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Sample records for indirect mechanism involving

  1. Involvement of Glutathione as a Mechanism of Indirect Protection against Spontaneous Ex Vivo Apoptosis Associated with Bovine Leukemia Virus

    PubMed Central

    Alcaraz, Teresa Sanchez; Kerkhofs, Pierre; Reichert, Michal; Kettmann, Richard; Willems, Luc

    2004-01-01

    Viruses have developed strategies to counteract the apoptotic response of the infected host cells. Modulation of apoptosis is also thought to be a major component of viral persistence and progression to leukemia induced by retroviruses like human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV). Here, we analyzed the mechanism of ex vivo apoptosis occurring after isolation of peripheral blood mononuclear cells from BLV-infected sheep. We show that spontaneous apoptosis of ovine B lymphocytes requires at least in part a caspase 8-dependent pathway regardless of viral infection. Cell death is independent of cytotoxic response and does not involve the tumor necrosis factor alpha/NF-κB/nitric oxide synthase/cyclooxygenase pathway. In contrast, pharmaceutical depletion of reduced glutathione (namely, γ-glutamyl-l-cysteinyl-glycine [GSH]) by using ethacrynic acid or 1-pyrrolidinecarbodithioic acid specifically reverts inhibition of spontaneous apoptosis conferred indirectly by protective BLV-conditioned media; inversely, exogenously provided membrane-permeable GSH-monoethyl ester restores cell viability in B lymphocytes of BLV-infected sheep. Most importantly, intracellular GSH levels correlate with virus-associated protection against apoptosis but not with general inhibition of cell death induced by polyclonal activators, such as phorbol esters and ionomycin. Finally, inhibition of apoptosis does not correlate with the activities of GSH peroxidase and GSH reductase. In summary, our data fit into a model in which modulation of the glutathione system is a key event involved in indirect inhibition of apoptosis associated with BLV. These observations could have decisive effects during therapeutic treatment of δ-retroviral pathogenesis. PMID:15163711

  2. 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.

  3. 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

  4. 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.

  5. 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…

  6. 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.

  7. 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

  8. Tricyclic Antidepressant Amitriptyline Indirectly Increases the Proliferation of Adult Dentate Gyrus-Derived Neural Precursors: An Involvement of Astrocytes

    PubMed Central

    Boku, Shuken; Hisaoka-Nakashima, Kazue; Nakagawa, Shin; Kato, Akiko; Kajitani, Naoto; Inoue, Takeshi; Kusumi, Ichiro; Takebayashi, Minoru

    2013-01-01

    Antidepressants increase the proliferation of neural precursors in adult dentate gyrus (DG), which is considered to be involved in the therapeutic action of antidepressants. However, the mechanism underlying it remains unclear. By using cultured adult rat DG-derived neural precursors (ADP), we have already shown that antidepressants have no direct effects on ADP. Therefore, antidepressants may increase the proliferation of neural precursors in adult DG via unknown indirect mechanism. We have also shown that amitriptyline (AMI), a tricyclic antidepressant, induces the expressions of GDNF, BDNF, FGF2 and VEGF, common neurogenic factors, in primary cultured astrocytes (PCA). These suggest that AMI-induced factors in astrocytes may increase the proliferation of neural precursors in adult DG. To test this hypothesis, we examined the effects of AMI-induced factors and conditioned medium (CM) from PCA treated with AMI on ADP proliferation. The effects of CM and factors on ADP proliferation were examined with BrdU immunocytochemistry. AMI had no effect on ADP proliferation, but AMI-treated CM increased it. The receptors of GDNF, BDNF and FGF2, but not VEGF, were expressed in ADP. FGF2 significantly increased ADP proliferation, but not BDNF and GDNF. In addition, both of a specific inhibitor of FGF receptors and anti-FGF2 antibody significantly counteracted the increasing effect of CM on ADP proliferation. In addition, FGF2 in brain is mainly derived from astrocytes that are key components of the neurogenic niches in adult DG. These suggest that AMI may increase ADP proliferation indirectly via PCA and that FGF2 may a potential candidate to mediate such an indirect effect of AMI on ADP proliferation via astrocytes. PMID:24260208

  9. 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

  10. 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

  11. 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.

  12. [Distinct roles of the direct and indirect pathways in the basal ganglia circuit mechanism].

    PubMed

    Morita, Makiko; Hikida, Takatoshi

    2015-11-01

    The basal ganglia are key neural substrates that control not only motor balance but also emotion, motivation, cognition, learning, and decision-making. Dysfunction of the basal ganglia leads to neurodegenerative diseases (e.g. Parkinson's disease and Huntington's disease) and psychiatric disorders (e.g. drug addiction, schizophrenia, and depression). In the basal ganglia circuit, there are two important pathways: the direct and indirect striatal pathways. Recently, new molecular techniques that activate or inactive selectively the direct or indirect pathway neurons have revealed the function of each pathway. Here we review the distinct roles of the direct and indirect striatal pathways in brain function and drug addiction. We have developed a reversible neurotransmission blocking technique, in which transmission of each pathway is selectively blocked by specific expression of transmission-blocking tetanus toxin, and revealed that the activation of D1 receptors in the direct pathway is critical for reward learning/cocaine addiction, and that the inactivation of D2 receptors is critical for aversive learning/learning flexibility. We propose a new circuit mechanism by which the dopaminergic input from the ventral tegmental area can switch the direct and indirect pathways in the nucleus accumbens. These basal ganglia circuit mechanisms will give us insights into the pathophysiology of mental diseases. PMID:26785520

  13. 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. PMID:27424205

  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.

  15. 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

  16. Mathematical Description of an Asynchronous Motor with the Indirect Control of the Output Mechanical Variables

    NASA Astrophysics Data System (ADS)

    Glazachev, A. V.; Dementyev, Yu. N.; Negodin, K. N.; Umursakova, A. D.

    2016-02-01

    The article gives the mathematical description of an asynchronous motor with the indirect control of the output mechanical variables of an asynchronous motor in the electric drive. To determine the electromagnetic torque and angular velocity of the asynchronous motor in the electric drive the mathematical description is used in which the values are determined by the readings of the motor and easily measured values by means of known in practice devices. The proposed in the article the mathematical description for the indirect measuring the electromagnetic torque and angular velocity of the asynchronous motor in the electric drive does not contain the integral components that introduce the great error into the value of the controlled electromagnetic torque and angular velocity.

  17. Parental Involvement, Homework, and TV Time: Direct and Indirect Effects on High School Achievement.

    ERIC Educational Resources Information Center

    Keith, Timothy Z.; And Others

    1986-01-01

    A set of High School and Beyond data was used to study the effect of three variables on academic achievement. Homework had a positive effect, TV a negative, and parental involvement no direct effect on seniors' achievement scores, but influenced the amount of time students spent on homework. (Author/JAZ)

  18. 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. PMID:18459344

  19. 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.

  20. 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.

  1. The mechanisms of action of flavonoids in the brain: Direct versus indirect effects.

    PubMed

    Rendeiro, Catarina; Rhodes, Justin S; Spencer, Jeremy P E

    2015-10-01

    The projected increase in the incidence of dementia in the population highlights the urgent need for a more comprehensive understanding of how different aspects of lifestyle, in particular exercise and diet, may affect neural function and consequent cognitive performance throughout the life course. In this regard, flavonoids, found in a variety of fruits, vegetables and derived beverages, have been identified as a group of promising bioactive compounds capable of influencing different aspects of brain function, including cerebrovascular blood flow and synaptic plasticity, both resulting in improvements in learning and memory in mammalian species. However, the precise mechanisms by which flavonoids exert these actions are yet to be fully established, although accumulating data indicate an ability to interact with neuronal receptors and kinase signaling pathways which are key to neuronal activation and communication and synaptic strengthening. Alternatively or concurrently, there is also compelling evidence derived from human clinical studies suggesting that flavonoids can positively affect peripheral and cerebrovascular blood flow, which may be an indirect effective mechanism by which dietary flavonoids can impact on brain health and cognition. The current review examines the beneficial effects of flavonoids on both human and animal brain function and attempts to address and link direct and indirect actions of flavonoids and their derivatives within the central nervous system (CNS).

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

    PubMed

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

    2016-06-01

    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

  3. Assessing the mechanism of DNA damage induced by lead through direct and indirect interactions.

    PubMed

    Zhang, Hao; Wei, Kai; Zhang, Mengyu; Liu, Rutao; Chen, Yadong

    2014-07-01

    Lead still possesses great threats to human health owing to its widespread distribution in the environment caused by human activities, although various actions have been taken to cut down the use and distribution of lead. In this work, mechanisms of DNA damage caused by lead through indirect and direct interactions were investigated. Results from comet assay showed lead at 1-10 μM induced DNA strand breaks in mice liver cells according to olive tail moment analysis. Signals of DNA-protein crosslinks (DPC) were not significantly detected until exposed at 100 μM Pb(2+). Further more, direct interactions between Pb(2+) and DNA were explored to determine the binding mode between them using spectra analysis, isothermal titration calorimetry studies and molecular docking investigations, which indicated that Pb(2+) could bind to DNA with four binding sites to form Pb(2)(+)-DNA complex by minor groove binding effects and electrostatic forces, resulting in damage to the structure of DNA double helix. Combined studies of lead genotoxicity in indirect (comet assay and DPC assay) and direct (binding mode investigations) interactions can be applied to study the potential damages to DNA induced by heavy metal pollutants.

  4. 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

  5. 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

  6. Glucan: mechanisms involved in its radioprotective effect

    SciTech Connect

    Patchen, M.L.; D'Alesandro, M.M.; Brook, I.; Blakely, W.F.; MacVittie, T.J.

    1987-08-01

    It has generally been accepted that most biologically derived agents that are radioprotective in the hemopoietic-syndrome dose range (eg, endotoxin, Bacillus Calmette Guerin, Corynebacterium parvum, etc) exert their beneficial properties by enhancing hemopoietic recovery and hence, by regenerating the host's ability to resist life-threatening opportunistic infections. However, using glucan as a hemopoietic stimulant/radioprotectant, we have demonstrated that host resistance to opportunistic infection is enhanced in these mice even prior to the detection of significant hemopoietic regeneration. This early enhanced resistance to microbial invasion in glucan-treated irradiated mice could be correlated with enhanced and/or prolonged macrophage (but not granulocyte) function. These results suggest that early after irradiation glucan may mediate its radioprotection by enhancing resistance to microbial invasion via mechanisms not necessarily predicated on hemopoietic recovery. In addition, preliminary evidence suggests that glucan can also function as an effective free-radical scavenger. Because macrophages have been shown to selectively phagocytize and sequester glucan, the possibility that these specific cells may be protected by virtue of glucan's scavenging ability is also suggested.

  7. 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.

  8. SAP97 increases Kv1.5 currents through an indirect N-terminal mechanism.

    PubMed

    Eldstrom, Jodene; Choi, Woo Sung; Steele, David F; Fedida, David

    2003-07-17

    The functional interaction of the voltage-gated potassium channel hKv1.5 with the PDZ domain containing protein SAP97 has been investigated. In marked contrast with the known dependence of SAP97-induced Kv1 potassium current down-regulation on the channel C-termini, SAP97 increased hKv1.5 current through an indirect interaction with the Kv1.5 N-terminus. Deletion of the Kv1.5 N-terminus eliminated the SAP97-mediated increase in potassium currents whereas deletion of the channel's C-terminal PDZ binding motif had no effect. In contrast with other Kv1-SAP97 interactions, no physical interaction could be detected in vivo or in vitro between the two proteins. The proteins did not co-localize in cardiac myocytes nor did they co-immunoprecipitate from transfected HEK cells. Yeast two-hybrid experiments also failed to detect any interaction between the two proteins, but in one experiment of six, Kv1.5 co-immunoprecipitated very inefficiently with SAP97 from rat ventricular myocytes. Thus, we conclude that the influence of SAP97 on Kv1.5 potassium current levels is dependent upon a novel regulatory mechanism. PMID:12860415

  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. 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.

  11. Factors involved in mechanical fatigue degradation of dental resin composites.

    PubMed

    Lohbauer, U; Belli, R; Ferracane, J L

    2013-07-01

    The design of clinical trials allows for limited insights into the fatigue processes occurring in resin composites and the factors involved therein. In vitro studies, in contrast, can fundamentally narrow study interests to focus on particular degradation mechanisms and, to date, represent the major contributors to the state of knowledge on the subject. These studies show that microstructural features are important in determining strength and fracture toughness, whereas fatigue resistance is mainly related to the susceptibility of the matrix and the filler/matrix interface to mechanical and chemical degradation. In this review, we focus on fracture mechanisms occurring during fatigue, on the methods used to assess them, and on additional phenomena involved in the degradation of initial mechanical properties of resin composites.

  12. 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

  13. 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

    2016-01-01

    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

  14. 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.

  15. 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

  16. Energy Flow in the Polar F-region Ionosphere-Thermosphere System through an Indirect Momentum-Energy Coupling Mechanism

    NASA Astrophysics Data System (ADS)

    Hsu, V.; Thayer, J. P.; Wang, W.; Burns, A. G.

    2015-12-01

    Thermospheric neutral properties, such as wind, temperature, and neutral mass density, are driven by momentum and energy sources. Much work has focused on the response of the thermosphere when driven by energy sources from the magnetosphere, resulting in direct heating of the neutral gas. This leads to a dynamical response of the thermosphere described as a direct wind circulation. However, sources that change the momentum transfer to the neutral gas can also lead to thermal changes through a dynamical response that would be characterized as an indirect wind circulation. The ionosphere-thermosphere (I/T) system is tightly coupled by momentum and energy. The path for a direct energy source is to change the energy and then the momentum, while the route for an indirect energy source is to change the momentum and then the energy. For the indirect energy source, changes in the ion drag force cause a divergence in the neutral wind field, which results in thermal changes due to adiabatic heating or cooling via vertical winds. All of the important forces and processes exist for describing both the direct and indirect energy sources, but it is the time evolution of the processes that will define how the thermosphere responds. In this work, we present an indirect energy mechanism that can alter the thermospheric neutral mass density and temperature in the polar F-region. Similar to energy partitioning within the high-latitude I/T from an external energy source, energy can be transferred from kinetic to internal energy from a momentum source. We use the NCAR TIEGCM to analyze quantitatively how energy flows through the polar I/T system due to an internal momentum modification. These results illustrate how changes in the ion drag force can affect the thermal energy of the polar F-region I/T system, and create neutral mass density and temperature anomalies.

  17. 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

  18. 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

  19. 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.

  20. Regulatory mechanisms of microRNAs involvement in cancer.

    PubMed

    Fabbri, Muller; Ivan, Mircea; Cimmino, Amelia; Negrini, Massimo; Calin, George A

    2007-07-01

    MicroRNAs (miRNAs) are 19-24 nucleotide noncoding RNAs that regulate the translation and degradation of target mRNAs and are extensively involved in human cancers. One unexpected conclusion of the profiling and functional studies in tumourigenesis is that some miRNAs behave in cancer cells in a dual mode, resembling the 'Dr Jekyll and Mr Hyde' story, which centers on a conception of humanity as dual in nature. The authors and others have found that onco-miRNAs and suppressor-miRNAs can represent two different looks of the same gene, behaving as oncogenes or tumour suppressors depending on tissue type and specific targets. In this review, the authors analyse the regulatory mechanisms of the main miRNA genes involved in human tumourigenesis. PMID:17665990

  1. 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

  2. Epigenetic mechanisms involved in the pathogenesis of hepatobiliary malignancies

    PubMed Central

    Hamilton, James P

    2010-01-01

    Primary tumors of the liver and biliary tree are increasing in frequency and portend a miserable prognosis. Epigenetic regulation of gene expression has emerged as a fundamental aspect of cancer development and progression. The molecular mechanisms of carcinogenesis in hepatocellular carcinoma and cholangiocarcinoma involve a complex interplay of both genetic and epigenetic factors. Recent studies investigating the possible epigenetic mechanisms induced in the disease have shed new light on the molecular underpinnings of hepatobiliary cancers. In addition, epigenetic modifications of DNA in cancer and precancerous lesions offer hope and the promise of novel biomarkers for early cancer detection, prediction, prognosis and response to treatment. Furthermore, the reversal of epigenetic changes represents a potential target for novel therapeutic strategies and medication design. PMID:20556199

  3. 3D finite element analysis on esthetic indirect dental restorations under thermal and mechanical loading.

    PubMed

    Cornacchia, Tulimar P M; Las Casas, Estevam B; Cimini, Carlos Alberto; Peixoto, Rodrigo G

    2010-11-01

    Thermo-mechanical finite element analyses in 3-D models are described for determination of the stress levels due to thermal and mechanical loads in a healthy and restored tooth. Transient thermo-mechanical analysis simulating the ingestion of cold and hot drinks was performed to determine the temperature distribution in the models of the teeth, followed by linear elastic stress analyses. The thermal loads were applied on the occlusal and lingual surfaces. Subsequently, coupled variation of the temperature and mastication loading was considered. The vertical loading was distributed at occlusal points, adding up to 180 N. Maximum stresses were verified in resin restoration under thermal loads. When studying coupled effect of mechanical loading with that arising from thermal effects, higher tensile stress values occurred in porcelain restorations, especially at the restoration-dentin interface. Regions of high tensile stress were detected and their possible clinical significance with respect to restoration damage and microleakage were discussed.

  4. 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

  5. Strain-engineered direct-indirect band gap transition and its mechanism in two-dimensional phosphorene

    NASA Astrophysics Data System (ADS)

    Peng, Xihong; Wei, Qun; Copple, Andrew

    2014-08-01

    Recently fabricated two-dimensional phosphorene crystal structures have demonstrated great potential in applications of electronics. In this paper, strain effect on the electronic band structure of phosphorene was studied using first-principles methods including density functional theory (DFT) and hybrid functionals. It was found that phosphorene can withstand a tensile stress and strain up to 10 N/m and 30%, respectively. The band gap of phosphorene experiences a direct-indirect-direct transition when axial strain is applied. A moderate -2% compression in the zigzag direction can trigger this gap transition. With sufficient expansion (+11.3%) or compression (-10.2% strains), the gap can be tuned from indirect to direct again. Five strain zones with distinct electronic band structure were identified, and the critical strains for the zone boundaries were determined. Although the DFT method is known to underestimate band gap of semiconductors, it was proven to correctly predict the strain effect on the electronic properties with validation from a hybrid functional method in this work. The origin of the gap transition was revealed, and a general mechanism was developed to explain energy shifts with strain according to the bond nature of near-band-edge electronic orbitals. Effective masses of carriers in the armchair direction are an order of magnitude smaller than that of the zigzag axis, indicating that the armchair direction is favored for carrier transport. In addition, the effective masses can be dramatically tuned by strain, in which its sharp jump/drop occurs at the zone boundaries of the direct-indirect gap transition.

  6. Neurophysiological mechanisms involved in language learning in adults.

    PubMed

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

    2009-12-27

    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

  7. 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

  8. Mechanisms involved in metalloid transport and tolerance acquisition.

    PubMed

    Tamás, M J; Wysocki, R

    2001-08-01

    Toxic metalloids such as arsenic and antimony have always been an integral part of the natural environment. To survive in such a hostile habitat, it is crucial to develop strategies to exclude toxic substances from the cell and to acquire tolerance. Cells remove metalloids from the cytosol either by active efflux or by sequestration in an internal organelle. Controlling the influx appears to be another way of maintaining a low intracellular metalloid content. Inside the cell, the metalloid can be reduced to a form that is recognised by the expulsion system(s). In addition, metalloid complexation and compartmentalisation contributes to enhanced cellular tolerance. Finally, the presence of metalloids activates transcription of various cellular defence genes. Metalloid-containing drugs are currently used to treat protozoan infections and promyelocytic leukaemia. Since metalloid resistance hampers efficient treatment, interest in identifying the mechanisms involved in tolerance acquisition has arisen. The possibility of using genetic approaches has made the yeast Saccharomyces cerevisiae a compelling model system to investigate the basis of metalloid tolerance at a molecular level. This review describes the recent progress made in elucidating the mechanisms involved in metalloid transport and tolerance in yeast and other organisms.

  9. [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.

  10. 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.

  11. Formation mechanism for a hybrid supramolecular network involving cooperative interactions.

    PubMed

    Mura, Manuela; Silly, Fabien; Burlakov, Victor; Castell, Martin R; Briggs, G Andrew D; Kantorovich, Lev N

    2012-04-27

    A novel mechanism of hybrid assembly of molecules on surfaces is proposed stemming from interactions between molecules and on-surface metal atoms which eventually got trapped inside the network pores. Based on state-of-the-art theoretical calculations, we find that the new mechanism relies on formation of molecule-metal atom pairs which, together with molecules themselves, participate in the assembly growth. Most remarkably, the dissociation of pairs is facilitated by a cooperative interaction involving many molecules. This new mechanism is illustrated on a low coverage Melamine hexagonal network on the Au(111) surface where multiple events of gold atoms trapping via a set of so-called "gate" transitions are found by kinetic Monte Carlo simulations based on transition rates obtained using ab initio density functional theory calculations and the nudged elastic band method. Simulated STM images of gold atoms trapped in the pores of the Melamine network predict that the atoms should appear as bright spots inside Melamine hexagons. No trapping was found at large Melamine coverages, however. These predictions have been supported by preliminary STM experiments which show bright spots inside Melamine hexagons at low Melamine coverages, while empty pores are mostly observed at large coverages. Therefore, we suggest that bright spots sometimes observed in the pores of molecular assemblies on metal surfaces may be attributed to trapped substrate metal atoms. We believe that this type of mechanism could be used for delivering adatom species of desired functionality (e.g., magnetic) into the pores of hydrogen-bonded networks serving as templates for their capture. PMID:22680886

  12. 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.

  13. FMR1 Premutation: Basic Mechanisms and Clinical Involvement.

    PubMed

    Milà, Montserrat; Rodriguez-Revenga, Laia; Matilla-Dueñas, Antoni

    2016-10-01

    The wide spectrum of clinical phenotypes associated with the FMR1 premutation affect more than two million people worldwide. The clinical implications have only been recognized recently despite this disorder constitutes a relevant health problem. The present issue of The Cerebellum is focused on the "2(nd) International Conference on the FMR1 Premutation: Basic Mechanisms and Clinical Involvement" held in Sitges, Barcelona (Spain), from September 30th to October 2nd, 2015. The conference was attended by professionals from different countries in Europe, the USA, Chile, Israel, Australia, and Indonesia and covered the latest clinical and molecular findings resulting from FMR1 premutation studies. Although the pathologies associated with the FMR1 premutation are considered as rare diseases, seventy abstracts were presented. This reflects the relevance of this topic in the medical community and the growing interest among professionals from other disciplines. The major topics discussed included why and how the mRNA toxicity due to a gain of function and non-canonical RAN are responsible for disorders associated with the premutation. Several presentations addressed the impact of these mechanisms in FXTAS and FXPOI, two clinical presentations caused by the FMR1 premutation. Interestingly, a deterioration of the DNA repair machinery was first proposed as the pathogenicity cause of premutation alleles. Communications related to FXTAS and FXPOI animal models were also presented. These models facilitate studies aimed to understand disease progression and early treatment interventions. Finally, there were presentations related to psychiatric, psychological, neurological, and radiological aspects. Interesting discussion on intermediate alleles and their involvement in clinical and reproductive aspects was generated. In this regards, genetic counselling is improved by taking into account the AGG interruptions and including information about the FMR1 premutation associated

  14. Potentiation of antidepressant-like activity with lithium: mechanism involved.

    PubMed

    Chenu, Franck; Bourin, Michel

    2006-02-01

    In the last decade, many augmentation strategies have been developed to increase the activity of antidepressant drugs or to reduce their long onset of action by acting on different targets. One of the first augmentation strategy used in psychiatric disorders is coadministration of lithium and antidepressant drugs. However, the underlaying mechanism of action involved in the potentiatory effect of lithium is still unclear and many hypotheses have been suggested such as activity on BDNF, ACTH, thyroid hormones and serotonin neurotransmission. All these systems being embedded in each other, we focused on the 5-HT neurotransmission-increase induced by lithium treatment. Based on neurobiochemical and behavioral results we tried to better understand its mechanism of action and we concluded that effect of lithium on 5-HT neurotransmission could be linked to a partial agonist activity on 5-HT1B autoreceptors, or to a modulatory activity on these receptors, located in the cortical area in the case of a short term treatment, or in the hippocampus in the case of a long term treatment. We also suggested that the anti-manic effect of lithium was linked to this activity on 5-HT1B receptors, occurring this time on 5-HT1B postsynaptic (heteroreceptors on dopaminergic pathways) receptors levels.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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. PMID:26987900

  20. Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing.

    PubMed

    Roelands, Bart; de Koning, Jos; Foster, Carl; Hettinga, Floor; Meeusen, Romain

    2013-05-01

    improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. Manipulations of serotonin and, especially, noradrenaline, have the opposite effect and force subjects to decrease power output early in the time trial. Interestingly, after manipulation of brain serotonin, subjects are often unable to perform an end sprint, indicating an absence of a reserve capacity or motivation to increase power output. Taken together, it appears that many factors, such as ambient conditions and manipulation of brain neurotransmitters, have the potential to influence power output during exercise, and might thus be involved as regulatory mechanisms in the complex skill of pacing.

  1. 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. PMID:26080475

  2. 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.

  3. 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.

  4. 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. PMID:26804251

  5. 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.

  6. 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

  7. MOLECULAR MECHANISMS INVOLVED IN PROGESTERONE RECEPTOR REGULATION OF UTERINE FUNCTION

    PubMed Central

    Lee, K.; Jeong, J.; Tsai, M.-J.; Tsai, S.; Lydon, J. P.; DeMayo, F. J.

    2007-01-01

    The ovarian steroid hormone progesterone is a major regulator of uterine function. The actions of this hormone is mediated through its cognate receptor, the progesterone receptor, Pgr. Ablation of the Pgr has shown that this receptor is critical for all female reproductive functions including the ability of the uterus to support and maintain the development of the implanting mouse embryo. High density DNA microarray analysis has identified direct and indirect targets of Pgr action. One of the targets of Pgr action is a member of the Hedgehog morphogen Indian hedgehog, Ihh. Ihh and members of the Hh signaling cascade show a coordinate expression pattern in the mouse uterus during the preimplantation period of pregnancy. The expression of Ihh and its receptor Patched-1, Ptc1, as well as, down stream targets of Ihh-Ptch1 signaling, such as the orphan nuclear receptor COUP-TF II show that this morphogen pathway mediates communication between the uterine epithelial and stromal compartments. The members of the Ihh signaling axis may function to coordinate the proliferation, vascularization and differentiation of the uterine stroma during pregnancy. This analysis demonstrates that progesterone regulates uterine function in the mouse by coordinating the signals from the uterine epithelium to stroma in the preimplantation mouse uterus. PMID:17067792

  8. 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

  9. 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.

  10. [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.

  11. Mechanisms Involved in Nematode Control by Endophytic Fungi.

    PubMed

    Schouten, Alexander

    2016-08-01

    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. PMID:27296146

  12. Mechanisms Involved in Nematode Control by Endophytic Fungi.

    PubMed

    Schouten, Alexander

    2016-08-01

    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.

  13. Indirect posterior composite resins.

    PubMed

    Leinfelder, Karl F

    2005-07-01

    The use of indirect posterior composite restorations has facilitated the generation of ideal anatomic form, marginal adaptation, and appropriate proximal contact and contour. Unfortunately, however, the use of post-cure heat treatments has done little to enhance the overall clinical performance of the restoration. The development of new curing techniques in conjunction with modifications of the formulae have contributed to a substantial improvement in both the mechanical characteristics and long-term clinical performance of indirect posterior composite resins.

  14. 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.

  15. 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

  16. Orosensory self-stimulation by sucrose involves brain dopaminergic mechanisms.

    PubMed

    Schneider, L H

    1989-01-01

    The most convincing body of evidence supporting a role for brain dopaminergic mechanisms in sweet taste reward has been obtained using the sham-feeding rat. In rats prepared with a chronic gastric fistula and tested with the cannula open, intake is a direct function of the palatability of the solution offered as well as of the state of food deprivation. Because essentially none of the ingested fluid passes on to the intestine, negative postingestive feedback is eliminated. Thus, the relative orosensory/hedonic potency of the food determines and sustains the rate of sham intake; long periods of food deprivation are not required. In this way, the sham feeding of sweet solutions may be considered a form of oral self-stimulation behavior and afford a preparation through which the neurochemical and neuranatomical substrates of sweet taste reward may be identified. The results obtained in the series of experiments summarized in this paper clearly indicate that central D-1 and D-2 receptor mechanisms are critical for the orosensory self-stimulation by sucrose in the rat. In conclusion, I suggest that such investigations of the roles of brain dopaminergic mechanisms in the sucrose sham-feeding rat preparation may further our understanding of normal and aberrant attractions to sweet fluids in humans (see Cabanac, Drewnowski, and Halmi, this volume), as an innate, positive affective response of human neonates to sucrose and the sustained positive hedonic ratings for glucose when tasted but not when consumed have demonstrated. PMID:2699194

  17. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements

    PubMed Central

    Liu, Pengfei; Erez, Ayelet; Sreenath Nagamani, Sandesh C.; 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

    2011-01-01

    SUMMARY Complex genomic rearrangements (CGR) 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. PMID:21925314

  18. 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.

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

    SciTech Connect

    None, None

    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

  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. 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.

  2. Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches.

    PubMed

    Robert, Claude; Bourgeais, Laurence; Arreto, Charles-Daniel; Condes-Lara, Miguel; Noseda, Rodrigo; Jay, Thérèse; Villanueva, Luis

    2013-05-15

    While functional imaging and deep brain stimulation studies point to a pivotal role of the hypothalamus in the pathophysiology of migraine and trigeminal autonomic cephalalgias, the circuitry and the mechanisms underlying the modulation of medullary trigeminovascular (Sp5C) neurons have not been fully identified. We investigated the existence of a direct anatomo-functional relationship between hypothalamic excitability disturbances and modifications of the activities of Sp5C neurons in the rat. Anterograde and retrograde neuronal anatomical tracing, intrahypothalamic microinjections, extracellular single-unit recordings of Sp5C neurons, and behavioral trials were used in this study. We found that neurons of the paraventricular nucleus of the hypothalamus (PVN) send descending projections to the superior salivatory nucleus, a region that gives rise to parasympathetic outflow to cephalic and ocular/nasal structures. PVN cells project also to laminae I and outer II of the Sp5C. Microinjections of the GABAA agonist muscimol into PVN inhibit both basal and meningeal-evoked activities of Sp5C neurons. Such inhibitions were reduced in acutely restrained stressed rats. GABAA antagonist gabazine infusions into the PVN facilitate meningeal-evoked responses of Sp5C neurons. PVN injections of the neuropeptide pituitary adenylate cyclase activating peptide (PACAP38) enhance Sp5C basal activities, whereas the antagonist PACAP6-38 depresses all types of Sp5C activities. 5-HT1B/D receptor agonist naratriptan infusion confined to the PVN depresses both basal and meningeal-evoked Sp5C activities. Our findings suggest that paraventricular hypothalamic neurons directly control both spontaneous and evoked activities of Sp5C neurons and could act either as modulators or triggers of migraine and/or trigeminal autonomic cephalalgias by integrating nociceptive, autonomic, and stress processing mechanisms.

  3. Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches.

    PubMed

    Robert, Claude; Bourgeais, Laurence; Arreto, Charles-Daniel; Condes-Lara, Miguel; Noseda, Rodrigo; Jay, Thérèse; Villanueva, Luis

    2013-05-15

    While functional imaging and deep brain stimulation studies point to a pivotal role of the hypothalamus in the pathophysiology of migraine and trigeminal autonomic cephalalgias, the circuitry and the mechanisms underlying the modulation of medullary trigeminovascular (Sp5C) neurons have not been fully identified. We investigated the existence of a direct anatomo-functional relationship between hypothalamic excitability disturbances and modifications of the activities of Sp5C neurons in the rat. Anterograde and retrograde neuronal anatomical tracing, intrahypothalamic microinjections, extracellular single-unit recordings of Sp5C neurons, and behavioral trials were used in this study. We found that neurons of the paraventricular nucleus of the hypothalamus (PVN) send descending projections to the superior salivatory nucleus, a region that gives rise to parasympathetic outflow to cephalic and ocular/nasal structures. PVN cells project also to laminae I and outer II of the Sp5C. Microinjections of the GABAA agonist muscimol into PVN inhibit both basal and meningeal-evoked activities of Sp5C neurons. Such inhibitions were reduced in acutely restrained stressed rats. GABAA antagonist gabazine infusions into the PVN facilitate meningeal-evoked responses of Sp5C neurons. PVN injections of the neuropeptide pituitary adenylate cyclase activating peptide (PACAP38) enhance Sp5C basal activities, whereas the antagonist PACAP6-38 depresses all types of Sp5C activities. 5-HT1B/D receptor agonist naratriptan infusion confined to the PVN depresses both basal and meningeal-evoked Sp5C activities. Our findings suggest that paraventricular hypothalamic neurons directly control both spontaneous and evoked activities of Sp5C neurons and could act either as modulators or triggers of migraine and/or trigeminal autonomic cephalalgias by integrating nociceptive, autonomic, and stress processing mechanisms. PMID:23678125

  4. 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

  5. The structure of Ca(2+) release units in arthropod body muscle indicates an indirect mechanism for excitation-contraction coupling.

    PubMed Central

    Takekura, Hiroaki; Franzini-Armstrong, Clara

    2002-01-01

    The relative disposition of ryanodine receptors (RyRs) and L-type Ca(2+) channels was examined in body muscles from three arthropods. In all muscles the disposition of ryanodine receptors in the junctional gap between apposed SR and T tubule elements is highly ordered. By contrast, the junctional membrane of the T tubule is occupied by distinctive large particles that are clustered within the small junctional domain, but show no order in their arrangement. We propose that the large particles of the junctional T tubules represent L-type Ca(2+) channels involved in excitation-contraction (e-c) coupling, based on their similarity in size and location with the L-type Ca(2+) channels or dihydropyridine receptors (DHPRs) of skeletal and cardiac muscle. The random arrangement of DHPRs in arthropod body muscles indicates that there is no close link between them and RyRs. This matches the architecture of vertebrate cardiac muscle and is in keeping with the similarity in e-c coupling mechanisms in cardiac and invertebrate striated muscles. PMID:12414707

  6. 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.

  7. 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.

  8. Indirect hemagglutination employing enterobacterial common antigen and Yersinia somatic antigen: a technique to differentiate brucellosis from infections involving cross-reacting Yersinia enterocolitica.

    PubMed Central

    Mittal, K R; Ricciardi, I D; Tizard, I R

    1980-01-01

    The existence of enterobacterial common antigen in Yersinia enterocolitica and its absence in Brucella abortus were utilized in an attempt to provide a method to distinguish Brucella infections from infections with cross-reacting Yersinia. The indirect hemagglutination test was employed for this purpose. In experimental laboratory animals, the presence of anti-enterobacterial common antigen was found to be indicative of prior exposure to Y. enterocolitica rather than B. abortus. In cattle, however, low titers of anti-enterobacterial common antigen were present in all animals. It was observed that anti-enterobacterial common antigen titers either equaled or exceeded anti-Yersinia O titers in Yersinia-exposed animals, whereas in animals infected with B. abortus the anti-Yersinia O titer generally exceeded the anti-enterobacterial common antigen titer. PMID:6766951

  9. 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. PMID:26242993

  10. 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.

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

    PubMed

    Borkowska, Malgorzata; 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

  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. Ecology: Dynamics of Indirect Extinction.

    PubMed

    Montoya, Jose M

    2015-12-01

    The experimental identification of the mechanism by which extinctions of predators trigger further predator extinctions emphasizes the role of indirect effects between species in disturbed ecosystems. It also has deep consequences for the hidden magnitude of the current biodiversity crisis.

  14. 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.

  15. 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

  16. Do infants detect indirect reciprocity?

    PubMed

    Meristo, Marek; Surian, Luca

    2013-10-01

    In social interactions involving indirect reciprocity, agent A acts prosocially towards B and this prompts C to act prosocially towards A. This happens because A's actions enhanced its reputation in the eyes of third parties. Indirect reciprocity may have been of central importance in the evolution of morality as one of the major mechanisms leading to the selection of helping and fair attitudes. Here we show that 10-month-old infants expect third parties to act positively towards fair donors who have distributed attractive resources equally between two recipients, rather than toward unfair donors who made unequal distributions. Infants' responses were dependent on the reciprocator's perceptual exposure to previous relevant events: they expected the reciprocator to reward the fair donor only when it had seen the distributive actions performed by the donors. We propose that infants were able to generate evaluations of agents that were based on the fairness of their distributive actions and to generate expectations about the social preferences of informed third parties.

  17. [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.

  18. 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.

  19. 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.

  20. Moral assessment in indirect reciprocity.

    PubMed

    Sigmund, Karl

    2012-04-21

    Indirect reciprocity is one of the mechanisms for cooperation, and seems to be of particular interest for the evolution of human societies. A large part is based on assessing reputations and acting accordingly. This paper gives a brief overview of different assessment rules for indirect reciprocity, and studies them by using evolutionary game dynamics. Even the simplest binary assessment rules lead to complex outcomes and require considerable cognitive abilities.

  1. Indirect activation of neuronal noncapacitative Ca2+ entry is the final step involved in the neurotoxic effect of Tityus serrulatus scorpion beta-toxin.

