblinks were increased more than 100% in DE rats compared to sham rats. MO (0.02-0.2%) caused dose-related increases in eyeblink and forelimb eyewipe behavior in DE and sham rats. Exorbital gland removal alone was sufficient to increase Fos-LI at the ventrolateral pole of trigeminal interpolaris/caudalis (Vi/Vc) transition region, but not at more caudal regions of the trigeminal brainstem. Under barbiturate anesthesia ocular surface application of MO (2-20%) produced Fos-LI in the Vi/Vc transition, in the mid-portions of Vc and in the trigeminal caudalis/upper cervical spinal cord (Vc/C1) region that was significantly greater in DE rats than in sham controls. MO caused an increase in Fos-LI ipsilaterally in superficial laminae at the mid-Vc and Vc/C1 regions in a dose-dependent manner. Smaller, but significant, increases in Fos-LI also were seen in the contralateral Vc/C1 region in DE rats. TRPA1 protein levels in trigeminal ganglia from DE rats ipsilateral and contralateral to gland removal were similar. Persistent tear reduction enhanced the behavioral and trigeminal brainstem neural responses to ocular surface stimulation by MO. These results suggested that TRPA1 mechanisms play a significant role in the sensitization of ocular-responsive trigeminal brainstem neurons in this model for tear deficient DE.

  6. Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin

    PubMed Central

    Zhou, Junmin; Donatelli, Sarah S.; Gilvary, Danielle L.; Tejera, Melba M.; Eksioglu, Erika A.; Chen, Xianghong; Coppola, Domenico; Wei, Sheng; Djeu, Julie Y.

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) constitute a key checkpoint that impedes tumor immunity against cancer. Chemotherapeutic intervention of MDSCs has gained ground as a strategy for cancer therapy but its mechanism remains obscure.We report here a unique mechanism by which monocytic (M)-MDSCs are spared, allowing them to polarize towards M1 macrophages for reactivation of immunity against breast cancer. We first demonstrated that curcumin, like docetaxel (DTX), can selectively target CD11b+Ly6G+Ly6Clow granulocytic (G)-MDSCs, sparing CD11b+Ly6G−Ly6Chigh M-MDSCs, with reduced tumor burden in 4T1-Neu tumor-bearing mice. Curcumin treatment polarized surviving M-MDSCs toward CCR7+ Dectin-1−M1 cells, accompanied by IFN-γ production and cytolytic function in T cells. Selective M-MDSC chemoresistence to curcumin and DTX was mediated by secretory/cytoplasmic clusterin (sCLU). sCLU functions by trapping Bax from mitochondrial translocation, preventing the apoptotic cascade. Importantly, sCLU was only found in M-MDSCs but not in G-MDSCs. Knockdown of sCLU in M-MDSCs and RAW264.7 macrophages was found to reverse their natural chemoresistance. Clinically, breast cancer patients possess sCLU expression only in mature CD68+ macrophages but not in immature CD33+ immunosuppressive myeloid cells infiltrating the tumors. We thus made the seminal discovery that sCLU expression in M-MDSCs accounts for positive immunomodulation by chemotherapeutic agents. PMID:27405665

  7. Attentional Biases toward Attractive Alternatives and Rivals: Mechanisms Involved in Relationship Maintenance among Chinese Women.

    PubMed

    Ma, Yidan; Zhao, Guang; Tu, Shen; Zheng, Yong

    2015-01-01

    A long-term romantic relationship can offer many benefits to committed individuals. Thus, humans possess relationship maintenance mechanisms to protect against threats from those who serve as attractive alternatives or intrasexual rivals. Many studies have indicated that romantic love can act as a commitment device to activate these mechanisms. To examine the attentional bias associated with relationship maintenance among 108 college students (49 single and 59 committed females) in China, we used a semantic priming procedure to activate mental representations associated with romantic love and then asked participants to complete a dot-probe task for the purpose of making a distinction between the engage and disengage components of attention. No significant engaging effects toward attractive faces were observed among committed females, but the following significant disengaging effects were found: when primed with romantic love, single females showed increased attention toward and difficulty in disengaging from attractive male faces, whereas females already in a committed relationship did not alter their attention, remaining as inattentive to attractive alternatives as they were in the baseline condition. In addition, committed females responded to love priming by exhibiting difficulty in disengaging from attractive rivals. The present findings provide evidence in the Chinese cultural context for the existence of early-stage attentional processes in the domain of relationship maintenance that committed Chinese females protected an ongoing relationship by not only being inattentive to attractive males who could serve as attractive alternatives, but also being more attentive to attractive females who could be potential rivals when mental representations associated with romantic love were primed.

  8. Mechanical stretch upregulates proteins involved in Ca2+ sensitization in urinary bladder smooth muscle hypertrophy

    PubMed Central

    Boopathi, Ettickan; Gomes, Cristiano; Zderic, Stephen A.; Malkowicz, Bruce; Chakrabarti, Ranjita; Patel, Darshan P.; Wein, Alan J.

    2014-01-01

    Partial bladder outlet obstruction (pBOO)-induced remodeling of bladder detrusor smooth muscle (DSM) is associated with the modulation of cell signals regulating contraction. We analyzed the DSM from obstructed murine urinary bladders for the temporal regulation of RhoA GTPase and Rho-activated kinase (ROCK), which are linked to Ca2+ sensitization. In addition, the effects of equibiaxial cell stretch, a condition thought to be associated with pBOO-induced bladder wall smooth muscle hypertrophy and voiding frequency, on the expression of RhoA, ROCK, and C-kinase-activated protein phosphatase I inhibitor (CPI-17) were investigated. DSM from 1-, 3-, 7-, and 14-day obstructed male mice bladders and benign prostatic hyperplasia (BPH)-induced obstructed human bladders revealed overexpression of RhoA and ROCK-β at the mRNA and protein levels compared with control. Primary human bladder myocytes seeded onto type I collagen-coated elastic silicone membranes were subjected to cyclic equibiaxial stretch, mimicking the cellular mechanical stretch in the bladder in vivo, and analyzed for the expression of RhoA, ROCK-β, and CPI-17. Stretch caused a significant increase of RhoA, ROCKβ, and CPI-17 expression. The stretch-induced increase in CPI-17 expression occurs at the transcriptional level and is associated with CPI-17 promoter binding by GATA-6 and NF-κB, the transcription factors responsible for CPI-17 gene transcription. Cell stretch caused by bladder overdistension in pBOO is the likely mechanism for initiating overexpression of the signaling proteins regulating DSM tone. PMID:25031021

  9. Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence.

    PubMed

    Guerri, Consuelo; Pascual, María

    2010-02-01

    Studies over the last decade demonstrate that adolescence is a brain maturation period from childhood to adulthood. Plastic and dynamic processes drive adolescent brain development, creating flexibility that allows the brain to refine itself, specialize, and sharpen its functions for specific demands. Maturing connections enable increased communication among brain regions, allowing greater integration and complexity. Compelling evidence has shown that the developing brain is vulnerable to the damaging effects of ethanol. It is possible to infer, therefore, that alcohol exposure during the critical adolescent developmental stages could disrupt the brain plasticity and maturation processes, resulting in behavioral and cognitive deficits. Recent neuroimaging studies have provided evidence of the impact of human adolescent drinking in brain structure and functions. Findings in experimental animals have also given new insight into the potential mechanisms of the toxic effects of ethanol on both adolescent brain maturation and the short- and long-term cognitive consequences of adolescent drinking. Adolescence is also characterized by the rapid maturation of brain systems mediating reward and by changes in the secretion of stress-related hormones, events that might participate in the increasing in anxiety and the initiation pattern of alcohol and drug consumption. Studies in human adolescents demonstrate that drinking at early ages can enhance the likelihood of developing alcohol-related problems. Experimental evidence suggests that early exposure to alcohol sensitizes the neurocircuitry of addiction and affects chromatin remodeling, events that could induce abnormal plasticity in reward-related learning processes that contribute to adolescents' vulnerability to drug addiction. In this article, we review the potential mechanisms by which ethanol impacts brain development and lead to brain impairments and cognitive and behavioral dysfunctions as well as the neurobiological

  10. Different mechanisms are involved in apoptosis induced by melanoma gangliosides on human monocyte-derived dendritic cells.

    PubMed

    Bennaceur, Karim; Popa, Iuliana; Chapman, Jessica Alice; Migdal, Camille; Péguet-Navarro, Josette; Touraine, Jean-Louis; Portoukalian, Jacques

    2009-06-01

    Tumor escape is linked to multiple mechanisms, notably the liberation, by tumor cells, of soluble factors that inhibit the function of dendritic cells (DC). We have shown that melanoma gangliosides impair DC differentiation and induce their apoptosis. The present study was aimed to give insight into the mechanisms involved. DC apoptosis was independent of the catabolism of gangliosides since lactosylceramide did not induce cell death. Apoptosis induced by GM3 and GD3 gangliosides was not blocked by inhibitors of de novo ceramide biosynthesis, whereas the acid sphingomyelinase inhibitor desipramine only prevented apoptosis induced by GM3. Furthermore, our results suggest that DC apoptosis was triggered via caspase activation, and it was ROS dependent with GD3 ganglioside, suggesting that GM3 and GD3 induced apoptosis through different mechanisms.