    PubMed

    Grolleau, Françoise; Stankiewicz, Maria; Kielbasiewicz, Ewa; Martin-Eauclaire, Marie-France; Lavialle, Céline; De Vente, Jan; Lapied, Bruno

    2006-03-01

    Interweaving strategies of electrophysiology, calcium imaging and immunocytochemistry bring new insights into the mode of action of the Brazilian scorpion Tityus serrulatusbeta-toxin VII. Pacemaker dorsal unpaired median neurons isolated from the cockroach central nervous system were used to study the effects of toxin VII. In current-clamp, 50 nm toxin VII produced a membrane depolarization and reduced spiking. At 200 nM, depolarization associated with multiphasic effects was seen. After artificial hyperpolarization, plateau potentials on which spontaneous electrical activity appeared were observed. In voltage clamp, toxin VII induced a negative shift of the voltage dependence of sodium current activation without significant effect on steady-state inactivation. In addition, toxin VII produced a permanent TTX-sensitive holding inward current, indicating that background sodium channels were targeted by beta-toxin. Cell-attached patch recordings indicated that these channels were switched from unclustered single openings to current fluctuating between distinct subconductance levels exhibiting increased open probability and open-time distribution. Toxin VII also produced a TTX-sensitive [Ca2+]i rise. Immunostaining with Cav2.2(alpha1b) antibodies and calcium imaging data obtained with omega-CgTx GVIA indicated that N-type high-voltage-activated calcium channels initiated calcium influx and were an essential intermediate in the pathway linking toxin VII-modified sodium channels to the activation of an additional route for calcium entry. By using inhibitors of (i) noncapacitative calcium entry (inhibitor LOE-908), (ii) NO-sensitive guanylyl cyclase (ODQ) and (iii) phosphodiesterase 2 (EHNA), together with cGMP antibodies, we demonstrated that noncapacitative calcium entry was the final step in a complex combination of events that was initiated by toxin VII-alteration of sodium channels and then involved successive activation of other membrane ion channels. PMID:16553610

  2. Seminal vesicle intraepithelial involvement by prostate cancer: putative mechanism and clinicopathological significance.

    PubMed

    Miyai, Kosuke; Kristiansen, Anna; Egevad, Lars; Pina-Oviedo, Sergio; Divatia, Mukul K; Shen, Steven S; Miles, Brian J; Ayala, Alberto G; Park, Yong Wook; Ro, Jae Y

    2014-09-01

    We have recently shown seminal vesicle intraepithelial involvement of prostate cancer in cases with seminal vesicle invasion (pT3b). Based on the manner of seminal vesicle invasion, there could be 2 possible mechanisms of seminal vesicle intraepithelial involvement: direct intraepithelial invasion from prostate carcinoma in the muscular wall of seminal vesicles or intraepithelial involvement of cancer from the invaginated extraprostatic space (IES)/ejaculatory duct system to extraprostatic seminal vesicle. We aimed to clarify the manner and clinicopathological significance of seminal vesicle intraepithelial involvement. Of 1629 consecutive radical prostatectomies, 109 cases (6.7%) showed seminal vesicle invasion in whole-mounted radical prostatectomy specimens. In these pT3b cases, 18 (17%) showed seminal vesicle intraepithelial involvement by prostate cancer. Stromal invasion of the IES/ejaculatory duct system and ejaculatory duct intraepithelial invasion by prostate cancer were identified in 62 and 5 of 109 pT3b cases, respectively. However, the presence/absence of IES/ejaculatory duct system involvement by prostate cancer does not predict seminal vesicle intraepithelial involvement. No statistically significant correlation was observed between all pathologic parameters/biochemical recurrence and the presence/absence of seminal vesicle intra-epithelial involvement in the pT3b cases. These findings suggest that seminal vesicle intraepithelial involvement is more likely due to direct invasion of carcinoma from the muscular wall of seminal vesicles rather than intraepithelial extension from the ejaculatory duct system in the IES. Further studies with a substantially greater case number are needed to clarify the clinicopathological significance of seminal vesicle intraepithelial involvement in a better manner.

  3. 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

  4. Mechanism of tumor remission by cytomegalovirus in a murine lymphoma model: evidence for involvement of virally induced cellular interleukin-15.

    PubMed

    Erlach, Katja C; Reddehase, Matthias J; Podlech, Jürgen

    2015-06-01

    A murine model of B and T cell lymphomas in recipients after hematoablative conditioning for hematopoietic cell transplantation (HCT) has previously revealed a tumor-repressive, metastasis-inhibiting function of murine cytomegalovirus (mCMV). More recently, this prediction from the experimental model was put on trial in several clinical studies that indeed gave evidence for a lower incidence of tumor relapse associated with early reactivation of latent human cytomegalovirus (hCMV) after allogeneic HCT in patients treated against different types of hematopoietic malignancies, including lymphoma and acute as well as chronic leukemias. Due to the limitations inherent to clinical studies, the tumor-repressive role of hCMV remained observational with no approach to clarify mechanisms. Although the tumor-repressive mechanisms of mCMV and hCMV may differ and depend on the type of tumor, experimental approaches in the murine model might give valuable hints for concepts to follow in clinical research. We have previously shown for the liver-adapted A20-derived B cell lymphoma E12E that mCMV does not infect the lymphoma cells for causing cell death by viral cytopathogenicity but triggers tumor-selective apoptosis at a tissue site of tumor metastasis distant from a local site of infection. This finding suggested involvement of a cytokine that triggers apoptosis, directly or indirectly. Here we used a series of differential high-density microarray analyses to identify cellular genes whose expression is specifically upregulated at the site of virus entry only by viruses capable of triggering lymphoma cell apoptosis. This strategy identified interleukin-15 (IL-15) as most promising candidate, eventually confirmed by lymphoma repression with recombinant IL-15. PMID:25805565

  5. 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

  6. 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.

  7. 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.

  8. DNA methylation, riboswitches, and transcription factor activity: fundamental mechanisms of gene-nutrient interactions involving vitamins.

    PubMed

    Huang, Janet; Vieira, Amandio

    2006-12-01

    Nutrient-gene interactions occur with a variety of nutrients including some minerals, vitamins, polyunsaturated fatty acids and other lipids. Fundamental molecular mechanisms that underlie many of the effects of nutrients on gene expression are presented herein. Two of the mechanisms described influence gene transcription: DNA methylation and transcription factor activation. Another mechanism, riboswitching, can regulate gene expression at different levels, for example, at the mRNA translation level. The first two mechanisms are widely distributed across animal phyla. Riboswitches are documented primarily in more primitive organisms, but may prove to be of wider relevance. Riboswitches are known for several vitamins; those involving thiamine are presented here. The role of folates and retinoids in DNA methylation and transcriptional factor (nuclear retinoid receptor) activities, respectively, is presented in the context of cell proliferation and differentiation, and related physiological or pathological effects during embryogenesis and cancer.

  9. [Genetic and biochemical mechanisms of involvement of antioxidant defense enzymes in the development of bronchial asthma].

    PubMed

    Polonikov, A V; Ivanov, V P; Bogomazov, A D; Solodilova, M A

    2015-01-01

    In the present review we have analyzed and summarized recent literature data on genetic and biochemical mechanisms responsible for involvement of antioxidant defense enzymes in the etiology and pathogenesis of bronchial asthma. It has been shown that the mechanisms of asthma development are linked with genetically determined abnormalities in the functioning of antioxidant defense enzymes. These alterations are accompanied by a systemic imbalance between oxidative and anti-oxidative reactions with the shift of the redox state toward increased free radical production and oxidative stress, a key element in the pathogenesis of bronchial asthma. PMID:26350733

  10. [Genetic and biochemical mechanisms of involvement of antioxidant defense enzymes in the development of bronchial asthma].

    PubMed

    Polonikov, A V; Ivanov, V P; Bogomazov, A D; Solodilova, M A

    2015-01-01

    In the present review we have analyzed and summarized recent literature data on genetic and biochemical mechanisms responsible for involvement of antioxidant defense enzymes in the etiology and pathogenesis of bronchial asthma. It has been shown that the mechanisms of asthma development are linked with genetically determined abnormalities in the functioning of antioxidant defense enzymes. These alterations are accompanied by a systemic imbalance between oxidative and anti-oxidative reactions with the shift of the redox state toward increased free radical production and oxidative stress, a key element in the pathogenesis of bronchial asthma.

  11. Cooperation under indirect reciprocity and imitative trust.

    PubMed

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

    2010-10-27

    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.

  12. 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

  13. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.

    PubMed

    Bond, Jacquelyn; Roberts, Emma; Springell, Kelly; Lizarraga, Sofia B; Lizarraga, Sophia; Scott, Sheila; Higgins, Julie; Hampshire, Daniel J; Morrison, Ewan E; Leal, Gabriella F; Silva, Elias O; Costa, Suzana M R; Baralle, Diana; Raponi, Michela; Karbani, Gulshan; Rashid, Yasmin; Jafri, Hussain; Bennett, Christopher; Corry, Peter; Walsh, Christopher A; Woods, C Geoffrey

    2005-04-01

    Autosomal recessive primary microcephaly is a potential model in which to research genes involved in human brain growth. We show that two forms of the disorder result from homozygous mutations in the genes CDK5RAP2 and CENPJ. We found neuroepithelial expression of the genes during prenatal neurogenesis and protein localization to the spindle poles of mitotic cells, suggesting that a centrosomal mechanism controls neuron number in the developing mammalian brain. PMID:15793586

  14. 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.

  15. 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

  16. Indirect traumatic optic neuropathy.

    PubMed

    Singman, Eric L; Daphalapurkar, Nitin; White, Helen; Nguyen, Thao D; Panghat, Lijo; Chang, Jessica; McCulley, Timothy

    2016-01-01

    Indirect traumatic optic neuropathy (ITON) refers to optic nerve injury resulting from impact remote to the optic nerve. The mechanism of injury is not understood, and there are no confirmed protocols for prevention, mitigation or treatment. Most data concerning this condition comes from case series of civilian patients suffering blunt injury, such as from sports- or motor vehicle-related concussion, rather than military-related ballistic or blast damage. Research in this field will likely require the development of robust databases to identify patients with ITON and follow related outcomes, in addition to both in-vivo animal and virtual human models to study the mechanisms of damage and potential therapies. PMID:26759722

  17. 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.

  18. Reflex hypertensive response induced by capsaicin involves endothelin-dependent mechanisms.

    PubMed

    Akella, Aparna; Deshpande, Shripad B

    2015-01-01

    Capsaicin, a nociceptive agent produces triphasic pressure response in rats. The mechanisms underlying capsaicin-induced pressure responses are not clear. Therefore, the present study was undertaken to determine the mechanisms involved in capsaicin - induced pressure responses. The trachea, jugular vein and femoral artery were cannulated in anaesthetized rats. Capsaicin (10 µg/kg; i.v) - induced reflex changes in the blood pressure, respiratory excursions and ECG were recorded before/after vagotomy in the absence/presence of antagonists. Capsaicin produced the triphasic pressure response characterized by immediate fall, recovery (intermediate phase) and delayed progressive fall. After vagotomy, the immediate hypotension was abolished and the intermediate pressure response was potentiated as a hypertensive response while the delayed hypotensive response persisted. The time-matched heart rate changes (bradycardia) and respiratory changes (tachypnea in delayed phase) were abolished after vagotomy. Pretreatment with endothelin receptor antagonist (bosentan; 10 mg/kg) blocked the capsiaicn-induced intermediate hypertensive response in vagotomised animals but not the delayed hypotension. Pretreatment with nitric oxide synthase (NOS) inhibitor (L-NAME; 30 pg/kg), prostaglandin synthase inhibitor (indomethacin; 10 mg/kg) and kinin synthase inhibitor (aprotinin; 6000 KIU) did not block the delayed hypotensive response. These results demonstrate that capsaicin-induced intermediate hypertensive response involves endothelin-dependent mechanisms and the delayed hypotensive response is independent of nitrergic, prostaglandinergic or kininergic mechanisms.

  19. 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

    2014-01-01

    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.

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

    PubMed Central

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

    2011-01-01

    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. PMID:21964384

  1. The logic of indirect speech.

    PubMed

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

    2008-01-22

    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.

  2. 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

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

    PubMed

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

    2016-07-01

    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

  4. 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

  5. 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.

  6. 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. PMID:9217317

  7. Novel molecular mechanisms involved in hormonal regulation of lactate production in Sertoli cells.

    PubMed

    Regueira, Mariana; Artagaveytia, Silvana Lucía; Galardo, María Noel; Pellizzari, Eliana Herminia; Cigorraga, Selva Beatriz; Meroni, Silvina Beatriz; Riera, María Fernanda

    2015-10-01

    The aim of the study was to analyze molecular mechanisms involved in FSH and basic fibroblast growth factor (bFGF) regulation of lactate production in rat Sertoli cells. The regulation of the availability of pyruvate, which is converted to lactate, could be a mechanism utilized by hormones to ensure lactate supply to germ cells. On one hand, the regulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) expression could result in increased glycolysis, while an increase in pyruvate availability may also result from a lower conversion to acetyl-CoA by negative regulation of pyruvate dehydrogenase complex (PDC) activity by phosphorylation. Sertoli cell cultures obtained from 20-day-old rats were used. Stimulation of the cultures with FSH or bFGF showed that FSH increases Pfkfb1 and Pfkfb3 expression while bFGF increases Pfkfb1 mRNA levels. Additionally, we observed that FSH-stimulated lactate production was inhibited in the presence of a PFKFB3 inhibitor, revealing the physiological relevance of this mechanism. As for the regulation of PDC, analysis of pyruvate dehydrogenase kinase (Pdk) expression showed that FSH increases Pdk3 and decreases Pdk4 mRNA levels while bFGF increases the expression of all Pdks. In addition, we showed that bFGF increases phosphorylated PDC levels and that bFGF-stimulated lactate production is partially inhibited in the presence of a PDK inhibitor. Altogether, these results add new information regarding novel molecular mechanisms involved in hormonal regulation of lactate production in Sertoli cells. Considering that lactate is essential for the production of energy in spermatocytes and spermatids, these mechanisms might be relevant in maintaining spermatogenesis and male fertility. PMID:26224098

  8. 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. PMID:26497928

  9. 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.

  10. Involvement of the mechanoreceptors in the sensory mechanisms of manual and electrical acupuncture.

    PubMed

    Yamamoto, Hiromi; Kawada, Toru; Kamiya, Atsunori; Miyazaki, Shunichi; Sugimachi, Masaru

    2011-02-24

    The modalities of acupuncture can be broadly classified into manual acupuncture (MA) and electroacupuncture (EA). Although MA has been reported to cause winding of tissue around the needle and subsequent activation of the sensory mechanoreceptors and nociceptors, the sensory mechanisms of acupuncture stimulation are not fully understood. To test the hypothesis that the involvement of the mechanoreceptors in the sensory mechanism is different in MA and EA, we examined the effects of a stretch-activated channel blocker gadolinium on the hemodynamic responses to hind limb MA and EA in anesthetized rats (n = 9). Gadolinium significantly attenuated the MA-induced bradycardic response (-22 ± 5 vs. -10 ± 3 bpm, P<0.05) and tended to attenuate the MA-induced depressor response (-30 ± 5 vs. -18 ± 4 mmHg, P = 0.06). On the other hand, gadolinium significantly attenuated both the EA-induced bradycardic (-22 ± 5 vs. -9 ± 4 bpm, P<0.01) and depressor responses (-32 ± 6 vs. -15 ± 5 mmHg, P<0.01). These results indicate that the mechanoreceptors are involved in the sensory mechanisms for both MA and EA.

  11. 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. PMID:26979563

  12. Transduction mechanism(s) of Na-saccharin in the blowfly Protophormia terraenovae: evidence for potassium and calcium conductance involvement.

    PubMed

    Masala, Carla; Solari, Paolo; Sollai, Giorgia; Crnjar, Roberto; Liscia, Anna

    2009-12-01

    The study on transduction mechanisms underlying bitter stimuli is a particularly intriguing challenge for taste researchers. The present study investigates, in the labellar chemosensilla of the blowfly Protophormia terraenovae, the transduction mechanism by which saccharin evokes the response of the "deterrent" cell, with particular attention to the contribution of K(+) and Ca(2+) current and the role of cyclic nucleotides, since second messengers modulate Ca(2+), Cl(-) and K(+) currents to different extents. As assessed by extracellular single-sensillum recordings, our results show that the addition of a Ca(2+) chelator such as EGTA or the Ca(2+) current blockers SK&F-96365, Mibefradil, Nifedipine and W-7 decrease the response of the "deterrent" cell to saccharin. A similar decreasing effect was also obtained following the addition of 4-aminopyridine, a K(+) current blocker. On the contrary, the membrane-permeable cyclic nucleotide 8-bromoguanosine 3',5'-cyclic monophosphate (8Br-cGMP) activates this cell and shows an additive effect when presented mixed with saccharin. Our results are consistent with the hypothesis that in the labellar chemosensilla of the blowfly both Ca(2+) and K(+) ions are involved in the transduction mechanism of the "deterrent" cell in response to saccharin. Our results also suggest a possible pathway common to saccharin and 8Br-cGMP.

  13. Thymus involvement in myasthenia gravis: Epidemiological and clinical impacts of different self-tolerance breakdown mechanisms.

    PubMed

    Karni, Arnon; Asmail, Ali; Drory, Vivian E; Kolb, Hadar; Kesler, Anat

    2016-09-15

    The reasons for the abrogation of self-immunological tolerance in patients with myasthenia gravis (MG) may be different between those with concomitant thymic hyperplasia or thymoma, and those with no evidence of thymic involvement. We conducted a retrospective observational case series study to investigate the epidemiology as well as the clinical, serologic, and electromyographic (EMG) characteristics of individuals diagnosed as having MG. We found that the average age at MG onset of patients with either thymic hyperplasia or thymoma was much younger (by ~20years) than that of MG patients without thymic involvement. Thymic hyperplasia was more common in females than males. There were no differences in the rates of ocular MG vs. generalized MG among those three study groups. There were also no group differences in the rates of neuromuscular junction disfunction, as observed on EMG or by the results of serology tests for acetyl choline receptor antibody. Interestingly, only patients without thymic involvement had other autoimmune diseases, and most of them were females. The patients with other coexisting autoimmune disease had a similar age at MG onset as the other patients with no thymic involvement. These results shed light on the impact of epidemiological and clinical factors that result from different mechanisms of self-immunological tolerance breakdown that occurs in MG. PMID:27609276

  14. Thymus involvement in myasthenia gravis: Epidemiological and clinical impacts of different self-tolerance breakdown mechanisms.

    PubMed

    Karni, Arnon; Asmail, Ali; Drory, Vivian E; Kolb, Hadar; Kesler, Anat

    2016-09-15

    The reasons for the abrogation of self-immunological tolerance in patients with myasthenia gravis (MG) may be different between those with concomitant thymic hyperplasia or thymoma, and those with no evidence of thymic involvement. We conducted a retrospective observational case series study to investigate the epidemiology as well as the clinical, serologic, and electromyographic (EMG) characteristics of individuals diagnosed as having MG. We found that the average age at MG onset of patients with either thymic hyperplasia or thymoma was much younger (by ~20years) than that of MG patients without thymic involvement. Thymic hyperplasia was more common in females than males. There were no differences in the rates of ocular MG vs. generalized MG among those three study groups. There were also no group differences in the rates of neuromuscular junction disfunction, as observed on EMG or by the results of serology tests for acetyl choline receptor antibody. Interestingly, only patients without thymic involvement had other autoimmune diseases, and most of them were females. The patients with other coexisting autoimmune disease had a similar age at MG onset as the other patients with no thymic involvement. These results shed light on the impact of epidemiological and clinical factors that result from different mechanisms of self-immunological tolerance breakdown that occurs in MG.

  15. Endocannabinoids are Involved in Male Vertebrate Reproduction: Regulatory Mechanisms at Central and Gonadal Level.

    PubMed

    Bovolin, Patrizia; Cottone, Erika; Pomatto, Valentina; Fasano, Silvia; Pierantoni, Riccardo; Cobellis, Gilda; Meccariello, Rosaria

    2014-01-01

    Endocannabinoids (eCBs) are natural lipids regulating a large array of physiological functions and behaviors in vertebrates. The eCB system is highly conserved in evolution and comprises several specific receptors (type-1 and type-2 cannabinoid receptors), their endogenous ligands (e.g., anandamide and 2-arachidonoylglycerol), and a number of biosynthetic and degradative enzymes. In the last few years, eCBs have been described as critical signals in the control of male and female reproduction at multiple levels: centrally, by targeting hypothalamic gonadotropin-releasing-hormone-secreting neurons and pituitary, and locally, with direct effects on the gonads. These functions are supported by the extensive localization of cannabinoid receptors and eCB metabolic enzymes at different levels of the hypothalamic-pituitary-gonadal axis in mammals, as well as bonyfish and amphibians. In vivo and in vitro studies indicate that eCBs centrally regulate gonadal functions by modulating the gonadotropin-releasing hormone-gonadotropin-steroid network through direct and indirect mechanisms. Several proofs of local eCB regulation have been found in the testis and male genital tracts, since eCBs control Sertoli and Leydig cells activity, germ cell progression, as well as the acquisition of sperm functions. A comparative approach usually is a key step in the study of physiological events leading to the building of a general model. Thus, in this review, we summarize the action of eCBs at different levels of the male reproductive axis, with special emphasis, where appropriate, on data from non-mammalian vertebrates.

  16. Endocannabinoids are Involved in Male Vertebrate Reproduction: Regulatory Mechanisms at Central and Gonadal Level

    PubMed Central

    Bovolin, Patrizia; Cottone, Erika; Pomatto, Valentina; Fasano, Silvia; Pierantoni, Riccardo; Cobellis, Gilda; Meccariello, Rosaria

    2014-01-01

    Endocannabinoids (eCBs) are natural lipids regulating a large array of physiological functions and behaviors in vertebrates. The eCB system is highly conserved in evolution and comprises several specific receptors (type-1 and type-2 cannabinoid receptors), their endogenous ligands (e.g., anandamide and 2-arachidonoylglycerol), and a number of biosynthetic and degradative enzymes. In the last few years, eCBs have been described as critical signals in the control of male and female reproduction at multiple levels: centrally, by targeting hypothalamic gonadotropin-releasing-hormone-secreting neurons and pituitary, and locally, with direct effects on the gonads. These functions are supported by the extensive localization of cannabinoid receptors and eCB metabolic enzymes at different levels of the hypothalamic–pituitary–gonadal axis in mammals, as well as bonyfish and amphibians. In vivo and in vitro studies indicate that eCBs centrally regulate gonadal functions by modulating the gonadotropin-releasing hormone–gonadotropin–steroid network through direct and indirect mechanisms. Several proofs of local eCB regulation have been found in the testis and male genital tracts, since eCBs control Sertoli and Leydig cells activity, germ cell progression, as well as the acquisition of sperm functions. A comparative approach usually is a key step in the study of physiological events leading to the building of a general model. Thus, in this review, we summarize the action of eCBs at different levels of the male reproductive axis, with special emphasis, where appropriate, on data from non-mammalian vertebrates. PMID:24782832

  17. Unifying mechanism for anticancer agents involving electron transfer and oxidative stress: clinical implications.

    PubMed

    Kovacic, Peter

    2007-01-01

    Extensive evidence supports involvement of electron transfer (ET), reactive oxygen species (ROS) and oxidative stress (OS) in the mechanism of many anticancer drugs. The common ET functionalities, usually present in the drug metabolites, are quinones (or precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species). The ET agents function catalytically in redox cycling with formation of ROS from oxygen. Electrochemical data add support to the mechanistic viewpoint. The generated metabolites generally possess reduction potentials amenable to ET in vivo, thus giving rise to ROS. The resulting OS is a participant in destruction of the cancer cell. It is important to recognize that drug action is often multipronged. The various modes of action are summarized. Most research has been devoted to development of new and improved chemotherapeutic agents. The need for more attention to measures for cancer prevention is addressed. One of the most promising involves use of antioxidants.

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

    PubMed

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

    2016-01-01

    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. PMID:27485232

  19. 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

  20. Brain structures and mechanisms involved in the generation of REM sleep.

    PubMed

    Reinoso-Suárez, Fernando; de Andrés, Isabel; Rodrigo-Angulo, Margarita L.; Garzón, Miguel

    2001-02-01

    This article reviews the central nervous mechanisms involved in the broad network that generates and maintains REM sleep. Experimental investigations have identified the pontine tegmentum as the critical substrate for REM sleep mechanisms. Several pontine structures are involved in the generation of each particular polygraphic event that characterizes REM sleep: desynchronization in the electroencephalogram, theta rhythm in the hippocampus, muscle atonia, pontogeniculooccipital waves and rapid eye movements. The pontine tegmentum also holds the region where cholinergic stimulation can trigger all the behavioural and bioelectric signs of REM sleep. The exact location has been investigated and amply discussed over the last few years. Studies in the authors> laboratory, mapping the pontine tegmentum with small volume carbachol (a cholinergic agonist) microinjections, have demonstrated that the executive neurons for REM sleep generation are neither located in the dorsal part of the pontine tegmentum, nor diffusely spread through the medial pontine reticular formation: they are concentrated in a discrete area in the ventral part of the oral pontine reticular nucleus (vRPO). In turn, the vRPO has connections with structures involved in the generation of the other states of the sleep-wake cycle as well as with structures responsible for the generation of each of the different events characterizing REM sleep. This allows us to propose the vRPO as the crucial region for REM sleep generation. Related research, with invivo and invitro experiments, into the actions of different neurotransmitters on vRPO neurones indicates that not only acetylcholine but other neurotransmitters have an active key role in vRPO REM sleep generation mechanisms.

  1. Mechanisms involved in Korean mistletoe lectin-induced apoptosis of cancer cells

    PubMed Central

    Khil, Lee-Yong; Kim, Wi; Lyu, Suyun; Park, Won Bong; Yoon, Ji-Won; Jun, Hee-Sook

    2007-01-01

    AIM: To investigate the anti-cancer mechanisms of Korean mistletoe lectin (Viscum album coloratum agglutinin, VCA) using a human colon cancer cell line (COLO). METHODS: Cytotoxic effects of VCA on COLO cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in vitro and tumor-killing effects in vivo. To study the mechanisms involved, the expression of various pro-caspases, anti-apoptotic proteins, and death receptors was determined by western blot. To determine which death receptor is involved in VCA-induced apoptosis of COLO cells, cytotoxicity was examined by MTT assay after treatment with agonists or antagonists of death receptors. RESULTS: VCA killed COLO cells in a time- and dose-dependent manner and induced complete regression of tumors in nude mice transplanted with COLO cells. Treatment of COLO cells with VCA activated caspase-2, -3, -8, and -9 and decreased expression of anti-apoptotic molecules including receptor interacting protein, nuclear factor-κB, X-linked inhibitor of apoptosis protein, and Akt/protein kinase B. We then examined the involvement of death receptors in VCA-induced apoptosis. Only tumor necrosis factor receptor 1, among the death receptors examined, was involved in apoptosis of COLO cells, evidenced by inhibition of VCA-induced apoptosis and decreased activation of caspases, particularly caspase-8, by tumor necrosis factor receptor 1 antagonizing antibody. CONCLUSION: VCA-induced apoptotic COLO cell death is due to the activation of caspases and inhibition of anti-apoptotic proteins, in part through the tumor necrosis factor receptor 1 signaling pathway. PMID:17569116

  2. 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.

  3. 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.

  4. 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. PMID:27050459

  5. 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

  6. 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

  7. Thermodynamic and mechanical timescales involved in foam film rupture and liquid foam coalescence.

    PubMed

    Rio, Emmanuelle; Biance, Anne-Laure

    2014-12-01

    Recent advances in the coalescence in liquid foams are reviewed, with a special focus on the multiscale structure of foams. Studies concerning the stability of isolated foam films, on the one hand, and the coalescence process in macroscopic foams, on the other hand, are not always in good agreement. This discrepancy reveals that two routes can induce coalescence in a foam. The first route is thermodynamic and shows that coalescence is governed by a stochastic rupture of foam films. The second route relies on a mechanically induced rupture of the films, due to the spontaneous evolution of foams. From a literature review, the evaluation of the different timescales involved in these mechanisms allows defining the limiting parameters of foam coalescence.

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

    PubMed Central

    Ngondo, Richard Patryk; Carbon, Philippe

    2014-01-01

    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. PMID:24234445

  9. Ecology: Dynamics of Indirect Extinction.

    PubMed

    Montoya, Jose M

    2015-12-01

    The experimental identification of the mechanism by which extinctions of predators trigger further predator extinctions emphasizes the role of indirect effects between species in disturbed ecosystems. It also has deep consequences for the hidden magnitude of the current biodiversity crisis. PMID:26654371

  10. Dura-evoked neck muscle activity involves purinergic and N-methyl-D-aspartate receptor mechanisms.

    PubMed

    Yao, Dongyuan; Yoshida, Mitsuhiro; Sessle, Barry J

    2015-12-16

    We have previously demonstrated that noxious stimulation of craniofacial tissues including the frontal dura reflexly evokes significant increases in neck muscle electromyographic (EMG) activity. The primary aim of this study was to determine whether purinergic receptor mechanisms may be involved in these EMG effects, and whether N-methyl-D-aspartate (NMDA) receptor processes modulate the purinergic mechanisms. Application of the P2X1, P2X3 and P2X2/3 receptor agonist α,β-methylene ATP (but not vehicle) to the dural surface evoked a significant (P<0.05) increase in ipsilateral neck EMG activity that could be suppressed by dural or intrathecal application of the selective P2X1, P2X3 and P2X2/3 receptor antagonist 2',3'-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP) but not by vehicle; the intrathecal application of 2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist, also significantly reduced the neck EMG activity evoked by dural application of α,β-methylene ATP. These data suggest that purinergic receptor mechanisms contribute to the increased neck activity that can be reflexly evoked by noxious stimulation of the frontal dura, and that NMDA as well as purinergic receptor mechanisms in the medulla may modulate these purinergic-related effects. PMID:26559728

  11. Some Novel Thought Experiments Involving Foundations of Quantum Mechanics and Quantum Information

    NASA Astrophysics Data System (ADS)

    Akhavan, Omid

    2004-02-01

    In this thesis, we have proposed some novel thought experiments involving foundations of quantum mechanics and quantum information theory, using quantum entanglement property. Concerning foundations of quantum mechanics, we have suggested some typical systems including two correlated particles which can distinguish between the two famous theories of quantum mechanics, i.e. the standard and Bohmian quantum mechanics, at the individual level of pair of particles. Meantime, the two theories present the same predictions at the ensemble level of particles. Regarding quantum information theory, two theoretical quantum communication schemes including quantum dense coding and quantum teleportation schemes have been proposed by using entangled spatial states of two EPR particles shared between two parties. It is shown that the rate of classical information gain in our dense coding scheme is greater than some previously proposed multi-qubit protocols by a logarithmic factor dependent on the dimension of Hilbert space. The proposed teleportation scheme can provide a complete wave function teleportation of an object having other degrees of freedom in our three-dimensional space, for the first time. All required unitary operators which are necessary in our state preparation and Bell state measurement processes are designed using symmetric normalized Hadamard matrix, some basic gates and one typical conditional gate, which are introduced here for the first time.

  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. Ellagic acid: Pharmacological activities and molecular mechanisms involved in liver protection.

    PubMed

    García-Niño, Wylly Ramsés; Zazueta, Cecilia

    2015-07-01

    Traditional drugs or therapies rarely have effects on regression of chronic liver diseases, which result in many cases from sustained oxidative stress. In recent years, ellagic acid (EA) has gained attention due to its multiple biological activities and several molecular targets. This is the first review focused on the pharmacological properties and on the molecular mechanisms activated by EA in terms of liver protection. EA possesses antioxidant, antihepatotoxic, antisteatosic, anticholestatic, antifibrogenic, antihepatocarcinogenic and antiviral properties that improves the hepatic architectural and functions against toxic and pathological conditions. The molecular mechanisms that EA activates include the scavenging of free radicals, regulation of phase I and II enzymes, modulation of proinflammatory and profibrotic cytokines synthesis, the regulation of biochemical pathways involved in the synthesis and degradation of lipids as well as the maintenance of essential trace elements levels. EA also inhibits hepatic stellate cells and mast cells activation, the proliferation of transformed cells, as well as viral replication by increasing antioxidant response, induction of apoptosis, downregulation of genes involved in cell cycle and angiogenesis, and stimulation of cellular immune response. Despite the enormous therapeutic potential of EA as an innovative pharmacological strategy, the number of phase I and II trials in patients is scarce, precluding its clinical application. In these sense, the use of new delivery systems that enhances EA bioavailability would improve the results already obtained. Also it remains to be determined if treatment with urolithins instead of EA would represent a better strategy in hepatic disease treatment.

  14. 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.

  15. 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

  16. 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. PMID:27420171

  17. 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

  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. Astrocytes are involved in trigeminal dynamic mechanical allodynia: potential role of D-serine.

    PubMed

    Dieb, W; Hafidi, A

    2013-09-01

    Trigeminal neuropathic pain affects millions of people worldwide. Despite decades of study on the neuronal processing of pain, mechanisms underlying enhanced pain states after injury remain unclear. N-methyl-D-aspartate (NMDA) receptor-dependent changes play a critical role in triggering central sensitization in neuropathic pain. These receptors are regulated at the glycine site through a mandatory endogenous co-agonist D-serine, which is synthesized by astrocytes. Therefore, the present study was carried out to determine whether astrocytes are involved, through D-serine secretion, in dynamic mechanical allodynia (DMA) obtained after chronic constriction of the infraorbital nerve (CCI-IoN) in rats. Two weeks after CCI-IoN, an important reaction of astrocytes was present in the medullary dorsal horn (MDH), as revealed by an up-regulation of glial fibrillary acidic protein (GFAP) in allodynic rats. In parallel, an increase in D-serine synthesis, which co-localized with its synthesis enzyme serine racemase, was strictly observed in astrocytes. Blocking astrocyte metabolism by intracisternal delivery of fluorocitrate alleviated DMA. Furthermore, the administration of D-amino-acid oxidase (DAAO), a D-serine-degrading enzyme, or that of L-serine O-sulfate (LSOS), a serine racemase inhibitor, significantly decreased pain behavior in allodynic rats. These results demonstrate that astrocytes are involved in the modulation of orofacial post-traumatic neuropathic pain via the release of the gliotransmitter D-serine.

  20. 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.

  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. 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. Ion channels and transporters involved in cell volume regulation and sensor mechanisms.

    PubMed

    Okada, Yasunobu

    2004-01-01

    All animal cell types have an appropriate volume. Even under physiological conditions of constant extracellular osmolarity, cells must regulate their volume. Cell volume is subjected to alterations because of persistent physicochemical osmotic load resulting from Donnan-type colloid osmotic pressure and of cell activity-associated changes in intracellular osmolarity resulting from osmolyte transport and metabolism. The strategy adopted by animal cells for coping with volume regulation on osmotic perturbation is to activate transport pathways, including channels and transporters, mainly for inorganic osmolytes to drive water flow. Under normotonic conditions, cells undergo volume regulation by pump-mediated mechanisms. Under anisotonic conditions, volume regulation occurs by additional channel/transporter-mediated mechanisms. Cell volume regulation is also attained through adjustment of intracellular levels not only of inorganic but also of organic osmolytes with changing the expression of their transporters or regulation of metabolism. In cell volume regulation mechanism, several "volume sensors" are thought to be involved. A volume-sensitive Cl- channel has lately attracted considerable attention in this regard. PMID:15475611

  4. A dp53-Dependent Mechanism Involved in Coordinating Tissue Growth in Drosophila

    PubMed Central

    Milán, Marco

    2010-01-01

    Coordination of growth between and within organs contributes to the generation of well-proportioned organs and functionally integrated adults. The mechanisms that help to coordinate the growth between different organs start to be unravelled. However, whether an organ is able to respond in a coordinated manner to local variations in growth caused by developmental or environmental stress and the nature of the underlying molecular mechanisms that contribute to generating well-proportioned adult organs under these circumstances remain largely unknown. By reducing the growth rates of defined territories in the developing wing primordium of Drosophila, we present evidence that the tissue responds as a whole and the adjacent cell populations decrease their growth and proliferation rates. This non-autonomous response occurs independently of where growth is affected, and it is functional all throughout development and contributes to generate well-proportioned adult structures. Strikingly, we underscore a central role of Drosophila p53 (dp53) and the apoptotic machinery in these processes. While activation of dp53 in the growth-depleted territory mediates the non-autonomous regulation of growth and proliferation rates, effector caspases have a unique role, downstream of dp53, in reducing proliferation rates in adjacent cell populations. These new findings indicate the existence of a stress response mechanism involved in the coordination of tissue growth between adjacent cell populations and that tissue size and cell cycle proliferation can be uncoupled and are independently and non-autonomously regulated by dp53. PMID:21179433

  5. Localization of mechanisms involved in hydropassive and hydroactive stomatal responses of Sambucus nigra to dry air.

    PubMed

    Kaiser, Hartmut; Legner, Nicole

    2007-02-01

    The response of stomata to a reduction of air humidity is composed of a hydropassive opening followed by active closure. Whereas the mechanisms behind the hydropassive opening are largely understood, the location and physiological basis of the sensing mechanisms leading to active closure are not yet known. This study attempts to evaluate the importance of a single pore's transpiration on its own response and that of adjacent pores. Selected stomata on attached intact leaves of Sambucus nigra were sealed with mineral oil and the response to a reduction of humidity was continuously observed in situ. Blocking a pore's transpiration had no appreciable effect on hydropassive opening and subsequent stomatal closure. If the adjacent stomata were additionally sealed, the closing response was reduced, but not the hydropassive opening. On the other hand, sealing the entire leaf surface, except a small area including the observed stomata, also reduced stomatal closure. These results indicate that strictly local processes triggered by a pore's own transpiration are not required to induce stomatal closure. To describe the effect of one pore's transpiration on the hydropassive and hydroactive responses of neighboring stomata, a simple spatial model was constructed. It suggests that 90% of the closing effect covers an area of approximately 0.5 mm2, whereas the effect on hydropassive opening affects an area of approximately 1 mm2. This divergence may suggest mechanisms other than or in addition to those involving changes of local leaf water potential. PMID:17158586

  6. Involvement of prolactin and somatostatin in depression and the mechanism of action of antidepressant drugs.

    PubMed

    Faron-Górecka, Agata; Kuśmider, Maciej; Solich, Joanna; Kolasa, Magdalena; Szafran, Kinga; Zurawek, Dariusz; Pabian, Paulina; Dziedzicka-Wasylewska, Marta

    2013-01-01

    Neuropeptides have been implicated in the physiology and pathophysiology of stress responses and therefore may play an important role in the pathogenesis of affective disorders such as Major Depression Disorder (MDD). The data presented in this mini-review demonstrate the role of prolactin (PRL) and somatostatin (STT) in the pathology and pharmacotherapy of MDD, focusing particularly on the response to antidepressant treatment, and compare the available data with the results obtained in our laboratory using the well-validated chronic mild stress (CMS) animal model of MDD. Despite the availability of many pharmacological therapies for depression, ca. 35% patients remain treatment resistant. This clinical situation is also true for rats subjected to CMS; some animals do not respond to antidepressant therapy and are considered treatment resistant. The most interesting results presented in this mini-review concern the changes in PRL and SST receptors in the brains of rats subjected to the full CMS procedure and IMI treatment and demonstrate the role of these receptors in the mechanisms of antidepressant action. The possible interaction between SST and PRL, the involvement of the D2 dopamine receptor, and their direct protein-protein interactions are also discussed, with the conclusion that these two neurohormones play an important role in the mechanism of resilience after stress as well as in the mechanism of action of antidepressant drugs.

  7. Indirect reciprocity under incomplete observation.

    PubMed

    Nakamura, Mitsuhiro; Masuda, Naoki

    2011-07-01

    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.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. Understanding the neural mechanisms involved in sensory control of voice production.

    PubMed

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

    2012-05-15

    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

  13. Recognition of mechanisms involved in bile resistance important to halting antimicrobial resistance in nontyphoidal Salmonella.

    PubMed

    Tsai, Ming-Han; Wu, Sih-Ru; Lee, Hao-Yuan; Chen, Chyi-Liang; Lin, Tzou-Yien; Huang, Yhu-Chering; Chiu, Cheng-Hsun

    2012-08-01

    Increasing antimicrobial resistance in nontyphoidal Salmonella (NTS) is a global public health problem that complicates antimicrobial therapy. As an enteric pathogen, Salmonella must endure the presence of bile in the intestinal tract during the course of infection. In this study, we sought to identify Salmonella genes necessary for bile resistance and to investigate their association with antimicrobial resistance. Four genes related to bile resistance were identified, namely rfaP, rfbK, dam and tolC. The first three genes are involved in lipopolysaccharide synthesis, and tolC is associated with an efflux pump. Antimicrobial susceptibility testing showed increased susceptibility to polymyxin B and ciprofloxacin in rfaP and tolC mutants of Salmonella, respectively. Genetic analysis of 45 clinical isolates of NTS revealed that all isolates with reduced susceptibility to fluoroquinolones (minimum inhibitory concentration ≥0.125 mg/L) were associated with point mutations in the quinolone resistance-determining regions of the gyrA and parC genes. The efflux pump also played a role, as evidenced by the reduction in fluoroquinolone resistance when the TolC efflux pump was inhibited by Phe-Arg-β-naphthylamide, a competitive efflux pump inhibitor. Based on these results, we conclude that an intact membrane structure and the efflux pump system provide mechanisms enabling NTS to resist bile. Caution should be taken when using ciprofloxacin and polymyxin B to treat Salmonella enteric infection, as resistance to these agents involves the same mechanisms. Addition of an efflux pump inhibitor to fluoroquinolones may be an effective strategy to deal with the increasing resistance in NTS.

  14. 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

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

    PubMed

    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.

  16. 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.

  17. Evolution of oropharyngeal patterning mechanisms involving Dlx and endothelins in vertebrates.

    PubMed

    Kuraku, Shigehiro; Takio, Yoko; Sugahara, Fumiaki; Takechi, Masaki; Kuratani, Shigeru

    2010-05-01

    In jawed vertebrates, the Dlx code, or nested expression patterns of Dlx genes, specify the dorsoventral polarity of pharyngeal arches, downstream of endothelin-1 (Edn-1) and its effectors, Bapx1 (Nkx3.2) and dHand (Hand2). To elucidate the evolution of the specification mechanism of the oropharyngeal skeletal system, lamprey homologs of Dlx, Edn, endothelin receptor (Ednr), Bapx1, and dHand were identified. Our analysis suggested that the Edn gene family emerged at the advent of vertebrates, and that gene duplications leading to the different Edn gnathostome subtypes (Edn1-3) occurred before the cyclostome-gnathostome split. This timing of gene duplications, giving rise to multiple subtypes, was also implied for Dlx, Ednr, Hand, and Bapx. In lamprey embryos, nested expressions of Dlx genes were not observed in pharyngeal arches, nor was any focal expression of Bapx1, known in gnathostomes to specify the jaw joint. The dHand homolog, however, was expressed more intensively ventrally, as in gnathostomes. Lamprey homologs of Edn-1 and EdnrA were also shown to be expressed as described in mice, indicating involvement of this signaling pathway in the craniofacial patterning early in vertebrate evolution. These results suggest that the last common ancestor of all the extant vertebrates would have possessed basic gene repertoires involved in oropharyngeal patterning in gnathostomes, but the elaborate genetic program leading to the Dlx code is likely to have been acquired uniquely in gnathostomes. PMID:20171204

  18. 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

  19. Mechanisms Involved in Governing Adherence of Vibrio cholerae to Granular Starch▿

    PubMed Central

    Niderman-Meyer, Orly; Zeidman, Tal; Shimoni, Eyal; Kashi, Yechezkel

    2010-01-01

    Vibrio cholerae has been shown to adhere to cornstarch granules. The present work explored the mechanisms involved in this adhesion and the possibility of its occurrence in vivo. The findings suggest that both specific and nonspecific interactions are involved in the adhesion. Nonspecific hydrophobic interactions may play a role, since both V. cholerae and cornstarch granules exhibited hydrophobic properties when they were tested using a xylene-water system. In addition, the presence of bile acids reduced the adhesion. The adhesion also involves some specific carbohydrate-binding moieties on the cell surface, as reflected by reduced adhesion following pretreatment of the bacteria with proteinase K and sodium m-periodate. Further investigations supported these observations and showed that media containing low-molecular-weight carbohydrates had a significant inhibitory effect. Binding cell lysate to starch granules and removing the adhered proteins using either glucose or bile acids led to identification (by liquid chromatography-tandem mass spectrometry analysis) of several candidate V. cholerae outer membrane-associated starch-binding proteins. Different sets of proteins were isolated by removal in a glucose solution or bile acids. When the upper gastrointestinal tract conditions were simulated in vitro, both bile salts and the amylolytic activity of the pancreatic juices were found to have an inhibitory effect on the adherence of V. cholerae to starch. However, during acute diarrhea, this inhibitory effect may be significantly reduced due to dilution, suggesting that adhesion does occur in vivo. Such adhesion may contribute to the beneficial effects observed following administration of granular starch-based oral rehydration solutions to cholera patients. PMID:20023099

  20. Target dependency of brain mechanism involved in dispositional inference: a PET study.

    PubMed

    Sugiura, Motoaki; Gotoh, Ryoi; Okada, Ken; Yamaguchi, Keiichiroh; Itoh, Masatoshi; Fukuda, Hiroshi; Kawashima, Ryuta

    2004-04-01

    The cognitive mechanism for inference of personal dispositions, such as personality traits and abilities, is postulated to be dependent on the amount of episodic memory concerning target persons. To examine whether there is such target dependency in the brain mechanism during dispositional inference, we measured brain activity of normal volunteers while they were performing seven dispositional inference tasks, each for a target person in different categories, using positron emission tomography (PET). Effect of the target-person category on activation was significant in the posterodorsal, polar, and ventral subdivisions of medial prefrontal cortex, right orbitoinsular junction, left temporal pole and superior temporal sulcus, cerebellum, and thalamus, suggesting the existence of target dependency in activation during dispositional inference. The amount of episodic memory concerning a target person measured using the self-evaluative questionnaire was positively correlated with the activation in the polar subdivision of the medial prefrontal cortex, and negatively with that in a region in the left superior temporal sulcus. Together with the available knowledge on the functional roles of these regions and the proposed cognitive model in social psychology, our results suggest that these two regions play roles supplementary to each other in dispositional inference; a region in the superior temporal sulcus is involved in the processing of relevant episodic exemplar and the polar subdivision of the medial prefrontal cortex in the processing of summarized value information about the target person. PMID:15050563

  1. Diosgenin Mitigates Streptozotocin Diabetes-induced Vascular Dysfunction of the Rat Aorta: The Involved Mechanisms.

    PubMed

    Roghani-Dehkordi, Farshad; Roghani, Mehrdad; Baluchnejadmojarad, Tourandokht

    2015-12-01

    Chronic diabetes mellitus finally leads to serious vascular dysfunction. Diosgenin is a natural steroidal saponin with potential cardiovascular protective effect. In this study, the protective effect of diosgenin was checked on the aorta from streptozotocin-induced diabetic rats. Diabetic rats received diosgenin (40 mg·kg·d) for 7 weeks starting 1 week after intraperitoneal injection of streptozotocin (60 mg/kg). Aortic reactivity of endothelium-intact and -denuded rings to potassium chloride, phenylephrine, acetylcholine, and isosorbide dinitrate were measured and some involved mechanisms were explored. The results showed that diosgenin has a hypoglycemic effect and attenuates maximum contractile response of endothelium-intact and -denuded rings to PE. In addition, endothelium-dependent relaxation to acetylcholine was greater in diosgenin-treated diabetics with no significant change for endothelium-independent relaxation to isosorbide dinitrate and addition of N(G)-nitro-L-arginine methyl ester, as a nitric oxide synthase inhibitor eliminated this beneficial effect. Furthermore, diosgenin significantly attenuated aortic DNA fragmentation as an index of apoptosis and malondialdehyde content, lowered the aortic expression of angiotensin converting enzyme and transcription factor nuclear factor-κB and raised expression of endothelial nitric oxide synthase with no significant effect on the activity of superoxide dismutase. Taken together, our study provides insight into the mechanisms underlying the beneficial effect of diosgenin as a potential therapeutic agent to mitigate vascular dysfunction in diabetes mellitus. PMID:26309100

  2. Mechanism of microglia neuroprotection: Involvement of P2X7, TNFα, and valproic acid.

    PubMed

    Masuch, Annette; Shieh, Chu-Hsin; van Rooijen, Nico; van Calker, Dietrich; Biber, Knut

    2016-01-01

    Recently, we have demonstrated that ramified microglia are neuroprotective in N-methyl-D-aspartate (NMDA)-induced excitotoxicity in organotypic hippocampal slice cultures (OHSCs). The present study aimed to elucidate the underlying neuron-glia communication mechanism. It is shown here that pretreatment of OHSC with high concentrations of adenosine 5'-triphosphate (ATP) reduced NMDA-induced neuronal death only in presence of microglia. Specific agonists and antagonists identified the P2X7 receptor as neuroprotective receptor which was confirmed by absence of ATP-dependent neuroprotection in P2X7-deficient OHSC. Microglia replenished chimeric OHSC consisting of wild-type tissue replenished with P2X7-deficient microglia confirmed the involvement of microglial P2X7 receptor in neuroprotection. Stimulation of P2X7 in primary microglia induced tumor necrosis factor α (TNFα) release and blocking TNFα by a neutralizing antibody in OHSC abolished neuroprotection by ATP. OHSC from TNFα-deficient mice show increased exicitoxicity and activation of P2X7 did not rescue neuronal survival in the absence of TNFα. The neuroprotective effect of valproic acid (VPA) was strictly dependent on the presence of microglia and was mediated by upregulation of P2X7 in the cells. The present study demonstrates that microglia-mediated neuroprotection depends on ATP-activated purine receptor P2X7 and induction of TNFα release. This neuroprotective pathway was strengthened by VPA elucidating a novel mechanism for the neuroprotective function of VPA.

  3. A cascade of recently discovered molecular mechanisms involved in abiotic stress tolerance of plants.

    PubMed

    Saeed, Muhammad; Dahab, Abdel hafiz Adam; Wangzhen, Guo; Tianzhen, Zhang

    2012-04-01

    Today, agriculture is facing a tremendous threat from the climate change menace. As human survival is dependent on a constant supply of food from plants as the primary producers, we must aware of the underlying molecular mechanisms that plants have acquired as a result of molecular evolution to cope this rapidly changing environment. This understanding will help us in designing programs aimed at developing crop plant cultivars best suited to our needs of a sustainable agriculture. The field of systems biology is rapidly progressing, and new insight is coming out about the molecular mechanisms involved in abiotic stress tolerance. There is a cascade of changes in transcriptome, proteome, and metabolome of plants during these stress responses. We have tried to cover most pronounced recent developments in the field of "omics" related to abiotic stress tolerance of plants. These changes are very coordinated, and often there is crosstalk between different components of stress tolerance. The functions of various molecular entities are becoming more clear and being associated with more precise biological phenomenon.

  4. Damage mechanism involved in the solid particle erosion of CVD diamond

    NASA Astrophysics Data System (ADS)

    Davies, Alun R.; Field, John E.

    2001-09-01

    Sophisticated electro-optic sensors are employed on aircraft and missiles, and it is essential to protect them from relatively high-speed impacts with airborne dust particles. A loss in transmission caused by such an event can impair guidance, and catastrophic failure may occur. Protection is afforded by the installation of a hard cover that is transparent in the relevant regime. Diamond is potentially by far the most attractive window material due to excellent optical and mechanical properties, but it is difficult to shape. Chemical vapor deposited (CVD) diamond is a polycrystalline synthetic with properties that approach those of single crystal diamond, and it can be more easily shaped. The aims of the present research were to quantify the erosion and transmission losses, and to understand the material removal mechanisms involved. Steady-state erosion rates were obtained for CVD diamond of different grain sizes, using 300-600 micrometers quartz erodent at velocities between 60 and 140 m/s. Images of CVD diamond at various stages of erosion, obtained using an optical microscope and an environmental scanning electron microscope (ESEM), reveal that erosion initially occurs at grain boundaries and that so-called micro-features also have some influence on erosion.

  5. Protein Machineries Involved in the Attachment of Heme to Cytochrome c: Protein Structures and Molecular Mechanisms

    PubMed Central

    Travaglini-Allocatelli, Carlo

    2013-01-01

    Cytochromes c (Cyt c) are ubiquitous heme-containing proteins, mainly involved in electron transfer processes, whose structure and functions have been and still are intensely studied. Surprisingly, our understanding of the molecular mechanism whereby the heme group is covalently attached to the apoprotein (apoCyt) in the cell is still largely unknown. This posttranslational process, known as Cyt c biogenesis or Cyt c maturation, ensures the stereospecific formation of the thioether bonds between the heme vinyl groups and the cysteine thiols of the apoCyt heme binding motif. To accomplish this task, prokaryotic and eukaryotic cells have evolved distinctive protein machineries composed of different proteins. In this review, the structural and functional properties of the main maturation apparatuses found in gram-negative and gram-positive bacteria and in the mitochondria of eukaryotic cells will be presented, dissecting the Cyt c maturation process into three functional steps: (i) heme translocation and delivery, (ii) apoCyt thioreductive pathway, and (iii) apoCyt chaperoning and heme ligation. Moreover, current hypotheses and open questions about the molecular mechanisms of each of the three steps will be discussed, with special attention to System I, the maturation apparatus found in gram-negative bacteria. PMID:24455431

  6. Inflammatory mechanisms involved in brain injury following cardiac arrest and cardiopulmonary resuscitation

    PubMed Central

    XIANG, YANXIAO; ZHAO, HUA; WANG, JIALI; ZHANG, LUETAO; LIU, ANCHANG; CHEN, YUGUO

    2016-01-01

    Cardiac arrest (CA) is a leading cause of fatality and long-term disability worldwide. Recent advances in cardiopulmonary resuscitation (CPR) have improved survival rates; however, the survivors are prone to severe neurological injury subsequent to successful CPR following CA. Effective therapeutic options to protect the brain from CA remain limited, due to the complexities of the injury cascades caused by global cerebral ischemia/reperfusion (I/R). Although the precise mechanisms of neurological impairment following CA-initiated I/R injury require further clarification, evidence supports that one of the key cellular pathways of cerebral injury is inflammation. The inflammatory response is orchestrated by activated glial cells in response to I/R injury. Increased release of danger-associated molecular pattern molecules and cellular dysfunction in activated microglia and astrocytes contribute to ischemia-induced cytotoxic and pro-inflammatory cytokines generation, and ultimately to delayed death of neurons. Furthermore, cytokines and adhesion molecules generated within activated microglia, as well as astrocytes, are involved in the innate immune response; modulate influx of peripheral immune and inflammatory cells into the brain, resulting in neurological injury. The present review discusses the molecular aspects of immune and inflammatory mechanisms in global cerebral I/R injury following CA and CPR, and the potential therapeutic strategies that target neuroinflammation and the innate immune system. PMID:27330748

  7. Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity

    PubMed Central

    Koltai, Tomas

    2015-01-01

    Objective: To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs) based on evidences reported in the published literature. Methods: We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed. Conclusions: The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress-unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down-regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes. PMID:26097685

  8. The involvement of dual mechanisms of photoinactivation of photosystem II in Capsicum annuum L. Plants.

    PubMed

    Oguchi, Riichi; Terashima, Ichiro; Chow, Wah Soon

    2009-10-01

    For plants, light is an indispensable resource. However, it also causes a loss of photosynthetic activity associated with photoinactivation of photosystem II (PSII). In studies of the mechanism of this photoinactivation, there are two conflicting hypotheses at present. One is that excess energy received by leaves, being neither utilized by photosynthesis nor dissipated safely in non-photochemical quenching, causes the photoinactivation. The other involves a two-step mechanism in which excitation of Mn by photons is the primary cause. In the former hypothesis, photoinactivation of PSII should not occur in low light that provides little excess energy, but in the latter hypothesis it should. Therefore, we tested these two hypotheses in different irradiances. We used a system that can measure the fraction of functional PSII complexes under natural conditions and over a long period in intact leaves, which were attached to a plant treated with lincomycin taken up via the roots. The leaves were photoinactivated in low, medium or high light (30, 60 or 950 micromol m(-2) s(-1)) with white, blue, green or red light-emitting diode arrays. Our results showed that the extent of photoinactivation per photon exposure was higher in high light than in low light, consistent with the abundance of excess energy. However, photoinactivation did occur in low light with little excess energy, and blue light caused the greatest extent of photoinactivation followed by white, green and red light in this order, an order that can be predicted from the Mn absorbance spectrum. These results suggest that both mechanisms occur in the photoinactivation process.

  9. Analyses of the involvement of PKA regulation mechanism in meiotic incompetence of porcine growing oocytes.

    PubMed

    Nishimura, Takanori; Fujii, Wataru; Kano, Kiyoshi; Sugiura, Koji; Naito, Kunihiko

    2012-09-01

    Mammalian growing oocytes (GOs) lack the ability to resume meiosis, although the molecular mechanism of this limitation is not fully understood. In the present study, we cloned cDNAs of cAMP-dependent protein-kinase (PKA) subunits from porcine oocytes and analyzed the involvement of the PKA regulation mechanism in the meiotic incompetence of GOs at the molecular level. We found a cAMP-independent high PKA activity in GOs throughout the in vitro culture using a porcine PKA assay system we established, and inhibition of the activity by injection of the antisense RNA of the PKA catalytic subunit (PKA-C) induced meiotic resumption in GOs. Then we examined the possibility that the amount of the PKA regulatory subunit (PKA-R), which can bind and inhibit PKA-C, was insufficient to suppress PKA activity in GOs because of the overexpression of two PKA-Rs, PRKAR1A and PRKAR2A. We found that neither of them affected PKA activity and induced meiotic resumption in GO although PRKAR2A could inhibit PKA activity and induce meiosis in cAMP-treated full-grown oocytes (FGOs). Finally, we analyzed the subcellular localization of PKA subunits and found that all the subunits were localized in the cytoplasm during meiotic arrest and that PKA-C and PRKAR2A, but not PRKAR1A, entered into the nucleus just before meiotic resumption in FGOs, whereas all of them remained in the cytoplasm in GOs throughout the culture period. Our findings suggest that the continuous high PKA activity is a primary cause of the meiotic incompetence of porcine GOs and that this PKA activity is not simply caused by an insufficient expression level of PKA-R, but can be attributed to more complex spatial-temporal regulation mechanisms. PMID:22674394

  10. Functional responses and molecular mechanisms involved in histone-mediated platelet activation.

    PubMed

    Carestia, A; Rivadeneyra, L; Romaniuk, M A; Fondevila, C; Negrotto, S; Schattner, M

    2013-11-01

    Histones are highly alkaline proteins found in cell nuclei and they can be released by either dying or inflammatory cells. The recent observations that histones are major components of neutrophil extracellular traps and promote platelet aggregation and platelet-dependent thrombin generation have shown that these proteins are potent prothrombotic molecules. Because the mechanism(s) of platelet activation by histones are not completely understood, we explored the ability of individual recombinant human histones H1, H2A, H2B, H3 and H4 to induce platelet activation as well as the possible molecular mechanisms involved. All histones were substrates for platelet adhesion and spreading and triggered fibrinogen binding, aggregation, von Willebrand factor release, P-selectin and phosphatidylserine (PS) exposure and the formation of platelet-leukocyte aggregates; however, H4 was the most potent. Histone-mediated fibrinogen binding, P-selectin and PS exposure and the formation of mixed aggregates were potentiated by thrombin. Histones induced the activation of ERK, Akt, p38 and NFκB. Accordingly, histone-induced platelet activation was significantly impaired by pretreatment of platelets with inhibitors of ERK (U 0126), PI3K/Akt (Ly 294002), p38 (SB 203580) and NFκB (BAY 11-7082 and Ro 106-9920). Preincubation of platelets with either aspirin or dexamethasone markedly decreased fibrinogen binding and the adhesion mediated by histones without affecting P-selectin exposure. Functional platelet responses induced by H3 and H4, but not H1, H2A and H2B, were partially mediated through interaction with Toll-like receptors -2 and -4. Our data identify histones as important triggers of haemostatic and proinflammatory platelet responses, and only haemostatic responses are partially inhibited by anti-inflammatory drugs. PMID:23965842

  11. 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

    2012-12-01

    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. PMID:23108553

  12. Photosynthesis Is Not Involved in the Mechanism of Action of Acifluorfen in Cucumber (Cucumis sativus L.)

    PubMed Central

    Duke, Stephen O.; Kenyon, William H.

    1986-01-01

    The possible role of photosynthesis in the mechanism of action of the herbicide acifluorfen (2-chloro-4-(trifluoromethyl)phenoxy-2-nitrobenzoate; AF) was examined. The sensitivity to AF of cotyledons of cucumber (Cucumis sativus L.) which had been grown under far red light (FR) and white light were compared. FR grown tissues which were photosynthetically imcompetent were hypersensitive to AF under white light and had approximately the same relative response to AF under blue and red light as green, white-light-grown tissues. Ultrastructural damage was apparent in FR-grown, AF-treated tissues within an hour after exposure to white light, with cytoplasmic and plastidic disorganization occurring simultaneously. In cucumber cotyledon tissue which had been greening for various time periods, there was no correlation between photosynthetic capacity and herbicidal efficacy of AF. PSII inhibitors (atrazine and DCMU) and the photophosphorylation inhibitor, tentoxin, had no effect on AF activity. Atrazine did not reduce AF activity at any concentration or light intensity tested, indicating that there is no second, photosynthetic-dependent mechanism of action operating at low AF concentrations or low fluence rates. Carbon dioxide-dependent O2 evolution of intact chloroplasts of spinach (Spinacia oleracea L.) had an AF I50 of 125 micromolar compared to 1000 micromolar for cucumber, whereas AF was much more herbicidally active in tissues of cucumber than of spinach. Differences in activity could not be accounted for by differences in uptake of AF. Our results indicate that there is no photosynthetic involvement in the mechanism of action of AF in cucumber. Images Fig. 2 PMID:16664919

  13. Functional responses and molecular mechanisms involved in histone-mediated platelet activation.

    PubMed

    Carestia, A; Rivadeneyra, L; Romaniuk, M A; Fondevila, C; Negrotto, S; Schattner, M

    2013-11-01

    Histones are highly alkaline proteins found in cell nuclei and they can be released by either dying or inflammatory cells. The recent observations that histones are major components of neutrophil extracellular traps and promote platelet aggregation and platelet-dependent thrombin generation have shown that these proteins are potent prothrombotic molecules. Because the mechanism(s) of platelet activation by histones are not completely understood, we explored the ability of individual recombinant human histones H1, H2A, H2B, H3 and H4 to induce platelet activation as well as the possible molecular mechanisms involved. All histones were substrates for platelet adhesion and spreading and triggered fibrinogen binding, aggregation, von Willebrand factor release, P-selectin and phosphatidylserine (PS) exposure and the formation of platelet-leukocyte aggregates; however, H4 was the most potent. Histone-mediated fibrinogen binding, P-selectin and PS exposure and the formation of mixed aggregates were potentiated by thrombin. Histones induced the activation of ERK, Akt, p38 and NFκB. Accordingly, histone-induced platelet activation was significantly impaired by pretreatment of platelets with inhibitors of ERK (U 0126), PI3K/Akt (Ly 294002), p38 (SB 203580) and NFκB (BAY 11-7082 and Ro 106-9920). Preincubation of platelets with either aspirin or dexamethasone markedly decreased fibrinogen binding and the adhesion mediated by histones without affecting P-selectin exposure. Functional platelet responses induced by H3 and H4, but not H1, H2A and H2B, were partially mediated through interaction with Toll-like receptors -2 and -4. Our data identify histones as important triggers of haemostatic and proinflammatory platelet responses, and only haemostatic responses are partially inhibited by anti-inflammatory drugs.

  14. Photosynthesis Is Not Involved in the Mechanism of Action of Acifluorfen in Cucumber (Cucumis sativus L.).

    PubMed

    Duke, S O; Kenyon, W H

    1986-07-01

    The possible role of photosynthesis in the mechanism of action of the herbicide acifluorfen (2-chloro-4-(trifluoromethyl)phenoxy-2-nitrobenzoate; AF) was examined. The sensitivity to AF of cotyledons of cucumber (Cucumis sativus L.) which had been grown under far red light (FR) and white light were compared. FR grown tissues which were photosynthetically imcompetent were hypersensitive to AF under white light and had approximately the same relative response to AF under blue and red light as green, white-light-grown tissues. Ultrastructural damage was apparent in FR-grown, AF-treated tissues within an hour after exposure to white light, with cytoplasmic and plastidic disorganization occurring simultaneously. In cucumber cotyledon tissue which had been greening for various time periods, there was no correlation between photosynthetic capacity and herbicidal efficacy of AF. PSII inhibitors (atrazine and DCMU) and the photophosphorylation inhibitor, tentoxin, had no effect on AF activity. Atrazine did not reduce AF activity at any concentration or light intensity tested, indicating that there is no second, photosynthetic-dependent mechanism of action operating at low AF concentrations or low fluence rates. Carbon dioxide-dependent O(2) evolution of intact chloroplasts of spinach (Spinacia oleracea L.) had an AF I(50) of 125 micromolar compared to 1000 micromolar for cucumber, whereas AF was much more herbicidally active in tissues of cucumber than of spinach. Differences in activity could not be accounted for by differences in uptake of AF. Our results indicate that there is no photosynthetic involvement in the mechanism of action of AF in cucumber.

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

    PubMed

    Akamatsu, Akira; Shimamoto, Ko; Kawano, Yoji

    2016-08-01

    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

  16. 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

    2012-12-01

    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.

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

    PubMed Central

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

    2012-01-01

    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 Δ9-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 (Ca2+) increase, etc.), on CBD behavioural effects. PMID:23108553

  18. 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

  19. Insights into Reference Point Indentation Involving Human Cortical Bone: Sensitivity to Tissue Anisotropy and Mechanical Behavior

    PubMed Central

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

    2014-01-01

    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 10 N 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 (~ 2 mm × 5 mm × 40 mm) 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 (r2=0.25, p=0.003) and toughness (r2=0.35, p=0

  20. Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection.

    PubMed

    Okada-Ogawa, Akiko; Nakaya, Yuka; Imamura, Yoshiki; Kobayashi, Masayuki; Shinoda, Masamichi; Kita, Kozue; Sessle, Barry J; Iwata, Koichi

    2015-05-01

    In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at

  1. Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection.

    PubMed

    Okada-Ogawa, Akiko; Nakaya, Yuka; Imamura, Yoshiki; Kobayashi, Masayuki; Shinoda, Masamichi; Kita, Kozue; Sessle, Barry J; Iwata, Koichi

    2015-05-01

    In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at

  2. Mechanisms involved in p53 downregulation by leptin in trophoblastic cells.

    PubMed

    Toro, Ayelén Rayen; Pérez-Pérez, Antonio; Corrales Gutiérrez, Isabel; Sánchez-Margalet, Víctor; Varone, Cecilia Laura

    2015-11-01

    Leptin, a 16-kDa polypeptide hormone, is produced by the adipocyte and can also be synthesized by placenta. We previously demonstrated that leptin promotes proliferation and survival in placenta, in part mediated by the p53 pathway. In this work, we investigated the mechanisms involved in leptin down-regulation of p53 level. The human first trimester cytotrophoblastic Swan-71 cell line and human placental explants at term were used. In order to study the late phase of apoptosis, triggered by serum deprivation, experiments of DNA fragmentation were carried out. Exogenous leptin added to human placental explants, showed a decrease on DNA ladder formation and MAPK pathway is involved in this leptin effect. We also found that under serum deprivation condition, leptin decreases p53 levels and the inhibitory leptin effect is lost when cells were pretreated with 50 μM PD98059 or 10 μM LY29004; or were transfected with dominant negative mutants of intermediates of these pathways, suggesting that MAPK and PI3K signaling pathways are necessaries for leptin action. Additionally, leptin diminished Ser-46 p53 phosphorylation and this effect in placental explants was mediated by the activation of MAPK and PI3K pathways. Finally, in order to assess leptin effect on p53 half-life experiments with cycloheximide were performed and MDM-2 expression was analyzed. Leptin diminished p53 half-life and up-regulated MDM-2 expression. In summary, we provided evidence suggesting that leptin anti-apoptotic effect is mediated by MAPK and PI3K pathways.

  3. Mechanisms involved in the selective transfer of long chain polyunsaturated Fatty acids to the fetus.

    PubMed

    Gil-Sánchez, Alfonso; Demmelmair, Hans; Parrilla, J J; Koletzko, Berthold; Larqué, Elvira

    2011-01-01

    The concentration of long chain polyunsaturated fatty acid (LCPUFA) in the fetal brain increases dramatically from the third trimester until 18 months of life. Several studies have shown an association between the percentage of maternal plasma docosahexaenoic acid (DHA) during gestation and development of cognitive functions in the neonate. Since only very low levels of LCPUFA are synthesized in the fetus and placenta, their primary source for the fetus is the maternal circulation. Both in vitro and human in vivo studies using labeled fatty acids have shown preferential transfer of LCPUFA from the placenta to the fetus compared with other fatty acids, although the mechanisms involved are still uncertain. The placenta takes up circulating maternal non-esterified fatty acids (NEFA) and fatty acids released mainly by maternal lipoprotein lipase and endothelial lipase. These NEFA may enter the cell by passive diffusion or by means of membrane carrier proteins. Once in the cytosol, NEFA bind to cytosolic fatty acid-binding proteins for transfer to the fetal circulation or can be oxidized within the trophoblasts, and even re-esterified and stored in lipid droplets. Although trophoblast cells are not specialized for lipid storage, LCPUFA may up-regulate peroxisome proliferator activated receptor-γ (PPARγ) and hence the gene expression of fatty acid transport carriers, fatty acid acyl-CoA-synthetases and adipophilin or other enzymes involved in lipolysis, modifying the rate of placental transfer, and metabolism. The placental transfer of LCPUFA during pregnancy seems to be a key factor in the neurological development of the fetus. Increased knowledge of the factors that modify placental transfer of fatty acids would contribute to our understanding of this complex process. PMID:22303352

  4. 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.

  5. 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

  6. Enzymatic Mechanisms Involved in Phenanthrene Degradation by the White Rot Fungus Pleurotus ostreatus

    PubMed Central

    Bezalel, L.; Hadar, Y.; Cerniglia, C. E.

    1997-01-01

    The enzymatic mechanisms involved in the degradation of phenanthrene by the white rot fungus Pleurotus ostreatus were examined. Phase I metabolism (cytochrome P-450 monooxygenase and epoxide hydrolase) and phase II conjugation (glutathione S-transferase, aryl sulfotransferase, UDP-glucuronosyltransferase, and UDP-glucosyltransferase) enzyme activities were determined for mycelial extracts of P. ostreatus. Cytochrome P-450 was detected in both cytosolic and microsomal fractions at 0.16 and 0.38 nmol min(sup-1) mg of protein(sup1), respectively. Both fractions oxidized [9,10-(sup14)C]phenanthrene to phenanthrene trans-9,10-dihydrodiol. The cytochrome P-450 inhibitors 1-aminobenzotriazole (0.1 mM), SKF-525A (proadifen, 0.1 mM), and carbon monoxide inhibited the cytosolic and microsomal P-450s differently. Cytosolic and microsomal epoxide hydrolase activities, with phenanthrene 9,10-oxide as the substrate, were similar, with specific activities of 0.50 and 0.41 nmol min(sup-1) mg of protein(sup-1), respectively. The epoxide hydrolase inhibitor cyclohexene oxide (5 mM) significantly inhibited the formation of phenanthrene trans-9,10-dihydrodiol in both fractions. The phase II enzyme 1-chloro-2,4-dinitrobenzene glutathione S-transferase was detected in the cytosolic fraction (4.16 nmol min(sup-1) mg of protein(sup-1)), whereas aryl adenosine-3(prm1)-phosphate-5(prm1)-phosphosulfate sulfotransferase (aryl PAPS sulfotransferase) UDP-glucuronosyltransferase, and UDP-glucosyltransferase had microsomal activities of 2.14, 4.25, and 4.21 nmol min(sup-1) mg of protein(sup-1), respectively, with low activity in the cytosolic fraction. However, when P. ostreatus culture broth incubated with phenanthrene was screened for phase II metabolites, no sulfate, glutathione, glucoside, or glucuronide conjugates of phenanthrene metabolites were detected. These experiments indicate the involvement of cytochrome P-450 monooxygenase and epoxide hydrolase in the initial phase I oxidation of

  7. Triskelion Structure of the Gli521 Protein, Involved in the Gliding Mechanism of Mycoplasma mobile▿

    PubMed Central

    Nonaka, Takahiro; Adan-Kubo, Jun; Miyata, Makoto

    2010-01-01

    Mycoplasma mobile binds to solid surfaces and glides smoothly and continuously by a unique mechanism. A huge protein, Gli521 (521 kDa), is involved in the gliding machinery, and it is localized in the cell neck, the base of the membrane protrusion. This protein is thought to have the role of force transmission. In this study, the Gli521 protein was purified from M. mobile cells, and its molecular shape was studied. Gel filtration analysis showed that the isolated Gli521 protein forms mainly a monomer in Tween 80-containing buffer and oligomers in Triton X-100-containing buffer. Rotary shadowing electron microscopy showed that the Gli521 monomer consisted of three parts: an oval, a rod, and a hook. The oval was 15 nm long by 11 nm wide, and the filamentous part composed of the rod and the hook was 106 nm long and 3 nm in diameter. The Gli521 molecules form a trimer, producing a “triskelion” reminiscent of eukaryotic clathrin, through association at the hook end. Image averaging of the central part of the triskelion suggested that there are stable and rigid structures. The binding site of a previously isolated monoclonal antibody on Gli521 images showed that the hook end and oval correspond to the C- and N-terminal regions, respectively. Partial digestion of Gli521 showed that the molecule could be divided into three domains, which we assigned to the oval, rod, and hook of the molecular image. The Gli521 molecule's role in the gliding mechanism is discussed. PMID:19915029

  8. 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

  9. Mechanisms involved in the swelling of erythrocytes caused by Pacific and Caribbean ciguatoxins.

    PubMed

    Sauviat, Martin-Pierre; Boydron-Le Garrec, Raphaële; Masson, Jean-Baptiste; Lewis, Richard L; Vernoux, Jean-Paul; Molgó, Jordi; Laurent, Dominique; Benoit, Evelyne

    2006-01-01

    The mechanisms underlying the swelling of frog red blood cells (RBC), induced by Pacific (P-CTX-1) and Caribbean (C-CTX-1) ciguatoxins (CTXs), were investigated by measuring the length, width and surface of their elliptic shape. P-CTX-1 (0.5 to 5 nM) and C-CTX-1 (1 nM) induced RBC swelling within 60 min. The CTXs-induced RBC swelling was blocked by apamin (1 microM) and by Sr(2+) (1 mM). P-CTX-1-induced RBC swelling was prevented and inhibited by H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (27 microM), an inhibitor of soluble guanylate cyclase (sGC), and NOS blockade by NG methyl-l-arginine (l-NMA; 10 microM). Cytochalasin D (cytD, 10 microM) increased RBC surface and mimicked CTX effect but did not prevent the P-CTX-1-induced l-NMA-sensitive extra increase. Calculations revealed that P-CTX-1 and cytD increase RBC total surface envelop and volume. These data strongly suggest that the molecular mechanisms underlying CTXs-induced RBC swelling involve the NO pathway by an activation of the inducible NOS, leading to sGC activation which modulates intracellular cGMP and regulates L-type Ca(2+) channels. The resulting increase in intracellular Ca(2+) content, in turn, disrupts the actin cytoskeleton, which causes a water influx and triggers a Ca(2+)-activated K(+) current through SK2 isoform channels. PMID:16364667

  10. 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. PMID:26086196

  11. 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.

  12. 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.