  11. Different mechanisms are involved in apoptosis induced by melanoma gangliosides on human monocyte-derived dendritic cells

    PubMed Central

    Bennaceur, Karim; Popa, Iuliana; Chapman, Jessica Alice; Migdal, Camille; Péguet-Navarro, Josette; Touraine, Jean-Louis; Portoukalian, Jacques

    2009-01-01

    Tumor escape is linked to multiple mechanisms, notably the liberation, by tumor cells, of soluble factors that inhibit the function of dendritic cells (DC). We have shown that melanoma gangliosides impair DC differentiation and induce their apoptosis. The present study was aimed to give insight into the mechanisms involved. DC apoptosis was independent of the catabolism of gangliosides since lactosylceramide did not induce cell death. Apoptosis induced by GM3 and GD3 gangliosides was not blocked by inhibitors of de novo ceramide biosynthesis, whereas the acid sphingomyelinase inhibitor desipramine only prevented apoptosis induced by GM3. Furthermore, our results suggest that DC apoptosis was triggered via caspase activation, and it was ROS dependent with GD3 ganglioside, suggesting that GM3 and GD3 induced apoptosis through different mechanisms. PMID:19240275

  12. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved.

    PubMed

    Comelli, Francesca; Giagnoni, Gabriella; Bettoni, Isabella; Colleoni, Mariapia; Costa, Barbara

    2008-08-01

    This study aimed to give a rationale for the employment of phytocannabinoid formulations to treat neuropathic pain. It was found that a controlled cannabis extract, containing multiple cannabinoids, in a defined ratio, and other non-cannabinoid fractions (terpenes and flavonoids) provided better antinociceptive efficacy than the single cannabinoid given alone, when tested in a rat model of neuropathic pain. The results also demonstrated that such an antihyperalgesic effect did not involve the cannabinoid CB1 and CB2 receptors, whereas it was mediated by vanilloid receptors TRPV1. The non-psychoactive compound, cannabidiol, is the only component present at a high level in the extract able to bind to this receptor: thus cannabidiol was the drug responsible for the antinociceptive behaviour observed. In addition, the results showed that after chronic oral treatment with cannabis extract the hepatic total content of cytochrome P450 was strongly inhibited as well as the intestinal P-glycoprotein activity. It is suggested that the inhibition of hepatic metabolism determined an increased bioavailability of cannabidiol resulting in a greater effect. However, in the light of the well known antioxidant and antiinflammatory properties of terpenes and flavonoids which could significantly contribute to the therapeutic effects, it cannot be excluded that the synergism observed might be achieved also in the absence of the cytochrome P450 inhibition.

  13. An intermolecular binding mechanism involving multiple LysM domains mediates carbohydrate recognition by an endopeptidase

    SciTech Connect

    Wong, Jaslyn E. M. M.; Midtgaard, Søren Roi; Gysel, Kira; Thygesen, Mikkel B.; Sørensen, Kasper K.; Jensen, Knud J.; Stougaard, Jens; Thirup, Søren; Blaise, Mickaël

    2015-03-01

    The crystal and solution structures of the T. thermophilus NlpC/P60 d, l-endopeptidase as well as the co-crystal structure of its N-terminal LysM domains bound to chitohexaose allow a proposal to be made regarding how the enzyme recognizes peptidoglycan. LysM domains, which are frequently present as repetitive entities in both bacterial and plant proteins, are known to interact with carbohydrates containing N-acetylglucosamine (GlcNAc) moieties, such as chitin and peptidoglycan. In bacteria, the functional significance of the involvement of multiple LysM domains in substrate binding has so far lacked support from high-resolution structures of ligand-bound complexes. Here, a structural study of the Thermus thermophilus NlpC/P60 endopeptidase containing two LysM domains is presented. The crystal structure and small-angle X-ray scattering solution studies of this endopeptidase revealed the presence of a homodimer. The structure of the two LysM domains co-crystallized with N-acetyl-chitohexaose revealed a new intermolecular binding mode that may explain the differential interaction between LysM domains and short or long chitin oligomers. By combining the structural information with the three-dimensional model of peptidoglycan, a model suggesting how protein dimerization enhances the recognition of peptidoglycan is proposed.

  14. Evolutionary mechanisms involved in the virulence of infectious salmon anaemia virus (ISAV), a piscine orthomyxovirus

    SciTech Connect

    Markussen, Turhan Jonassen, Christine Monceyron Numanovic, Sanela Braaen, Stine Hjortaas, Monika Nilsen, Hanne Mjaaland, Siri

    2008-05-10

    Infectious salmon anaemia virus (ISAV) is an orthomyxovirus causing a multisystemic, emerging disease in Atlantic salmon. Here we present, for the first time, detailed sequence analyses of the full-genome sequence of a presumed avirulent isolate displaying a full-length hemagglutinin-esterase (HE) gene (HPR0), and compare this with full-genome sequences of 11 Norwegian ISAV isolates from clinically diseased fish. These analyses revealed the presence of a virulence marker right upstream of the putative cleavage site R{sub 267} in the fusion (F) protein, suggesting a Q{sub 266} {yields} L{sub 266} substitution to be a prerequisite for virulence. To gain virulence in isolates lacking this substitution, a sequence insertion near the cleavage site seems to be required. This strongly suggests the involvement of a protease recognition pattern at the cleavage site of the fusion protein as a determinant of virulence, as seen in highly pathogenic influenza A virus H5 or H7 and the paramyxovirus Newcastle disease virus.

  15. Ion channels involved in cold detection in mammals: TRP and non-TRP mechanisms.

    PubMed

    Babes, Alexandru

    2009-12-01

    Substantial progress in understanding thermal transduction in peripheral sensory nerve endings was achieved with the recent cloning of six thermally gated ion channels from the TRP (transient receptor potential) super-family. Two of these channels, TRP melastatin 8 (TRPM8) and TRP ankyrin 1 (TRPA1), are expressed in dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons, are activated by various degrees of cooling, and are candidates for mediating gentle cooling and noxious cold, respectively. However, accumulating evidence suggests that more than just these two channels are involved in cold sensing in mammals. A recent report described a critical role of the voltage-gated tetrodotoxin-resistant sodium channel Nav1.8 in perceiving intense cold and noxious stimuli at cold temperatures. Other ion channels, such as two-pore domain background potassium channels (K2P), are known to be expressed in peripheral nerves, have pronounced temperature dependence, and may contribute to cold sensing and/or cold hypersensitivity in pain states. This article reviews the evidence supporting a role for each of these channels in cold transduction, focusing on their biophysical properties, expression pattern, and modulation by pro-inflammatory mediators.

  16. HSP27 Alleviates Cardiac Aging in Mice via a Mechanism Involving Antioxidation and Mitophagy Activation

    PubMed Central

    Lin, Shenglan; Wang, Yana; Zhang, Xiaojin; Kong, Qiuyue; Li, Chuanfu; Li, Yuehua; Ding, Zhengnian

    2016-01-01

    Aging-induced cardiac dysfunction is a prominent feature of cardiac aging. Heat shock protein 27 (HSP27) protects cardiac function against ischemia or chemical challenge. We hypothesized that HSP27 attenuates cardiac aging. Transgenic (Tg) mice with cardiac-specific expression of the HSP27 gene and wild-type (WT) littermates were employed in the experiments. Echocardiography revealed a significant decline in the cardiac function of old WT mice compared with young WT mice. In striking contrast, the aging-induced impairment of cardiac function was attenuated in old Tg mice compared with old WT mice. Levels of cardiac aging markers were lower in old Tg mouse hearts than in old WT mouse hearts. Less interstitial fibrosis and lower contents of reactive oxygen species and ubiquitin-conjugated proteins were detected in old Tg hearts than in old WT hearts. Furthermore, old Tg hearts demonstrated lower accumulation of LC3-II and p62 than old WT hearts. Levels of Atg13, Vps34, and Rab7 were also higher in old Tg hearts than in old WT hearts. Additionally, old Tg hearts had higher levels of PINK1 and Parkin than old WT hearts, suggesting that mitophagy was activated in old Tg hearts. Taken together, HSP27 alleviated cardiac aging and this action involved antioxidation and mitophagy activation. PMID:27110324

  17. Modelling and pathway identification involving the transport mechanism of a complex metabolic system in batch culture

    NASA Astrophysics Data System (ADS)

    Yuan, Jinlong; Zhang, Xu; Zhu, Xi; Feng, Enmin; Yin, Hongchao; Xiu, Zhilong

    2014-06-01

    The bio-dissimilation of glycerol to 1,3-propanediol (1,3-PD) by Klebsiella pneumoniae (K. pneumoniae) can be characterized by a complex metabolic system of interactions among biochemical fluxes, metabolic compounds, key enzymes and genetic regulation. In this paper, in consideration of the fact that the transport ways of 1,3-PD and glycerol with different weights across cell membrane are still unclear in batch culture, we consider 121 possible metabolic pathways and establish a novel mathematical model which is represented by a complex metabolic system. Taking into account the difficulty in accurately measuring the concentration of intracellular substances and the absence of equilibrium point for the metabolic system of batch culture, the novel approach used here is to define quantitatively biological robustness of the intracellular substance concentrations for the overall process of batch culture. To determine the most possible metabolic pathway, we take the defined biological robustness as cost function and establish an identification model, in which 1452 system parameters and 484 pathway parameters are involved. Simultaneously, the identification model is subject to the metabolic system, continuous state constraints and parameter constraints. As such, solving the identification model by a serial program is a very complicated task. We propose a parallel migration particle swarm optimization algorithm (MPSO) capable of solving the identification model in conjunction with the constraint transcription and smoothing approximation techniques. Numerical results show that the most possible metabolic pathway and the corresponding metabolic system can reasonably describe the process of batch culture.

  18. Molecular Dissection of the Cellular Mechanisms Involved in Nickel Hyperaccumulation in Plants

    SciTech Connect

    Salt, David E.