  13. Feedback control indirect response models.

    PubMed

    Zhang, Yaping; D'Argenio, David Z

    2016-08-01

    A general framework is introduced for modeling pharmacodynamic processes that are subject to autoregulation, which combines the indirect response (IDR) model approach with methods from classical feedback control of engineered systems. The canonical IDR models are modified to incorporate linear combinations of feedback control terms related to the time course of the difference (the error signal) between the pharmacodynamic response and its basal value. Following the well-established approach of traditional engineering control theory, the proposed feedback control indirect response models incorporate terms proportional to the error signal itself, the integral of the error signal, the derivative of the error signal or combinations thereof. Simulations are presented to illustrate the types of responses produced by the proposed feedback control indirect response model framework, and to illustrate comparisons with other PK/PD modeling approaches incorporating feedback. In addition, four examples from literature are used to illustrate the implementation and applicability of the proposed feedback control framework. The examples reflect each of the four mechanisms of drug action as modeled by each of the four canonical IDR models and include: selective serotonin reuptake inhibitors and extracellular serotonin; histamine H2-receptor antagonists and gastric acid; growth hormone secretagogues and circulating growth hormone; β2-selective adrenergic agonists and potassium. The proposed feedback control indirect response approach may serve as an exploratory modeling tool and may provide a bridge for development of more mechanistic systems pharmacology models. PMID:27394724

  14. Memory improving actions of gabapentin in mice: possible involvement of central muscarinic cholinergic mechanism.

    PubMed

    Boccia, M M; Acosta, G B; Baratti, C M

    2001-10-01

    Male CF-1 mice were tested 48 h after training on a one trial step-through inhibitory avoidance task. Immediately post-training, intraperitoneal (i.p.) injections of the antiepileptic gabapentin (1-(aminomethyl) cyclohexaneacetic acid) (GBP, 10 mg/kg) enhanced retention performance. The effect was prevented by atropine, a central muscarinic cholinergic receptor antagonist (0.5 mg/kg, i.p.) administered after training but 10 min prior to GBP treatment. In contrast, neither methylatropine (0.5 mg/kg, i.p.), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training GBP on retention performance. Low subeffective doses of the central acting anticholinesterase physostigmine (35 mg/kg, i.p.) administered immediately after training, and GBP (5 mg/kg, i.p.), given 10 min after training, significantly enhanced retention performance. The effects of GBP (5 mg/kg, i.p.) were not influenced by the peripherally acting anticholinesterase neostigmine (150 mg/kg, i.p.). Considered together, these findings suggest a disinhibitory action of GBP on the activity of central muscarinic cholinergic mechanisms that are involved in memory consolidation. PMID:11578817

  15. Mechanisms involved in spinal cord central synapse loss in a mouse model of spinal muscular atrophy.

    PubMed

    Tarabal, Olga; Caraballo-Miralles, Víctor; Cardona-Rossinyol, Andrea; Correa, Francisco J; Olmos, Gabriel; Lladó, Jerònia; Esquerda, Josep E; Calderó, Jordi

    2014-06-01

    Motoneuron (MN) cell death is the histopathologic hallmark of spinal muscular atrophy (SMA), although MN loss seems to be a late event. Conversely, disruption of afferent synapses on MNs has been shown to occur early in SMA. Using a mouse model of severe SMA (SMNΔ7), we examined the mechanisms involved in impairment of central synapses. We found that MNs underwent progressive degeneration in the course of SMA, with MN loss still occurring at late stages. Loss of afferent inputs to SMA MNs was detected at embryonic stages, long before MN death. Reactive microgliosis and astrogliosis were present in the spinal cord of diseased animals after the onset of MN loss. Ultrastructural observations indicate that dendrites and microglia phagocytose adjacent degenerating presynaptic terminals. Neuronal nitric oxide synthase was upregulated in SMNΔ7 MNs, and there was an increase in phosphorylated myosin light chain expression in synaptic afferents on MNs; these observations implicate nitric oxide in MN deafferentation and suggest that the RhoA/ROCK pathway is activated. Together, our observations suggest that the earliest change occurring in SMNΔ7 mice is the loss of excitatory glutamatergic synaptic inputs to MNs; reduced excitability may enhance their vulnerability to degeneration and death.

  16. Visfatin is involved in promotion of colorectal carcinoma malignancy through an inducing EMT mechanism.

    PubMed

    Yang, Jing; Zhang, Kun; Song, Haixing; Wu, Mingbo; Li, Jingyi; Yong, Ziyi; Jiang, Sheng; Kuang, Xi; Zhang, Tao

    2016-05-31

    Increasing evidences suggested visfatin, a newly discovered obesity-induced adipocytokine, is involved in promotion of cancer malignancy and correlated with worse clinical prognosis. While its effects and mechanisms on progression of colorectal cancer (CRC) remain unclear. Our clinical data show that visfatin protein is over expressed, positive associated with lymph node metastasis, high-grade tumor, and poor prognosis in 87 CRC patients. The levels of plasma visfatin are significantly upregulated in Stage IV colon cancer. Visfatin can significantly promote the in vitro migration and invasion of CRC cells via induction epithelial mesenchymal transition (EMT). It can increase the expression and nuclear translocation of Snail, a key transcription factor in regulating EMT. While silencing of Snail attenuates visfatin induced EMT. Further studies reveal visfatin can inhibit the association of Snail with GSK-3β and subsequently suppress ubiquitylation of Snail. In addition, visfatin can increase the expression and nuclear translocation of β-catenin, elevate its binding with Snail promoter, and then increase the transcription of Snail. While inhibitor of PI3K/Akt, LY294002, abolishes visfatin induced up regulation of Snail, Vimentin (Vim), β-catenin, and phosphorylated GSK-3β. In summary, our data suggest that increased expression of visfatin are associated with a more aggressive phenotype of CRC patients. It can trigger the EMT of CRC cells via Akt/GSK-3β/β-catenin signals.

  17. Identification of plant genetic loci involved in a posttranscriptional mechanism for meiotically reversible transgene silencing.

    PubMed Central

    Dehio, C; Schell, J

    1994-01-01

    Numerous reports describe phenomena of transgene silencing in plants, yet the underlying genetic and molecular mechanisms are poorly understood. We observed that regeneration of Arabidopsis thaliana plants transgenic for the rolB gene of Agrobacterium rhizogenes results in a selection for transgene silencing. Transgene silencing could be monitored in this system by reversion of the visible RolB phenotype. We report a phenotypic, molecular, and genetic characterization of a meiotically reversible transgene silencing phenomenon observed in a rolB transgenic line. In this line, the rolB gene is expressed strongly and uniformly in seedlings, but in the course of further development, the rolB gene is silenced erratically at a frequency that depends on the dosage of rolB. The silenced state is mitotically stable, while complete resetting of rolB gene expression occurs in seedlings of the following generation. The silencing of rolB correlates with a dramatic reduction of steady-state rolB transcripts, while rolB nuclear run-off transcripts are only moderately reduced. Therefore, rolB gene silencing seems to act predominantly at the posttranscriptional level. The process of rolB gene silencing was found to be affected by two extragenic modifier loci that influence both the frequency and the timing of rolB gene silencing during plant development. These genetic data demonstrate a direct involvement of defined plant genes in this form of gene silencing. Images PMID:8202523

  18. Molecular Mechanisms Involved in the Pathogenesis of Alphavirus-Induced Arthritis

    PubMed Central

    Assunção-Miranda, Iranaia; 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. PMID:24069610

  19. Molecular and cellular mechanisms involved in Helicobacter pylori-induced inflammation and oxidative stress.

    PubMed

    Naito, Yuji; Yoshikawa, Toshikazu

    2002-08-01

    Helicobacter pylori (H. pylori)-infection leads to different clinical and pathological outcomes in humans, including chronic gastritis, peptic ulcer disease, and gastric neoplasia. The key determinants of these outcomes are the severity and distribution of the H. pylori-induced inflammation. Antral-type gastritis is associated with excessive acid secretion and a high risk of duodenal ulcer. In contrast, gastritis that involves the acid-secreting corpus region leads to hypochlorhydria, progressive gastric atrophy, and an increased risk of gastric cancer. The key pathophysiological event in H. pylori infection is initiation and continuance of an inflammatory response. Bacteria or their products trigger this inflammatory process and the main mediators are cytokines. Identification of both host- and bacterial-factors that mediate is an intense area of interest in current researches. Recent data indicates that the cag pathogenicity island plays a crucial role in H. pylori-induced gastric inflammation via the activation of gene transcription. It has been demonstrated that oxidative and nitrosative stress associated with inflammation plays an important role in gastric carcinogenesis as a mediator of carcinogenic compound formation, DNA damage, and cell proliferation. Genetic information regulating such stress would be one of the host factors determining the outcome--particularly when the outcome is gastric cancer--of H. pylori infection, and the compound that attenuates such stress may be a candidate for use in chemoprevention. This review highlights recent advances in understanding of the mechanisms underlying chronic inflammation following infection with H. pylori.

  20. Memory improving actions of gabapentin in mice: possible involvement of central muscarinic cholinergic mechanism.

    PubMed

    Boccia, M M; Acosta, G B; Baratti, C M

    2001-10-01

    Male CF-1 mice were tested 48 h after training on a one trial step-through inhibitory avoidance task. Immediately post-training, intraperitoneal (i.p.) injections of the antiepileptic gabapentin (1-(aminomethyl) cyclohexaneacetic acid) (GBP, 10 mg/kg) enhanced retention performance. The effect was prevented by atropine, a central muscarinic cholinergic receptor antagonist (0.5 mg/kg, i.p.) administered after training but 10 min prior to GBP treatment. In contrast, neither methylatropine (0.5 mg/kg, i.p.), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training GBP on retention performance. Low subeffective doses of the central acting anticholinesterase physostigmine (35 mg/kg, i.p.) administered immediately after training, and GBP (5 mg/kg, i.p.), given 10 min after training, significantly enhanced retention performance. The effects of GBP (5 mg/kg, i.p.) were not influenced by the peripherally acting anticholinesterase neostigmine (150 mg/kg, i.p.). Considered together, these findings suggest a disinhibitory action of GBP on the activity of central muscarinic cholinergic mechanisms that are involved in memory consolidation.

  1. Molecular mechanisms involved in muscle wasting in cancer and ageing: cachexia versus sarcopenia.

    PubMed

    Argilés, Josep M; Busquets, Sílvia; Felipe, Antonio; López-Soriano, Francisco J

    2005-05-01

    The aim of the present review is to summarize and evaluate the different mechanisms and catabolic mediators involved in cancer cachexia and ageing sarcopenia since they may represent targets for future promising clinical investigations. Cancer cachexia is a syndrome characterized by a marked weight loss, anorexia, asthenia and anemia. In fact, many patients who die with advanced cancer suffer from cachexia. The degree of cachexia is inversely correlated with the survival time of the patient and it always implies a poor prognosis. Unfortunately, at the clinical level, cachexia is not treated until the patient suffers from a considerable weight loss and wasting. At this point, the cachectic syndrome is almost irreversible. The cachectic state is often associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia. In recent years, age-related diseases and disabilities have become of major health interest and importance. This holds particularly for muscle wasting, also known as sarcopenia, that decreases the quality of life of the geriatric population, increasing morbidity and decreasing life expectancy. The cachectic factors (associated with both depletion of fat stores and muscular tissue) can be divided into two categories: of tumour origin and humoural factors. In conclusion, more research should be devoted to the understanding of muscle wasting mediators, both in cancer and ageing, in particular the identification of common mediators may prove as a good therapeutic strategies for both prevention and treatment of wasting both in disease and during healthy ageing.

  2. 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

  3. 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

  4. Molecular mechanisms of hormone-mediated Müllerian duct regression: involvement of beta-catenin.

    PubMed

    Allard, S; Adin, P; Gouédard, L; di Clemente, N; Josso, N; Orgebin-Crist, M C; Picard, J Y; Xavier, F

    2000-08-01

    Regression of the Müllerian duct in the male embryo is one unequivocal effect of anti-Müllerian hormone, a glycoprotein secreted by the Sertoli cells of the testis. This hormone induces ductal epithelial regression through a paracrine mechanism originating in periductal mesenchyme. To probe the mechanisms of action of anti-Müllerian hormone, we have studied the sequence of cellular and molecular events involved in duct regression. Studies were performed in male rat embryos and in transgenic mice overexpressing or lacking anti-Müllerian hormone, both in vivo and in vitro. Anti-Müllerian hormone causes regression of the cranial part of the Müllerian duct whereas it continues to grow caudally. Our work shows that this pattern of regression is correlated with a cranial to caudal gradient of anti-Müllerian hormone receptor protein, followed by a wave of apoptosis spreading along the Müllerian duct as its progresses caudally. Apoptosis is also induced by AMH in female Müllerian duct in vitro. Furthermore, apoptotic indexes are increased in Müllerian epithelium of transgenic mice of both sexes overexpressing the human anti-Müllerian hormone gene, exhibiting a positive correlation with serum hormone concentration. Inversely, apoptosis is reduced in male anti-Müllerian hormone-deficient mice. We also show that apoptosis is a decisive but not sufficient process, and that epitheliomesenchymal transformation is an important event of Müllerian regression. The most striking result of this study is that anti-Müllerian hormone action in peri-Müllerian mesenchyme leads in vivo and in vitro to an accumulation of cytoplasmic beta-catenin. The co-localization of beta-catenin with lymphoid enhancer factor 1 in the nucleus of peri-Müllerian mesenchymal cells, demonstrated in primary culture, suggests that overexpressed beta-catenin in association with lymphoid enhancer factor 1 may alter transcription of target genes and may lead to changes in mesenchymal gene expression

  5. 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

  6. Involvement of histaminergic receptor mechanisms in the stimulation of NT-3 synthesis in astrocytes.

    PubMed

    Jurič, Damijana M; Mele, Tina; Carman-Kržan, Marija

    2011-06-01

    Neurotrophin-3 (NT-3) is produced by astrocytes, in addition to neurons, and monoamine neurotransmitters play a role in controlling NT-3 synthesis. The impact of histamine (HA) on the regulation of NT-3 synthesis in cultured astrocytes has not been studied. We evaluated the involvement of histamine receptors and intracellular mechanisms in the regulation of NT-3 production by HA. Real-time PCR was performed to examine the expression of all known histamine receptor subtypes in cultured rat cortical astrocytes. Pharmacological tools, selective for the H₁, H₂ and H₃ receptors and intracellular systems, were utilized to confirm functional properties of HA receptors in histaminergic up-regulation of astrocytic NT-3 synthesis. HA potently and transiently elevated NT-3 expression and protein levels by more than twofold. In addition to H₁ and H₂ receptors, cultured astrocytes also express H₃ receptors, which activate G(i/o) proteins to inhibit adenylyl cyclase and modulate MAP kinase activity. Histaminergic stimulation was partly inhibited by selective H₁, H₂, and H₃ antagonists whereas selective H₁, H₂, and H₃ agonists or mediators of the intracellular histaminergic pathways increased NT-3 levels. Inhibitors of PKA, PKC, and CaMK II significantly reduced the HA-induced increase in NT-3 cellular levels whereas the MAP kinase cascade inhibitor completely blocked the stimulatory action of HA and all selective agonists. In conclusion, the synthesis of astrocytic NT-3 stimulated by HA is a receptor-mediated process, which is fine-tuned via subtle modulation of parallel histaminergic H₁, H₂, and H₃ pathways that converge at the level of MAP kinase activity. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

  7. Memory-improving actions of glucose: involvement of a central cholinergic muscarinic mechanism.

    PubMed

    Kopf, S R; Baratti, C M

    1994-11-01

    Post-training intraperitoneal administration of alpha-D[+]-glucose (10-300 mg/kg) facilitated 24-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. The dose-response curve was an inverted U. Glucose did not increase the retention latencies of mice that had not received a footshock during training. The effect of glucose (30 mg/kg, ip) on retention was time-dependent, which suggests that the drug facilitated memory storage. The memory facilitation induced by glucose (30 mg/kg, ip) was prevented by atropine (0.5 mg/kg, ip) administered after training, but 10 min prior to glucose treatment. In contrast, neither methylatropine (0.5 mg/kg, ip), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, ip) or hexamethonium (5 mg/kg, ip), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training glucose on retention. Low subeffective doses of the central acting anticholinesterase physostigmine (35 micrograms/kg, ip), administered immediately after training, and glucose (10 mg/kg, ip), given 10 min after training, acted synergistically to improve retention. The effects of glucose (10 mg/kg, ip) were not influenced by the peripherally acting anticholinesterase neostigmine (35 micrograms/kg, ip). Considered together, these findings suggest that the memory facilitation induced by post-training administration of glucose could result from an enhancement of brain acetylcholine synthesis and/or its release that, in turn, might modulate the activity of muscarinic cholinergic mechanisms that are critically involved in memory storage. PMID:7857246

  8. Memory-improving actions of glucose: involvement of a central cholinergic muscarinic mechanism.

    PubMed

    Kopf, S R; Baratti, C M

    1994-11-01

    Post-training intraperitoneal administration of alpha-D[+]-glucose (10-300 mg/kg) facilitated 24-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. The dose-response curve was an inverted U. Glucose did not increase the retention latencies of mice that had not received a footshock during training. The effect of glucose (30 mg/kg, ip) on retention was time-dependent, which suggests that the drug facilitated memory storage. The memory facilitation induced by glucose (30 mg/kg, ip) was prevented by atropine (0.5 mg/kg, ip) administered after training, but 10 min prior to glucose treatment. In contrast, neither methylatropine (0.5 mg/kg, ip), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, ip) or hexamethonium (5 mg/kg, ip), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training glucose on retention. Low subeffective doses of the central acting anticholinesterase physostigmine (35 micrograms/kg, ip), administered immediately after training, and glucose (10 mg/kg, ip), given 10 min after training, acted synergistically to improve retention. The effects of glucose (10 mg/kg, ip) were not influenced by the peripherally acting anticholinesterase neostigmine (35 micrograms/kg, ip). Considered together, these findings suggest that the memory facilitation induced by post-training administration of glucose could result from an enhancement of brain acetylcholine synthesis and/or its release that, in turn, might modulate the activity of muscarinic cholinergic mechanisms that are critically involved in memory storage.

  9. An indirect approach to imply trade-off shapes: population level patterns in resistance suggest a decreasingly costly resistance mechanism in a model insect system.

    PubMed

    Mealor, M A; Boots, M

    2006-03-01

    Trade-offs between life history and other traits play a key role in shaping the evolution of individuals. It is well established theoretically that the shapes of trade-off curves are as crucial to the evolutionary outcome as their strengths. However, measuring the shape of these relationships directly is often impractical. Here we use an indirect approach that examines the patterns seen within a population and then use theory to infer the shape of the trade-off curve. Using a bioassay we found that most individuals had either high susceptibility or relatively high resistance to a microparasite in a lepidopteran host population. According to general theory, this type of pattern in resistance would be most likely with a deceleratingly costly impact on fitness of increasing resistance. The implications and generality of the approach are discussed, along with the implications of the results to our understanding of the nature of innate resistance to parasites.

  10. Involvement of lignin and hormones in the response of woody poplar taproots to mechanical stress.

    PubMed

    Trupiano, Dalila; Di Iorio, Antonino; Montagnoli, Antonio; Lasserre, Bruno; Rocco, Mariapina; Grosso, Alessandro; Scaloni, Andrea; Marra, Mauro; Chiatante, Donato; Scippa, Gabriella S

    2012-09-01

    Mechanical stress is a widespread condition caused by numerous environmental factors that severely affect plant stability. In response to mechanical stress, plants have evolved complex response pathways able to detect mechanical perturbations and inducing a suite of modifications in order to improve anchorage. The response of woody roots to mechanical stresses has been studied mainly at the morphological and biomechanical level, whereas investigations on the factors triggering these important alterations are still at the initial stage. Populus has been widely used to study the response of stem to different mechanical stresses and, since it has the first forest tree genome to be decoded, represents a model woody plant for addressing questions on the mechanisms controlling adaptation of woody roots to changing environments. In this study, a morphological and physiological analysis was used to investigate factors controlling modifications in Populus nigra woody taproots subjected to mechanical stress. An experimental model analyzing spatial and temporal mechanical force distribution along the woody taproot axis enabled us to compare the events occurring in its above-, central- and below-bending sectors. Different morphogenetic responses and local variations of lignin and plant hormones content have been observed, and a relation with the distribution of the mechanical forces along the stressed woody taproots is hypothesized. We investigated the differences of the response to mechanical stress induction during the time; in this regard, we present data referring to the effect of mechanical stress on plant transition from its condition of winter dormancy to that of full vegetative activity.

  11. 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

  12. Indirect composite resin materials for posterior applications.

    PubMed

    Shellard, E; Duke, E S

    1999-12-01

    Indirect composite resin restorations were introduced a number of years ago as possible alternatives to traditional metallic or ceramic-based indirect restorations. However, the earlier formulations did not provide evidence of improvement in mechanical and physical properties over chairside-placed direct composite resin materials. Because they required more tooth structure removal than direct restorations, their use became unpopular and was abandoned by most clinicians. Over the past few years, a new class of composite resin indirect materials has surfaced in the profession. Various technologies have been suggested as reinforcement mechanisms. Fibers, matrix modifications, and an assortment of innovations have been proposed for enhancing indirect composite resin restorations. Applications are from inlay restorations all the way to multi-unit fixed prostheses. This manuscript summarizes some of the progress made in this area. When available, data is presented to provide clinicians with guidelines and indications for the use of these materials.

  13. 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.; Marina, Alberto

    2016-01-01

    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

  14. 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.

  15. Indirect airway challenges.

    PubMed

    Joos, G F; O'Connor, B; Anderson, S D; Chung, F; Cockcroft, D W; Dahlén, B; DiMaria, G; Foresi, A; Hargreave, F E; Holgate, S T; Inman, M; Lötvall, J; Magnussen, H; Polosa, R; Postma, D S; Riedler, J

    2003-06-01

    Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle. Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving. Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.

  16. 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. PMID:26923153

  17. 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

  18. Swarming mechanisms in the yellow fever mosquito: aggregation pheromones involved in the mating behavior of Aedes aegypti

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  19. 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.

  20. 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.

  1. 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.

  2. 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…

  3. 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.

  4. Evaluation of forcefields for molecular mechanics/dynamics calculations involving halogenated anesthetics.

    PubMed

    Trudell, J R; Bertaccini, E

    1998-11-23

    (1) Successful application of molecular mechanics and molecular dynamics calculations to the binding of halogenated anesthetics requires forcefields with correct parameters for halocarbons. (2) Unfortunately, our survey of six popular forcefields revealed that some of them provide a very poor representation of electrostatic interactions for the halogens. (3) This problem is due to poor or missing assignments of partial atomic charges to the halogen atoms. (4) We describe the forcefields most appropriate for use with halogenated anesthetics and suggest a general method for editing the assignment of partial atomic charges by performing an initial quantum mechanics calculation. PMID:10049174

  5. Tibolone protects astrocytic cells from glucose deprivation through a mechanism involving estrogen receptor beta and the upregulation of neuroglobin expression.

    PubMed

    Avila-Rodriguez, Marco; Garcia-Segura, Luis Miguel; Hidalgo-Lanussa, Oscar; Baez, Eliana; Gonzalez, Janneth; Barreto, George E

    2016-09-15

    Tibolone, a synthetic steroid used for the prevention of osteoporosis and the treatment of climacteric symptoms in post-menopausal women, may exert tissue selective estrogenic actions acting on estrogen receptors (ERs). We previously showed that tibolone protects human T98G astroglial cells against glucose deprivation (GD). In this study we have explored whether the protective effect of tibolone on these cells is mediated by ERs. Experimental studies showed that both ERα and ERβ were involved in the protection by tibolone on GD cells, being ERβ preferentially involved on these actions over ERα. Tibolone increased viability of GD cells by a mechanism fully blocked by an ERβ antagonist and partially blocked by an ERα antagonist. Furthermore, ERβ inhibition prevented the effect of tibolone on nuclear fragmentation, ROS and mitochondrial membrane potential in GD cells. The protective effect of tibolone was mediated by neuroglobin. Tibolone upregulated neuroglobin in T98G cells and primary mouse astrocytes by a mechanism involving ERβ and neuroglobin silencing prevented the protective action of tibolone on GD cells. In summary, tibolone protects T98G cells by a mechanism involving ERβ and the upregulation of neuroglobin. PMID:27250720

  6. 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

  7. Biodegradation of endocrine-disrupting compounds by ligninolytic fungi: mechanisms involved in the degradation.

    PubMed

    Cajthaml, Tomáš

    2015-12-01

    Without any doubt, endocrine-disrupting compounds (EDCs) represent an environmental risk for wildlife and human beings. Endocrine-disrupting effects were found for many chemicals in products for personal use, industrial compounds and even in classical persistent organic pollutants (POPs). In order to understand the fate of EDCs in the environment, it is highly important to identify and to clarify the biodegradation mechanisms that can lead to their decomposition. Ligninolytic fungi (LF) are interesting microorganisms that are capable of participating in a variety of versatile decomposition mechanisms. The microorganisms represent a useful model group and, moreover, LF or their enzymes can be actively used for decontamination. Potential optimization of the decontamination process provides another important reason why it is necessary for understanding the mechanisms of EDC transformation. This minireview summarizes current knowledge about the LF biodegradation mechanisms of the most important micropollutants (xenoestrogens), including nonylphenols, bisphenol A and 17α-ethinylestradiol and polychlorinated biphenyls as POPs with endocrine-disrupting potency. Generally, LF exhibit the ability to either polymerize the target pollutants or to substantially decompose the original structure using ligninolytic enzymes and cytochrome P-450. Moreover, most of the transformation processes are accompanied by reduction of the endocrine-disrupting activity or ecotoxicity. PMID:24650234

  8. Biodegradation of endocrine-disrupting compounds by ligninolytic fungi: mechanisms involved in the degradation.

    PubMed

    Cajthaml, Tomáš

    2015-12-01

    Without any doubt, endocrine-disrupting compounds (EDCs) represent an environmental risk for wildlife and human beings. Endocrine-disrupting effects were found for many chemicals in products for personal use, industrial compounds and even in classical persistent organic pollutants (POPs). In order to understand the fate of EDCs in the environment, it is highly important to identify and to clarify the biodegradation mechanisms that can lead to their decomposition. Ligninolytic fungi (LF) are interesting microorganisms that are capable of participating in a variety of versatile decomposition mechanisms. The microorganisms represent a useful model group and, moreover, LF or their enzymes can be actively used for decontamination. Potential optimization of the decontamination process provides another important reason why it is necessary for understanding the mechanisms of EDC transformation. This minireview summarizes current knowledge about the LF biodegradation mechanisms of the most important micropollutants (xenoestrogens), including nonylphenols, bisphenol A and 17α-ethinylestradiol and polychlorinated biphenyls as POPs with endocrine-disrupting potency. Generally, LF exhibit the ability to either polymerize the target pollutants or to substantially decompose the original structure using ligninolytic enzymes and cytochrome P-450. Moreover, most of the transformation processes are accompanied by reduction of the endocrine-disrupting activity or ecotoxicity.

  9. A moving image of flagella: news and views on the mechanisms involved in axonemal beating.

    PubMed

    Cosson, J

    1996-02-01

    Beating of cilia and flagellae allows movement of the fluid surrounding isolated cells (for example: protists) or epithelia (bronchial tissue) but is also responsible for the movement of unicellular organisms in this medium (such as spermatozoa or protists). This paper aims to describe: (1) the biochemical and structural elements of the '9 + 2' structure called the axoneme; (2) the mechanisms of wave generation and propagation along the axoneme of cilia and flagellae are then described, stating that in most models of wave propagation, a clear distinction is made between the dynein-dependent microtubule sliding which represents the oscillatory motor and the bending mechanism which regulates wave propagation. In current models, the bending propagation is supported by a bind/relax cyclic mechanism which propagates in register, but frame-shifted, with the powering action of the dynein motor along the axoneme. While a large amount of knowledge was accumulated about the motor, little is known about the resisting elements regulating the bending. (3) The present study also puts forward ideas as to how these organelles have been highly conserved throughout eucaryotic evolution, and concludes with suggestions for further fields of investigation into this unique mechanical device used for cell movement.

  10. 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

  11. 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.

  12. 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

  13. The global allostery model of hemoglobin: an allosteric mechanism involving homotropic and heterotropic interactions.

    PubMed

    Yonetani, Takashi; Tsuneshige, Antonio

    2003-06-01

    Studies of the allosteric mechanism of hemoglobin (Hb) have evolved from phenomenological descriptions to structure-based molecular mechanisms, as the molecular structures of Hb in deoxy and ligated states have been elucidated. The MWC two-state concerted model has been the widely accepted as the most plausible of the allosteric mechanisms of Hb. It assumes that the O2-affinity of Hb is regulated/controlled primarily by the T/R quaternary structural transition and that heterotropic effectors bind preferentially to T (deoxy) Hb to shift the T/R allosteric equilibrium toward the T state. However, recent more comprehensive O2-binding measurements of Hb have revealed a new mechanism, the Global Allostery model. It describes that the O2-affinity and the cooperativity are modulated in greater extents and the Bohr effect is generated primarily by the tertiary structural changes in both T (deoxy) and R (ligated) states of Hb. Differential interactions of heterotropic allosteric effectors with both T (deoxy) and R (ligated) states of Hb induce these tertiary structural changes. The X-ray structure of a complex of R (ligated) Hb with BZF, a potent heterotropic effector, has revealed the stereo-chemical influence of these effectors on the structure of R (ligated) Hb, resulting in the reduction of the ligand affinity in R (ligated) Hb. This model stresses the fundamental importance of the heterotropic interactions in regulation/control of the functionality of Hb. They alter the tertiary structures of both T (deoxy) and R (oxy) Hb, leading to large-scale modulations of the O2 affinity (KT and KR), and consequently the cooperativity (KR/KT) and the Bohr effect (delta P50/delta pH) from a global viewpoint of allostery in Hb.

  14. 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

  15. Goshajinkigan reduces bortezomib-induced mechanical allodynia in rats: Possible involvement of kappa opioid receptor.

    PubMed

    Higuchi, Hitomi; Yamamoto, Shota; Ushio, Soichiro; Kawashiri, Takehiro; Egashira, Nobuaki

    2015-11-01

    In the present study, we investigated the effect of a Kampo medicine Goshajinkigan (GJG) on the bortezomib-induced mechanical allodynia in von Frey test in rats. The single administration of tramadol (10 mg/kg), GJG (1.0 g/kg) and its component processed Aconiti tuber (0.1 g/kg) significantly reversed the reduction in withdrawal threshold by bortezomib. These effects were abolished by the intrathecal injection of nor-binaltorphimine (10 μg/body), kappa opioid receptor antagonist. These findings suggest that kappa opioid receptor is involved in the effect of GJG on the bortezomib-induced mechanical allodynia.

  16. Direct and indirect inversions

    NASA Astrophysics Data System (ADS)

    Virieux, Jean; Brossier, Romain; Métivier, Ludovic; Operto, Stéphane; Ribodetti, Alessandra

    2016-06-01

    A bridge is highlighted between the direct inversion and the indirect inversion. They are based on fundamental different approaches: one is looking after a projection from the data space to the model space while the other one is reducing a misfit between observed data and synthetic data obtained from a given model. However, it is possible to obtain similar structures for model perturbation, and we shall focus on P-wave velocity reconstruction. This bridge is built up through the Born approximation linearizing the forward problem with respect to model perturbation and through asymptotic approximations of the Green functions of the wave propagation equation. We first describe the direct inversion and its ingredients and then we focus on a specific misfit function design leading to a indirect inversion. Finally, we shall compare this indirect inversion with more standard least-squares inversion as the FWI, enabling the focus on small weak velocity perturbations on one side and the speed-up of the velocity perturbation reconstruction on the other side. This bridge has been proposed by the group led by Raul Madariaga in the early nineties, emphasizing his leading role in efficient imaging workflows for seismic velocity reconstruction, a drastic requirement at that time.

  17. Molecular mechanisms involved in secretory vesicle recruitment to the plasma membrane in beta-cells.

    PubMed

    Varadi, Aniko; Ainscow, E K; Allan, V J; Rutter, G A

    2002-04-01

    Glucose stimulates the release of insulin in part by activating the recruitment of secretory vesicles to the cell surface. While this movement is known to be microtubule-dependent, the molecular motors involved are undefined. Active kinesin was found to be essential for vesicle translocation in live beta-cells, since microinjection of cDNA encoding dominant-negative KHC(mut) (motor domain of kinesin heavy chain containing a Thr(93)-->Asn point mutation) blocked vesicular movements. Moreover, expression of KHC(mut) strongly inhibited the sustained, but not acute, stimulation of secretion by glucose. Thus, vesicles released during the first phase of insulin secretion exist largely within a translocation-independent pool. Kinesin-driven anterograde movement of vesicles is then necessary for the sustained (second phase) of insulin release. Kinesin may, therefore, represent a novel target for increases in intracellular ATP concentrations in response to elevated extracellular glucose and may be involved in the ATP-sensitive K+channel-independent stimulation of secretion by the sugar.

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. 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)

  4. 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

  5. Involvement of reactive oxygen species in the mechanisms associated with cervical cancer specific treatment.

    PubMed

    Marinescu, S; Anghel, R; Gruia, M I; Beuran, M

    2014-01-01

    Cervical cancer represents a genuine health issue in Romania.The courses of treatment applied are complex, and the accompanying biochemical mechanisms are yet to be fully understood. Thus, radiotherapy, which induces reactive oxygen species, can lead to failure of treatment in hypoxic tissues,tissues which are difficult to identify due to the small quantity in which these cytotoxic species are produced. As a result, the aim of this paper is to identify the production and role of reactive oxygen species, as well as the manner of activation of endogenous antioxidant defense mechanisms in cervical cancer patients admitted to the Oncologic Institute of Bucharest. To this purpose the biochemical parameters of oxidative stress were identified in 30 patients with cervical tumour localization, prior to surgery. The results obtained have showed that a production of reactive oxygen species is identifiable in these patients, having lipids as a primary target and leading to their peroxidation. The extension of protein oxidative degradation takes place at a much lower value, as well as the activation of endogenous antioxidant defence systems, comparing to our expectations. To conclude,we consider that when the production of active oxygen metabolites takes place in small concentrations, associated with hypoxia, the signals transmitted are towards modifying the phenotype under anaerobic conditions into one activating neo vascularization, angiogenesis initiation, new cell growth and proliferation. The moment that this phase is overcome anew oxidative stress is installed, one potentially destructive for biomolecules essential to life, but also useful for further treatment, such as radiotherapy.

  6. 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.

  7. 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

    2016-02-01

    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. PMID:26712379

  8. Activity-Dependent Dendritic Spine Shrinkage and Growth Involve Downregulation of Cofilin via Distinct Mechanisms

    PubMed Central

    Calabrese, Barbara; Saffin, Jean-Michel; Halpain, Shelley

    2014-01-01

    A current model posits that cofilin-dependent actin severing negatively impacts dendritic spine volume. Studies suggested that increased cofilin activity underlies activity-dependent spine shrinkage, and that reduced cofilin activity induces activity-dependent spine growth. We suggest instead that both types of structural plasticity correlate with decreased cofilin activity. However, the mechanism of inhibition determines the outcome for spine morphology. RNAi in rat hippocampal cultures demonstrates that cofilin is essential for normal spine maintenance. Cofilin-F-actin binding and filament barbed-end production decrease during the early phase of activity-dependent spine shrinkage; cofilin concentration also decreases. Inhibition of the cathepsin B/L family of proteases prevents both cofilin loss and spine shrinkage. Conversely, during activity-dependent spine growth, LIM kinase stimulates cofilin phosphorylation, which activates phospholipase D-1 to promote actin polymerization. These results implicate novel molecular mechanisms and prompt a revision of the current model for how cofilin functions in activity-dependent structural plasticity. PMID:24740405

  9. 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.

  10. 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

  11. 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.

  12. Successful retrieval of competing spatial environments in humans involves hippocampal pattern separation mechanisms.

    PubMed

    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. PMID:26613414

  13. Facilitation of memory processing by posttrial morphine: possible involvement of reinforcement mechanisms?

    PubMed

    Mondadori, C; Waser, P G

    1979-06-21

    Posttrial administration of 40 mg/kg and 100 mg/kg, but not of 1 mg/kg, of morphine hydrochloride facilitates learning of a one-trial passive avoidance task in drug-naive mice. The effect does not depend on the punishing properties of the morphine injection, since in injection of LiCl (a strong punisher) fails to enhance learning in a similar way. After the establishment of tolerance by several morphone administrations, the 100 mg/kg, but not the 40 mg/kg, dose level resulted in memory facilitation. The data are discussed in connection with the hypothesis that morphine acts directly on reinforcement mechanisms by activating the opiate receptor. PMID:113818

  14. 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

  15. Biochemistry and therapeutic implications of mechanisms involved in FOXP3 activity in immune suppression.

    PubMed

    Li, Bin; Saouaf, Sandra J; Samanta, Arabinda; Shen, Yuan; Hancock, Wayne W; Greene, Mark I

    2007-10-01

    While mutations in human FOXP3 predispose individuals to autoimmune conditions, it is unclear how the mutant protein fails to function as a transcriptional regulator. There is also limited detail of how FOXP3 itself interacts with the transcriptional machinery and which components of the FOXP3 ensembles exert phenotypic changes to render cells able to mediate suppression. Increasing evidence indicates that the level and duration of FOXP3 expression plays a crucial role in the development and function of natural regulatory T cells (Tregs). Our studies focus on the post-translational modification of the FOXP3 protein, and how the FOXP3 complex ensemble, containing histone modification and chromatin-remodeling enzymes, defines its functional role in regulatory T cells. Understanding the molecular mechanisms underlying FOXP3 activity will provide therapeutic implications for transplantation, allergy, autoimmune disease and cancer. PMID:17703930

  16. 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.

  17. Breast cancer: mechanisms involved in action of phytoestrogens and epigenetic changes.

    PubMed

    Dagdemir, Aslihan; Durif, Julie; Ngollo, Marjolaine; Bignon, Yves-Jean; Bernard-Gallon, Dominique

    2013-01-01

    In this review, we consider phytoestrogens and different epigenetic modifications in breast cancer. Epigenetic phenomena are mediated by several molecular mechanisms comprising histone modifications, small non-coding or anti-sense RNA and DNA methylation. These different modifications are closely interrelated. De-regulation of gene expression is a hallmark of cancer. Although genetic lesions have been the focus of cancer research for many years, it has become increasingly recognized that aberrant epigenetic modifications also play major roles in breast carcinogenesis. The incidence and mortality rates of breast cancer are high in the Western world compared with countries in Asia. There are also differences in the breast cancer incidence rates in different Western countries. This could be related to phytoestrogens.

  18. 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

  19. Chemical reactions involved in penicillin allergy: kinetics and mechanism of penicillin aminolysis.

    PubMed

    Tsuji, A; Yamana, T; Miyamoto, E; Kiya, E

    1975-08-01

    In view of the fundamental importance of the reaction of penicillins with amino groups of proteins to the penicillin allergy, the aminolysis of benzylpenicillin by various amines was kinetically investigated. The formation rate constants, kamide, of benzylpenicilloylamides were determined at 35 degrees, 45 degrees and 60 degrees (mu equals 0.5), and found to obey the general rate law: kamide equals k1[amine] + k2[amine H+] [amine] + k3[amine]2 + k4[amine]aoh. All of the amines exhibited the unassisted nucleophilic rate constant, k1. The relative importance of the other kinetic terms depends on the basicity and the chemical structure of amines. The reaction mechanism of penicillin aminolysis was discussed. Bronsted relations for k1, k2 and k3, except for hydrazines, were satisfactory.

  20. Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin.

    PubMed

    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(+)Ly6C(low) granulocytic (G)-MDSCs, sparing CD11b(+)Ly6G(-)Ly6C(high) 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

  1. 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

  2. β-adrenergic antagonists influence abdominal aorta contractility by mechanisms not involving β-adrenergic receptors.

    PubMed

    Hauzer, Willy; Bujok, Jolanta; Czerski, Albert; Rusiecka, Agnieszka; Pecka, Ewa; Gnus, Jan; Zawadzki, Wojciech; Witkiewicz, Wojciech

    2014-01-01

    β-adrenergic receptors (β-AR) are widely distributed in the cardiovascular system, where they considerably contribute to the control of its functions. β-blockers are commonly used in the treatment of disorders of the circulatory system. They act primarily by inhibiting cardiac β-receptors. However, there are also reports of pleiotropic action of β-blockers as well as of new compounds created to study β3 adrenergic receptors. The study aimed to investigate additional mechanisms of action of β-AR inhibitors in the rabbit abdominal aorta with emphasis on their action on α-adrenergic receptors and calcium influx. Responses to propranolol, betaxolol, metoprolol and SR59230A were evaluated in phenylephrine and PGF(2alpha) precontracted aortic rings. The effect of propranolol on the phenylephrine concentration-contraction curve was examined. Propranolol (≥ 10 μM) and SR59230A (≥ 0.1 μM) induced relaxations in phenylephrine-precontracted rings, while betaxolol and metoprolol had little effect. The β-AR inhibitors produced further contraction of tissues preincubated with PGF(2alpha), excluding SR59230A, which after initial contraction, elicited marked relaxation at a concentration above 1 ĕM. 100 μM of propranolol caused a significant rightward shift of the concentration-contraction curve to phenylephrine with no reduction in the maximum response. Incubation of aortic rings in phentolamine reduced the maximal contraction to propranolol; verapamil pretreatment by contrast enhanced contractile response. In conclusion, SR59230A and propranolol most probably act as α1-AR competitive antagonists in the presence of phenylephrine in rabbit abdominal aortic rings. After α-ARs blockade, propranolol exerts a weak relaxing activity connected with Ca2+ channel inactivation. SR59230A at a high concentration acts on the rabbit aorta by an additional mechanism needing further investigation.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. Cortical mechanisms involved in the processing of verbs: an fMRI study.

    PubMed

    Yokoyama, Satoru; Miyamoto, Tadao; Riera, Jorge; Kim, Jungho; Akitsuki, Yuko; Iwata, Kazuki; Yoshimoto, Kei; Horie, Kaoru; Sato, Shigeru; Kawashima, Ryuta

    2006-08-01

    In this study, we investigated two aspects of verb processing: first, whether verbs are processed differently from nouns; and second, how verbal morphology is processed. For this purpose, we used functional magnetic resonance imaging to compare three types of lexical processing in Japanese: the processing of nouns, unmarked active verbs, and inflected passive verbs. Twenty-eight healthy subjects were shown a lexical item and asked to judge whether the presented item was a legal word. Although all three conditions activated the bilateral inferior frontal, occipital, the left middle, and inferior temporal cortices, we found differences in the degree of activation for each condition. Verbs elicited greater activation in the left middle temporal gyrus than nouns, and inflected verbs showed greater activation in the left inferior frontal gyrus than unmarked verbs. This study demonstrates that although verbs are basically processed in the same cortical network as nouns, nouns and verbs elicit different degrees of activation due to the cognitive demands involved in lexical semantic processing. Furthermore, this study also shows that the left inferior frontal cortex is related to the processing of verbal inflectional morphology.

  8. Involvement of spinal cord opioid mechanisms in the acute antinociceptive effect of hyperbaric oxygen in mice.

    PubMed

    Heeman, Jacqueline H; Zhang, Yangmiao; Shirachi, Donald Y; Quock, Raymond M

    2013-12-01

    Earlier research has demonstrated that treatment with hyperbaric oxygen (HBO2) can elicit an antinociceptive response in models of acute pain. We have demonstrated that this antinociceptive effect is centrally-mediated and is dependent on opioid receptors. The purpose of the present study was to examine the role of endogenous opioid peptides and opioid receptors specifically in the spinal cord in the acute antinociceptive effect of HBO2 in mice. Male NIH Swiss mice were exposed to HBO2 (100% oxygen at 3.5atm absolute) for 11min and their antinociceptive responsiveness was determined using the glacial acetic acid-induced abdominal constriction test. HBO2-induced antinociception was sensitive to antagonism by intrathecal (i.t.) pretreatment with the κ- and μ-selective opioid antagonists norbinaltorphimine and β-funaltrexamine, respectively, but not the δ-selective antagonist naltrindole. The antinociceptive effect of HBO2 was also significantly attenuated by i.t. pretreatment with a rabbit antiserum against rat dynorphin1-13 but not antisera against β-endorphin or methionine-enkephalin. Based on these experimental findings, the acute antinociceptive effect of HBO2 appears to involve neuronal release of dynorphin and activation of κ- and μ-opioid receptors in the spinal cord. PMID:24113418

  9. 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.

  10. 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.

  11. 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.

  12. Glibenclamide attenuates the antiarrhythmic effect of endotoxin with a mechanism not involving K(ATP) channels.

    PubMed

    Iskit, Alper B; Erkent, Ulkem; Ertunc, Mert; Guc, M Oguz; Ilhan, Mustafa; Onur, Rustu

    2007-02-01

    The role of K(ATP) channels in the antiarrhythmic effect of Escherichia coli endotoxin-induced nitric oxide synthase (iNOS) was examined in an anesthetised rat model of myocardial ischemia and reperfusion arrhythmia by using glibenclamide (1 mg kg(-1)), nateglinide (10 mg kg(-1)) and repaglinide (0.5 mg kg(-1)). Endotoxin (1 mg kg(-1)) was administered intraperitoneally 4 h before the occlusion of the left coronary artery and glibenclamide, nateglinide or repaglinide was administered 30 min before coronary artery occlusion. We also evaluated the effects of K(ATP) channel blockers and nonselective K(+) channel blocker tetraethylammonium (TEA) on cardiac action potential configuration in the atria obtained from endotoxemic rats. The mean arterial blood pressure of rats receiving endotoxin was lower during both the occlusion and reperfusion periods. Endotoxin significantly reduced the total number of ectopic beats and the duration of ventricular tachycardia. Glibenclamide, but not nateglinide and repaglinide, prevented the hypotension and antiarrhythmic effects of endotoxin. Atria obtained from endotoxin-treated rats had prolonged action potential duration. This effect was abolished with pretreatment of iNOS inhibitors, l-canavanine and dexamethasone and perfusion of glibenclamide, but not with TEA and non-sulfonylurea drug, nateglinide. We demonstrated that glibenclamide inhibits the antiarrhythmic effect of endotoxin and this effect does not appear to involve K(ATP) channels.

  13. 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

  14. 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.

  15. 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. PMID:23123557

  16. 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.

  17. Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis.

    PubMed

    Robert, Sacha; Gicquel, Thomas; Victoni, Tatiana; Valença, Samuel; Barreto, Emiliano; Bailly-Maître, Béatrice; Boichot, Elisabeth; Lagente, Vincent

    2016-08-01

    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.

  18. 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.

  19. Sex differences in cerebellar mechanisms involved in pain-related safety learning.

    PubMed

    Labrenz, Franziska; Icenhour, Adriane; Thürling, Markus; Schlamann, Marc; Forsting, Michael; Timmann, Dagmar; Elsenbruch, Sigrid

    2015-09-01

    Recent studies have suggested that the cerebellum contributes to the central processing of pain, including pain-related learning and memory processes. As a complex experience with multiple emotional and cognitive facets, the response to pain and its underlying neural correlates differ between men and women. However, it remains poorly understood whether and to what extent sex differences exist in the cerebellar contribution to pain-related associative learning processes. In the present conditioning study with experimental abdominal pain as unconditioned stimuli (US), we assessed sex-dependent differences in behavioral and neural responses to conditioned warning and safety cues in healthy volunteers. The results revealed that in response to visual stimuli signaling safety from abdominal pain (CS(-)), women showed enhanced cerebellar activation in lobules I-IV, V, VI, VIIIa, IX and X as well as Crus II and the dentate nucleus, which are mostly representative of somatomotor networks. On the other hand, men showed enhanced neural activation in lobules I-IV, VI, VIIb, VIIIb, IX as well as Crus I and II in response to CS(-), which are representative of frontoparietal and ventral attention networks. No sex differences were observed in response to pain-predictive warning signals (CS(+)). Similarly, men and women did not differ in behavioral measures of conditioning, including conditioned changes in CS valence and contingency awareness. Together, we could demonstrate that the cerebellum is involved in associative learning processes of conditioned anticipatory safety from pain and mediates sex differences in the underlying neural processes. Given the high prevalence of chronic pain conditions in women, these results may contribute to improve our understanding of the acquisition and manifestation of chronic abdominal pain syndromes. PMID:26004678

  20. Mechanism of cancer drug resistance and the involvement of noncoding RNAs.

    PubMed

    Xia, Hongping; Hui, Kam M

    2014-01-01

    Drug resistance is one of the major reasons for the failure of cancer therapies. Although our understanding of resistance to targeted cancer drugs remains incomplete, new and more creative approaches are being exploited to intercept this phenomenon. Considerable advances have been made in our understanding that cancer drug resistance can be caused by alterations of drug efflux, increases in drug metabolism, mutations of drug targets, alterations in DNA repair and cell cycle, changes in cell apoptosis and autophagy, induction of epithelial-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs). Furthermore, intracellular signalling pathways have been shown to play key physiological roles and the abnormal activation of signalling pathways may be correlated with drug resistance. Recently, noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as important regulators of gene expression and alternative splicing, which provides cells with yet another mode to greatly increase regulatory complexity and fine-tune their transcriptome and can rapidly adjust their proteome in response to stimuli. Consequently, a wide variety of biological functions have been shown to depend on the coordinated interactions between noncoding RNAs and cellular signalling networks to achieve a concerted desired physiological outcome, whereas mutations and dysregulation of ncRNAs have been linked to diverse human diseases, including cancer drug resistance. In this review, we will discuss recent findings on the multiple molecular roles of regulatory ncRNAs on the signalling pathways involved in cancer drug resistance and the therapeutic potential of reverse drug resistance.

  1. 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

  2. Na+/K+ATPase Regulates Sperm Capacitation Through a Mechanism Involving Kinases and Redistribution of Its Testis-Specific Isoform

    PubMed Central

    NEWTON, LARISSA D.; KRISHNAKUMAR, SULOCHANA; MENON, AJITKUMAR GOPINADHA; KASTELIC, JOHN P.; VAN DER HOORN, FRANS A.; THUNDATHIL, JACOB C.

    2016-01-01

    SUMMARY Incubation of bovine sperm with ouabain, an endogenous cardiac glycoside that inhibits both the ubiquitous (ATP1A1) and testis-specific α4 (ATP1A4) isoforms of Na+/K+ATPase, induces tyrosine phosphorylation and capacitation. The objectives of this study were to investigate: (1) fertilizing ability of bovine sperm capacitated by incubating with ouabain; (2) involvement of ATP1A4 in this process; and (3) signaling mechanisms involved in the regulation of sperm capacitation induced by inhibition of Na+/K+ATPase activity. Fresh sperm capacitated by incubating with ouabain (inhibits both ATP1A1 and ATP1A4) or with anti-ATP1A4 immunoserum fertilized bovine oocytes in vitro. Capacitation was associated with relocalization of ATP1A4 from the entire sperm head to the post-acrosomal region. To investigate signaling mechanisms involved in oubain-induced regulation of sperm capacitation, sperm preparations were pre-incubated with inhibitors of specific signaling molecules, followed by incubation with ouabain. The phosphotyrosine content of sperm preparations was determined by immunoblotting, and capacitation status of these sperm preparations were evaluated through an acrosome reaction assay. We inferred that Na+/K+ATPase was involved in the regulation of tyrosine phosphorylation in sperm proteins through receptor tyrosine kinase, nonreceptor type protein kinase, and protein kinases A and C. In conclusion, inhibition of Na+/K+ATPase induced tyrosine phosphorylation and capacitation through multiple signal transduction pathways, imparting fertilizing ability in bovine sperm. To our knowledge, this is the first report documenting both the involvement of ATP1A4 in the regulation of bovine sperm capacitation and that fresh bovine sperm capacitated by the inhibition of Na+/K+ATPase can fertilize oocytes in vitro. PMID:19834983

  3. Involvement of Epigenetic Mechanisms in the Regulation of Secreted Phospholipase A2 Expressions in Jurkat Leukemia Cells

    PubMed Central

    Menschikowski, Mario; Hagelgans, Albert; Kostka, Heike; Eisenhofer, Graeme; Siegert, Gabriele

    2008-01-01

    Epigenetic changes provide a frequent mechanism for transcriptional silencing of genes in cancer cells. We previously established that epigenetic mechanisms are important for control of group IIA phospholipase A2 (PLA2G2A) gene transcription in human DU-145 prostate cells. In this study, we analyzed the involvement of such mechanisms in the regulation of five sPLA2 isozymes and the M-type receptor of sPLA2 (sPLA2-R) in human leukemic Jurkat cells. These cells constitutively expressed sPLA2-IB, sPLA2-III, sPLA2-X, and sPLA2-R but not sPLA2-IIA and sPLA2-V. Transcription of sPLA2-IIA and sPLA2-V was, however, detected after exposure of cells to the DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC). Expression of sPLA2-IIA was further enhanced by additional exposure to interferon-γ and blocked by inhibitors of specificity protein 1, nuclear factor κB, and Janus kinase/signal transducer and activator of transcription-dependent pathways. Sequence analysis and methylation-specific polymerase chain reaction of bisulfite-modified genomic DNA revealed two 5′-CpG sites (-111 and -82) in the sPLA2-IIA proximal promoter that were demethylated after 5-aza-dC treatment. These sites may be involved in the DNA binding of specificity protein 1 and other transcription factors. Similar findings after treatment of human U937 leukemia cells with 5-aza-dC indicate that this mechanism of PLA2G2A gene silencing is not restricted to Jurkat and DU-145 cells. These data establish that regulation of sPLA2-IIA and sPLA2-V in Jurkat and other cells involves epigenetic silencing by DNA hypermethylation. PMID:18953428

  4. Paracrine Mechanisms Involved in the Control of Early Stages of Mammalian Spermatogenesis

    PubMed Central

    Rossi, Pellegrino; Dolci, Susanna

    2013-01-01

    Within the testis, Sertoli-cell is the primary target of pituitary FSH. Several growth factors have been described to be produced specifically by Sertoli cells and modulate male germ cell development through paracrine mechanisms. Some have been shown to act directly on spermatogonia such as GDNF, which acts on self-renewal of spermatogonial stem cells (SSCs) while inhibiting their differentiation; BMP4, which has both a proliferative and differentiative effect on these cells, and KIT ligand (KL), which stimulates the KIT tyrosine-kinase receptor expressed by differentiating spermatogonia (but not by SSCs). KL not only controls the proliferative cycles of KIT-positive spermatogonia, but it also stimulates the expression of genes that are specific of the early phases of meiosis, whereas the expression of typical spermatogonial markers is down-regulated. On the contrary, FGF9 acts as a meiotic inhibiting substance both in fetal gonocytes and in post-natal spermatogonia through the induction of the RNA-binding protein NANOS2. Vitamin A, which is metabolized to Retinoic Acid in Sertoli cells, controls both SSCs differentiation through KIT induction and NANOS2 inhibition, and meiotic entry of differentiating spermatogonia through STRA8 upregulation. PMID:24324457

  5. Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet.

    PubMed

    Buchanan, Lauren E; Dunkelberger, Emily B; Tran, Huong Q; Cheng, Pin-Nan; Chiu, Chi-Cheng; Cao, Ping; Raleigh, Daniel P; de Pablo, Juan J; Nowick, James S; Zanni, Martin T

    2013-11-26

    Amyloid formation is implicated in more than 20 human diseases, yet the mechanism by which fibrils form is not well understood. We use 2D infrared spectroscopy and isotope labeling to monitor the kinetics of fibril formation by human islet amyloid polypeptide (hIAPP or amylin) that is associated with type 2 diabetes. We find that an oligomeric intermediate forms during the lag phase with parallel β-sheet structure in a region that is ultimately a partially disordered loop in the fibril. We confirm the presence of this intermediate, using a set of homologous macrocyclic peptides designed to recognize β-sheets. Mutations and molecular dynamics simulations indicate that the intermediate is on pathway. Disrupting the oligomeric β-sheet to form the partially disordered loop of the fibrils creates a free energy barrier that is the origin of the lag phase during aggregation. These results help rationalize a wide range of previous fragment and mutation studies including mutations in other species that prevent the formation of amyloid plaques.

  6. Involvement of interleukin-1 receptor mechanisms in development of arterial hypotension in rat heatstroke.

    PubMed

    Lin, M T; Liu, H H; Yang, Y L

    1997-10-01

    Rats, under urethan anesthesia, were exposed to a high ambient temperature (42 degrees C) to induce heatstroke and to assess the hemodynamic changes associated with heatstroke. Compared with normothermic controls, rats with heatstroke showed higher values of colonic temperature, heart rate, and plasma levels of interleukin (IL)-1 but lower values of R wave amplitude, P-R and Q-T intervals, systolic wave amplitude, diastolic and dicrotic wave duration, mean arterial pressure, stroke volume, and cardiac output. Animals injected intravenously with an IL-1-receptor antagonist at the time of heatstroke induction were protected from some of the cardiovascular effects of heatstroke, such as depressed ventricular depolarization, decreased stroke volume, decreased cardiac output, and arterial hypotension. The hemodynamic changes associated with heatstroke could be mimicked by IL-1beta administration. Other cardiovascular parameters such as total peripheral vascular resistance were unaffected by heatstroke induction or IL-1beta treatment. The results indicate that a selective decline in stroke volume or ventricular depolarization resulting from increased plasma levels of IL-1 may be an important mechanism signaling arterial hypotension or circulatory failure in rat heatstroke.

  7. 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.

  8. Effects of nitric oxide on magnocellular neurons of the supraoptic nucleus involve multiple mechanisms.

    PubMed

    Silva, M P da; Cedraz-Mercez, P L; Varanda, W A

    2014-02-01

    Physiological evidence indicates that the supraoptic nucleus (SON) is an important region for integrating information related to homeostasis of body fluids. Located bilaterally to the optic chiasm, this nucleus is composed of magnocellular neurosecretory cells (MNCs) responsible for the synthesis and release of vasopressin and oxytocin to the neurohypophysis. At the cellular level, the control of vasopressin and oxytocin release is directly linked to the firing frequency of MNCs. In general, we can say that the excitability of these cells can be controlled via two distinct mechanisms: 1) the intrinsic membrane properties of the MNCs themselves and 2) synaptic input from circumventricular organs that contain osmosensitive neurons. It has also been demonstrated that MNCs are sensitive to osmotic stimuli in the physiological range. Therefore, the study of their intrinsic membrane properties became imperative to explain the osmosensitivity of MNCs. In addition to this, the discovery that several neurotransmitters and neuropeptides can modulate their electrical activity greatly increased our knowledge about the role played by the MNCs in fluid homeostasis. In particular, nitric oxide (NO) may be an important player in fluid balance homeostasis, because it has been demonstrated that the enzyme responsible for its production has an increased activity following a hypertonic stimulation of the system. At the cellular level, NO has been shown to change the electrical excitability of MNCs. Therefore, in this review, we focus on some important points concerning nitrergic modulation of the neuroendocrine system, particularly the effects of NO on the SON.

  9. Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms

    PubMed Central

    Wei, Chen; Lin, Ma; Jinjun, Bian; Su, Feng; Dan, Cao; Yan, Chen; Jie, Yang; Jin, Zhang; Zi-Chun, Hua; Wu, Yin

    2015-01-01

    General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na+,K+-ATPase ligand–induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na+,K+-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2–β-arrestin–NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na+,K+-ATPase ligand–induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na+,K+-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling. PMID:25589675

  10. Effects of nitric oxide on magnocellular neurons of the supraoptic nucleus involve multiple mechanisms

    PubMed Central

    da Silva, M.P.; Cedraz-Mercez, P.L.; Varanda, W.A.

    2014-01-01

    Physiological evidence indicates that the supraoptic nucleus (SON) is an important region for integrating information related to homeostasis of body fluids. Located bilaterally to the optic chiasm, this nucleus is composed of magnocellular neurosecretory cells (MNCs) responsible for the synthesis and release of vasopressin and oxytocin to the neurohypophysis. At the cellular level, the control of vasopressin and oxytocin release is directly linked to the firing frequency of MNCs. In general, we can say that the excitability of these cells can be controlled via two distinct mechanisms: 1) the intrinsic membrane properties of the MNCs themselves and 2) synaptic input from circumventricular organs that contain osmosensitive neurons. It has also been demonstrated that MNCs are sensitive to osmotic stimuli in the physiological range. Therefore, the study of their intrinsic membrane properties became imperative to explain the osmosensitivity of MNCs. In addition to this, the discovery that several neurotransmitters and neuropeptides can modulate their electrical activity greatly increased our knowledge about the role played by the MNCs in fluid homeostasis. In particular, nitric oxide (NO) may be an important player in fluid balance homeostasis, because it has been demonstrated that the enzyme responsible for its production has an increased activity following a hypertonic stimulation of the system. At the cellular level, NO has been shown to change the electrical excitability of MNCs. Therefore, in this review, we focus on some important points concerning nitrergic modulation of the neuroendocrine system, particularly the effects of NO on the SON. PMID:24519124

  11. What Do Effective Treatments for Multiple Sclerosis Tell Us about the Molecular Mechanisms Involved in Pathogenesis?

    PubMed Central

    Buzzard, Katherine A.; Broadley, Simon A.; Butzkueven, Helmut

    2012-01-01

    Multiple sclerosis is a potentially debilitating disease of the central nervous system. A concerted program of research by many centers around the world has consistently demonstrated the importance of the immune system in its pathogenesis. This knowledge has led to the formal testing of a number of therapeutic agents in both animal models and humans. These clinical trials have shed yet further light on the pathogenesis of MS through their sometimes unexpected effects and by their differential effects in terms of impact on relapses, progression of the disease, paraclinical parameters (MRI) and the adverse events that are experienced. Here we review the currently approved medications for the commonest form of multiple sclerosis (relapsing-remitting) and the emerging therapies for which preliminary results from phase II/III clinical trials are available. A detailed analysis of the molecular mechanisms responsible for the efficacy of these medications in multiple sclerosis indicates that blockade or modulation of both T- and B-cell activation and migration pathways in the periphery or CNS can lead to amelioration of the disease. It is hoped that further therapeutic trials will better delineate the pathogenesis of MS, ultimately leading to even better treatments with fewer adverse effects. PMID:23202920

  12. Mechanisms Involved in Fe(III) Respiration by the Hyperthermophilic Archaeon Ferroglobus placidus

    PubMed Central

    Smith, Jessica A.; Aklujkar, Muktak; Risso, Carla; Leang, Ching; Giloteaux, Ludovic

    2015-01-01

    The hyperthermophilic archaeon Ferroglobus placidus can utilize a wide variety of electron donors, including hydrocarbons and aromatic compounds, with Fe(III) serving as an electron acceptor. In Fe(III)-reducing bacteria that have been studied to date, this process is mediated by c-type cytochromes and type IV pili. However, there currently is little information available about how this process is accomplished in archaea. In silico analysis of the F. placidus genome revealed the presence of 30 genes coding for putative c-type cytochrome proteins (more than any other archaeon that has been sequenced to date), five of which contained 10 or more heme-binding motifs. When cell extracts were analyzed by SDS-PAGE followed by heme staining, multiple bands corresponding to c-type cytochromes were detected. Different protein expression patterns were observed in F. placidus cells grown on soluble and insoluble iron forms. In order to explore this result further, transcriptomic studies were performed. Eight genes corresponding to multiheme c-type cytochromes were upregulated when F. placidus was grown with insoluble Fe(III) oxide compared to soluble Fe(III) citrate as an electron acceptor. Numerous archaella (archaeal flagella) also were observed on Fe(III)-grown cells, and genes coding for two type IV pilin-like domain proteins were differentially expressed in Fe(III) oxide-grown cells. This study provides insight into the mechanisms for dissimilatory Fe(III) respiration by hyperthermophilic archaea. PMID:25662973

  13. Clostridium beijerinckii and Clostridium difficile Detoxify Methylglyoxal by a Novel Mechanism Involving Glycerol Dehydrogenase

    PubMed Central

    Liyanage, Hemachandra; Kashket, Shelby; Young, Michael; Kashket, Eva R.

    2001-01-01

    In contrast to gram-negative bacteria, little is known about the mechanisms by which gram-positive bacteria degrade the toxic metabolic intermediate methylglyoxal (MG). Clostridium beijerinckii BR54, a Tn1545 insertion mutant of the NCIMB 8052 strain, formed cultures that contained significantly more (free) MG than wild-type cultures. Moreover, BR54 was more sensitive to growth inhibition by added MG than the wild type, suggesting that it has a reduced ability to degrade MG. The single copy of Tn1545 in this strain lies just downstream from gldA, encoding glycerol dehydrogenase. As a result of antisense RNA production, cell extracts of BR54 possess significantly less glycerol dehydrogenase activity than wild-type cell extracts (H. Liyanage, M. Young, and E. R. Kashket, J. Mol. Microbiol. Biotechnol. 2:87–93, 2000). Inactivation of gldA in both C. beijerinckii and Clostridium difficile gave rise to pinpoint colonies that could not be subcultured, indicating that glycerol dehydrogenase performs an essential function in both organisms. We propose that this role is detoxification of MG. To our knowledge, this is the first report of targeted gene disruption in the C. difficile chromosome. PMID:11319074

  14. Involvement of a joker mutation in a polymerase-independent lethal mutagenesis escape mechanism.

    PubMed

    Agudo, Rubén; de la Higuera, Ignacio; Arias, Armando; Grande-Pérez, Ana; Domingo, Esteban

    2016-07-01

    We previously characterized a foot-and-mouth disease virus (FMDV) with three amino acid replacements in its polymerase (3D) that conferred resistance to the mutagenic nucleoside analogue ribavirin. Here we show that passage of this mutant in the presence of high ribavirin concentrations resulted in selection of viruses with the additional replacement I248T in 2C. This 2C substitution alone (even in the absence of replacements in 3D) increased FMDV fitness mainly in the presence of ribavirin, prevented an incorporation bias in favor of A and U associated with ribavirin mutagenesis, and conferred the ATPase activity of 2C decreased sensitivity to ribavirin-triphosphate. Since in previous studies we described that 2C with I248T was selected under different selective pressures, this replacement qualifies as a joker substitution in FMDV evolution. The results have identified a role of 2C in nucleotide incorporation, and have unveiled a new polymerase-independent mechanism of virus escape to lethal mutagenesis. PMID:27136067

  15. Immune enhancement of yellow fever virus neurovirulence for mice: studies of mechanisms involved.

    PubMed

    Gould, E A; Buckley, A; Groeger, B K; Cane, P A; Doenhoff, M

    1987-12-01

    Enhancement of yellow fever virus neurovirulence for mice by specific antibody was studied with the French neurotropic vaccine strain. Experimental conditions for enhancement required mice between 14 and 40 days old and intraperitoneal administration of a selected monoclonal antibody 24 h before or up to 72 h after intracerebral virus challenge. Virus infectivity titrations were similar in brains of antibody-treated and untreated mice. Virus recovered from brains of mice with enhanced viral infections was neither qualitatively nor quantitatively different from standard virus. Humoral immune responses in enhanced infections were normal, macrophages did not become infected and viraemia was not significant. Both hydrocortisone treatment and complement depletion with cobra venom resulted in prolongation of mouse survival times but virulence enhancement persisted. Antithymocyte serum had no effect on enhancement although it reduced the humoral immune response. It is proposed that virulence enhancement is due to the combined effects of virus-specific antibody on infected cells, complement-mediated cytolysis and resultant host anti-cellular activity. There is no analogy between mechanisms effecting increased arbovirus growth in vitro in the presence of specific antibody and increased yellow fever virus neurovirulence in vivo after parenteral administration of antibody.

  16. Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration.

    PubMed

    Yao, Honghong; Yang, Yanjing; Kim, Kee Jun; Bethel-Brown, Crystal; Gong, Nan; Funa, Keiko; Gendelman, Howard E; Su, Tsung-Ping; Wang, John Q; Buch, Shilpa

    2010-06-10

    Cocaine abuse hastens the neurodegeneration often associated with advanced HIV-1 infection. The mechanisms, in part, revolve around the neuroinflammatory processes mediated by the chemokine monocyte chemotactic protein-1 (MCP-1/CCL2). Understanding factors that modulate MCP-1 and, in turn, facilitate monocyte extravasation in the brain is thus of paramount importance. We now demonstrate that cocaine induces MCP-1 in rodent microglia through translocation of the sigma receptor to the lipid raft microdomains of the plasma membrane. Sequential activation of Src, mitogen-activated protein kinases (MAPKs), and phosphatidylinositol-3' kinase (PI3K)/Akt and nuclear factor kappaB (NF-kappaB) pathways resulted in increased MCP-1 expression. Furthermore, conditioned media from cocaine-exposed microglia increased monocyte transmigration, and thus was blocked by antagonists for CCR2 or sigma receptor. These findings were corroborated by demonstrating increased monocyte transmigration in mice exposed to cocaine, which was attenuated by pretreatment of mice with the sigma receptor antagonist. Interestingly, cocaine-mediated transmigratory effects were not observed in CCR2 knockout mice. We conclude that cocaine-mediated induction of MCP-1 accelerates monocyte extravasation across the endothelium. Understanding the regulation of MCP-1 expression and functional changes by cocaine/sigma receptor system may provide insights into the development of potential therapeutic targets for HIV-1-associated neurocognitive disorders. PMID:20354174

  17. Overcoming NS1-mediated immune antagonism involves both interferon-dependent and independent mechanisms.

    PubMed

    Thakar, Juilee; Schmid, Sonja; Duke, Jamie L; García-Sastre, Adolfo; Kleinstein, Steven H

    2013-11-01

    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.

  18. 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.

  19. 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

  20. Involvement of oxidative stress in the mechanism of cadmium-induced toxicity on rat uterus.

    PubMed

    Nasiadek, Marzenna; Skrzypińska-Gawrysiak, Małgorzata; Daragó, Adam; Zwierzyńska, Ewa; Kilanowicz, Anna

    2014-09-01

    The study was undertaken to explore whether cadmium bioaccumulation can induce oxidative stress in the uterus of rats. Cadmium (0.09, 0.9, 1.8 or 4.5mgCd/kg b.w.) was administered by gavage for 28 days. The animals were dissected on the first day and then after 90 days post exposure (second group of animals). The results show that cadmium accumulates in the uterus in a dose-dependent manner. The uterine Cd concentrations were almost the same in both groups, which is indicative of its long half-life in this organ. The accumulated cadmium caused significant changes in catalase (CAT) activity and lipid peroxidation (MDA) levels at concentrations from 0.09 to 0.35μgCd/g wet uterine tissue. In summary our results show that the induction of oxidative stress and lipid peroxidation in the uterus may play important roles in the mechanism of toxicity in this organ and may have a negative impact on reproductive processes.

  1. Insecticide Resistance Status of United States Populations of Aedes albopictus and Mechanisms Involved

    PubMed Central

    Marcombe, Sébastien; Farajollahi, Ary; Healy, Sean P.; Clark, Gary G.; Fonseca, Dina M.

    2014-01-01

    Aedes albopictus (Skuse) is an invasive mosquito that has become an important vector of chikungunya and dengue viruses. Immature Ae. albopictus thrive in backyard household containers that require treatment with larvicides and when adult populations reach pest levels or disease transmission is ongoing, adulticiding is often required. To assess the feasibility of control of USA populations, we tested the susceptibility of Ae. albopictus to chemicals representing the main insecticide classes with different modes of action: organochlorines, organophosphates, carbamates, pyrethroids, insect growth regulators (IGR), naturalytes, and biolarvicides. We characterized a susceptible reference strain of Ae. albopictus, ATM95, and tested the susceptibility of eight USA populations to five adulticides and six larvicides. We found that USA populations are broadly susceptible to currently available larvicides and adulticides. Unexpectedly, however, we found significant resistance to dichlorodiphenyltrichloroethane (DDT) in two Florida populations and in a New Jersey population. We also found resistance to malathion, an organophosphate, in Florida and New Jersey and reduced susceptibility to the IGRs pyriproxyfen and methoprene. All populations tested were fully susceptible to pyrethroids. Biochemical assays revealed a significant up-regulation of GSTs in DDT-resistant populations in both larval and adult stages. Also, β-esterases were up-regulated in the populations with suspected resistance to malathion. Of note, we identified a previously unknown amino acid polymorphism (Phe → Leu) in domain III of the VGSC, in a location known to be associated with pyrethroid resistance in another container-inhabiting mosquito, Aedes aegypti L. The observed DDT resistance in populations from Florida may indicate multiple introductions of this species into the USA, possibly from tropical populations. In addition, the mechanisms underlying DDT resistance often result in pyrethroid resistance

  2. Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism.

    PubMed Central

    Di Minno, G; Davì, G; Margaglione, M; Cirillo, F; Grandone, E; Ciabattoni, G; Catalano, I; Strisciuglio, P; Andria, G; Patrono, C

    1993-01-01

    Homocystinuria due to homozygous cystathionine beta-synthase deficiency is an inborn error of metabolism characterized by a high incidence of thrombosis and premature atherosclerosis. We evaluated TXA2 biosynthesis in vivo and several in vitro tests of platelet function in 11 homocystinuric patients and 12 healthy controls. In vitro, patients' platelet aggregation was within control values as were TXB2 formation, fibrinogen binding, and ATP secretion in response to thrombin. In contrast, the urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was > 2 SD of controls in all patients (1,724 +/- 828 pg/mg creatinine, mean +/- SD, in patients vs. 345 +/- 136 in controls, P < 0.001). The administration to four patients of low-dose aspirin (50 mg/d for 1 wk) reduced metabolite excretion by > 80%. The recovery of 11-dehydro-TXB2 excretion over the 10 d that followed aspirin cessation occurred with a pattern consistent with the entry into the circulation of platelets with intact cyclooxygenase activity. Prolonged partial reduction in the abnormally high excretion of both 11-dehydro-TXB2 and 2,3-dinor-TXB2, was also observed in seven patients who ingested 500 mg daily for 3 wk of the antioxidant drug probucol. These results provide evidence for enhanced thromboxane biosynthesis in homocystinuria and for its partial dependence on probucol-sensitive mechanisms. Furthermore, the elevated TXA2 formation in homocystinuria is likely to reflect, at least in part, in vivo platelet activation. PMID:8376592

  3. Study of catalase adsorption on two mixed-mode ligands and the mechanism involved therein.

    PubMed

    Shiva Ranjini, S; Vijayalakshmi, M A

    2012-11-01

    Mixed-mode chromatography sorbents n-hexylamine HyperCel™ (HEA) and phenylpropylamine HyperCel™ (PPA) were evaluated for the study of adsorption of catalase from two different sources. Various parameters such as buffer composition, ionic strength and pH were investigated to study the mechanism of interaction of commercially available pre-purified catalase from Bovine liver, purified catalase from black gram (Vigna mungo) and crude extract of black gram containing catalase with these mixed-mode ligands. A simple and economical screening protocol for identifying optimal buffer conditions for adsorption and desorption of catalase was established with micro volumes of the sorbent in batch mode. With HEA HyperCel, it was observed that pre-purified catalase from both bovine liver and black gram was completely retained at pH 7.0, irrespective of the presence or absence of NaCl in the adsorption buffer, whereas the catalase from crude extract of black gram was completely retained only in the presence of 0.2 M salt in the adsorption buffer. The elution of catalase from both the sources was accomplished by lowering the pH to 4.5 in absence of salt. In case of PPA HyperCel, catalase from both the sources was very strongly adsorbed under different buffer conditions studied, and elution did not yield a significant catalase activity. From the screening experiments, it could be concluded that the interaction of catalase with HEA HyperCel could be dominated by hydrophobic forces with minor contributions from ionic interaction and with PPA HyperCel, it could be a combination of different non-covalent interactions acting on different loci on the surface of the protein.