    1999-06-01

    Phytoremediation, the use of plants for environmental cleanup of pollutants, including toxic metals, holds the potential to allow the economic restoration of heavy metal and radionuclide contaminated sites. A number of terrestrial plants are known to naturally accumulate high levels of metals in their shoots (1-2% dry weight), and these plants have been termed metal-hyperaccumulators. Clearly, the genetic traits that determines metal-hyperaccumulation offers the potential for the development of practical phytoremediation processes. Our long-term objective is to rationally design and generate plants ideally suited for phytoremediation using this unique genetic material. Initially, our strategy will focus on isolating and characterizing the key genetic information needed for expression of the metal-hyperaccumulation phenotype. Recently, histidine has been shown to play a major role in Ni hyperaccumulation. Based on this information we propose to investigate, at the molecular level, the role of histidine biosynthesis in Ni hyperaccumulation in Thlaspi goesingense, a Ni hyperaccumulator species. We will clone key genes involved in histidine biosynthesis. We will characterize their transcriptional and post transcriptional regulation by histidine, Ni. We will determine if any of these genes are essential and sufficient for Ni hyperaccumulation by their expression in the non-hyperaccumulator Arabidopsis thaliana.

  19. New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism.

    PubMed

    Fernández-Rebollo, Eduardo; Lecumberri, Beatriz; Garin, Intza; Arroyo, Javier; Bernal-Chico, Ana; Goñi, Fernando; Orduña, Rosa; Castaño, Luis; de Nanclares, Guiomar Pérez

    2010-12-01

    Type I pseudohypoparathyroidism (PHP-I) can be subclassified into Ia and Ib, depending on the presence or absence of Albright's hereditary osteodystrophy's phenotype, diminished α-subunit of the stimulatory G protein (G(s)α) activity and multihormonal resistance. Whereas PHP-Ia is mainly associated with heterozygous inactivating mutations in G(s)α-coding exons of GNAS, PHP-Ib is caused by imprinting defects of GNAS. To date, just one patient with PHP and complete paternal uniparental disomy (UPD) has been described. We sought to identify the underlining molecular defect in twenty patients with parathyroid hormone resistance, hypocalcemia and hyperphosphatemia, and abnormal methylation pattern at GNAS locus. Microsatellite typing and comparative genome hybridization were performed for proband and parents. We describe four patients with partial paternal UPD of chromosome 20 involving pat20qUPD in one case, from 20q13.13-qter in two cases, and pat20p heterodisomy plus interstitial 20q isodisomy in one patient. These observations demonstrate that mitotic recombination of chromosome 20 can also give rise to UPD and PHP, a situation similar to other imprinting disorders, such as Beckwith-Wiedemann syndrome or neonatal diabetes.

  20. An intermolecular binding mechanism involving multiple LysM domains mediates carbohydrate recognition by an endopeptidase.

    PubMed

    Wong, Jaslyn E M M; Midtgaard, Søren Roi; Gysel, Kira; Thygesen, Mikkel B; Sørensen, Kasper K; Jensen, Knud J; Stougaard, Jens; Thirup, Søren; Blaise, Mickaël

    2015-03-01

    LysM domains, which are frequently present as repetitive entities in both bacterial and plant proteins, are known to interact with carbohydrates containing N-acetylglucosamine (GlcNAc) moieties, such as chitin and peptidoglycan. In bacteria, the functional significance of the involvement of multiple LysM domains in substrate binding has so far lacked support from high-resolution structures of ligand-bound complexes. Here, a structural study of the Thermus thermophilus NlpC/P60 endopeptidase containing two LysM domains is presented. The crystal structure and small-angle X-ray scattering solution studies of this endopeptidase revealed the presence of a homodimer. The structure of the two LysM domains co-crystallized with N-acetyl-chitohexaose revealed a new intermolecular binding mode that may explain the differential interaction between LysM domains and short or long chitin oligomers. By combining the structural information with the three-dimensional model of peptidoglycan, a model suggesting how protein dimerization enhances the recognition of peptidoglycan is proposed.

  1. An intermolecular binding mechanism involving multiple LysM domains mediates carbohydrate recognition by an endopeptidase

    PubMed Central

    Wong, Jaslyn E. M. M.; Midtgaard, Søren Roi; Gysel, Kira; Thygesen, Mikkel B.; Sørensen, Kasper K.; Jensen, Knud J.; Stougaard, Jens; Thirup, Søren; Blaise, Mickaël

    2015-01-01

    LysM domains, which are frequently present as repetitive entities in both bacterial and plant proteins, are known to interact with carbohydrates containing N-acetylglucosamine (GlcNAc) moieties, such as chitin and peptidoglycan. In bacteria, the functional significance of the involvement of multiple LysM domains in substrate binding has so far lacked support from high-resolution structures of ligand-bound complexes. Here, a structural study of the Thermus thermophilus NlpC/P60 endopeptidase containing two LysM domains is presented. The crystal structure and small-angle X-ray scattering solution studies of this endopeptidase revealed the presence of a homodimer. The structure of the two LysM domains co-crystallized with N-acetyl-chitohexaose revealed a new intermolecular binding mode that may explain the differential interaction between LysM domains and short or long chitin oligomers. By combining the structural information with the three-dimensional model of peptidoglycan, a model suggesting how protein dimerization enhances the recognition of peptidoglycan is proposed. PMID:25760608

  2. An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields

    PubMed Central

    Tuszynski, Jack A.; Wenger, Cornelia; Friesen, Douglas E.; Preto, Jordane

    2016-01-01

    Long-standing research on electric and electromagnetic field interactions with biological cells and their subcellular structures has mainly focused on the low- and high-frequency regimes. Biological effects at intermediate frequencies between 100 and 300 kHz have been recently discovered and applied to cancer cells as a therapeutic modality called Tumor Treating Fields (TTFields). TTFields are clinically applied to disrupt cell division, primarily for the treatment of glioblastoma multiforme (GBM). In this review, we provide an assessment of possible physical interactions between 100 kHz range alternating electric fields and biological cells in general and their nano-scale subcellular structures in particular. This is intended to mechanistically elucidate the observed strong disruptive effects in cancer cells. Computational models of isolated cells subject to TTFields predict that for intermediate frequencies the intracellular electric field strength significantly increases and that peak dielectrophoretic forces develop in dividing cells. These findings are in agreement with in vitro observations of TTFields’ disruptive effects on cellular function. We conclude that the most likely candidates to provide a quantitative explanation of these effects are ionic condensation waves around microtubules as well as dielectrophoretic effects on the dipole moments of microtubules. A less likely possibility is the involvement of actin filaments or ion channels. PMID:27845746

  3. Mechanisms involved in the anti-inflammatory action of inhaled tea tree oil in mice.

    PubMed

    Golab, Mateusz; Skwarlo-Sonta, Krystyna

    2007-03-01

    Tea tree oil (TTO) is well known as an antimicrobial and immunomodulatory agent. In the present study we confirmed the anti-inflammatory properties of TTO and investigated the involvement of the hypothalamic-pituitary-adrenal (HPA) axis in the immunomodulatory action of TTO administered by inhalation. Sexually mature, 6-8-week-old, C(57)BI(10) x CBA/H (F(1)) male mice were used. One group of animals was injected intra-peritoneally (ip) with Zymosan to elicit peritoneal inflammation and was then submitted to four sessions of TTO inhalation (15 mins each). Some of the mice were simultaneously injected ip with Antalarmin, a CRH-1 receptor antagonist, to block HPA axis functions. Twenty-four hours after the injections the mice were killed by CO(2) asphyxia, and peritoneal leukocytes (PTLs) were isolated and counted. Levels of reactive oxygen species (ROS) and cyclooxygenase (COX) activity in PTLs were assessed by fluorimetric and colorimetric assays, respectively. The results obtained show that sessions of TTO inhalation exert a strong anti-inflammatory influence on the immune system stimulated by Zymosan injection, while having no influence on PTL number, ROS level, and COX activity in mice without inflammation. The HPA axis was shown to mediate the anti-inflammatory effect of TTO; Antalarmin abolished the influence of inhaled TTO on PTL number and their ROS production in mice with experimental peritonitis, but it had no effect on these parameters in mice without inflammation.

  4. Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids☆

    PubMed Central

    Harrison, Earl H.

    2012-01-01

    Vitamin A is an essential nutrient for humans and is converted to the visual chromophore, 11-cis-retinal, and to the hormone, retinoic acid. Vitamin A in animal-derived foods is found as long chain acyl esters of retinol and these are digested to free fatty acids and retinol before uptake by the intestinal mucosal cell. The retinol is then reesterified to retinyl esters for incorporation into chlylomicrons and absorbed via the lymphatics or effluxed into the portal circulation facilitated by the lipid transporter, ABCA1. Provitamin A carotenoids such as β-carotene are found in plant-derived foods. These and other carotenoids are transported into the mucosal cell by scavenger receptor class B type I (SR-BI). Provitamin A carotenoids are partly converted to retinol by oxygenase and reductase enzymes and the retinol so produced is available for absorption via the two pathways described above. The efficiency of vitamin A and carotenoid intestinal absorption is determined by the regulation of a number of proteins involved in the process. Polymorphisms in genes for these proteins lead to individual variability in the metabolism and transport of vitamin A and carotenoids. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. PMID:21718801

  5. Phospholipase A{sub 2} is involved in the mechanism of activation of neutrophils by polychlorinated biphenyls

    SciTech Connect

    Tithof, P.K.; Schiamberg, E.; Ganey, P.E.; Peters-Golden, M.

    1996-01-01

    Aroclor 1242, a mixture of polychlorinated biphenyls (PCBs), activates neutrophils to produce superoxide anion (O{sub 2}{sup {minus}}) by a mechanism that involves phospholipase C-dependent hydrolysis of membrane phosphoinositides; however, subsequent signal transduction mechanisms are unknown. This study determines whether phospholipase A{sub 2}-dependent release of arachidonic acid is involved in PCB-induced O{sub 2}{sup {minus}} production. O{sub 2}{sup {minus}} production was measured in vitro in glycogen-elicited, rat neutrophils in the presence and absence of the inhibitors of phospholipase A{sub 2}: quinacrine, 4-bromophenacyl bromide (BPB), and manoalide. All three agents significantly decreased the amount of O{sub 2}{sup {minus}} detected during stimulation of neutrophils with Aroclor 1242. Similar inhibition occurred when neutrophils were activated with the classical stimuli, formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate. The effects of BPB and manoalide were not a result of cytotoxicity or other nonspecific effects. Significant release of {sup 3}H-arachidonic acid preceded O{sub 2}{sup {minus}} production in neutrophils stimulated with Aroclor 1242 or fMLP. Manoalide, at a concentration that abolished O{sub 2}{sup {minus}} production, also inhibited the release of {sup 3}H-arachidonate. Aspirin, zileuton, or WEB 2086 did not affect Aroclor 1242-induced O{sub 2}{sup {minus}} production, suggesting that eicosanoids and platelet-activating factor are not needed for neutrophil activation by PCBs. Activation of phos-pholipase A{sub 2} and O{sub 2}{sup {minus}} production do not appear to involve the Ah receptor. These data suggest that Aroclor 1242 stimulates neutrophils to produce O{sub 2}{sup {minus}} by a mechanism that involves phospholipase A{sub 2}-dependent release of arachiodonic acid. 49 refs., 6 figs., 2 tabs.

  6. Antioxidant mechanism of black garlic extract involving nuclear factor erythroid 2-like factor 2 pathway

    PubMed Central

    Ha, Ae Wha

    2017-01-01

    BACKGROUN/OBJECTIVES Although studies have revealed that black garlic is a potent antioxidant, its antioxidant mechanism remains unclear. The objective of this study was to determine black garlic's antioxidant activities and possible antioxidant mechanisms related to nuclear factor erythroid 2-like factor 2 (Nrf2)-Keap1 complex. METHODS/MATERIALS After four weeks of feeding rats with a normal fat diet (NF), a high-fat diet (HF), a high-fat diet with 0.5% black garlic extract (HF+BGE 0.5), a high-fat diet with 1.0% black garlic extract (HF+BGE 1.0), or a high-fat diet with 1.5% black garlic extract (HF+BGE 1.5), plasma concentrations of glucose, insulin,homeostatic model assessment of insulin resistance (HOMA-IR) were determined. As oxidative stress indices, plasma concentrations of thiobarbituric acid reactive substances (TBARS) and 8-isoprostaglandin F2α (8-iso-PGF) were determined. To measure antioxidant capacities, plasma total antioxidant capacity (TAC) and activities of antioxidant enzymes in plasma and liver were determined. The mRNA expression levels of antioxidant related proteins such as Nrf2, NAD(P)H: quinone-oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), glutathione reductase (GR), and glutathione S-transferase alpha 2 (GSTA2) were examined. RESULTS Plasma glucose level, plasma insulin level, and HOMA-IR in black garlic supplemented groups were significantly (P < 0.05) lower than those in the HF group without dose-dependent effect. Plasma TBARS concentration and TAC in the HF+BGE 1.5 group were significantly decreased compared to those of the HF group. The activities of catalase and glutathione peroxidase were significantly (P < 0.05) increased in the HF+BGE 1.0 and HF+BGE 1.5 groups compared to those of the HF group. The mRNA expression levels of hepatic Nrf2, NQO1, HO-1, and GSTA2 were significantly (P < 0.05) increased in the HF with BGE groups compared to those in the HF group. CONCLUSIONS The improvements of blood glucose homeostasis and

  7. Antioxidant mechanism of black garlic extract involving nuclear factor erythroid 2-like factor 2 pathway.

    PubMed

    Ha, Ae Wha; Kim, Woo Kyoung

    2017-06-01

    Although studies have revealed that black garlic is a potent antioxidant, its antioxidant mechanism remains unclear. The objective of this study was to determine black garlic's antioxidant activities and possible antioxidant mechanisms related to nuclear factor erythroid 2-like factor 2 (Nrf2)-Keap1 complex. After four weeks of feeding rats with a normal fat diet (NF), a high-fat diet (HF), a high-fat diet with 0.5% black garlic extract (HF+BGE 0.5), a high-fat diet with 1.0% black garlic extract (HF+BGE 1.0), or a high-fat diet with 1.5% black garlic extract (HF+BGE 1.5), plasma concentrations of glucose, insulin,homeostatic model assessment of insulin resistance (HOMA-IR) were determined. As oxidative stress indices, plasma concentrations of thiobarbituric acid reactive substances (TBARS) and 8-isoprostaglandin F2α (8-iso-PGF) were determined. To measure antioxidant capacities, plasma total antioxidant capacity (TAC) and activities of antioxidant enzymes in plasma and liver were determined. The mRNA expression levels of antioxidant related proteins such as Nrf2, NAD(P)H: quinone-oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), glutathione reductase (GR), and glutathione S-transferase alpha 2 (GSTA2) were examined. Plasma glucose level, plasma insulin level, and HOMA-IR in black garlic supplemented groups were significantly (P < 0.05) lower than those in the HF group without dose-dependent effect. Plasma TBARS concentration and TAC in the HF+BGE 1.5 group were significantly decreased compared to those of the HF group. The activities of catalase and glutathione peroxidase were significantly (P < 0.05) increased in the HF+BGE 1.0 and HF+BGE 1.5 groups compared to those of the HF group. The mRNA expression levels of hepatic Nrf2, NQO1, HO-1, and GSTA2 were significantly (P < 0.05) increased in the HF with BGE groups compared to those in the HF group. The improvements of blood glucose homeostasis and antioxidant systems in rats fed with black garlic extract were

  8. Malaria vectors resistance to insecticides in Benin: current trends and mechanisms involved.

    PubMed

    Gnanguenon, Virgile; Agossa, Fiacre R; Badirou, Kefilath; Govoetchan, Renaud; Anagonou, Rodrigue; Oke-Agbo, Fredéric; Azondekon, Roseric; AgbanrinYoussouf, Ramziath; Attolou, Roseline; Tokponnon, Filemon T; Aïkpon, Rock; Ossè, Razaki; Akogbeto, Martin C

    2015-04-12

    Bendiocarb and detection of insensitive acetylcholinesterase-1 from northern Benin, and a wide distribution of susceptible vectors to Pirimiphos methyl and Fenitrothion. This study showed a widespread resistance of malaria vectors to pyrethroid previously located in southern Benin, an early emergence of carbamates resistance from northern Benin and a full susceptibility to organophosphates. Several resistance mechanisms were detected in vectors with a potential cross resistance to pyrethroids through Knock-down and metabolic resistance mechanisms.

  9. Dopamine receptor-mediated mechanisms involved in the expression of learned activity of primate striatal neurons.

    PubMed

    Watanabe, K; Kimura, M

    1998-05-01

    To understand the mechanisms by which basal ganglia neurons express acquired activities during and after behavioral learning, selective dopamine (DA) receptor antagonists were applied while recording the activity of striatal neurons in monkeys performing behavioral tasks. In experiment 1, a monkey was trained to associate a click sound with a drop of reward water. DA receptor antagonists were administered by micropressure using a stainless steel injection cannula (300 microm ID) through which a Teflon-coated tungsten wire for recording neuronal activity had been threaded. Responses to sound by tonically active neurons (TANs), a class of neurons in the primate striatum, were recorded through a tungsten wire electrode during the application of either D1- or D2-class DA receptor antagonists (total volume <1 microl, at a rate of 1 microl/5-10 min). Application of the D2-class antagonist, (-)-sulpiride (20 micrograms/microl, 58 mM, pH 6.8), abolished the responses of four of five TANs examined. In another five TANs, neither the D2-class antagonist nor the D1-class antagonists, SCH23390 (10 micrograms/microl, 31 mM, pH 5.7) or cis-flupenthixol (30 micrograms/microl, 59 mM, pH 6.6) significantly suppressed responses. In experiment 2, four- or five-barreled glass microelectrodes were inserted into the striatum. The central barrel was used for extracellular recording of activity of TANs. Each DA receptor antagonist was iontophoretically applied through one of the surrounding barrels. SCH23390 (10 mM, pH 4.5) and (-)-sulpiride (10 mM, pH 4.5) were used. The effects of iontophoresis of both D1- and D2-class antagonists were examined in 40 TANs. Of 40 TANs from which recordings were made, responses were suppressed exclusively by the D2-class antagonist in 19 TANs, exclusively by the D1-class antagonist in 3 TANs, and by both D1- and D2-class antagonists in 7 TANs. When 0.9% NaCl, saline, was applied by pressure (<1 microl) or by iontophoresis (<30 nA) as a control, neither the

  10. Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway

    PubMed Central

    Gurusamy, Narasimman; Lekli, Istvan; Mukherjee, Subhendu; Ray, Diptarka; Ahsan, Md. Kaimul; Gherghiceanu, Mihaela; Popescu, Lawrence M.; Das, Dipak K.