  4. The mechanism involved in the loss of PTEN expression in NSCLC tumor cells

    SciTech Connect

    Li, Gang; Zhao, Jingfeng; Peng, Xianjing; Liang, Jian; Deng, Xin; Chen, Yuxiang

    2012-02-17

    Highlights: Black-Right-Pointing-Pointer Radiation stimulates PTEN reexpression in NSCLC independent of p53 activation. Black-Right-Pointing-Pointer PTEN reexpression is mediated by miR-29b overexpression. Black-Right-Pointing-Pointer miR-29b regulates Dnmts expression in NSCLC tumor cells. Black-Right-Pointing-Pointer Target therapy could be established by overexpressing miR-29b expression. -- Abstract: Loss of PTEN expression is observed in most non-small cell lung cancers (NSCLC). However, the mechanism by which PTEN expression is regulated in NSCLC has not been fully elucidated. In this study, we investigated the role of DNA methyltransferases (Dnmts), microRNA-29b (miR-29b), and anti-miR-29b inhibitor in PTEN promoter methylation and PTEN gene expression in H358 NSCLC cells in vitro and in vivo. PTEN mRNA was measured by RT-PCR. PTEN and Dnmts protein levels were measured by Western blot. miR-29b expression was detected by Northern blot. A xenograft H358 tumor mouse model was established by subcutaneously inoculating H358 cells into the right hind limbs of nude mice. We found that radiation induced cell apoptosis and hypomethylation in PTEN promoter, PTEN and miR-29b expression, and downregulation of Dnmt1, 3a and 3b expression in H358 tumor cells. The effect of radiation on gene expression and apoptosis was blocked by anti-miR-29b inhibitor. In the xenograft H358 tumor model, anti-miR-29b inhibitor reversed radiation-induced tumor growth delay, PTEN reexpression and downregulation of Dnmts expression. Our study suggested that miR-29b is an upstream molecule of PTEN. miR-29b regulates PTEN gene expression through downregulating Dnmts expression and subsequently induces hypomethylation in PTEN promoter. Targeting therapy could be established in NSCLC by upregulating miR-29b expression.

  5. Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1

    PubMed Central

    Heyward, Frankie D.; Gilliam, Daniel; Coleman, Mark A.; Gavin, Cristin F.; Wang, Jing; Kaas, Garrett; Trieu, Richard; Lewis, John; Moulden, Jerome

    2016-01-01

    Aberrant gene expression within the hippocampus has recently been implicated in the pathogenesis of obesity-induced memory impairment. Whether a dysregulation of epigenetic modifications mediates this disruption in gene transcription has yet to be established. Here we report evidence of obesity-induced alterations in DNA methylation of memory-associated genes, including Sirtuin 1 (Sirt1), within the hippocampus, and thus offer a novel mechanism by which SIRT1 expression within the hippocampus is suppressed during obesity. Forebrain neuron-specific Sirt1 knock-out closely recapitulated the memory deficits exhibited by obese mice, consistent with the hypothesis that the high-fat diet-mediated reduction of hippocampal SIRT1 could be responsible for obesity-linked memory impairment. Obese mice fed a diet supplemented with the SIRT1-activating molecule resveratrol exhibited increased hippocampal SIRT1 activity and preserved hippocampus-dependent memory, further strengthening this conclusion. Thus, our findings suggest that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic dysregulation of SIRT1 within the hippocampus. SIGNIFICANCE STATEMENT Previous studies have implicated transcriptional dysregulation within the hippocampus as being a relevant pathological concomitant of obesity-induced memory impairment, yet a deeper understanding of the basis for, and etiological significance of, transcriptional dysregulation in this context is lacking. Here we present the first evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, including Sirt1, within the hippocampus of obese mice. Furthermore, experiments using transgenic and pharmacological approaches strongly implicate reduced hippocampal SIRT1 as being a principal pathogenic mediator of obesity-induced memory impairment. This paper offers a novel working model that may serve as a conceptual basis for the

  6. Study of catalase adsorption on two mixed-mode ligands and the mechanism involved therein.

    PubMed

    Shiva Ranjini, S; Vijayalakshmi, M A

    2012-11-01

    Mixed-mode chromatography sorbents n-hexylamine HyperCel™ (HEA) and phenylpropylamine HyperCel™ (PPA) were evaluated for the study of adsorption of catalase from two different sources. Various parameters such as buffer composition, ionic strength and pH were investigated to study the mechanism of interaction of commercially available pre-purified catalase from Bovine liver, purified catalase from black gram (Vigna mungo) and crude extract of black gram containing catalase with these mixed-mode ligands. A simple and economical screening protocol for identifying optimal buffer conditions for adsorption and desorption of catalase was established with micro volumes of the sorbent in batch mode. With HEA HyperCel, it was observed that pre-purified catalase from both bovine liver and black gram was completely retained at pH 7.0, irrespective of the presence or absence of NaCl in the adsorption buffer, whereas the catalase from crude extract of black gram was completely retained only in the presence of 0.2 M salt in the adsorption buffer. The elution of catalase from both the sources was accomplished by lowering the pH to 4.5 in absence of salt. In case of PPA HyperCel, catalase from both the sources was very strongly adsorbed under different buffer conditions studied, and elution did not yield a significant catalase activity. From the screening experiments, it could be concluded that the interaction of catalase with HEA HyperCel could be dominated by hydrophobic forces with minor contributions from ionic interaction and with PPA HyperCel, it could be a combination of different non-covalent interactions acting on different loci on the surface of the protein. PMID:23108613

  7. Mechanisms Involved in the Association between Periodontitis and Complications in Pregnancy

    PubMed Central

    Zi, Marcela Yang Hui; Longo, Priscila Larcher; Bueno-Silva, Bruno; Mayer, Marcia Pinto Alves

    2015-01-01

    The association between periodontitis and some of the problems with pregnancy such as premature delivery, low weight at birth, and preeclampsia (PE) has been suggested. Nevertheless, epidemiological data have shown contradictory data, mainly due to differences in clinical parameters of periodontitis assessment. Furthermore, differences in microbial composition and immune response between aggressive and chronic periodontitis are not addressed by these epidemiological studies. We aimed to review the current data on the association between some of these problems with pregnancy and periodontitis, and the mechanisms underlying this association. Shifts in the microbial composition of the subgingival biofilm may occur during pregnancy, leading to a potentially more hazardous microbial community. Pregnancy is characterized by physiological immune tolerance. However, the infection leads to a shift in maternal immune response to a pathogenic pro-inflammatory response, with production of inflammatory cytokines and toxic products. In women with periodontitis, the infected periodontal tissues may act as reservoirs of bacteria and their products that can disseminate to the fetus-placenta unit. In severe periodontitis patients, the infection agents and their products are able to activate inflammatory signaling pathways locally and in extra-oral sites, including the placenta-fetal unit, which may not only induce preterm labor but also lead to PE and restrict intrauterine growth. Despite these evidences, the effectiveness of periodontal treatment in preventing gestational complications was still not established since it may be influenced by several factors such as severity of disease, composition of microbial community, treatment strategy, and period of treatment throughout pregnancy. This lack of scientific evidence does not exclude the need to control infection and inflammation in periodontitis patients during pregnancy, and treatment protocols should be validated. PMID:25688342

  8. Insecticide resistance status of United States populations of Aedes albopictus and mechanisms involved.

    PubMed

    Marcombe, Sébastien; Farajollahi, Ary; Healy, Sean P; Clark, Gary G; Fonseca, Dina M

    2014-01-01

    Aedes albopictus (Skuse) is an invasive mosquito that has become an important vector of chikungunya and dengue viruses. Immature Ae. albopictus thrive in backyard household containers that require treatment with larvicides and when adult populations reach pest levels or disease transmission is ongoing, adulticiding is often required. To assess the feasibility of control of USA populations, we tested the susceptibility of Ae. albopictus to chemicals representing the main insecticide classes with different modes of action: organochlorines, organophosphates, carbamates, pyrethroids, insect growth regulators (IGR), naturalytes, and biolarvicides. We characterized a susceptible reference strain of Ae. albopictus, ATM95, and tested the susceptibility of eight USA populations to five adulticides and six larvicides. We found that USA populations are broadly susceptible to currently available larvicides and adulticides. Unexpectedly, however, we found significant resistance to dichlorodiphenyltrichloroethane (DDT) in two Florida populations and in a New Jersey population. We also found resistance to malathion, an organophosphate, in Florida and New Jersey and reduced susceptibility to the IGRs pyriproxyfen and methoprene. All populations tested were fully susceptible to pyrethroids. Biochemical assays revealed a significant up-regulation of GSTs in DDT-resistant populations in both larval and adult stages. Also, β-esterases were up-regulated in the populations with suspected resistance to malathion. Of note, we identified a previously unknown amino acid polymorphism (Phe → Leu) in domain III of the VGSC, in a location known to be associated with pyrethroid resistance in another container-inhabiting mosquito, Aedes aegypti L. The observed DDT resistance in populations from Florida may indicate multiple introductions of this species into the USA, possibly from tropical populations. In addition, the mechanisms underlying DDT resistance often result in pyrethroid resistance

  9. Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms

    PubMed Central

    Bishayee, Anupam; Bhatia, Deepak; Thoppil, Roslin J.; Darvesh, Altaf S.; Nevo, Eviatar; Lansky, Ephraim P.

    2011-01-01

    Hepatocellular carcinoma (HCC), one of the most prevalent and lethal cancers, has shown an alarming rise in the USA. Without effective therapy for HCC, novel chemopreventive strategies may effectively circumvent the current morbidity and mortality. Oxidative stress predisposes to hepatocarcinogenesis and is the major driving force of HCC. Pomegranate, an ancient fruit, is gaining tremendous attention due to its powerful antioxidant properties. Here, we examined mechanism-based chemopreventive potential of a pomegranate emulsion (PE) against dietary carcinogen diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis that mimics human HCC. PE treatment (1 or 10 g/kg), started 4 weeks prior to the DENA challenge and continued for 18 weeks thereafter, showed striking chemopreventive activity demonstrated by reduced incidence, number, multiplicity, size and volume of hepatic nodules, precursors of HCC. Both doses of PE significantly attenuated the number and area of γ-glutamyl transpeptidase-positive hepatic foci compared with the DENA control. PE also attenuated DENA-induced hepatic lipid peroxidation and protein oxidation. Mechanistic studies revealed that PE elevated gene expression of an array of hepatic antioxidant and carcinogen detoxifying enzymes in DENA-exposed animals. PE elevated protein and messenger RNA expression of the hepatic nuclear factor E2-related factor 2 (Nrf2). Our results provide substantial evidence, for the first time, that pomegranate constituents afford chemoprevention of hepatocarcinogenesis possibly through potent antioxidant activity achieved by upregulation of several housekeeping genes under the control of Nrf2 without toxicity. The outcome of this study strongly supports the development of pomegranate-derived products in the prevention and treatment of human HCC, which remains a devastating disease. PMID:21389260

  10. The Vulnerability of Vessels Involved in the Role of Embolism and Hypoperfusion in the Mechanisms of Ischemic Cerebrovascular Diseases

    PubMed Central

    2016-01-01

    Accurate definition and better understanding of the mechanisms of stroke are crucial as this will guide the effective care and therapy. In this paper, we review the previous basic and clinical researches on the causes or mechanisms of ischemic cerebrovascular diseases (ICVD) and interpret the correlation between embolism and hypoperfusion based on vascular stenosis and arterial intimal lesions. It was suggested that if there is no embolus (dynamic or in situ emboli), there might be no cerebral infarction. Three kinds of different clinical outcomes of TIA were theoretically interpreted based on its mechanisms. We suppose that there is a correlation between embolism and hypoperfusion, and which mechanisms (hypoperfusion or hypoperfusion induced microemboli) playing the dominant role in each type of ICVD depends on the unique background of arterial intimal lesions (the vulnerability of vessels). That is to say, the vulnerability of vessels is involved in the role of embolism and hypoperfusion in the mechanisms of ischemic cerebrovascular diseases. This inference might enrich and provide better understandings for the underlying etiologies of ischemic cerebrovascular events. PMID:27314040

  11. Kinetics and mechanisms of reactions involving small aromatic reactive intermediates. Annual report

    SciTech Connect

    Lin, M.C.

    1994-04-01

    Phenyl (C{sub 6}H{sub 5}), phenoxy (C{sub 6}H{sub 5}O) and benzyne (C{sub 6}H{sub 4}) are fundamentally important prototype molecules. C{sub 6}H{sub 5} and C{sub 6}H{sub 5}O are also very important reactive intermediates in hydrocarbon combustion systems, particularly with regard to soot formation chemistry, as well as to the combustion chemistry of aromatic additives in gasoline. The authors proposed to study the kinetics and mechanisms of these three benchmark reactive intermediates using two complementary laser diagnostic techniques -- laser resonance absorption (LRA) and resonance enhanced multiphoton ionization mass spectrometry (REMPI/MS). In the first year of this contractual work, they have employed a new type of LRA, i.e. the intra-cavity resonance absorption technique, to measure the rate constants for C{sub 6}H{sub 5} reactions, extending the limit of rate constant measurement down to 10{sup {minus}18} cm{sup 3}/s. They have tested this method for the following reactions: C{sub 6}H{sub 5} + HBr, CH{sub 2}O, O{sub 2}, C{sub 2}H{sub 2} and C{sub 2}H{sub 4} at 297 K and obtained their rate constants to be 3.0 {times} 10{sup {minus}11}, 1.2 {times} 10{sup {minus}14}, 1.0 {times} 10{sup {minus}16}, 7.0 {times} 10{sup {minus}18} and 6.7 {times} 10{sup {minus}18} cm{sup 3}/s, respectively. In the second study, the REMPI spectroscopy of C{sub 6}H{sub 5} is being investigated with the two laser pump-probe surface photolysis method. The desorbed C{sub 6}H{sub 5} photofragment is ionized by (1+1) MPI in the spectral range 200--260 nm. Similarly, the NO photofragment is also detected by (1+1) MPI in the same spectral region. The detailed photofragmentation of the absorbed C{sub 6}H{sub 5}NO at 193 and 248 nm is being analyzed presently and a new experiment with acetophenone on a quartz surface is under way.

  12. The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds

    PubMed Central

    Gray, A M; Spencer, P S J; Sewell, R D E

    1998-01-01

    Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception.All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay.Opioid antagonists, naloxone (0.5 mg kg−1, s.c.) and naltrindole (1 mg kg−1, s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists.The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg−1 (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction.When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception.Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs.These data

  13. Peripheral involvement of PKA and PKC in subcutaneous bee venom-induced persistent nociception, mechanical hyperalgesia, and inflammation in rats.

    PubMed

    Chen, Hui-Sheng; Lei, Jing; He, Xiang; Qu, Fang; Wang, Yang; Wen, Wei-Wei; You, Hao-Jun; Arendt-Nielsen, Lars

    2008-03-01

    The roles of central protein kinases A and C (PKA and PKC) in various pain states have intensively been investigated during the past decade. The aim of the present study was to investigate the peripheral involvement of PKA and PKC in persistent nociceptive response, evoked pain behaviors, and inflammation induced by subcutaneous (s.c.) injection of bee venom (BV, 0.2mg/50 microl) in rats. The effects of intraplantar injection of H-89 (a PKA inhibitor, 5-100 microg/50 microl) and chelerythrine chloride (a PKC inhibitor, 5-100 microg/50 microl) on BV-elicited persistent nociception (nociceptive flinching reflex), mechanical hyperalgesia, and inflammation were systematically investigated. Pre-treatment with H-89 dose-dependently inhibited only BV-induced mechanical hyperalgesia, but not the persistent nociception and inflammation. In contrast, pre-treatment with chelerythrine chloride dose-dependently inhibited BV-induced sustained nociception and inflammation, but not the mechanical hyperalgesia. Topical pre-treatment of the sciatic nerve with 1% capsaicin significantly blocked the inhibitory effects of the PKC inhibitor on BV-induced inflammation, but not the persistent flinching response. These results indicate that peripheral PKA and PKC involvements in BV-induced pain behaviors differ, and capsaicin-sensitive afferents appear to participate in the pro-inflammatory role of PKC in the BV pain model. Findings from the present study also suggest that targeting specific peripheral protein kinases might prove effective in the treatment of persistent pain and inflammation.

  14. New enzymes involved in the mechanism of action of epidermal growth factor in a clonal strain of Leydig tumor cells.

    PubMed

    Castilla, Rocío; Gadaleta, Mariana; Castillo, Ana Fernanda; Duarte, Alejandra; Neuman, Isabel; Paz, Cristina; Cornejo Maciel, Fabiana; Podestá, Ernesto J

    2008-07-01

    The studies presented herein were designed to investigate the effect of mouse epidermal growth factor (mEGF) on arachidonic acid (AA) release in a clonal strain of cultured murine Leydig cells (designed MA-10). In MA-10 cells, mEGF promotes AA release and metabolism to lipoxygenated products to induce the steroidogenic acute regulatory (StAR) protein. However, the mechanism by which mEGF releases AA in these cells is not totally elucidated. We show that mEGF produces an increment in the mitochondrial AA content in a short-term incubation (30 min). This AA is released by the action of a mitochondrial acyl-CoA thioesterase (Acot2), as demonstrated in experiments in which Acot2 was down or overexpressed. This AA in turn regulates the StAR protein expression, indirect evidence of its metabolism to lipoxygenated products. We also show that mEGF induces the expression (mRNA and protein) of Acot2 and an acyl-CoA synthetase that provides the substrate, arachidonyl-CoA, to Acot2. This effect is also observed in another steroidogenic cell line, the adrenocortical Y1 cells. Taken together, our results show that: 1) mEGF can induce the generation of AA in a specific compartment of the cells, i.e. the mitochondria; 2) mEGF can up-regulate acyl-CoA synthetase and Acot2 mRNA and protein levels; and 3) mEGF-stimulated intramitochondrial AA release leads to StAR protein induction.

  15. Transcriptional reporters for genes activated by cell wall stress through a non-catalytic mechanism involving Mpk1 and SBF

    PubMed Central

    Kim, Ki-Young; Levin, David E.

    2011-01-01

    The Mpk1 MAP kinase of the Cell Wall Integrity (CWI) signaling pathway induces transcription of the FKS2 gene in response to cell wall stress through a non-catalytic mechanism that involves stable association of Mpk1 with the Swi4 transcription factor. This dimeric complex binds to a Swi4 recognition site in the FKS2 promoter. The Swi6 transcription factor is also required to bind this ternary complex for transcription initiation to ensue. In this context, the Mlp1 pseudokinase serves a redundant function with Mpk1. We have identified three additional genes, CHA1, YLR042c, and YKR013w that are induced by cell wall stress through the same mechanism. We report on the behavior of several promoter-lacZ reporter plasmids designed to detect cell wall stress transcription through this pathway. PMID:20641022

  16. General Mechanism Involved in Subwavelength Optics of Conducting Microstructures: Charge-Oscillation-Induced Light Emission and Interference

    SciTech Connect

    Huang, X.R.; Peng, Ru-Wen

    2010-03-15

    Interactions between light and conducting microstructures or nanostructures can result in a variety of novel phenomena, but their underlying mechanisms have not been completely understood. From calculations of surface charge density waves on conducting gratings and by comparing them with classical surface plasmons, we revealed a general yet concrete picture regarding the coupling of light to free electron oscillation on structured conducting surfaces that can lead to oscillating subwavelength charge patterns (i.e., structured surface plasmons). New wavelets emitted from these light sources then destructively interfere to form evanescent waves. This principle, usually combined with other mechanisms, is mainly a geometrical effect that can be universally involved in light scattering from all periodic and non-periodic structures containing free electrons. This picture may provide clear guidelines for developing conductor-based nano-optical devices.

  17. Novel Mechanism for Scavenging of Hypochlorite Involving a Periplasmic Methionine-Rich Peptide and Methionine Sulfoxide Reductase

    PubMed Central

    Melnyk, Ryan A.; Youngblut, Matthew D.; Clark, Iain C.; Carlson, Hans K.; Wetmore, Kelly M.; Price, Morgan N.; Iavarone, Anthony T.; Deutschbauer, Adam M.; Arkin, Adam P.

    2015-01-01

    ABSTRACT Reactive chlorine species (RCS) defense mechanisms are important for bacterial fitness in diverse environments. In addition to the anthropogenic use of RCS in the form of bleach, these compounds are also produced naturally through photochemical reactions of natural organic matter and in vivo by the mammalian immune system in response to invading microorganisms. To gain insight into bacterial RCS defense mechanisms, we investigated Azospira suillum strain PS, which produces periplasmic RCS as an intermediate of perchlorate respiration. Our studies identified an RCS response involving an RCS stress-sensing sigma/anti-sigma factor system (SigF/NrsF), a soluble hypochlorite-scavenging methionine-rich periplasmic protein (MrpX), and a putative periplasmic methionine sulfoxide reductase (YedY1). We investigated the underlying mechanism by phenotypic characterization of appropriate gene deletions, chemogenomic profiling of barcoded transposon pools, transcriptome sequencing, and biochemical assessment of methionine oxidation. Our results demonstrated that SigF was specifically activated by RCS and initiated the transcription of a small regulon centering around yedY1 and mrpX. A yedY1 paralog (yedY2) was found to have a similar fitness to yedY1 despite not being regulated by SigF. Markerless deletions of yedY2 confirmed its synergy with the SigF regulon. MrpX was strongly induced and rapidly oxidized by RCS, especially hypochlorite. Our results suggest a mechanism involving hypochlorite scavenging by sacrificial oxidation of the MrpX in the periplasm. Reduced MrpX is regenerated by the YedY methionine sulfoxide reductase activity. The phylogenomic distribution of this system revealed conservation in several Proteobacteria of clinical importance, including uropathogenic Escherichia coli and Brucella spp., implying a putative role in immune response evasion in vivo. PMID:25968643

  18. Arbuscular Mycorrhizal Fungi for the Biocontrol of Plant-Parasitic Nematodes: A Review of the Mechanisms Involved

    PubMed Central

    Schouteden, Nele; De Waele, Dirk; Panis, Bart; Vos, Christine M.

    2015-01-01

    Arbuscular mycorrhizal fungi (AMF) are obligate root symbionts that can protect their host plant against biotic stress factors such as plant-parasitic nematode (PPN) infection. PPN consist of a wide range of species with different life styles that can cause major damage in many important crops worldwide. Various mechanisms have been proposed to play a role in the biocontrol effect of AMF against PPN. This review presents an overview of the different mechanisms that have been proposed, and discusses into more detail the plausibility of their involvement in the biocontrol against PPN specifically. The proposed mechanisms include enhanced plant tolerance, direct competition for nutrients and space, induced systemic resistance (ISR) and altered rhizosphere interactions. Recent studies have emphasized the importance of ISR in biocontrol and are increasingly placing rhizosphere effects on the foreground as well, both of which will be the focal point of this review. Though AMF are not yet widely used in conventional agriculture, recent data help to develop a better insight into the modes of action, which will eventually lead toward future field applications of AMF against PPN. The scientific community has entered an exciting era that provides the tools to actually unravel the underlying molecular mechanisms, making this a timely opportunity for a review of our current knowledge and the challenges ahead. PMID:26635750

  19. Arbuscular Mycorrhizal Fungi for the Biocontrol of Plant-Parasitic Nematodes: A Review of the Mechanisms Involved.

    PubMed

    Schouteden, Nele; De Waele, Dirk; Panis, Bart; Vos, Christine M

    2015-01-01

    Arbuscular mycorrhizal fungi (AMF) are obligate root symbionts that can protect their host plant against biotic stress factors such as plant-parasitic nematode (PPN) infection. PPN consist of a wide range of species with different life styles that can cause major damage in many important crops worldwide. Various mechanisms have been proposed to play a role in the biocontrol effect of AMF against PPN. This review presents an overview of the different mechanisms that have been proposed, and discusses into more detail the plausibility of their involvement in the biocontrol against PPN specifically. The proposed mechanisms include enhanced plant tolerance, direct competition for nutrients and space, induced systemic resistance (ISR) and altered rhizosphere interactions. Recent studies have emphasized the importance of ISR in biocontrol and are increasingly placing rhizosphere effects on the foreground as well, both of which will be the focal point of this review. Though AMF are not yet widely used in conventional agriculture, recent data help to develop a better insight into the modes of action, which will eventually lead toward future field applications of AMF against PPN. The scientific community has entered an exciting era that provides the tools to actually unravel the underlying molecular mechanisms, making this a timely opportunity for a review of our current knowledge and the challenges ahead. PMID:26635750

  20. A novel mechanism involving four-and-a-half LIM domain protein-1 and extracellular signal-regulated kinase-2 regulates titin phosphorylation and mechanics.

    PubMed

    Raskin, Anna; Lange, Stephan; Banares, Katherine; Lyon, Robert C; Zieseniss, Anke; Lee, Leonard K; Yamazaki, Katrina G; Granzier, Henk L; Gregorio, Carol C; McCulloch, Andrew D; Omens, Jeffrey H; Sheikh, Farah

    2012-08-24

    Understanding mechanisms underlying titin regulation in cardiac muscle function is of critical importance given recent compelling evidence that highlight titin mutations as major determinants of human cardiomyopathy. We previously identified a cardiac biomechanical stress-regulated complex at the cardiac-specific N2B region of titin that includes four-and-a-half LIM domain protein-1 (Fhl1) and components of the mitogen-activated protein signaling cascade, which impacted muscle compliance in Fhl1 knock-out cardiac muscle. However, direct regulation of these molecular components in mediating titin N2B function remained unresolved. Here we identify Fhl1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics. We specifically identify titin N2B as a novel substrate of extracellular signal regulated-kinase-2 (Erk2) and demonstrate that Fhl1 directly interferes with Erk2-mediated titin-N2B phosphorylation. We highlight the critical region in titin-N2B that interacts with Fhl1 and residues that are dependent on Erk2-mediated phosphorylation in situ. We also propose a potential mechanism for a known titin-N2B cardiomyopathy-causing mutation that involves this regulatory complex. These studies shed light on a novel mechanism regulating titin-N2B mechano-signaling as well as suggest that dysfunction of these pathways could be important in cardiac disease states affecting muscle compliance.

  1. 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.

  2. Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase.

    PubMed

    Jongkon, Nathjanan; Chotpatiwetchkul, Warot; Gleeson, M Paul

    2015-09-01

    The isocitrate lyase (ICL) superfamily catalyzes the cleavage of the C(2)-C(3) bond of various α-hydroxy acid substrates. Members of the family are found in bacteria, fungi, and plants and include ICL itself, oxaloacetate hydrolase (OAH), 2-methylisocitrate lyase (MICL), and (2R,3S)-dimethylmalate lyase (DMML) among others. ICL and related targets have been the focus of recent studies to treat bacterial and fungal infections, including tuberculosis. The catalytic process by which this family achieves C(2)-C(3) bond breaking is still not clear. Extensive structural studies have been performed on this family, leading to a number of plausible proposals for the catalytic mechanism. In this paper, we have applied quantum mechanical/molecular mechanical (QM/MM) methods to the most recently reported family member, DMML, to assess whether any of the mechanistic proposals offers a clear energetic advantage over the others. Our results suggest that Arg161 is the general base in the reaction and Cys124 is the general acid, giving rise to a rate-determining barrier of approximately 10 kcal/mol. PMID:26224328

  3. Novel mechanism for scavenging of hypochlorite involving a periplasmic methionine-rich peptide and methionine sulfoxide reductase

    DOE PAGES

    Melnyk, Ryan A.; Youngblut, Matthew D.; Clark, Iain C.; Carlson, Hans K.; Wetmore, Kelly M.; Price, Morgan N.; Lavarone, Anthony T.; Deutschbauer, Adam M.; Arkin, Adam P.; Coates, John D.

    2015-05-12

    Reactive chlorine species (RCS) defense mechanisms are important for bacterial fitness in diverse environments. In addition to the anthropogenic use of RCS in the form of bleach, these compounds are also produced naturally through photochemical reactions of natural organic matter and in vivo by the mammalian immune system in response to invading microorganisms. To gain insight into bacterial RCS defense mechanisms, we investigated Azospira suillum strain PS, which produces periplasmic RCS as an intermediate of perchlorate respiration. Our studies identified an RCS response involving an RCS stress-sensing sigma/anti-sigma factor system (SigF/NrsF), a soluble hypochlorite-scavenging methionine-rich periplasmic protein (MrpX), and amore » putative periplasmic methionine sulfoxide reductase (YedY1). We investigated the underlying mechanism by phenotypic characterization of appropriate gene deletions, chemogenomic profiling of barcoded transposon pools, transcriptome sequencing, and biochemical assessment of methionine oxidation. Our results demonstrated that SigF was specifically activated by RCS and initiated the transcription of a small regulon centering around yedY1 and mrpX. A yedY1 paralog (yedY2) was found to have a similar fitness to yedY1 despite not being regulated by SigF. Markerless deletions of yedY2 confirmed its synergy with the SigF regulon. MrpX was strongly induced and rapidly oxidized by RCS, especially hypochlorite. Our results suggest a mechanism involving hypochlorite scavenging by sacrificial oxidation of the MrpX in the periplasm. Reduced MrpX is regenerated by the YedY methionine sulfoxide reductase activity. The phylogenomic distribution of this system revealed conservation in several Proteobacteria of clinical importance, including uropathogenic Escherichia coli and Brucella spp., implying a putative role in immune response evasion in vivo. In addition, bacteria are often stressed in the environment by reactive chlorine species (RCS) of

  4. Novel mechanism for scavenging of hypochlorite involving a periplasmic methionine-rich peptide and methionine sulfoxide reductase

    SciTech Connect

    Melnyk, Ryan A.; Youngblut, Matthew D.; Clark, Iain C.; Carlson, Hans K.; Wetmore, Kelly M.; Price, Morgan N.; Lavarone, Anthony T.; Deutschbauer, Adam M.; Arkin, Adam P.; Coates, John D.

    2015-05-12

    Reactive chlorine species (RCS) defense mechanisms are important for bacterial fitness in diverse environments. In addition to the anthropogenic use of RCS in the form of bleach, these compounds are also produced naturally through photochemical reactions of natural organic matter and in vivo by the mammalian immune system in response to invading microorganisms. To gain insight into bacterial RCS defense mechanisms, we investigated Azospira suillum strain PS, which produces periplasmic RCS as an intermediate of perchlorate respiration. Our studies identified an RCS response involving an RCS stress-sensing sigma/anti-sigma factor system (SigF/NrsF), a soluble hypochlorite-scavenging methionine-rich periplasmic protein (MrpX), and a putative periplasmic methionine sulfoxide reductase (YedY1). We investigated the underlying mechanism by phenotypic characterization of appropriate gene deletions, chemogenomic profiling of barcoded transposon pools, transcriptome sequencing, and biochemical assessment of methionine oxidation. Our results demonstrated that SigF was specifically activated by RCS and initiated the transcription of a small regulon centering around yedY1 and mrpX. A yedY1 paralog (yedY2) was found to have a similar fitness to yedY1 despite not being regulated by SigF. Markerless deletions of yedY2 confirmed its synergy with the SigF regulon. MrpX was strongly induced and rapidly oxidized by RCS, especially hypochlorite. Our results suggest a mechanism involving hypochlorite scavenging by sacrificial oxidation of the MrpX in the periplasm. Reduced MrpX is regenerated by the YedY methionine sulfoxide reductase activity. The phylogenomic distribution of this system revealed conservation in several Proteobacteria of clinical importance, including uropathogenic Escherichia coli and Brucella spp., implying a putative role in immune response evasion in vivo. In addition, bacteria are often

  5. Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries.

    PubMed

    Hedegaard, Elise R; Gouliaev, Anja; Winther, Anna K; Arcanjo, Daniel D R; Aalling, Mathilde; Renaltan, Nirthika S; Wood, Mark E; Whiteman, Matthew; Skovgaard, Nini; Simonsen, Ulf

    2016-01-01

    Endogenous hydrogen sulfide (H2S) is involved in the regulation of vascular tone. We hypothesized that the lowering of calcium and opening of potassium (K) channels as well as calcium-independent mechanisms are involved in H2S-induced relaxation in rat mesenteric small arteries. Amperometric recordings revealed that free [H2S] after addition to closed tubes of sodium hydrosulfide (NaHS), Na2S, and GYY4137 [P-(4-methoxyphenyl)-P-4-morpholinyl-phosphinodithioic acid] were, respectively, 14%, 17%, and 1% of added amount. The compounds caused equipotent relaxations in isometric myographs, but based on the measured free [H2S], GYY4137 caused more relaxation in relation to released free H2S than NaHS and Na2S in rat mesenteric small arteries. Simultaneous measurements of [H2S] and tension showed that 15 µM of free H2S caused 61% relaxation in superior mesenteric arteries. Simultaneous measurements of smooth muscle calcium and tension revealed that NaHS lowered calcium and caused relaxation of NE-contracted arteries, while high extracellular potassium reduced NaHS relaxation without corresponding calcium changes. In NE-contracted arteries, NaHS (1 mM) lowered the phosphorylation of myosin light chain, while phosphorylation of myosin phosphatase target subunit 1 remained unchanged. Protein kinase A and G, inhibitors of guanylate cyclase, failed to reduce NaHS relaxation, whereas blockers of voltage-gated KV7 channels inhibited NaHS relaxation, and blockers of mitochondrial complex I and III abolished NaHS relaxation. Our findings suggest that low micromolar concentrations of free H2S open K channels followed by lowering of smooth muscle calcium, and by another mechanism involving mitochondrial complex I and III leads to uncoupling of force, and hence vasodilation. PMID:26493746

  6. Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries.

    PubMed

    Hedegaard, Elise R; Gouliaev, Anja; Winther, Anna K; Arcanjo, Daniel D R; Aalling, Mathilde; Renaltan, Nirthika S; Wood, Mark E; Whiteman, Matthew; Skovgaard, Nini; Simonsen, Ulf

    2016-01-01

    Endogenous hydrogen sulfide (H2S) is involved in the regulation of vascular tone. We hypothesized that the lowering of calcium and opening of potassium (K) channels as well as calcium-independent mechanisms are involved in H2S-induced relaxation in rat mesenteric small arteries. Amperometric recordings revealed that free [H2S] after addition to closed tubes of sodium hydrosulfide (NaHS), Na2S, and GYY4137 [P-(4-methoxyphenyl)-P-4-morpholinyl-phosphinodithioic acid] were, respectively, 14%, 17%, and 1% of added amount. The compounds caused equipotent relaxations in isometric myographs, but based on the measured free [H2S], GYY4137 caused more relaxation in relation to released free H2S than NaHS and Na2S in rat mesenteric small arteries. Simultaneous measurements of [H2S] and tension showed that 15 µM of free H2S caused 61% relaxation in superior mesenteric arteries. Simultaneous measurements of smooth muscle calcium and tension revealed that NaHS lowered calcium and caused relaxation of NE-contracted arteries, while high extracellular potassium reduced NaHS relaxation without corresponding calcium changes. In NE-contracted arteries, NaHS (1 mM) lowered the phosphorylation of myosin light chain, while phosphorylation of myosin phosphatase target subunit 1 remained unchanged. Protein kinase A and G, inhibitors of guanylate cyclase, failed to reduce NaHS relaxation, whereas blockers of voltage-gated KV7 channels inhibited NaHS relaxation, and blockers of mitochondrial complex I and III abolished NaHS relaxation. Our findings suggest that low micromolar concentrations of free H2S open K channels followed by lowering of smooth muscle calcium, and by another mechanism involving mitochondrial complex I and III leads to uncoupling of force, and hence vasodilation.

  7. Bifidobacterium breve MCC-117 Induces Tolerance in Porcine Intestinal Epithelial Cells: Study of the Mechanisms Involved in the Immunoregulatory Effect

    PubMed Central

    MURATA, Kozue; TOMOSADA, Yohsuke; VILLENA, Julio; CHIBA, Eriko; SHIMAZU, Tomoyuki; ASO, Hisashi; IWABUCHI, Noriyuki; XIAO, Jin-zhong; SAITO, Tadao; KITAZAWA, Haruki

    2014-01-01

    Bifidobacterium breve MCC-117 is able to significantly reduce the expression of inflammatory cytokines in porcine intestinal epithelial (PIE) cells and to improve IL-10 levels in CD4+CD25high Foxp3+ lymphocytes in response to heat-stable enterotoxigenic Escherichia coli (ETEC) pathogen-associated molecular patterns (PAMPs), while the immunoregulatory effect of B. adolescentis ATCC15705 was significantly lower than that observed for the MCC-117 strain. Considering the different capacities of the two bifidobacterium strains to activate toll-like receptor (TLR)-2 and their differential immunoregulatory activities in PIE and immune cells, we hypothesized that comparative studies with both strains could provide important information regarding the molecular mechanism(s) involved in the anti-inflammatory activity of bifidobacteria. In this work, we demonstrated that the anti-inflammatory effect of B. breve MCC-117 was achieved by a complex interaction of multiple negative regulators of TLRs as well as inhibition of multiple signaling pathways. We showed that B. breve MCC-117 reduced heat-stable ETEC PAMP-induced NF-κB, p38 MAPK and PI3 K activation and expression of pro-inflammatory cytokines in PIE cells. In addition, we demonstrated that B. breve MCC-117 may activate TLR2 synergistically and cooperatively with one or more other pattern recognition receptors (PRRs), and that interactions may result in a coordinated sum of signals that induce the upregulation of A20, Bcl-3, Tollip and SIGIRR. Upregulation of these negative regulators could have an important physiological impact on maintaining or reestablishing homeostatic TLR signals in PIE cells. Therefore, in the present study, we gained insight into the molecular mechanisms involved in the immunoregulatory effect of B. breve MCC-117. PMID:24936377

  8. Indirect Cost Recovery as an Issue of Science Policy.

    ERIC Educational Resources Information Center

    Rosenzweig, Robert M.

    1987-01-01

    The history of the debate over federal efforts to reduce indirect cost recovery in federal research grants to universities is outlined and discussed by a former university administrator involved in the policy's formation. (MSE)

  9. Dynamin-2 regulates fusion pore expansion and quantal release through a mechanism that involves actin dynamics in neuroendocrine chromaffin cells.