    2010-01-01

    Aims On the basis of our previous reports that cardioprotection induced by ischaemic preconditioning induces autophagy and that resveratrol, a polyphenolic antioxidant present in grapes and red wine induces preconditioning-like effects, we sought to determine if resveratrol could induce autophagy. Methods and results Resveratrol at lower doses (0.1 and 1 µM in H9c2 cardiac myoblast cells and 2.5 mg/kg/day in rats) induced cardiac autophagy shown by enhanced formation of autophagosomes and its component LC3-II after hypoxia–reoxygenation or ischaemia–reperfusion. The autophagy was attenuated with the higher dose of resveratrol. The induction of autophagy was correlated with enhanced cell survival and decreased apoptosis. Treatment with rapamycin (100 nM), a known inducer of autophagy, did not further increase autophagy compared with resveratrol alone. Autophagic inhibitors, wortmannin (2 µM) and 3-methyladenine (10 mM), significantly attenuated the resveratrol-induced autophagy and induced cell death. The activation of mammalian target of rapamycin (mTOR) was differentially regulated by low-dose resveratrol, i.e. the phosphorylation of mTOR at serine 2448 was inhibited, whereas the phosphorylation of mTOR at serine 2481 was increased, which was attenuated with a higher dose of resveratrol. Although resveratrol attenuated the activation of mTOR complex 1, low-dose resveratrol significantly induced the expression of Rictor, a component of mTOR complex 2, and activated its downstream survival kinase Akt (Ser 473). Resveratrol-induced Rictor was found to bind with mTOR. Furthermore, treatment with Rictor siRNA attenuated the resveratrol-induced autophagy. Conclusion Our results indicate that at lower dose, resveratrol-mediated cell survival is, in part, mediated through the induction of autophagy involving the mTOR-Rictor survival pathway. PMID:19959541

  11. Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications.

    PubMed

    Maeda, Hiroshi; Fang, Jun; Inutsuka, Takao; Kitamoto, Yasunori

    2003-03-01

    Most solid tumors are known to exhibit highly enhanced vascular permeability, similar to or more than the inflammatory tissues. Common denominators affecting both cancer and inflammatory lesions are now well known: bradykinin (BK), nitric oxide (NO), peroxynitrite (ONOO(-)), prostaglandins (PGs), collagenases or matrix metalloproteinases (MMPs) and others. Incidentally, enzymes involved in these mediator syntheses are upregulated or activated. Initially described vascular permeability factor (VPF) (proteinaceous) was later identified to be the same as vascular endothelial growth factor (VEGF), which promotes angiogenesis of cancer tissues as well. These mediators cross-talk or co-upregulate each other, such as BK-NO-PGs system. Therefore, vascular permeability observed in solid tumor may reflect the other side of the coin (angiogenesis). The vascular permeability and accumulation of plasma components in the interstitium described here is applicable for predominantly macromolecules (molecular weight, Mw>45 kDa), but not for low molecular compounds as most anticancer agents are. Macromolecular compounds (e.g., albumin, transferrin) or many biocompatible water-soluble polymers show this effect. Furthermore, they are not cleared rapidly from the sites of lesion (cancer/inflammatory tissue), thus, remain for prolonged time, usually for more than a few days. This phenomenon of "enhanced permeability and retention effect" observed in cancer tissue for macromolecules and lipids is coined "EPR effect", which is now widely accepted as a gold standard for anticancer drug designing to seek more cancer-selective targeting using macromolecular drugs. Consequently, drastic reduction of the systemic side effect is observed, while the macromolecular drugs will continuously exert antitumor activity. Other advantages of macromolecular drugs are also discussed.

  12. A systems toxicology approach to elucidate the mechanisms involved in RDX species-specific sensitivity.

    PubMed

    Warner, Christopher M; Gust, Kurt A; Stanley, Jacob K; Habib, Tanwir; Wilbanks, Mitchell S; Garcia-Reyero, Natàlia; Perkins, Edward J

    2012-07-17

    Interspecies uncertainty factors in ecological risk assessment provide conservative estimates of risk where limited or no toxicity data is available. We quantitatively examined the validity of interspecies uncertainty factors by comparing the responses of zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) to the energetic compound 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), a known neurotoxicant. Relative toxicity was measured through transcriptional, morphological, and behavioral end points in zebrafish and fathead minnow fry exposed for 96 h to RDX concentrations ranging from 0.9 to 27.7 mg/L. Spinal deformities and lethality occurred at 1.8 and 3.5 mg/L RDX respectively for fathead minnow and at 13.8 and 27.7 mg/L for zebrafish, indicating that zebrafish have an 8-fold greater tolerance for RDX than fathead minnow fry. The number and magnitude of differentially expressed transcripts increased with increasing RDX concentration for both species. Differentially expressed genes were enriched in functions related to neurological disease, oxidative-stress, acute-phase response, vitamin/mineral metabolism and skeletal/muscular disorders. Decreased expression of collagen-coding transcripts were associated with spinal deformity and likely involved in sensitivity to RDX. Our work provides a mechanistic explanation for species-specific sensitivity to RDX where zebrafish responded at lower concentrations with greater numbers of functions related to RDX tolerance than fathead minnow. While the 10-fold interspecies uncertainty factor does provide a reasonable cross-species estimate of toxicity in the present study, the observation that the responses between ZF and FHM are markedly different does initiate a call for concern regarding establishment of broad ecotoxicological conclusions based on model species such as zebrafish.

  13. Vacuolar Sequestration of Paraquat Is Involved in the Resistance Mechanism in Lolium perenne L. spp. multiflorum

    PubMed Central

    Brunharo, Caio A. C. G.; Hanson, Bradley D.

    2017-01-01

    . These results strongly indicate that vacuolar sequestration is involved in the resistance to paraquat in this population of LOLMU. PMID:28890724

  14. Mechanisms involved in the antiplatelet activity of magnesium in human platelets.

    PubMed

    Sheu, Joen-Rong; Hsiao, George; Shen, Ming-Yi; Fong, Tsorng-Harn; Chen, Yi-Win; Lin, Chien-Huang; Chou, Duen-Suey

    2002-12-01

    In this study, magnesium sulphate dose-dependently (0.6-3.0 mmol/l) inhibited platelet aggregation in human platelets stimulated by agonists. Furthermore, magnesium sulphate (3.0 mmol/l) markedly interfered with the binding of fluorescein isothiocanate-triflavin to the glycoprotein (GP)IIb/IIIa complex in platelets stimulated by collagen. Magnesium sulphate (1.5 and 3.0 mmol/l) also inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in human platelets stimulated by collagen. Magnesium sulphate (3.0 mmol/l) significantly inhibited thromboxane A2 formation stimulated by collagen in platelets. Moreover, magnesium sulphate (1.5 and 3.0 mmol/l) obviously increased the fluorescence of platelet membranes tagged with diphenylhexatriene. In addition, magnesium sulphate (1.5 and 3.0 mmol/l) increased the formation of cyclic adenosine monophosphate (AMP) in platelets. Phosphorylation of a protein of Mr 47 000 (P47) was markedly inhibited by magnesium sulphate (1.5 mmol/l). In conclusion, the antiplatelet activity of magnesium sulphate may involve the following two pathways. (1) Magnesium sulphate may initially induce membrane fluidity changes with resulting interference of fibrinogen binding to the GPIIb/IIIa complex, followed by inhibition of phosphoinositide breakdown and thromboxane A2 formation, thereby leading to inhibition of both intracellular Ca2+ mobilization and phosphorylation of P47. (2) Magnesium sulphate might also trigger the formation of cyclic AM, ultimately resulting in inhibition of the phosphorylation of P47 and intracellular Ca+2 mobilization.

  15. Permeability of membranes to amino acids and modified amino acids: mechanisms involved in translocation

    NASA Technical Reports Server (NTRS)

    Chakrabarti, A. C.; Deamer, D. W. (Principal Investigator); Miller, S. L. (Principal Investigator)

    1994-01-01

    The amino acid permeability of membranes is of interest because they are one of the key solutes involved in cell function. Membrane permeability coefficients (P) for amino acid classes, including neutral, polar, hydrophobic, and charged species, have been measured and compared using a variety of techniques. Decreasing lipid chain length increased permeability slightly (5-fold), while variations in pH had only minor effects on the permeability coefficients of the amino acids tested in liposomes. Increasing the membrane surface charge increased the permeability of amino acids of the opposite charge, while increasing the cholesterol content decreased membrane permeability. The permeability coefficients for most amino acids tested were surprisingly similar to those previously measured for monovalent cations such as sodium and potassium (approximately 10(-12)-10(-13) cm s-1). This observation suggests that the permeation rates for the neutral, polar and charged amino acids are controlled by bilayer fluctuations and transient defects, rather than partition coefficients and Born energy barriers. Hydrophobic amino acids were 10(2) more permeable than the hydrophilic forms, reflecting their increased partition coefficient values. External pH had dramatic effects on the permeation rates for the modified amino acid lysine methyl ester in response to transmembrane pH gradients. It was established that lysine methyl ester and other modified short peptides permeate rapidly (P = 10(-2) cm s-1) as neutral (deprotonated) molecules. It was also shown that charge distributions dramatically alter permeation rates for modified di-peptides. These results may relate to the movement of peptides through membranes during protein translocation and to the origin of cellular membrane transport on the early Earth.

  16. Clinical--imaging aspects of young permanent teeth traumas and the ethiopatogenic mechanisms involved.

    PubMed

    Nemţoi, A; Dănila, I; Lăduncă, Oana; Petcu, Ana; Bamboi, Ana; Haba, Danisia

    2013-01-01

    Dental trauma occurring to children and teenagers all over the world represents a serious issue in Public Health. This present study wants to investigate the etiology and the environment in which the dental trauma occurs and also wants to establish a connection between dental trauma and social-economic status. The study was made to collect information about dental trauma on human subjects involving 372 children and teenagers, both female and male, between 8 and 20 years of age. The data obtained from the clinical and radiological exams for each patient have been registered in a special conceived register, which represented a stage of the study. The frequency of dental trauma varied from 62.1% for males to 37.9% for women. Most of them have suffered from dental trauma between the age of 14 and 16 (30.1%), and a few between 18 and 20 years (2.2%). Dental trauma has occurred most frequently in school, during sports lessons, followed by those in public places like the street (23.1%), from which 17.1% have been associated with bicycle accidents, 3.5% with scooter accidents and 2.5% with car accidents. Children and teenagers who live in areas with a low social economic level have been the fewest to seek medical attention due to difficult access to medical services. Overall, this study wanted to present the importance of knowing the frequency of dental trauma in children and teenagers and to point out the need of promoting medical education to parents regarding the means they can use to reduce the risk factors associated with dental trauma.

  17. Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis

    PubMed Central

    Robert, Sacha; Gicquel, Thomas; Victoni, Tatiana; Valença, Samuel; Barreto, Emiliano; Bailly-Maître, Béatrice; Boichot, Elisabeth; Lagente, Vincent

    2016-01-01

    Fibrosis is a basic connective tissue lesion defined by the increase in the fibrillar extracellular matrix (ECM) components in tissue or organ. Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turn-over of ECM and so they are suggested to be important in tissue remodelling observed during fibrogenic process associated with chronic inflammation. Tissue remodelling is the result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of ECM components markedly controlled by the MMPs/TIMP imbalance. We previously showed an association of the differences in collagen deposition in the lungs of bleomycin-treated mice with a reduced molar pro-MMP-9/TIMP-1 ratio. Using the carbon tetrachloride (CCl4) preclinical model of liver fibrosis in mice, we observed a significant increase in collagen deposition with increased expression and release of tissue inhibitors of metalloproteinase (TIMP)-1 both at 24 h and 3 weeks later. This suggests an early altered regulation of matrix turnover involved in the development of fibrosis. We also demonstrated an activation of NLRP3-inflammasome pathway associated with the IL-1R/MyD88 signalling in the development of experimental fibrosis both in lung and liver. This was also associated with an increased expression of purinergic receptors mainly P2X7. Finally, these observations emphasize those effective therapies for these disorders must be given early in the natural history of the disease, prior to the development of tissue remodelling and fibrosis. PMID:27247426

  18. Motor and attentional mechanisms involved in social interaction--evidence from mu and alpha EEG suppression.

    PubMed

    Perry, Anat; Stein, Libi; Bentin, Shlomo

    2011-10-01

    Mu rhythms are EEG oscillations in the 8-13 Hz recorded at sites located roughly over the sensory-motor cortex. There is reliable evidence that the amplitude of mu rhythms is reduced when the participant performs a motor act (mu suppression). Recent studies found mu suppression not only in response to actual movements but also while the participant observes actions executed by someone else. This finding putatively associates the mu suppression to the activity of a mirror neurons system which, in humans, has been suggested to contribute to social skills. In the present study we explored the effects of different levels of social interaction on mu suppression. Participants observed dynamic displays of hand gestures performing actions used in the Rock-Scissors-Paper game. In different blocks, participants passively viewed identical video clips with no game context and in the context of a game, or while being actually engaged in the game either by imagining actions or by actual playing. As a baseline for calculating mu suppression we used a dynamic display of a rolling ball. In addition, to isolate the social aspect of the actual movements, participants performed the same acts outside the game context. Mu suppression was larger while participants were engaged in the social game than when they passively looked at the "opponent" actions or when they performed movements without the game context. This effect was found while viewing the opponent play as well as while actually playing, which supports the view that mu suppression is affected not only by motion, but also by the social context of the motion. However, we did not find differences in mu suppression between perception segments in which the participant did not actually play. Furthermore, in all perception segments occipital alpha suppression was more robust than mu suppression suggesting the involvement of a strong attentional component. While actually playing, however, mu suppression was stronger than alpha

  19. Mechanism of phytohormone involvement in feedback regulation of cotton leaf senescence induced by potassium deficiency

    PubMed Central

    Tian, Xiaoli

    2012-01-01

    To elucidate the phytohormonal basis of the feedback regulation of leaf senescence induced by potassium (K) deficiency in cotton (Gossypium hirsutum L.), two cultivars contrasting in sensitivity to K deficiency were self- and reciprocally grafted hypocotyl-to-hypocotyl, using standard grafting (one scion grafted onto one rootstock), Y grafting (two scions grafted onto one rootstock), and inverted Y grafting (one scion grafted onto two rootstocks) at the seedling stage. K deficiency (0.03mM for standard and Y grafting, and 0.01mM for inverted Y grafting) increased the root abscisic acid (ABA) concentration by 1.6- to 3.1-fold and xylem ABA delivery rates by 1.8- to 4.6-fold. The K deficiency also decreased the delivery rates of xylem cytokinins [CKs; including the zeatin riboside (ZR) and isopentenyl adenosine (iPA) type] by 29–65% and leaf CK concentration by 16–57%. The leaf ABA concentration and xylem ABA deliveries were consistently greater in CCRI41 (more sensitive to K deficiency) than in SCRC22 (less sensitive to K deficiency) scions under K deficiency, and ZR- and iPA-type levels were consistently lower in the former than in the latter, irrespective of rootstock cultivar or grafting type, indicating that cotton shoot influences the levels of ABA and CKs in leaves and xylem sap. Because the scions had little influence on phytohormone levels in the roots (rootstocks) of all three types of grafts and rootstock xylem sap (collected below the graft union) of Y and inverted Y grafts, it appears that the site for basipetal feedback signal(s) involved in the regulation of xylem phytohormones is the hypocotyl of cotton seedlings. Also, the target of this feedback signal(s) is more likely to be the changes in xylem phytohormones within tissues of the hypocotyl rather than the export of phytohormones from the roots. PMID:22962680

  20. Modeling the mechanism involved during the sorption of methylene blue onto fly ash.

    PubMed

    Kumar, K Vasanth; Ramamurthi, V; Sivanesan, S

    2005-04-01

    Batch sorption experiments were carried out to remove methylene blue from its aqueous solutions using fly ash as an adsorbent. Operating variables studied were initial dye concentration, fly ash mass, pH, and contact time. Maximum color removal was observed at a basic pH of 8. Equilibrium data were represented well by a Langmuir isotherm equation with a monolayer sorption capacity of 5.718 mg/g. Sorption data were fitted to both Lagergren first-order and pseudo-second-order kinetic models and the data were found to follow pseudo-second-order kinetics. Rate constants at different initial concentrations were estimated. The process mechanism was found to be complex, consisting of both surface adsorption and pore diffusion. The effective diffusion parameter D(i) values were estimated at different initial concentrations and the average value was determined to be 2.063 x 10(-9)cm2/s. Analysis of sorption data using a Boyd plot confirms the particle diffusion as the rate-limiting step for the dye concentration ranges studied in the present investigation (20 to 60 mg/L).

  1. Auxin-induced growth of Avena coleoptiles involves two mechanisms with different pH optima

    NASA Technical Reports Server (NTRS)

    Cleland, R. E.

    1992-01-01

    Although rapid auxin-induced growth of coleoptile sections can persist for at least 18 hours, acid-induced growth lasts for a much shorter period of time. Three theories have been proposed to explain this difference in persistence. To distinguish between these theories, the pH dependence for auxin-induced growth of oat (Avena sativa L.) coleoptiles has been determined early and late in the elongation process. Coleoptile sections from which the outer epidermis was removed to facilitate buffer entry were incubated, with or without 10 micromolar indoleacetic acid, in 20 millimolar buffers at pH 4.5 to 7.0 to maintain a fixed wall pH. During the first 1 to 2 hours after addition of auxin, elongation occurs by acid-induced extension (i.e. the pH optimum is <5 and the elongation varies inversely with the solution pH). Auxin causes no additional elongation because the buffers prevent further changes in wall pH. After 60 to 90 minutes, a second mechanism of auxin-induced growth, whose pH optimum is 5.5 to 6.0, predominates. It is proposed that rapid growth responses to changes in auxin concentration are mediated by auxin-induced changes in wall pH, whereas the prolonged, steady-state growth rate is controlled by a second, auxin-mediated process whose pH optimum is less acidic.

  2. The mechanism of nuclear export of Smad3 involves exportin 4 and Ran.

    PubMed

    Kurisaki, Akira; Kurisaki, Keiko; Kowanetz, Marcin; Sugino, Hiromu; Yoneda, Yoshihiro; Heldin, Carl-Henrik; Moustakas, Aristidis

    2006-02-01

    Transforming growth factor beta (TGF-beta) receptors phosphorylate Smad3 and induce its nuclear import so it can regulate gene transcription. Smad3 can return to the cytoplasm to propagate further cycles of signal transduction or to be degraded. We demonstrate that Smad3 is exported by a constitutive mechanism that is insensitive to leptomycin B. The Mad homology 2 (MH2) domain is responsible for Smad3 export, which requires the GTPase Ran. Inactive, GDP-locked RanT24N or nuclear microinjection of Ran GTPase activating protein 1 blocked Smad3 export. Inactivation of the Ran guanine nucleotide exchange factor RCC1 inhibited Smad3 export and led to nuclear accumulation of phosphorylated Smad3. A screen for importin/exportin family members that associate with Smad3 identified exportin 4, which binds a conserved peptide sequence in the MH2 domain of Smad3 in a Ran-dependent manner. Exportin 4 is sufficient for carrying the in vitro nuclear export of Smad3 in cooperation with Ran. Knockdown of endogenous exportin 4 completely abrogates the export of endogenous Smad3. A short peptide representing the minimal interaction domain in Smad3 effectively competes with Smad3 association to exportin 4 and blocks nuclear export of Smad3 in vivo. We thus delineate a novel nuclear export pathway for Smad3.