    PubMed

    González-Jamett, Arlek M; Momboisse, Fanny; Guerra, María José; Ory, Stéphane; Báez-Matus, Ximena; Barraza, Natalia; Calco, Valerie; Houy, Sébastien; Couve, Eduardo; Neely, Alan; Martínez, Agustín D; Gasman, Stéphane; Cárdenas, Ana M

    2013-01-01

    Over the past years, dynamin has been implicated in tuning the amount and nature of transmitter released during exocytosis. However, the mechanism involved remains poorly understood. Here, using bovine adrenal chromaffin cells, we investigated whether this mechanism rely on dynamin's ability to remodel actin cytoskeleton. According to this idea, inhibition of dynamin GTPase activity suppressed the calcium-dependent de novo cortical actin and altered the cortical actin network. Similarly, expression of a small interfering RNA directed against dynamin-2, an isoform highly expressed in chromaffin cells, changed the cortical actin network pattern. Disruption of dynamin-2 function, as well as the pharmacological inhibition of actin polymerization with cytochalasine-D, slowed down fusion pore expansion and increased the quantal size of individual exocytotic events. The effects of cytochalasine-D and dynamin-2 disruption were not additive indicating that dynamin-2 and F-actin regulate the late steps of exocytosis by a common mechanism. Together our data support a model in which dynamin-2 directs actin polymerization at the exocytosis site where both, in concert, adjust the hormone quantal release to efficiently respond to physiological demands.

  10. On the Path of Election and Martyrdom: Some Psychic Mechanisms Involved in the Anders Behring Breivik's Determination as a Terrorist.

    PubMed

    Cotti, Patricia

    2015-08-01

    On 22 July 2011, the Norwegian Anders Behring Breivik carried out two attacks in Oslo that cost the lives of 77 people, injured many others, and plunged the entire Norwegian nation into mourning. When he was arrested, Breivik presented himself as a member of the Knights Templar, whose mission is to defend the Christian Western world. He considers that he has sacrificed himself by his actions for his people and says that he has prepared himself for martyrdom. In analysing Breivik's words and writings, this article attempts to identify the thought mechanisms involved in Breivik's idea of election (megalomania) and martyrology. It highlights the importance of a mechanism of "return to the sender," whereby Breivik returns the reproaches directed at him by an agency of judgment (ego ideal or superegoic object). It emphasizes the existence of a "burning desire" and yearning (Sehnsucht) for this same persecuting superegoic object, an object that Breivik constantly wants to find again, even if in death. Taking into consideration Searles's hypothesis that the sense of being persecuted is a defence against the impossibility of mourning, and also H. Blum's hypothesis that persecutory feelings are indicative of fears of a "regressive loss of object constancy," the different psychic mechanisms and modes of functioning underlying Breivik's terrorist determination are related here to what we know about his affective development and infantile relationships.

  11. On the Path of Election and Martyrdom: Some Psychic Mechanisms Involved in the Anders Behring Breivik's Determination as a Terrorist.

    PubMed

    Cotti, Patricia

    2015-08-01

    On 22 July 2011, the Norwegian Anders Behring Breivik carried out two attacks in Oslo that cost the lives of 77 people, injured many others, and plunged the entire Norwegian nation into mourning. When he was arrested, Breivik presented himself as a member of the Knights Templar, whose mission is to defend the Christian Western world. He considers that he has sacrificed himself by his actions for his people and says that he has prepared himself for martyrdom. In analysing Breivik's words and writings, this article attempts to identify the thought mechanisms involved in Breivik's idea of election (megalomania) and martyrology. It highlights the importance of a mechanism of "return to the sender," whereby Breivik returns the reproaches directed at him by an agency of judgment (ego ideal or superegoic object). It emphasizes the existence of a "burning desire" and yearning (Sehnsucht) for this same persecuting superegoic object, an object that Breivik constantly wants to find again, even if in death. Taking into consideration Searles's hypothesis that the sense of being persecuted is a defence against the impossibility of mourning, and also H. Blum's hypothesis that persecutory feelings are indicative of fears of a "regressive loss of object constancy," the different psychic mechanisms and modes of functioning underlying Breivik's terrorist determination are related here to what we know about his affective development and infantile relationships. PMID:26290947

  12. Opioid Mechanism Involvement in the Synergism Produced by the Combination of Diclofenac and Caffeine in the Formalin Model

    PubMed Central

    Flores-Ramos, José María; Díaz-Reval, M. Irene

    2013-01-01

    Analgesics can be administered in combination with caffeine for improved analgesic effectiveness in a process known as synergism. The mechanisms by which these combinations produce synergism are not yet fully understood. The aim of this study was to analyze whether the administration of diclofenac combined with caffeine produced antinociceptive synergism and whether opioid mechanisms played a role in this event. The formalin model was used to evaluate the antinociception produced by the oral administration of diclofenac, caffeine, or their combination. Opioid involvement was analyzed through intracerebroventricular (i.c.v.) administration of naloxone followed by the oral administration of the study drugs. Diclofenac presented a dose-dependent effect, with a mean effective dose (ED50) of 6.7 mg/kg. Caffeine presented an analgesic effect with a 17–36% range. The combination of subeffective doses of each of the two drugs presented the greatest synergism with an effect of 57.7 ± 5.6%. The maximal antinociceptive effect was obtained with the combination of 10.0 mg/kg diclofenac and 1.0 mg/kg of caffeine, with an effect of 76.7 ± 5.6%. The i.c.v. administration of naloxone inhibited the effect of diclofenac, both separately and combined. In conclusion, caffeine produces antinociceptive synergism when administered in combination with diclofenac, and this synergism is partially mediated by opioid mechanisms at the central level. PMID:27335871

  13. Endosome acidification and receptor trafficking: bafilomycin A1 slows receptor externalization by a mechanism involving the receptor's internalization motif.

    PubMed Central

    Johnson, L S; Dunn, K W; Pytowski, B; McGraw, T E

    1993-01-01

    To examine the relationship between endosome acidification and receptor trafficking, transferrin receptor trafficking was characterized in Chinese hamster ovary cells in which endosome acidification was blocked by treatment with the specific inhibitor of the vacuolar H(+)-ATPase, bafilomycin A1. Elevating endosome pH slowed the receptor externalization rate to approximately one-half of control but did not affect receptor internalization kinetics. The slowed receptor externalization required the receptor's cytoplasmic domain and was largely eliminated by substitutions replacing either of two aromatic amino acids within the receptor's cytoplasmic YTRF internalization motif. These results confirm, using a specific inhibitor of the vacuolar proton pump, that proper endosome acidification is necessary to maintain rapid recycling of intracellular receptors back to the plasma membrane. Moreover, receptor return to the plasma membrane is slowed in the absence of proper endosome acidification by a signal-dependent mechanism involving the receptor's cytoplasmic tyrosine-containing internalization motif. These results, in conjunction with results from other studies, suggest that the mechanism for clustering receptors in plasma membrane clathrin-coated pits may be an example of a more general mechanism that determines the dynamic distribution of membrane proteins among various compartments with luminal acidification playing a crucial role in this process. Images PMID:8167408

  14. Theoretical study of the reaction mechanisms involved in the thermal intramolecular reactions of 1,6-fullerenynes.

    PubMed

    Güell, Mireia; Martín, Nazario; Altable, Margarita; Filippone, Salvatore; Martín-Domenech, Angel; Solà, Miquel

    2007-06-21

    Substitution of a H atom by an alkyl group on the terminal carbon of the alkyne moiety of 1,6-fullerenynes has a strong impact on the products of the reaction undergone by this species after thermal treatment. While the reaction of 1,6-fullerenynes bearing an unsubstituted alkyne moiety results in the cycloaddition of the alkyne group to the fullerene double bond leading to cyclobutene-fused derivatives, the presence of an alkyl substituent leads to the formation of allenes. In the present work, we have performed an exhaustive theoretical analysis of all possible reaction mechanisms leading to cyclobutene-fused derivatives and allenes to offer an explanation of the reactivity differences observed. The results obtained show that formation of cyclobutene-fused derivatives occurs through a stepwise diradical reaction mechanism, while allene formation proceeds through a concerted way involving an uncommon intramolecular ene process. For the 1,6-fullerenynes bearing a substituted alkyne, the ene reaction path leading to allenes has an energy barrier somewhat lower than the stepwise diradical mechanism for the cyclobutene-fused derivative formation, thus explaining the outcome of the reaction.

  15. Indirect combustion noise of auxiliary power units

    NASA Astrophysics Data System (ADS)

    Tam, Christopher K. W.; Parrish, Sarah A.; Xu, Jun; Schuster, Bill

    2013-08-01

    Recent advances in noise suppression technology have significantly reduced jet and fan noise from commercial jet engines. This leads many investigators in the aeroacoustics community to suggest that core noise could well be the next aircraft noise barrier. Core noise consists of turbine noise and combustion noise. There is direct combustion noise generated by the combustion processes, and there is indirect combustion noise generated by the passage of combustion hot spots, or entropy waves, through constrictions in an engine. The present work focuses on indirect combustion noise. Indirect combustion noise has now been found in laboratory experiments. The primary objective of this work is to investigate whether indirect combustion noise is also generated in jet and other engines. In a jet engine, there are numerous noise sources. This makes the identification of indirect combustion noise a formidable task. Here, our effort concentrates exclusively on auxiliary power units (APUs). This choice is motivated by the fact that APUs are relatively simple engines with only a few noise sources. It is, therefore, expected that the chance of success is higher. Accordingly, a theoretical model study of the generation of indirect combustion noise in an Auxiliary Power Unit (APU) is carried out. The cross-sectional areas of an APU from the combustor to the turbine exit are scaled off to form an equivalent nozzle. A principal function of a turbine in an APU is to extract mechanical energy from the flow stream through the exertion of a resistive force. Therefore, the turbine is modeled by adding a negative body force to the momentum equation. This model is used to predict the ranges of frequencies over which there is a high probability for indirect combustion noise generation. Experimental spectra of internal pressure fluctuations and far-field noise of an RE220 APU are examined to identify anomalous peaks. These peaks are possible indirection combustion noise. In the case of the

  16. Light induces changes in activities of Na+/K+-ATPase, H+/K+-ATPase and glutamine synthetase in tissues involved directly or indirectly in light-enhanced calcification in the giant clam, Tridacna squamosa

    PubMed Central

    Ip, Yuen K.; Ching, Biyun; Hiong, Kum C.; Choo, Celine Y. L.; Boo, Mel V.; Wong, Wai P.; Chew, Shit F.

    2015-01-01

    The objective of this study was to determine the effects of 12 h of exposure to light, as compared with 12 h of exposure to darkness (control), on enzymatic activities of transporters involved in the transport of NH+4 or H+, and activities of enzymes involved in converting NH+4 to glutamate/glutamine in inner mantle, outer mantle, and ctenidia of the giant clam, Tridacna squamosa. Exposure to light resulted in a significant increase in the effectiveness of NH+4 in substitution for K+ to activate Na+/K+-ATPase (NKA), manifested as a significant increase in the Na+/NH+4-activated-NKA activity in the inner mantle. However, similar phenomena were not observed in the extensible outer mantle, which contained abundant symbiotic zooxanthellae. Hence, during light-enhanced calcification, H+ released from CaCO3 deposition could react with NH3 to form NH+4 in the extrapallial fluid, and NH+4 could probably be transported into the shell-facing inner mantle epithelium through NKA. Light also induced an increase in the activity of glutamine synthetase, which converts NH+4 and glutamate to glutamine, in the inner mantle. Taken together, these results explained observations reported elsewhere that light induced a significant increase in pH and a significant decrease in ammonia concentration in the extrapallial fluid, as well as a significant increase in the glutamine concentration in the inner mantle, of T. squamosa. Exposure of T. squamosa to light also led to a significant decrease in the N-ethylmaleimide (NEM)-sensitive-V-H+-ATPase (VATPase) in the inner mantle, and significant increases in the Na+/K+-activated-NKA, H+/NH+4-activated-H+/K+-ATPase, and NEM-sensitive-VATPase activities in ctenidia, indicating that light-enhanced calcification might perturb Na+ homeostasis and acid/base balance in the hemolymph, and might involve the active uptake of NH+4 from the environment. This is the first report on light having direct enhancing effects on activities of certain transporters

  17. Light induces changes in activities of Na(+)/K(+)-ATPase, H(+)/K(+)-ATPase and glutamine synthetase in tissues involved directly or indirectly in light-enhanced calcification in the giant clam, Tridacna squamosa.

    PubMed

    Ip, Yuen K; Ching, Biyun; Hiong, Kum C; Choo, Celine Y L; Boo, Mel V; Wong, Wai P; Chew, Shit F

    2015-01-01

    The objective of this study was to determine the effects of 12 h of exposure to light, as compared with 12 h of exposure to darkness (control), on enzymatic activities of transporters involved in the transport of NH(+) 4 or H(+), and activities of enzymes involved in converting NH(+) 4 to glutamate/glutamine in inner mantle, outer mantle, and ctenidia of the giant clam, Tridacna squamosa. Exposure to light resulted in a significant increase in the effectiveness of NH(+) 4 in substitution for K(+) to activate Na(+)/K(+)-ATPase (NKA), manifested as a significant increase in the Na(+)/NH(+) 4-activated-NKA activity in the inner mantle. However, similar phenomena were not observed in the extensible outer mantle, which contained abundant symbiotic zooxanthellae. Hence, during light-enhanced calcification, H(+) released from CaCO3 deposition could react with NH3 to form NH(+) 4 in the extrapallial fluid, and NH(+) 4 could probably be transported into the shell-facing inner mantle epithelium through NKA. Light also induced an increase in the activity of glutamine synthetase, which converts NH(+) 4 and glutamate to glutamine, in the inner mantle. Taken together, these results explained observations reported elsewhere that light induced a significant increase in pH and a significant decrease in ammonia concentration in the extrapallial fluid, as well as a significant increase in the glutamine concentration in the inner mantle, of T. squamosa. Exposure of T. squamosa to light also led to a significant decrease in the N-ethylmaleimide (NEM)-sensitive-V-H(+)-ATPase (VATPase) in the inner mantle, and significant increases in the Na(+)/K(+)-activated-NKA, H(+)/NH(+) 4-activated-H(+)/K(+)-ATPase, and NEM-sensitive-VATPase activities in ctenidia, indicating that light-enhanced calcification might perturb Na(+) homeostasis and acid/base balance in the hemolymph, and might involve the active uptake of NH(+) 4 from the environment. This is the first report on light having direct

  18. Mechanism of action of peptidoglycan O-acetyltransferase B involves a Ser-His-Asp catalytic triad.

    PubMed

    Moynihan, Patrick J; Clarke, Anthony J

    2014-10-01

    The O-acetylation of the essential cell wall polymer peptidoglycan is essential in many bacteria for their integrity and survival, and it is catalyzed by peptidoglycan O-acetlytransferase B (PatB). Using PatB from Neisseria gonorrhoeae as the model, we have shown previously that the enzyme has specificity for polymeric muropeptides that possess tri- and tetrapeptide stems and that rates of reaction increase with increasing degrees of polymerization. Here, we present the catalytic mechanism of action of PatB, the first to be described for an O-acetyltransferase of any bacterial exopolysaccharide. The influence of pH on PatB activity was investigated, and pKa values of 6.4-6.45 and 6.25-6.35 for the enzyme-substrate complex (kcat vs pH) and the free enzyme (kcat·KM(-1) vs pH), respectively, were determined for the respective cosubstrates. The enzyme is partially inactivated by sulfonyl fluorides but not by EDTA, suggesting the participation of a serine residue in its catalytic mechanism. Alignment of the known and hypothetical PatB amino acid sequences identified Ser133, Asp302, and His305 as three invariant amino acid residues that could potentially serve as a catalytic triad. Replacement of Asp302 with Ala resulted in an enzyme with less than 20% residual activity, whereas activity was barely detectable with (His305 → Ala)PatB and (Ser133 → Ala)PatB was totally inactive. The reaction intermediate of the transferase reaction involving acetyl- and propionyl-acyl donors was trapped on both the wild-type and (Asp302 → Ala) enzymes and LC-MS/MS analysis of tryptic peptides identified Ser133 as the catalytic nucleophile. A transacetylase mechanism is proposed based on the mechanism of action of serine esterases. PMID:25215566

  19. Effects of spinal cord stimulation on the flexor reflex and involvement of supraspinal mechanisms: an experimental study in mononeuropathic rats.

    PubMed

    Ren, B; Linderoth, B; Meyerson, B A

    1996-02-01

    The physiological mechanisms responsible for pain relief caused by spinal cord stimulation (SCS) are essentially unknown and recent experimental data are sparse. In the present study the authors explored the possible involvement of supraspinal mechanisms in the effects of SCS applied in rats with experimental mononeuropathy produced by sciatic nerve ligation according to the method of Bennett and Xie or that of Seltzer, et al. Confirming results of a previous study undertaken by the authors, the thresholds of the early component of the flexor reflex (latency 8-12 msec), which is mediated by A fibers, were significantly lower in the nerve-ligated than in the intact leg. In halothane-anesthetized animals the spinal cord was exposed and SCS was applied with parameters similar to those used in clinical SCS. Ten minutes of SCS produced a significant elevation of the lowered threshold of the early flexor component only in the nerve-ligated leg, and this augmentatory effect of SCS persisted for 30 to 40 minutes after cessation of the stimulation. The threshold elevation amounted to between 50% and 80% of the prestimulatory value and it was related to the intensity of SCS. The threshold of the late, C-fiber-mediated component of the flexor reflex was not influenced in either of the legs. After transection of the spinal cord at the T-6 level, there was a moderate threshold increase in both the early and late components in both legs, but the threshold of the early component in the nerve-ligated leg remained lower. Spinal cord stimulation produced an almost identical threshold increase in the early component in the nerve-ligated leg with the same time course as before the transection. There was no effect on the late component of the reflex in either leg. The results indicate that this effect of SCS in mononeuropathic rats does not necessarily involve supraspinal mechanisms; instead SCS is operative at a spinal, segmental level. In view of the similarities between the effects

  20. Mechanisms of a novel anticancer therapeutic strategy involving atmospheric pressure plasma-mediated apoptosis and DNA strand break formation.

    PubMed

    Chung, Woo-Hyun

    2016-01-01

    Atmospheric pressure plasma has been developed for a variety of biomedical applications due to its chemically reactive components. Recently, the plasma has emerged as a promising novel cancer therapy based on its ability to selectively ablate cancer cells while leaving normal cells essentially unaffected. The therapeutic effect of plasma is attributed to intracellular generation of reactive oxygen/nitrogen species (ROS/RNS) leading to mitochondria-mediated apoptosis and to activation of the DNA damage checkpoint signaling pathway via severe DNA strand break formation. However, the biochemical mechanisms responsible for appropriate activation of these physiological events and which pathway is more crucial for plasma-mediated cytotoxicity have not been clarified. Understanding the molecular link between ROS/RNS-mediated apoptosis and DNA damage-involved chromosome instability is critical for the development of more efficacious therapeutic strategies for selective killing of diverse cancer cells.

  1. Metal and metalloid foliar uptake by various plant species exposed to atmospheric industrial fallout: mechanisms involved for lead.

    PubMed

    Schreck, E; Foucault, Y; Sarret, G; Sobanska, S; Cécillon, L; Castrec-Rouelle, M; Uzu, G; Dumat, C

    2012-06-15

    Fine and ultrafine metallic particulate matters (PMs) are emitted from metallurgic activities in peri-urban zones into the atmosphere and can be deposited in terrestrial ecosystems. The foliar transfer of metals and metalloids and their fate in plant leaves remain unclear, although this way of penetration may be a major contributor to the transfer of metals into plants. This study focused on the foliar uptake of various metals and metalloids from enriched PM (Cu, Zn, Cd, Sn, Sb, As, and especially lead (Pb)) resulting from the emissions of a battery-recycling factory. Metal and metalloid foliar uptake by various vegetable species, exhibiting different morphologies, use (food or fodder) and life-cycle (lettuce, parsley and rye-grass) were studied. The mechanisms involved in foliar metal transfer from atmospheric particulate matter fallout, using lead (Pb) as a model element was also investigated. Several complementary techniques (micro-X-ray fluorescence, scanning electron microscopy coupled with energy dispersive X-ray microanalysis and time-of-flight secondary ion mass spectrometry) were used to investigate the localization and the speciation of lead in their edible parts, i.e. leaves. The results showed lead-enriched PM on the surface of plant leaves. Biogeochemical transformations occurred on the leaf surfaces with the formation of lead secondary species (PbCO(3) and organic Pb). Some compounds were internalized in their primary form (PbSO(4)) underneath an organic layer. Internalization through the cuticle or penetration through stomata openings are proposed as two major mechanisms involved in foliar uptake of particulate matter. PMID:22560244

  2. Metal and metalloid foliar uptake by various plant species exposed to atmospheric industrial fallout: mechanisms involved for lead.

    PubMed

    Schreck, E; Foucault, Y; Sarret, G; Sobanska, S; Cécillon, L; Castrec-Rouelle, M; Uzu, G; Dumat, C

    2012-06-15

    Fine and ultrafine metallic particulate matters (PMs) are emitted from metallurgic activities in peri-urban zones into the atmosphere and can be deposited in terrestrial ecosystems. The foliar transfer of metals and metalloids and their fate in plant leaves remain unclear, although this way of penetration may be a major contributor to the transfer of metals into plants. This study focused on the foliar uptake of various metals and metalloids from enriched PM (Cu, Zn, Cd, Sn, Sb, As, and especially lead (Pb)) resulting from the emissions of a battery-recycling factory. Metal and metalloid foliar uptake by various vegetable species, exhibiting different morphologies, use (food or fodder) and life-cycle (lettuce, parsley and rye-grass) were studied. The mechanisms involved in foliar metal transfer from atmospheric particulate matter fallout, using lead (Pb) as a model element was also investigated. Several complementary techniques (micro-X-ray fluorescence, scanning electron microscopy coupled with energy dispersive X-ray microanalysis and time-of-flight secondary ion mass spectrometry) were used to investigate the localization and the speciation of lead in their edible parts, i.e. leaves. The results showed lead-enriched PM on the surface of plant leaves. Biogeochemical transformations occurred on the leaf surfaces with the formation of lead secondary species (PbCO(3) and organic Pb). Some compounds were internalized in their primary form (PbSO(4)) underneath an organic layer. Internalization through the cuticle or penetration through stomata openings are proposed as two major mechanisms involved in foliar uptake of particulate matter.

  3. Involvement of a chromatin modifier in response to mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell injury: Probably an indirect action via the regulation of NFκB/FasL circuitry

    SciTech Connect

    Chen, Shiwei; Dong, Yushu; Xu, Chun; Jiang, Liming; Chen, Yongjie; Jiang, Cheng; Hou, Wugang; Li, Wei

    2013-11-01

    Highlights: •MTA1 expression is upregulated in SCs upon MEHP treatment. •Knockdown of MTA1 in SCs impairs the MEHP-induced NFκB signaling activation. •Knockdown of MTA1 inhibits recruitment of NFκB onto FasL promoter in MEHP-treated SCs. -- Abstract: The Fas/FasL signaling pathway, controlled by nuclear factor-κB (NFκB) at the transcriptional level, is critical for triggering germ cell apoptosis in response to mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell (SC) injury, but the exact regulation mechanism remain unknown. Here, we discovered that expression level of Metastasis associated protein 1 (MTA1), a component of the Mi-2/nucleosome remodeling and deacetylase complex, was upregulated in SCs during the early recovery after MEHP exposure. This expression change was in line with the dynamic changes in germ cell apoptosis in response to MEHP treatment. Furthermore, a knockdown of MTA1 by RNAi in SCs was found to impair the MEHP-induced early activation of NFκB pathway and abolish the recruitment of NFκB onto FasL promoter, which consequently diminished the MEHP-triggered FasL induction. Considering that Fas/FasL is a well characterized apoptosis initiating signaling during SCs injury, our results point to a potential “switch on” effect of MTA1, which may govern the activation of NFκB/FasL cascade in MEHP-insulted SCs. Overall, the MTA1/NFκB/FasL circuit may serve as an important defensive/repairing mechanism to help to control the germ cell quality after SCs injury.

  4. Initial study on the possible mechanisms involved in the effects of high doses of perfluorooctane sulfonate (PFOS) on prolactin secretion.

    PubMed

    Salgado, R; Pereiro, N; López-Doval, S; Lafuente, A

    2015-09-01

    Perfluorooctane sulfonate (PFOS) is a fluorinated organic compound. This chemical is neurotoxic and can alter the pituitary secretion. This is an initial study aimed at knowing the toxic effects of high doses of PFOS on prolactin secretion and the possible mechanisms involved in these alterations. For that, adult male rats were orally treated with 3.0 and 6.0 mg of PFOS/kg body weight (b.w.)/day for 28 days. At the end of the treatment, the serum levels of prolactin and estradiol as well as the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were quantified in the anterior and in the mediobasal hypothalamus. PFOS, at the administered doses, reduced prolactin and estradiol secretion, increased the concentration of dopamine and GABA in the anterior hypothalamus, and decreased the ratios DOPAC/dopamine and HVA/dopamine in this same hypothalamic area. The outcomes reported in this study suggest that (1) high doses of PFOS inhibit prolactin secretion in adult male rats; (2) only the periventricular-hypophysial dopaminergic (PHDA) neurons seem to be involved in this inhibitory effect but not the tuberoinfundibular dopaminergic (TIDA) and the tuberohypophysial dopaminergic (THDA) systems; (3) GABAergic cells from the paraventricular and supraoptic nuclei could be partially responsible for the PFOS action on prolactin secretion; and finally (4) estradiol might take part in the inhibition exerted by elevated concentration of PFOS on prolactin release. PMID:26032630

  5. Rat epileptic seizures evoked by BmK {alpha}IV and its possible mechanisms involved in sodium channels

    SciTech Connect

    Chai Zhifang; Bai Zhantao; Zhang Xuying; Liu Tong; Pang Xueyan; Ji Yonghua . E-mail: yhji@server.shcnc.ac.cn

    2007-05-01

    This study showed that rat unilateral intracerebroventricular injection of BmK {alpha}IV, a sodium channel modulator derived from scorpion Buthus martensi Karsch, induced clusters of spikes, epileptic discharges and convulsion-related behavioral changes. BmK {alpha}IV potently promoted the release of endogenous glutamate from rat cerebrocortical synaptosomes. In vitro examination of the effect of BmK {alpha}IV on intrasynaptosomal free calcium concentration [Ca{sup 2+}]{sub i} and sodium concentration [Na{sup +}]{sub i} revealed that BmK {alpha}IV-evoked glutamate release from synaptosomes was associated with an increase in Ca{sup 2+} and Na{sup +} influx. Moreover, BmK {alpha}IV-mediated glutamate release and ion influx was completely blocked by tetrodotoxin, a blocker of sodium channel. Together, these results suggest that the induction of BmK {alpha}IV-evoked epileptic seizures may be involved in the modulation of BmK {alpha}IV on tetrodotoxin-sensitive sodium channels located on the nerve terminal, which subsequently enhances the Ca{sup 2+} influx to cause an increase of glutamate release. These findings may provide some insight regarding the mechanism of neuronal action of BmK {alpha}IV in the central nervous system for understanding epileptogenesis involved in sodium channels.

  6. Disentangling self- and fairness-related neural mechanisms involved in the ultimatum game: an fMRI study.

    PubMed

    Corradi-Dell'Acqua, Corrado; Civai, Claudia; Rumiati, Raffaella I; Fink, Gereon R

    2013-04-01

    Rejections of unfair offers in the ultimatum game (UG) are commonly assumed to reflect negative emotional arousal mediated by the anterior insula and medial prefrontal cortex. We aimed to disentangle those neural mechanisms associated with direct personal involvement ('I have been treated unfairly') from those associated with fairness considerations, such as the wish to discourage unfair behavior or social norm violations ('this person has been treated unfairly'). For this purpose, we used fMRI and asked participants to play the UG as responders either for themselves (myself) or on behalf of another person (third party). Unfair offers were equally often rejected in both conditions. Neuroimaging data revealed a dissociation between the medial prefrontal cortex, specifically associated with rejections in the myself condition, thus confirming its role in self-related emotional responses, and the left anterior insula, associated with rejections in both myself and third-party conditions, suggesting a role in promoting fair behavior also toward third parties. Our data extend the current understanding of the neural substrate of social decision making, by disentangling the structures sensitive to direct emotional involvement of the self from those implicated in pure fairness considerations.

  7. Tetrahydrocannabinol Induces Brain Mitochondrial Respiratory Chain Dysfunction and Increases Oxidative Stress: A Potential Mechanism Involved in Cannabis-Related Stroke

    PubMed Central

    Wolff, Valérie; Schlagowski, Anna-Isabel; Rouyer, Olivier; Charles, Anne-Laure; Singh, François; Auger, Cyril; Schini-Kerth, Valérie; Marescaux, Christian; Raul, Jean-Sébastien; Zoll, Joffrey; Geny, Bernard

    2015-01-01

    Cannabis has potential therapeutic use but tetrahydrocannabinol (THC), its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities Vmax (complexes I, III, and IV activities), Vsucc (complexes II, III, and IV activities), Vtmpd (complex IV activity), together with mitochondrial coupling (Vmax/V0), were determined in control conditions and after exposure to THC in isolated mitochondria extracted from rat brain, using differential centrifugations. Oxidative stress was also assessed through hydrogen peroxide (H2O2) production, measured with Amplex Red. THC significantly decreased Vmax (−71%; P < 0.0001), Vsucc (−65%; P < 0.0001), and Vtmpd (−3.5%; P < 0.001). Mitochondrial coupling (Vmax/V0) was also significantly decreased after THC exposure (1.8±0.2 versus 6.3±0.7; P < 0.001). Furthermore, THC significantly enhanced H2O2 production by cerebral mitochondria (+171%; P < 0.05) and mitochondrial free radical leak was increased from 0.01±0.01 to 0.10±0.01% (P < 0.001). Thus, THC increases oxidative stress and induces cerebral mitochondrial dysfunction. This mechanism may be involved in young cannabis users who develop ischemic stroke since THC might increase patient's vulnerability to stroke. PMID:25654095

  8. Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms

    PubMed Central

    Shelkovnikova, Tatyana A.; Robinson, Hannah K.; Southcombe, Joshua A.; Ninkina, Natalia; Buchman, Vladimir L.

    2014-01-01

    Fused in sarcoma (FUS) is an RNA-binding protein involved in pathogenesis of several neurodegenerative diseases. Aggregation of mislocalized FUS into non-amyloid inclusions is believed to be pivotal in the development of cell dysfunction, but the mechanism of their formation is unclear. Using transient expression of a panel of deletion and chimeric FUS variants in various cultured cells, we demonstrated that FUS accumulating in the cytoplasm nucleates a novel type of RNA granules, FUS granules (FGs), that are structurally similar but not identical to physiological RNA transport granules. Formation of FGs requires FUS N-terminal prion-like domain and the ability to bind specific RNAs. Clustering of FGs coupled with further recruitment of RNA and proteins produce larger structures, FUS aggregates (FAs), that resemble but are clearly distinct from stress granules. In conditions of attenuated transcription, FAs lose RNA and dissociate into RNA-free FUS complexes that become precursors of large aggresome-like structures. We propose a model of multistep FUS aggregation involving RNA-dependent and RNA-independent stages. This model can be extrapolated to formation of pathological inclusions in human FUSopathies. PMID:24842888

  9. Mechanisms involved in the vasorelaxant effects produced by the acute application of amfepramone in vitro to rat aortic rings

    PubMed Central

    López-Canales, J.S.; Lozano-Cuenca, J.; Muãoz-Islas, E.; Aguilar-Carrasco, J.C.; López-Canales, O.A.; López-Mayorga, R.M.; Castillo-Henkel, E.F.; Valencia-Hernández, I.; Castillo-Henkel, C.

    2015-01-01

    Amfepramone (diethylpropion) is an appetite-suppressant drug used for the treatment of overweight and obesity. It has been suggested that the systemic and central activity of amfepramone produces cardiovascular effects such as transient ischemic attacks and primary pulmonary hypertension. However, it is not known whether amfepramone produces immediate vascular effects when applied in vitro to rat aortic rings and, if so, what mechanisms may be involved. We analyzed the effect of amfepramone on phenylephrine-precontracted rat aortic rings with or without endothelium and the influence of inhibitors or blockers on this effect. Amfepramone produced a concentration-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings that was not affected by the vehicle, atropine, 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. The vasorelaxant effect of amfepramone was significantly attenuated by NG-nitro-L-arginine methyl ester (L-NAME) and tetraethylammonium (TEA), and was blocked by removal of the vascular endothelium. These results suggest that amfepramone had a direct vasorelaxant effect on phenylephrine-precontracted rat aortic rings, and that inhibition of endothelial nitric oxide synthase and the opening of Ca2+-activated K+ channels were involved in this effect. PMID:25831200

  10. Initial study on the possible mechanisms involved in the effects of high doses of perfluorooctane sulfonate (PFOS) on prolactin secretion.

    PubMed

    Salgado, R; Pereiro, N; López-Doval, S; Lafuente, A

    2015-09-01

    Perfluorooctane sulfonate (PFOS) is a fluorinated organic compound. This chemical is neurotoxic and can alter the pituitary secretion. This is an initial study aimed at knowing the toxic effects of high doses of PFOS on prolactin secretion and the possible mechanisms involved in these alterations. For that, adult male rats were orally treated with 3.0 and 6.0 mg of PFOS/kg body weight (b.w.)/day for 28 days. At the end of the treatment, the serum levels of prolactin and estradiol as well as the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were quantified in the anterior and in the mediobasal hypothalamus. PFOS, at the administered doses, reduced prolactin and estradiol secretion, increased the concentration of dopamine and GABA in the anterior hypothalamus, and decreased the ratios DOPAC/dopamine and HVA/dopamine in this same hypothalamic area. The outcomes reported in this study suggest that (1) high doses of PFOS inhibit prolactin secretion in adult male rats; (2) only the periventricular-hypophysial dopaminergic (PHDA) neurons seem to be involved in this inhibitory effect but not the tuberoinfundibular dopaminergic (TIDA) and the tuberohypophysial dopaminergic (THDA) systems; (3) GABAergic cells from the paraventricular and supraoptic nuclei could be partially responsible for the PFOS action on prolactin secretion; and finally (4) estradiol might take part in the inhibition exerted by elevated concentration of PFOS on prolactin release.

  11. Mesobuthus tamulus venom induces acute respiratory distress syndrome in rats involving additional mechanisms as compared to oleic acid model.

    PubMed

    Akella, Aparna; Tiwari, Anil K; Patne, Shashikant C U; Deshpande, Shripad B

    2015-04-01

    The present study was undertaken to determine whether acute respiratory distress syndrome (ARDS) is produced after Mesobuthus tamulus (MBT) envenomation and compared it with oleic acid (OA)-induced ARDS. The trachea, jugular vein and femoral artery were cannulated in anesthetized adult rats. Lethal dose of MBT venom (5 mg/kg) or OA (75 μL) was administered intravenously and the time-dependent changes in respiratory frequency (RF), heart rate (HR) and mean arterial pressure (MAP) were recorded. Minute ventilation (MV) and the PaO2/FiO2 (P/F) ratio were also determined. At the end lungs were excised, one lung was used for histopathological examination and the other was used for determination of pulmonary water content physically. MBT venom or OA produced hypoxemia, pulmonary pathology (alveolar damage, infiltration of inflammatory cells, capillary damage and exudation) and pulmonary edema implicating for ARDS. However, the hypoxemia in MBT venom group was associated with decreased MV, apnea/bradypnea, and bradycardia whereas, in OA group it was seen with increased MV, tachypnea, and tachycardia. Lack of effect of hypoxemic drive on RF/MV or HR in MBT venom group unlike OA group, suggests the involvement of medullary centers. The present results demonstrate that MBT venom produces ARDS. However MBT venom-induced ARDS involves pulmonary as well as extrapulmonary mechanisms.

  12. Evidence for the involvement of descending pain-inhibitory mechanisms in the antinociceptive effect of hecogenin acetate.