  3. A novel mechanism is involved in cationic lipid-mediated functional siRNA delivery.

    PubMed

    Lu, James J; Langer, Robert; Chen, Jianzhu

    2009-01-01

    A key challenge for therapeutic application of RNA interference is to efficiently deliver synthetic small interfering RNAs (siRNAs) into target cells that will lead to the knockdown of the target transcript (functional siRNA delivery). To facilitate rational development of nonviral carriers, we have investigated by imaging, pharmacological and genetic approaches the mechanisms by which a cationic lipid carrier mediates siRNA delivery into mammalian cells. We show that approximately 95% of siRNA lipoplexes enter the cells through endocytosis and persist in endolysosomes for a prolonged period of time. However, inhibition of clathrin-, caveolin-, or lipid-raft-mediated endocytosis or macropinocytosis fails to inhibit the knockdown of the target transcript. In contrast, depletion of cholesterol from the plasma membrane has little effect on the cellular uptake of siRNA lipoplexes, but it abolishes the target transcript knockdown. Furthermore, functional siRNA delivery occurs within a few hours and is gradually inhibited by lowering temperatures. These results demonstrate that although endocytosis is responsible for the majority of cellular uptake of siRNA lipoplexes, a minor pathway, probably mediated by fusion between siRNA lipoplexes and the plasma membrane, is responsible for the functional siRNA delivery. Our findings suggest possible directions for improving functional siRNA delivery by cationic lipids.

  4. A Novel Mechanism Is Involved in Cationic Lipid-Mediated Functional siRNA Delivery

    PubMed Central

    2009-01-01

    A key challenge for therapeutic application of RNA interference is to efficiently deliver synthetic small interfering RNAs (siRNAs) into target cells that will lead to the knockdown of the target transcript (functional siRNA delivery). To facilitate rational development of nonviral carriers, we have investigated by imaging, pharmacological and genetic approaches the mechanisms by which a cationic lipid carrier mediates siRNA delivery into mammalian cells. We show that ∼95% of siRNA lipoplexes enter the cells through endocytosis and persist in endolysosomes for a prolonged period of time. However, inhibition of clathrin-, caveolin-, or lipid-raft-mediated endocytosis or macropinocytosis fails to inhibit the knockdown of the target transcript. In contrast, depletion of cholesterol from the plasma membrane has little effect on the cellular uptake of siRNA lipoplexes, but it abolishes the target transcript knockdown. Furthermore, functional siRNA delivery occurs within a few hours and is gradually inhibited by lowering temperatures. These results demonstrate that although endocytosis is responsible for the majority of cellular uptake of siRNA lipoplexes, a minor pathway, probably mediated by fusion between siRNA lipoplexes and the plasma membrane, is responsible for the functional siRNA delivery. Our findings suggest possible directions for improving functional siRNA delivery by cationic lipids. PMID:19292453

  5. Pathogenic Mechanism of an Autism-Associated Neuroligin Mutation Involves Altered AMPA-Receptor Trafficking

    PubMed Central

    Chanda, Soham; Aoto, Jason; Lee, Sung-Jin; Wernig, Marius; Südhof, Thomas C.

    2015-01-01

    Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Although the general synaptic role of neuroligins is undisputed, their specific functions at a synapse remain unclear, even controversial. Moreover, many neuroligin gene mutations were associated with autism, but the pathophysiological relevance of these mutations is often unknown, and their mechanisms of action uninvestigated. Here, we examine the synaptic effects of an autism-associated neuroligin-4 substitution (called R704C) which mutates a cytoplasmic arginine residue that is conserved in all neuroligins. We show that the R704C mutation, when introduced into neuroligin-3, enhances the interaction between neuroligin-3 and AMPA-receptors, increases AMPA-receptor internalization, and decreases postsynaptic AMPA-receptor levels. When introduced into neuroligin-4, conversely, the R704C mutation unexpectedly elevated AMPA-receptor mediated synaptic responses. These results suggest a general functional link between neuroligins and AMPA-receptors, indicate that both neuroligin-3 and -4 act at excitatory synapses but perform surprisingly distinct functions, and demonstrate that the R704C mutation significantly impairs the normal function of neuroligin-4, thereby validating its pathogenicity. PMID:25778475

  6. [The adrenergic mechanisms are involved in the pulmonary hemodynamics changes following experimental myocardial ischemia in rabbits].

    PubMed

    Evlakhov, V I; Poiasov, I Z

    2012-05-01

    In acute experiments in anesthetized rabbits the changes of the pulmonary hemodynamics following myocardial ischemia in the region of the descendent left coronary artery were studied in control animals and after the blockade of alpha-adrenoreceptors by phentolamine or N-cholinoreceptors of autonomic ganglia by hexamethonium. Following myocardial ischemia in control animals the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance was elevated not significantly, the cardiac output decreased more than pulmonary artery flow. Following myocardial ischemia after the blockade of alpha-adrenoreceptors the pulmonary artery flow and cardiac output decreased in the same level and the pulmonary vascular resistance was decreased. In these conditions the pulmonary artery pressure decreased more than in control animals, meanwhile the pulmonary artery flow was decreased in the same level as in the last case. Following myocardial ischemia after the blockade of N-cholinoreceptors the pulmonary hemodynamics changes were the same as they were following myocardial ischemia in the control rabbits, the cardiac output decreased more than pulmonary artery flow. The disbalance of the cardiac output and pulmonary artery flow changes in the case of myocardial ischemia was caused by the pulmonary vessel reactions following activations of the humoral adrenergic mechanisms.

  7. Mild mitochondrial depolarization is involved in a neuroprotective mechanism of Citrus sunki peel extract.

    PubMed

    Wu, Jin-Ji; Cui, Yanji; Yang, Yoon-Sil; Jung, Sung-Cherl; Hyun, Jin Won; Maeng, Young-Hee; Park, Deok-Bae; Lee, Sun-Ryung; Kim, Se-Jae; Eun, Su-Yong

    2013-04-01

    Mitochondrial membrane potential (∆Ψm ) contributes to determining a driving force for calcium to enter the mitochondria. It has been demonstrated that even a small mitochondrial depolarization is sufficient to prevent mitochondrial calcium overload and the subsequent apoptosis. Therefore, mild mitochondrial depolarization has been recently evaluated as a novel mechanism of neuroprotection via inhibiting neurotoxic mitochondrial calcium overload during neuronal insults. In the present study, using both real-time recording and flow cytometric analyses of ∆Ψm , we demonstrated that ethanolic peel extract of Citrus sunki Hort. ex Tanaka (CPE) and its active compounds are capable of inducing a mild mitochondrial depolarization. Polymethoxylated flavones such as nobiletin and tangeretin were found as the active compounds responsible for CPE effects on ∆Ψm . Neuronal viability was significantly increased in a dose-dependent manner by CPE treatment in H2 O2 -stimulated HT-22 cells as an in vitro neuronal insult model. CPE treatment significantly inhibited H2 O2 -induced apoptotic processes such as chromatin condensation, caspase 3 activation and anti-poly (ADP-ribose) polymerase (PARP) cleavage. CPE treatment significantly blocked mitochondrial calcium overload in H2 O2 -stimulated HT-22 neurons as indicated by rhod-2 acetoxymethyl ester. Taken together, our findings suggest that CPE and its active compounds may be considered as promising neuroprotective agents via inducing a mild mitochondrial depolarization.

  8. Kindling-induced learning deficiency and possible cellular and molecular involved mechanisms.

    PubMed

    Sherafat, Mohammad Amin; Ronaghi, Abdolaziz; Ahmad-Molaei, Leila; Nejadhoseynian, Mohammad; Ghasemi, Rasoul; Hosseini, Arman; Naderi, Nima; Motamedi, Fereshteh

    2013-06-01

    Hippocampus learning disturbance is a major symptom of patients with seizure, hence hippocampal dysfunction has essential role in worsening the disease. Hippocampal formation includes neurons and myelinated fibers that are necessary for acquisition and consolidation of memory, long-term potentiation and learning activity. The exact mechanism by which seizure can decrease memory and learning activity of hippocampus remains unknown. In the present study, electrical kindling-induced learning deficit in rats was evaluated by Morris water maze (MWM) test. The hippocampus was removed and changes in neurons and myelin sheaths around hippocampal fibers were investigated using histological and immunohistochemical methods. Demyelination was assessed by luxol fast blue staining, and immunohistological staining of myelin-binding protein (MBP). The TUNEL assay was used for evaluation of neuronal apoptosis and the glial fibriliary acetic protein (GFAP) was used for assessment of inflammatory reaction. The results indicated that electrical kindling of hippocampus could induce deficiency in spatial learning and memory as compared to control group. In addition, electrical kindling caused damage to the myelin sheath around hippocampal fibers and produced vast demyelination. Furthermore, an increase in the number of apoptotic cells in hippocampal slices was observed. In addition, inflammatory response was higher in kindled animals as compared to the control group. The results suggested that the decrease in learning and memory in kindled animals is likely due to demyelination and augmentation in apoptosis rate accompanied by inflammatory reaction in hippocampal neurons of kindled rats.

  9. Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1

    PubMed Central

    Kojo, Satoshi; Elly, Chris; Harada, Yohsuke; Langdon, Wallace Y.; Kronenberg, Mitchell; Liu, Yun-Cai

    2009-01-01

    Repeated injection of α-galactosylceramide, an agonistic ligand for natural killer T (NKT) cells, results in long-term unresponsiveness or anergy, which severely limits its clinical application. However, the molecular mechanisms leading to NKT anergy induction remain unclear. We show here that the decreased IFN-γ production and failed tumor rejection observed in anergized NKT cells are rescued by Cbl-b deficiency. Cbl-b E3 ligase activity is critical for the anergy induction, as revealed by the similarity between Cbl-b−/− and its RING finger mutant NKT cells. Cbl-b binds and promotes monoubiquitination to CARMA1, a critical signaling molecule in NFκB activation. Ubiquitin conjugation to CARMA1 disrupts its complex formation with Bcl10 without affecting its protein stability. In addition, CARMA1−/− NKT cells are defective in IFN-γ production. The study identifies an important signaling pathway linking Cbl-b-induced monoubiquitination to NFκB activation in NKT cell anergy induction, which may help design approaches for human cancer therapy. PMID:19815501

  10. Biochemical Mechanisms and Microorganisms Involved in Anaerobic Testosterone Metabolism in Estuarine Sediments

    PubMed Central

    Shih, Chao-Jen; Chen, Yi-Lung; Wang, Chia-Hsiang; Wei, Sean T.-S.; Lin, I-Ting; Ismail, Wael A.; Chiang, Yin-Ru

    2017-01-01

    Current knowledge on the biochemical mechanisms underlying microbial steroid metabolism in anaerobic ecosystems is extremely limited. Sulfate, nitrate, and iron [Fe (III)] are common electron acceptors for anaerobes in estuarine sediments. Here, we investigated anaerobic testosterone metabolism in anaerobic sediments collected from the estuary of Tamsui River, Taiwan. The anaerobic sediment samples were spiked with testosterone (1 mM) and individual electron acceptors (10 mM), including nitrate, Fe3+, and sulfate. The analysis of androgen metabolites indicated that testosterone biodegradation under denitrifying conditions proceeds through the 2,3-seco pathway, whereas testosterone biodegradation under iron-reducing conditions may proceed through an unidentified alternative pathway. Metagenomic analysis and PCR-based functional assays suggested that Thauera spp. were the major testosterone degraders in estuarine sediment samples incubated with testosterone and nitrate. Thauera sp. strain GDN1, a testosterone-degrading betaproteobacterium, was isolated from the denitrifying sediment sample. This strain tolerates a broad range of salinity (0–30 ppt). Although testosterone biodegradation did not occur under sulfate-reducing conditions, we observed the anaerobic biotransformation of testosterone to estrogens in some testosterone-spiked sediment samples. This is unprecedented since biotransformation of androgens to estrogens is known to occur only under oxic conditions. Our metagenomic analysis suggested that Clostridium spp. might play a role in this anaerobic biotransformation. These results expand our understanding of microbial metabolism of steroids under strictly anoxic conditions. PMID:28848528

  11. Successful retrieval of competing spatial environments in humans involves hippocampal pattern separation mechanisms

    PubMed Central

    Kyle, Colin T; Stokes, Jared D; Lieberman, Jennifer S; Hassan, Abdul S; Ekstrom, Arne D

    2015-01-01

    The rodent hippocampus represents different spatial environments distinctly via changes in the pattern of “place cell” firing. It remains unclear, though, how spatial remapping in rodents relates more generally to human memory. Here participants retrieved four virtual reality environments with repeating or novel landmarks and configurations during high-resolution functional magnetic resonance imaging (fMRI). Both neural decoding performance and neural pattern similarity measures revealed environment-specific hippocampal neural codes. Conversely, an interfering spatial environment did not elicit neural codes specific to that environment, with neural activity patterns instead resembling those of competing environments, an effect linked to lower retrieval performance. We find that orthogonalized neural patterns accompany successful disambiguation of spatial environments while erroneous reinstatement of competing patterns characterized interference errors. These results provide the first evidence for environment-specific neural codes in the human hippocampus, suggesting that pattern separation/completion mechanisms play an important role in how we successfully retrieve memories. DOI: http://dx.doi.org/10.7554/eLife.10499.001 PMID:26613414

  12. An embryonic demethylation mechanism involving binding of transcription factors to replicating DNA.

    PubMed

    Matsuo, K; Silke, J; Georgiev, O; Marti, P; Giovannini, N; Rungger, D

    1998-03-02

    In vertebrates, transcriptionally active promoters are undermethylated. Since the transcription factor Sp1, and more recently NF-kappaB, have been implicated in the demethylation process, we examined the effect of transcription factors on demethylation by injecting in vitro methylated plasmid DNA into Xenopus fertilized eggs. We found that various transactivation domains, including a strong acidic activation domain from the viral protein VP16, can enhance demethylation of a promoter region when fused to a DNA binding domain which recognizes the promoter. Furthermore, demethylation occurs only after the midblastula transition, when the general transcription machinery of the host embryo becomes available. Nevertheless, transcription factor binding need not be followed by actual transcription, since demethylation is not blocked by alpha-amanitin treatment. Finally, replication of the target DNA is a prerequisite for efficient demethylation since only plasmids that carry the bovine papilloma virus sequences which support plasmid replication after the midblastula transition are demethylated. No demethylation is detectable in the oocyte system where DNA is not replicated. These results suggest that, in the Xenopus embryo, promoters for which transcription factors are available are demethylated by a replication-dependent, possibly passive mechanism.

  13. Overcoming NS1-Mediated Immune Antagonism Involves Both Interferon-Dependent and Independent Mechanisms

    PubMed Central

    Thakar, Juilee; Schmid, Sonja; Duke, Jamie L.; García-Sastre, Adolfo

    2013-01-01

    To ensure survival, our immune system must overcome the action of pathogen-encoded immune antagonists, such as influenza A nonstructural protein-1 (NS1). NS1 subverts the host interferon (IFN) response at multiple levels and blocks the induction of IFN-β, a critical antiviral cytokine. This immune antagonism can be overcome in some cases. It has been shown that IFN-β is upregulated by 48 h in the lungs of wild-type C57BL/6 mice infected with influenza A. In contrast, it is shown here that IFNB1 continues to be repressed in IFNAR1−/− IL28Rα−/− mice, which are deficient in Type-I and III IFN signaling, implying induction of IFNB1 depends on effective IFN signaling. Despite the complete lack of IFN signaling in this system, some IFN stimulated genes (ISGs) were induced following infection with a Flu strain lacking NS1. While the expression of these viral stress-inducible genes (VSIGs) was initially repressed following infection with wild-type Flu, many of these genes became upregulated by 48 h postinfection. These results demonstrate the existence of IFN-independent mechanisms that can overcome NS1-mediated immune antagonism of VSIGs. PMID:23772952

  14. Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury.

    PubMed

    Slezak, Jan; Kura, Branislav; Babal, Pavel; Barancik, Miroslav; Ferko, Miroslav; Frimmel, Karel; Kalocayova, Barbora; Kukreja, Rakesh C; Lazou, Antigone; Mezesova, Lucia; Okruhlicova, Ludmila; Ravingerova, Tanya; Singal, Pawan K; Szeiffova Bacova, Barbara; Viczenczova, Csilla; Vrbjar, Norbert; Tribulova, Narcis

    2017-10-01

    Irradiation of normal tissues leads to acute increase in reactive oxygen/nitrogen species that serve as intra- and inter-cellular signaling to alter cell and tissue function. In the case of chest irradiation, it can affect the heart, blood vessels, and lungs, with consequent tissue remodelation and adverse side effects and symptoms. This complex process is orchestrated by a large number of interacting molecular signals, including cytokines, chemokines, and growth factors. Inflammation, endothelial cell dysfunction, thrombogenesis, organ dysfunction, and ultimate failing of the heart occur as a pathological entity - "radiation-induced heart disease" (RIHD) that is major source of morbidity and mortality. The purpose of this review is to bring insights into the basic mechanisms of RIHD that may lead to the identification of targets for intervention in the radiotherapy side effect. Studies of authors also provide knowledge about how to select targeted drugs or biological molecules to modify the progression of radiation damage in the heart. New prospective studies are needed to validate that assessed factors and changes are useful as early markers of cardiac damage.

  15. Mechanism of activation of methyltransferases involved in translation by the Trm112 ‘hub’ protein

    PubMed Central

    Liger, Dominique; Mora, Liliana; Lazar, Noureddine; Figaro, Sabine; Henri, Julien; Scrima, Nathalie; Buckingham, Richard H.; van Tilbeurgh, Herman; Heurgué-Hamard, Valérie; Graille, Marc

    2011-01-01

    Methylation is a common modification encountered in DNA, RNA and proteins. It plays a central role in gene expression, protein function and mRNA translation. Prokaryotic and eukaryotic class I translation termination factors are methylated on the glutamine of the essential and universally conserved GGQ motif, in line with an important cellular role. In eukaryotes, this modification is performed by the Mtq2-Trm112 holoenzyme. Trm112 activates not only the Mtq2 catalytic subunit but also two other tRNA methyltransferases (Trm9 and Trm11). To understand the molecular mechanisms underlying methyltransferase activation by Trm112, we have determined the 3D structure of the Mtq2-Trm112 complex and mapped its active site. Using site-directed mutagenesis and in vivo functional experiments, we show that this structure can also serve as a model for the Trm9-Trm112 complex, supporting our hypothesis that Trm112 uses a common strategy to activate these three methyltransferases. PMID:21478168

  16. Involvement of efflux mechanisms in biocide resistance of Campylobacter jejuni and Campylobacter coli.

    PubMed

    Mavri, Ana; Mozina, Sonja Smole

    2012-06-01

    Active efflux has an important role in the antimicrobial resistance of Campylobacter jejuni and Campylobacter coli. The effects of two putative efflux pump inhibitors (EPIs), phenylalanine-arginine β-naphthylamide and 1-(1-naphthylmethyl)-piperazine, and the effects of inactivation of the cmeB,cmeF and cmeR genes on resistance to a broad range of antimicrobials were studied using the broth microdilution method. The antimicrobials tested in C. jejuni and C. coli were the biocides triclosan, benzalkonium chloride, chlorhexidine diacetate, cetylpyridinium chloride and trisodium phosphate, along with the anionic surfactant SDS and the antibiotics erythromycin and ciprofloxacin. Both EPIs partially reversed the resistance to all of these antimicrobials. Differences between these EPIs were seen for substrate preference and reductions in MIC. The MICs of the antimicrobials were reduced in the cmeB and cmeF mutants and increased in the cmeR mutant, with few exceptions. Both of these putative EPIs further decreased the MICs of the antimicrobials in these mutant strains. These data confirm that active efflux is an important mechanism in biocide resistance in C. jejuni and C. coli. At least one non-CmeABC efflux system or reduced uptake is responsible for resistance to biocides.

  17. Mechanism of IAPP amyloid fibril formation involves an intermediate with a tra