    PubMed

    Gama, Kelly Barbosa; Quintans, Jullyana S S; Antoniolli, Angelo R; Quintans-Júnior, Lucindo J; Santana, Wagno Alcântara; Branco, Alexsandro; Soares, Milena Botelho Pereira; Villarreal, Cristiane Flora

    2013-04-26

    Hecogenin is a sapogenin present in the leaves of species from the Agave genus, with a wide spectrum of reported pharmacological activities. The present study was undertaken to evaluate whether hecogenin acetate (1) has antinociceptive properties and to determine its mechanism of action. The nociceptive threshold was evaluated using the tail flick test in mice. Mice motor performance was evaluated in a Rotarod test. By using Fos expression as a marker of neural activation, the involvement of the periaqueductal gray in 1-induced antinociception was evaluated. Intraperitoneal administration of 1 (5-40 mg/kg) produced a dose-dependent increase in the tail flick latency time compared to vehicle-treated group (p < 0.01). Mice treated with 1 (40 mg/kg) did not show motor performance alterations. The antinociception of 1 (40 mg/kg) was prevented by naloxone (nonselective opioid receptor antagonist; 5 mg/kg), CTOP (μ-opioid receptor antagonist; 1 mg/kg), nor-BNI (κ-opioid receptor antagonist; 0.5 mg/kg), naltrindole (δ-opioid receptor antagonist; 3 mg/kg), or glibenclamide (ATP-sensitive K(+) channel blocker; 2 mg/kg). Systemic administration of 1 (5-40 mg/kg) increased the number of Fos positive cells in the periaqueductal gray. The present study has demonstrated for the first time that 1 produces consistent antinociception mediated by opioid receptors and endogenous analgesic mechanisms. PMID:23437926

  13. Induction of nerve growth factor expression and release by mechanical and inflammatory stimuli in chondrocytes: possible involvement in osteoarthritis pain

    PubMed Central

    2014-01-01

    Introduction Nerve growth factor (NGF) level is increased in osteoarthritis (OA) joints and is involved in pain associated with OA. Stimuli responsible for NGF stimulation in chondrocytes are unknown. We investigated whether mechanical stress and proinflammatory cytokines may influence NGF synthesis by chondrocytes. Methods Primary cultures of human OA chondrocytes, newborn mouse articular chondrocytes or cartilage explants were stimulated by increasing amounts of IL-1β, prostaglandin E2 (PGE2), visfatin/nicotinamide phosphoribosyltransferase (NAMPT) or by cyclic mechanical compression (0.5 Hz, 1 MPa). Before stimulation, chondrocytes were pretreated with indomethacin, Apo866, a specific inhibitor of NAMPT enzymatic activity, or transfected by siRNA targeting visfatin/NAMPT. mRNA NGF levels were assessed by real-time quantitative PCR and NGF released into media was determined by ELISA. Results Unstimulated human and mouse articular chondrocytes expressed low levels of NGF (19.2 ± 8.7 pg/mL, 13.5 ± 1.0 pg/mL and 4.4 ± 0.8 pg/mL/mg tissue for human and mouse articular chondrocytes and costal explants, respectively). Mechanical stress induced NGF release in conditioned media. When stimulated by IL-1β or visfatin/NAMPT, a proinflammatory adipokine produced by chondocytes in response to IL-1β, a dose-dependent increase in NGF mRNA expression and NGF release in both human and mouse chondrocyte conditioned media was observed. Visfatin/NAMPT is also an intracellular enzyme acting as the rate-limiting enzyme of the generation of NAD. The expression of NGF induced by visfatin/NAMPT was inhibited by Apo866, whereas IL-1β-mediated NGF expression was not modified by siRNA targeting visfatin/NAMPT. Interestingly, PGE2, which is produced by chondrocytes in response to IL-1β and visfatin/NAMPT, did not stimulate NGF production. Consistently, indomethacin, a cyclooxygenase inhibitor, did not counteract IL-1β-induced NGF production. Conclusions These

  14. The oxidized soot surface: Theoretical study of desorption mechanisms involving oxygenated functionalities and comparison with temperature programed desorption experiments

    NASA Astrophysics Data System (ADS)

    Barco, Gianluca; Maranzana, Andrea; Ghigo, Giovanni; Causà, Mauro; Tonachini, Glauco

    2006-11-01

    The desorption mechanism for oxygenated functionalities on soot is investigated by quantum mechanical calculations on functionalized polycyclic aromatic hydrocarbon (PAH) models and compared with recently published temperature programed desorption-mass spectrometry results. Substituents on PAHs of increasing size (up to 46 carbon atoms in the parent PAH) are chosen to reproduce the local features of an oxidized graphenic soot platelet. Initially, the study is carried out on unimolecular fragmentation (extrusion, in some cases) processes producing HO, CO, or CO2, in model ketones, carboxylic acids, lactones, anhydrides, in one aldehyde, one peroxyacid, one hydroperoxide, one secondary alcohol, and one phenol. Then, a bimolecular process is considered for one of the carboxylic acids. Furthermore, some cooperative effect which can take place by involving two vicinal carboxylic groups (derived from anhydride hydrolysis) is investigated for other four bifunctionalized models. The comparison between the computed fragmentation (desorption) barriers for the assessed mechanisms and the temperature at which maxima occur in TPD spectra (for HO, CO, or CO2 desorption) offers a suggestion for the assignment of these maxima to specific functional groups, i.e., a key to the description of the oxidized surface. Notably, the computations suggest that (1) the desorption mode from a portion of a graphenic platelet functionalized by a carboxylic or lactone groups is significantly dependent from the chemical and geometric local environment. Consequently, we propose that (2) not all carboxylic groups go lost at the relatively low temperatures generally stated, and (3) lactone groups can be identified as producing not only CO2 but also CO.

  15. Spatio-Temporal Expression and Functional Involvement of Transient Receptor Potential Vanilloid 1 in Diabetic Mechanical Allodynia in Rats

    PubMed Central

    Wu, Huang-Hui; Qi, Jian; Shi, Juan; Li, Yun-Qing

    2014-01-01

    Diabetic neuropathic pain (DNP) is one of the most common clinical manifestations of diabetes mellitus (DM), which is characterized by prominent mechanical allodynia (DMA). However, the molecular mechanism underlying it has not fully been elucidated. In this study, we examined the spatio-temporal expression of a major nociceptive channel protein transient receptor potential vanilloid 1 (TRPV1) and analyzed its functional involvement by intrathecal (i.t.) application of TRPV1 antagonists in streptozocin (STZ)-induced DMA rat models. Western blot and immunofluorescent staining results showed that TRPV1 protein level was significantly increased in the soma of the dorsal root ganglion (DRG) neurons on 14 days after STZ treatment (DMA 14 d), whereas those in spinal cord and skin (mainly from the central and peripheral processes of DRG neurons) had already been enhanced on DMA 7 d to peak on DMA 14 d. qRT-PCR experiments confirmed that TRPV1 mRNA level was significantly up-regulated in the DRG on DMA 7 d, indicating a preceding translation of TRPV1 protein in the soma but preferential distribution of this protein to the processes under the DMA conditions. Cell counting assay based on double immunostaining suggested that increased TRPV1-immunoreactive neurons were likely to be small-sized and CGRP-ergic. Finally, single or multiple intrathecal applications of non-specific or specific TRPV1 antagonists, ruthenium red and capsazepine, at varying doses, effectively alleviated DMA, although the effect of the former was more prominent and long-lasting. These results collectively indicate that TRPV1 expression dynamically changes during the development of DMA and this protein may play important roles in mechanical nociception in DRG neurons, presumably through facilitating the release of CGRP. PMID:25020137

  16. Effects and Mechanisms of 3α,5α,-THP on Emotion, Motivation, and Reward Functions Involving Pregnane Xenobiotic Receptor

    PubMed Central

    Frye, Cheryl A.; Paris, J. J.; Walf, A. A.; Rusconi, J. C.

    2011-01-01

    Progestogens [progesterone (P4) and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mechanisms, and sources of neurosteroids have challenged traditional dogma about steroid action. How the P4 metabolite and neurosteroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), influences cellular functions and behavioral processes involved in emotion/affect, motivation, and reward, is the focus of the present review. To further understand these processes, we have utilized an animal model assessing the effects, mechanisms, and sources of 3α,5α-THP. In the ventral tegmental area (VTA), 3α,5α-THP has actions to facilitate affective, and motivated, social behaviors through non-traditional targets, such as GABA, glutamate, and dopamine receptors. 3α,5α-THP levels in the midbrain VTA both facilitate, and/or are enhanced by, affective and social behavior. The pregnane xenobiotic receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. The role of PXR to influence 3α,5α-THP production from central biosynthesis, and/or metabolism of peripheral P4, in the VTA, as well as its role to facilitate, or be increased by, affective/social behaviors is under investigation. Investigating novel behavioral functions of 3α,5α-THP extends our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate affect and motivated processes, such as those important for stress regulation and neuropsychiatric disorders (anxiety, depression, schizophrenia, drug dependence). Thus, further understanding of 3α,5α-THP’s role and mechanisms to enhance affective and motivated processes is

  17. Formation of conical fractures in sedimentary basins: Experiments involving pore fluids and implications for sandstone intrusion mechanisms

    NASA Astrophysics Data System (ADS)

    Mourgues, R.; Bureau, D.; Bodet, L.; Gay, A.; Gressier, J. B.

    2012-01-01

    a flat cone. We make use of a P.I.V. (Particle Imaging Velocimetry) technique to analyse plastic deformation, showing that these inclined fractures are opened in mixed modes. Close to the surface, they change into steep shear bands where fluids can infiltrate. The final morphology of the fracture network is very similar to the common tripartite architecture of various injection complexes, indicating that different mechanisms may be involved in the formation of dykes. Feeder dykes under the sill zones may open as tensile fractures, while overlying dykes may be guided by the deformation induced by the growth of sills. These deformation conditions may also favour the formation of fluid escape structures and pockmarks.

  18. Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy.

    PubMed

    Hu, C; Sun, L; Xiao, L; Han, Y; Fu, X; Xiong, X; Xu, X; Liu, Y; Yang, S; Liu, F; Kanwar, Y S

    2015-01-01

    Diabetic Nephropathy (DN) is believed to be a major microvascular complication of diabetes. The hallmark of DN includes deposition of Extracellular Matrix (ECM) proteins, such as, collagen, laminin and fibronectin in the mesangium and renal tubulo-interstitium of the glomerulus and basement membranes. Such an increased expression of ECM leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis. The characteristic morphologic glomerular mesangial lesion has been described as Kimmelstiel-Wilson nodule, and the process at times is referred to as diabetic nodular glomerulosclerosis. Thus, the accumulation of ECM proteins plays a critical role in the development of DN. The relevant mechanism(s) involved in the increased ECM expression and their regulation in the kidney in diabetic state has been extensively investigated and documented in the literature. Nevertheless, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules including, Notch, Wnt, mTOR, TLRs and small GTPase may play a pivotal role in the modulation of ECM regulation and expression in DN. Such modulation could be operational for instance Notch through Notch1/Jagged1 signaling, Wnt by Wnt/β- catenin pathway and mTOR via PI3-K/Akt/mTOR signaling pathways. All these pathways may be critical in the modulation of ECM expression and tubulo-interstitial fibrosis. In addition, TLRs, mainly the TLR2 and TLR4, by TLR2- dependent and TGF-β-dependent conduits, may modulate ECM expression and generate a fibrogenic response. Small GTPase like Rho, Ras and Rab family by targeting relevant genes may also influence the accumulation of ECM proteins and renal fibrosis in hyperglycemic states. This review summarizes the recent information about the role and mechanisms by which these molecules and signaling pathways

  19. Involvement of RVM-expressed P2X7 receptor in bone cancer pain: mechanism of descending facilitation.

    PubMed

    Huang, Zhang Xiang; Lu, Zhi Jie; Ma, Wei Qing; Wu, Fei Xiang; Zhang, Yu Qiu; Yu, Wei-Feng; Zhao, Zhi Qi

    2014-04-01

    Patients with bone cancer commonly experience bone pain that is severe, intolerable, and difficult to manage. The rostral ventromedial medulla (RVM) plays an important role in the development of chronic pain via descending facilitation of spinal nociception. The compelling evidence shows that glial P2X7 receptor (P2X7R) is involved in the induction and maintenance of chronic pain syndromes. The present study explored the mechanism of glial activation and P2X7R expression underlying the induction of bone cancer pain. The results demonstrated that microglia and astrocytes in the RVM were markedly activated in bone cancer rats, and the expression of P2X7R was significantly upregulated. Injection of Brilliant Blue G (BBG), an inhibitor of P2X7R, into the RVM significantly alleviated pain behaviors of cancer rats, which was supported by intra-RVM injection of RNA interference targeting the P2X7R in the RVM. It is suggested that activation of microglia-expressed P2X7R in the RVM contributes to bone cancer pain. Given that 5-HT in the RVM is involved in modulating spinal nociception, changes in 5-HT and Fos expression were addressed in the spinal cord. Inhibition of P2X7R by BBG or small-interference RNA targeting P2X7 in the RVM markedly reduced 5-HT level and Fos expression in the spinal cord. The data clearly suggest that the activation of microglial P2X7R in the RVM contributes to the development of bone cancer pain via upregulation of spinal 5HT levels by the descending pain facilitatory system.

  20. Amino acid residues involved in the catalytic mechanism of NAD-dependent glutamate dehydrogenase from Halobacterium salinarum.

    PubMed

    Pérez-Pomares, F; Ferrer, J; Camacho, M; Pire, C; LLorca, F; Bonete, M J

    1999-02-01

    The pH dependence of kinetic parameters for a competitive inhibitor (glutarate) was determined in order to obtain information on the chemical mechanism for NAD-dependent glutamate dehydrogenase from Halobacterium salinarum. The maximum velocity is pH dependent, decreasing at low pHs giving a pK value of 7.19+/-0.13, while the V/K for l-glutamate at 30 degrees C decreases at low and high pHs, yielding pK values of 7.9+/-0.2 and 9.8+/-0.2, respectively. The glutarate pKis profile decreases at high pHs, yielding a pK of 9. 59+/-0.09 at 30 degrees C. The values of ionization heat calculated from the change in pK with temperature are: 1.19 x 10(4), 5.7 x 10(3), 7 x 10(3), 6.6 x 10(3) cal mol-1, for the residues involved. All these data suggest that the groups required for catalysis and/or binding are lysine, histidine and tyrosine. The enzyme shows a time-dependent loss in glutamate oxidation activity when incubated with diethyl pyrocarbonate (DEPC). Inactivation follows pseudo-first-order kinetics with a second-order rate constant of 53 M-1min-1. The pKa of the titratable group was pK1=6.6+/-0.6. Inactivation with ethyl acetimidate also shows pseudo-first-order kinetics as well as inactivation with TNM yielding second-order constants of 1.2 M-1min-1 and 2.8 M-1min-1, and pKas of 8.36 and 9.0, respectively. The proposed mechanism involves hydrogen binding of each of the two carboxylic groups to tyrosyl residues; histidine interacts with one of the N-hydrogens of the l-glutamate amino group. We also corroborate the presence of a conservative lysine that has a remarkable ability to coordinate a water molecule that would act as general base.

  1. Effect of supplementation with different fat sources on the mechanisms involved in reproductive performance in lactating dairy cattle.

    PubMed

    Hutchinson, I A; Hennessy, A A; Waters, S M; Dewhurst, R J; Evans, A C O; Lonergan, P; Butler, S T

    2012-07-01

    Supplementary fat positively influences reproductive performance in dairy cattle, although the mechanisms involved are not clearly defined. Our objective was to determine the effects of four different fat supplements on follicle development, plasma steroid hormone concentrations and prostaglandin (PG) synthesis in lactating dairy cattle. Forty-eight early lactation Holstein-Friesian cows (21 primiparous, 27 multiparous) were used in a completely randomized block design. Cows were fed the same basal TMR diet and received one of four fat supplements: (i) palmitic acid (18:0 fatty acid; Control), (ii) flaxseed (rich in 18:3 n-3 fatty acid; Flax), (iii) conjugated linoleic acid (a mixture of cis-9, trans-11 and trans-10, cis-12 isomers; CLA), and (iv) fish oil (rich in 20:5 and 22:6 n-3 fatty acids; FO). All lipid supplements were formulated to be isolipidic; palmitic acid was added as necessary to provide a total lipid supplement intake of 500 g/day. Cows were synchronized to be in estrus on Day 15 of dietary treatment. All antral follicles were counted, and dominant follicles, subordinate follicles and corpora lutea were measured daily via transrectal ovarian ultrasonography for one complete estrous cycle. Blood samples were collected daily, and selected samples were analyzed for progesterone, estradiol, insulin-like growth factor-1, insulin, cholesterol and non-esterified fatty acids. Estrus was synchronized a second time, and liver and endometrial biopsies were collected on Day 7 of the estrous cycle. Gene expression was evaluated for a number of genes involved in prostaglandin synthesis (endometrium) and fatty acid uptake and utilization (liver). Fat supplementation had little effect on follicle development. Cows receiving supplementary n-3 fatty acids had lesser plasma progesterone (P4) and smaller corpora lutea than cows receiving the CLA or Control supplements. Effects of fat supplementation on the endometrial expression of genes involved in PG synthesis were

  2. Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: involvement of glutamate excitotoxicity.

    PubMed

    Cattani, Daiane; de Liz Oliveira Cavalli, Vera Lúcia; Heinz Rieg, Carla Elise; Domingues, Juliana Tonietto; Dal-Cim, Tharine; Tasca, Carla Inês; Mena Barreto Silva, Fátima Regina; Zamoner, Ariane

    2014-06-01

    Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. The aim of this study was to investigate whether Roundup(®) (a glyphosate-based herbicide) leads to neurotoxicity in hippocampus of immature rats following acute (30min) and chronic (pregnancy and lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally with 1% Roundup(®) (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal slices from 15 day old rats were acutely exposed to Roundup(®) (0.00005-0.1%) during 30min and experiments were carried out to determine whether glyphosate affects (45)Ca(2+) influx and cell viability. Moreover, we investigated the pesticide effects on oxidative stress parameters, (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that acute exposure to Roundup(®) (30min) increases (45)Ca(2+) influx by activating NMDA receptors and voltage-dependent Ca(2+) channels, leading to oxidative stress and neural cell death. The mechanisms underlying Roundup(®)-induced neurotoxicity also involve the activation of CaMKII and ERK. Moreover, acute exposure to Roundup(®) increased (3)H-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed that both acute and chronic exposure to Roundup(®) decreased (3)H-glutamate uptake and metabolism, while induced (45)Ca(2+) uptake and (14)C-MeAIB accumulation in immature rat hippocampus. Taken together, these results demonstrated that Roundup(®) might lead to excessive extracellular glutamate levels and consequently to glutamate excitotoxicity and oxidative stress in rat hippocampus.

  3. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability

    PubMed Central

    Cani, P D; Possemiers, S; Van de Wiele, T; Guiot, Y; Everard, A; Rottier, O; Geurts, L; Naslain, D; Neyrinck, A; Lambert, D M; Muccioli, G G; Delzenne, N M

    2009-01-01

    Background and aims: Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes. Methods: Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation. Results: Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota. Conclusion: We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism

  4. Mechanism of Ghrelin-Induced Gastric Contractions in Suncus murinus (House Musk Shrew): Involvement of Intrinsic Primary Afferent Neurons

    PubMed Central

    Mondal, Anupom; Aizawa, Sayaka; Sakata, Ichiro; Goswami, Chayon; Oda, Sen-ichi; Sakai, Takafumi

    2013-01-01

    Here, we have reported that motilin can induce contractions in a dose-dependent manner in isolated Suncus murinus (house musk shrew) stomach. We have also shown that after pretreatment with a low dose of motilin (10−10 M), ghrelin also induces gastric contractions at levels of 10−10 M to 10−7 M. However, the neural mechanism of ghrelin action in the stomach has not been fully revealed. In the present study, we studied the mechanism of ghrelin-induced contraction in vitro using a pharmacological method. The responses to ghrelin in the stomach were almost completely abolished by hexamethonium and were significantly suppressed by the administration of phentolamine, prazosin, ondansetron, and naloxone. Additionally, N-nitro-l-arginine methylester significantly potentiated the contractions. Importantly, the mucosa is essential for ghrelin-induced, but not motilin-induced, gastric contractions. To evaluate the involvement of intrinsic primary afferent neurons (IPANs), which are multiaxonal neurons that pass signals from the mucosa to the myenteric plexus, we examined the effect of the IPAN-related pathway on ghrelin-induced contractions and found that pretreatment with adenosine and tachykinergic receptor 3 antagonists (SR142801) significantly eliminated the contractions and GR113808 (5-hydroxytryptamine receptor 4 antagonist) almost completely eliminated it. The results indicate that ghrelin stimulates and modulates suncus gastric contractions through cholinergic, adrenergic, serotonergic, opioidergic neurons and nitric oxide synthases in the myenteric plexus. The mucosa is also important for ghrelin-induced gastric contractions, and IPANs may be the important interneurons that pass the signal from the mucosa to the myenteric plexus. PMID:23565235

  5. Oral Efficacy of Apigenin against Cutaneous Leishmaniasis: Involvement of Reactive Oxygen Species and Autophagy as a Mechanism of Action

    PubMed Central

    Fonseca-Silva, Fernanda; Inacio, Job D. F.; Canto-Cavalheiro, Marilene M.; Menna-Barreto, Rubem F. S.; Almeida-Amaral, Elmo E.

    2016-01-01

    Background The treatment for leishmaniasis is currently based on pentavalent antimonials and amphotericin B; however, these drugs result in numerous adverse side effects. The lack of affordable therapy has necessitated the urgent development of new drugs that are efficacious, safe, and more accessible to patients. Natural products are a major source for the discovery of new and selective molecules for neglected diseases. In this paper, we evaluated the effect of apigenin on Leishmania amazonensis in vitro and in vivo and described the mechanism of action against intracellular amastigotes of L. amazonensis. Methodology/Principal Finding Apigenin reduced the infection index in a dose-dependent manner, with IC50 values of 4.3 μM and a selectivity index of 18.2. Apigenin induced ROS production in the L. amazonensis-infected macrophage, and the effects were reversed by NAC and GSH. Additionally, apigenin induced an increase in the number of macrophages autophagosomes after the infection, surrounding the parasitophorous vacuole, suggestive of the involvement of host autophagy probably due to ROS generation induced by apigenin. Furthermore, apigenin treatment was also effective in vivo, demonstrating oral bioavailability and reduced parasitic loads without altering serological toxicity markers. Conclusions/Significance In conclusion, our study suggests that apigenin exhibits leishmanicidal effects against L. amazonensis-infected macrophages. ROS production, as part of the mechanism of action, could occur through the increase in host autophagy and thereby promoting parasite death. Furthermore, our data suggest that apigenin is effective in the treatment of L. amazonensis-infected BALB/c mice by oral administration, without altering serological toxicity markers. The selective in vitro activity of apigenin, together with excellent theoretical predictions of oral availability, clear decreases in parasite load and lesion size, and no observed compromises to the overall health

  6. Reversible oxidation of vicinal-thiols motif in sarcoplasmic reticulum calcium regulatory proteins is involved in muscle fatigue mechanism.

    PubMed

    Vázquez, Pável; Tirado-Cortés, Aldo; Álvarez, Rocío; Ronjat, Michel; Amaya, Araceli; Ortega, Alicia

    2016-10-01

    The mechanism underlying fatigue in skeletal muscle (SM) related to the redox-potential hypothesis, ranges from a direct effect of oxygen reactive species, to a number of other free radical intermediates targeting specific amino acids in the Ca(2+)-regulatory proteins of the sarcoplasmic reticulum (SR). In the present study, we investigate the selective oxidation/reduction of the protein motif Cys-(Xn=2-6)-Cys, known as a vicinal thiol group (VTG), present in the SR Ca(2+)-ATPase (SERCA) and in the Ca(2+)-channel ryanodine receptor (RyR) which are modified during muscle fatigue in SM. Selective oxidation of VTG with phenyl arsine oxide (PAO) increases fatigue in rat isolated SM and fatigue is prevented when muscle is previously incubated with a VTG selective reducing agent, 2,3-dimercaptopropanol (British anti-Lewisite (BAL)). In isolated SR membranes, PAO [<0.1mM] modifies SERCA conformation and inhibits ATPase activity but does not affect Ca(2+)-release. However, PAO at [>0.1mM] inhibits SERCA and RyR activities in a reversible manner by selectively reducing them. Interestingly, as observed by differential scanning calorimetry, the conformation of SERCA from fatigued muscle changed in a similar manner as when SERCA VTG where oxidized. The addition of BAL to fatigued muscle restored the structural conformation and activity of SERCA with full recovery of muscle force production after fatigue. We conclude that VTG reversible oxidation of SR Ca(2+) regulatory proteins are involved in muscle contraction/relaxation and are a molecular mechanism to be considered for muscle fatigue.

  7. Gut microbiota-involved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysaccharides in ginseng decoction

    PubMed Central

    Zhou, Shan-Shan; Xu, Jun; Zhu, He; Wu, Jie; Xu, Jin-Di; Yan, Ru; Li, Xiu-Yang; Liu, Huan-Huan; Duan, Su-Min; Wang, Zhuo; Chen, Hu-Biao; Shen, Hong; Li, Song-Lin

    2016-01-01

    Oral decoctions of traditional Chinese medicines (TCMs) serve for therapeutic and prophylactic management of diseases for centuries. Small molecules and polysaccharides are the dominant chemicals co-occurred in the TCM decoction. Small molecules are well-studied by multidisciplinary elaborations, whereas the role of polysaccharides remains largely elusive. Here we explore a gut microbiota-involved mechanism by which TCM polysaccharides restore the homeostasis of gut microbiota and consequently promote the systemic exposure of concomitant small molecules in the decoction. As a case study, ginseng polysaccharides and ginsenosides in Du-Shen-Tang, the decoction of ginseng, were investigated on an over-fatigue and acute cold stress model. The results indicated that ginseng polysaccharides improved intestinal metabolism and absorption of certain ginsenosides, meanwhile reinstated the perturbed holistic gut microbiota, and particularly enhanced the growth of Lactobacillus spp. and Bacteroides spp., two major metabolic bacteria of ginsenosides. By exploring the synergistic actions of polysaccharides with small molecules, these findings shed new light on scientization and rationalization of the classic TCM decoctions in human health care. PMID:26932472

  8. Immunological mechanisms involved in the protection against intestinal taeniosis elicited by oral immunization with Taenia solium calreticulin.

    PubMed

    Leon-Cabrera, Sonia; Cruz-Rivera, Mayra; Mendlovic, Fela; Romero-Valdovinos, Mirza; Vaughan, Gilberto; Salazar, Ana María; Avila, Guillermina; Flisser, Ana

    2012-11-01

    Oral immunization with functional recombinant Taenia solium calreticulin (rTsCRT) induces 37% reduction in tapeworm burden in the experimental model of intestinal taeniosis in hamsters. Furthermore, tapeworms recovered from vaccinated animals exhibit diminished length, being frequently found in more posterior parts of the small intestine. The aim of this study was to analyze the immunological mechanisms involved in protection in response to rTsCRT oral immunization. Hamsters were orally immunized with rTsCRT using cholera toxin (CT) as adjuvant, weekly for 4 weeks. Fifteen days after the last boost animals were challenged with four T. solium cysticerci. Reduction in the adult worm recovery and increased transcription of mRNA for IL-4 and IFN-γ in the mucosa of rTsCRT+CT immunized animals were observed. Immunization also induced goblet cell hyperplasia in the mucosa surrounding the implantation site of the parasite. Specific IgG and IgA antibodies in serum and fecal supernatants were detected after the second immunization, being more pronounced after challenge. Our data suggest that oral vaccination with rTsCRT+CT regulates a local expression of IL-4 and IFN-γ, stimulating secretion of IgA that, together with the increase of goblet cells and mucin production, could result in an unfavorable environment for T. solium promoting an impaired tapeworm development.

  9. The Prothrombotic Tendency in Metabolic Syndrome: Focus on the Potential Mechanisms Involved in Impaired Haemostasis and Fibrinolytic Balance

    PubMed Central

    Russo, Isabella

    2012-01-01

    The metabolic syndrome is a clinical disorder characterized by impairment of glucose metabolism, increased arterial blood pressure, and abdominal obesity. The presence of these clinical features exposes patients to a high risk of atherothrombotic cardiovascular events. The pathogenesis of atherothrombosis in the metabolic syndrome is multifactorial, requiring a close relationship among the main components of the metabolic syndrome, including insulin resistance, alterations of glycaemic and lipid pattern, haemodynamic impairment, and early appearance of endothelial dysfunction. Furthermore, haemostatic alterations involving coagulation balance, fibrinolysis, and platelet function play a relevant role both in the progression of the arterial wall damage and in acute vascular events. The mechanisms linking abdominal obesity with prothrombotic changes in the metabolic syndrome have been identified and partially elucidated on the basis of alterations of each haemostatic variable and defined through the evidence of peculiar dysfunctions in the endocrine activity of adipose tissue responsible of vascular impairment, prothrombotic tendency, and low-grade chronic inflammation. This paper will focus on the direct role of adipose tissue on prothrombotic tendency in patients affected by metabolic syndrome, with adipocytes being able to produce and/or release cytokines and adipokines which deeply influence haemostatic/fibrinolytic balance, platelet function, and proinflammatory state. PMID:24278711

  10. The Deceptively Simple N170 Reflects Network Information Processing Mechanisms Involving Visual Feature Coding and Transfer Across Hemispheres

    PubMed Central

    Ince, Robin A. A.; Jaworska, Katarzyna; Gross, Joachim; Panzeri, Stefano; van Rijsbergen, Nicola J.; Rousselet, Guillaume A.; Schyns, Philippe G.

    2016-01-01

    A key to understanding visual cognition is to determine “where”, “when”, and “how” brain responses reflect the processing of the specific visual features that modulate categorization behavior—the “what”. The N170 is the earliest Event-Related Potential (ERP) that preferentially responds to faces. Here, we demonstrate that a paradigmatic shift is necessary to interpret the N170 as the product of an information processing network that dynamically codes and transfers face features across hemispheres, rather than as a local stimulus-driven event. Reverse-correlation methods coupled with information-theoretic analyses revealed that visibility of the eyes influences face detection behavior. The N170 initially reflects coding of the behaviorally relevant eye contralateral to the sensor, followed by a causal communication of the other eye from the other hemisphere. These findings demonstrate that the deceptively simple N170 ERP hides a complex network information processing mechanism involving initial coding and subsequent cross-hemispheric transfer of visual features. PMID:27550865

  11. Plant-Plant-Microbe Mechanisms Involved in Soil-Borne Disease Suppression on a Maize and Pepper Intercropping System

    PubMed Central

    Mei, Xinyue; Liao, Jingjing; Ding, Xupo; Deng, Weiping; Fan, Limin; He, Xiahong; Vivanco, Jorge M.; Li, Chengyun; Zhu, Youyong; Zhu, Shusheng

    2014-01-01

    Background Intercropping systems could increase crop diversity and avoid vulnerability to biotic stresses. Most studies have shown that intercropping can provide relief to crops against wind-dispersed pathogens. However, there was limited data on how the practice of intercropping help crops against soil-borne Phytophthora disease. Principal Findings Compared to pepper monoculture, a large scale intercropping study of maize grown between pepper rows reduced disease levels of the soil-borne pepper Phytophthora blight. These reduced disease levels of Phytophthora in the intercropping system were correlated with the ability of maize plants to form a “root wall” that restricted the movement of Phytophthora capsici across rows. Experimentally, it was found that maize roots attracted the zoospores of P. capsici and then inhibited their growth. When maize plants were grown in close proximity to each other, the roots produced and secreted larger quantities of 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA) and 6-methoxy-2-benzoxazolinone (MBOA). Furthermore, MBOA, benzothiazole (BZO), and 2-(methylthio)-benzothiazole (MBZO) were identified in root exudates of maize and showed antimicrobial activity against P. capsici. Conclusions Maize could form a “root wall” to restrict the spread of P. capsici across rows in maize and pepper intercropping systems. Antimicrobe compounds secreted by maize root were one of the factors that resulted in the inhibition of P. capsici. These results provide new insights into plant-plant-microbe mechanisms involved in intercropping systems. PMID:25551554

  12. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism.

    PubMed

    Martínez-Vega, Raquel; Garrido, Francisco; Partearroyo, Teresa; Cediel, Rafael; Zeisel, Steven H; Martínez-Álvarez, Concepción; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel; Pajares, María A

    2015-02-01

    Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-related hearing loss. The purpose of this study was to address the impact of folate deficiency on hearing loss and to examine the underlying mechanisms. For this purpose, 2-mo-old C57BL/6J mice (Animalia Chordata Mus musculus) were randomly divided into 2 groups (n = 65 each) that were fed folate-deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7-fold decline in serum folate and a 3-fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL-positive-apoptotic cochlear cells. RT-quantitative PCR and Western blotting showed reduced levels of enzymes catalyzing homocysteine (Hcy) production and recycling, together with a 30% increase in protein homocysteinylation. Redox stress was demonstrated by decreased expression of catalase, glutathione peroxidase 4, and glutathione synthetase genes, increased levels of manganese superoxide dismutase, and NADPH oxidase-complex adaptor cytochrome b-245, α-polypeptide (p22phox) proteins, and elevated concentrations of glutathione species. Altogether, our findings demonstrate, for the first time, that the relationship between hyperhomocysteinemia induced by folate deficiency and premature hearing loss involves impairment of cochlear Hcy metabolism and associated oxidative stress.

  13. Cellular and genetic mechanisms involved in the generation of protective and pathogenic immune responses in human Chagas disease

    PubMed Central

    Dutra, Walderez Ornelas; Menezes, Cristiane Alves Silva; Villani, Fernanda Nobre Amaral; da Costa, Germano Carneiro; da Silveira, Alexandre Barcelos Morais; d’Ávila Reis, Débora; Gollob, Kenneth J

    2012-01-01

    Perhaps one of the most intriguing aspects of human Chagas disease is the complex network of events that underlie the generation of protective versus pathogenic immune responses during the chronic phase of the disease. While most individuals do not develop patent disease, a large percentage may develop severe forms that eventually lead to death. Although many efforts have been devoted to deciphering these mechanisms, there is still much to be learned before we can fully understand the pathogenesis of Chagas disease. It is clear that the host’s immune response is decisive in this process. While characteristics of the parasite influence the immune response, it is becoming evident that the host genetic background plays a fundamental role in the establishment of pathogenic versus protective responses. The involvement of three complex organisms, host, parasite and vector, is certainly one of the key aspects that calls for multidisciplinary approaches towards the understanding of Chagas disease. We believe that now, one hundred years after the discovery of Chagas disease, it is imperative to continue with highly interactive research in order to elucidate the immune response associated with disease evolution, which will be essential in designing prophylactic or therapeutic interventions. PMID:19753476

  14. Gut microbiota-involved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysaccharides in ginseng decoction

    NASA Astrophysics Data System (ADS)

    Zhou, Shan-Shan; Xu, Jun; Zhu, He; Wu, Jie; Xu, Jin-Di; Yan, Ru; Li, Xiu-Yang; Liu, Huan-Huan; Duan, Su-Min; Wang, Zhuo; Chen, Hu-Biao; Shen, Hong; Li, Song-Lin

    2016-03-01

    Oral decoctions of traditional Chinese medicines (TCMs) serve for therapeutic and prophylactic management of diseases for centuries. Small molecules and polysaccharides are the dominant chemicals co-occurred in the TCM decoction. Small molecules are well-studied by multidisciplinary elaborations, whereas the role of polysaccharides remains largely elusive. Here we explore a gut microbiota-involved mechanism by which TCM polysaccharides restore the homeostasis of gut microbiota and consequently promote the systemic exposure of concomitant small molecules in the decoction. As a case study, ginseng polysaccharides and ginsenosides in Du-Shen-Tang, the decoction of ginseng, were investigated on an over-fatigue and acute cold stress model. The results indicated that ginseng polysaccharides improved intestinal metabolism and absorption of certain ginsenosides, meanwhile reinstated the perturbed holistic gut microbiota, and particularly enhanced the growth of Lactobacillus spp. and Bacteroides spp., two major metabolic bacteria of ginsenosides. By exploring the synergistic actions of polysaccharides with small molecules, these findings shed new light on scientization and rationalization of the classic TCM decoctions in human health care.

  15. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels.

    PubMed

    Green, Kim N; Martinez-Coria, Hilda; Khashwji, Hasan; Hall, Eileen B; Yurko-Mauro, Karin A; Ellis, Lorie; LaFerla, Frank M

    2007-04-18

    The underlying cause of sporadic Alzheimer disease (AD) is unknown, but a number of environmental and genetic factors are likely to be involved. One environmental factor that is increasingly being recognized as contributing to brain aging is diet, which has evolved markedly over modern history. Here we show that dietary supplementation with docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, in the 3xTg-AD mouse model of AD reduced the intraneuronal accumulation of both amyloid-beta (Abeta) and tau. In contrast, combining DHA with n-6 fatty acids, either arachidonic acid or docosapentaenoic acid (DPAn-6), diminished the efficacy of DHA over a 12 month period. Here we report the novel finding that the mechanism accounting for the reduction in soluble Abeta was attributable to a decrease in steady-state levels of presenilin 1, and not to altered processing of the amyloid precursor protein by either the alpha- or beta-secretase. Furthermore, the presence of DPAn-6 in the diet reduced levels of early-stage phospho-tau epitopes, which correlated with a reduction in phosphorylated c-Jun N-terminal kinase, a putative tau kinase. Collectively, these results suggest that DHA and DPAn-6 supplementations could be a beneficial natural therapy for AD.

  16. Potential mechanisms involved in resistant phenotype of MCF-7 breast carcinoma cells to ionizing radiation induced apoptosis

    NASA Astrophysics Data System (ADS)

    Wang, Yan-ling; Zhang, Hong; Li, Ning; Wang, Xiao-hu; Hao, Ji-fang; Zhao, Wei-ping

    2009-03-01

    In the present study, we investigated the mechanisms of apoptosis resistance and the roles of the phosphorylation of BRCA1, p21, the Bax/Bcl-2 protein ratio and cell cycle arrest in IR-induced apoptosis in MCF-7 cells. X-irradiation, in particular at low dose (1 Gy), but not carbon ion irradiation, had a significant antiproliferative effect on the growth of MCF-7 cells. 1 Gy X-irradiation resulted in G1 and G2 phase arrest, but 4 Gy induced a significant G1 block. In contrast, carbon ion irradiation resulted in a significant accumulation in the G2 phase. Concomitant with the phosphorylation of H2AX induced by DNA damage, carbon ion irradiation resulted in an approximately 1.9-2.8-fold increase in the phosphorylation of BRCA1 on serine residue 1524, significantly greater than that detected for X-irradiation. Carbon ion irradiation caused a dramatic increase in p21 expression and drastic decrease in Bax expression compared with X-irradiation. The data implicated that phosphorylation of BRCA1 on serine residue 1524 might, at least partially, induce p21 expression but repress Bax expression. Together, our results suggested that the phosphorylation of BRCA1 at Ser-1524 might contribute to the G2 phase arrest and might be an upstream signal involved in preventing apoptosis signal via upregulation of p21 and downregulation of the Bax/Bcl-2 ratio.

  17. A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors

    PubMed Central

    Vicente-Dueñas, Carolina; Romero-Camarero, Isabel; González-Herrero, Inés; Alonso-Escudero, Esther; Abollo-Jiménez, Fernando; Jiang, Xiaoyu; Gutierrez, Norma C; Orfao, Alberto; Marín, Nieves; Villar, Luisa María; Criado, Ma Carmen Fernández; Pintado, Belén; Flores, Teresa; Alonso-López, Diego; De Las Rivas, Javier; Jiménez, Rafael; Criado, Francisco Javier García; Cenador, María Begoña García; Lossos, Izidore S; Cobaleda, César; Sánchez-García, Isidro

    2012-01-01

    Understanding the cellular origin of cancer can help to improve disease prevention and therapeutics. Human plasma cell neoplasias are thought to develop from either differentiated B cells or plasma cells. However, when the expression of Maf oncogenes (associated to human plasma cell neoplasias) is targeted to mouse B cells, the resulting animals fail to reproduce the human disease. Here, to explore early cellular changes that might take place in the development of plasma cell neoplasias, we engineered transgenic mice to express MafB in haematopoietic stem/progenitor cells (HS/PCs). Unexpectedly, we show that plasma cell neoplasias arise in the MafB-transgenic mice. Beyond their clinical resemblance to human disease, these neoplasias highly express genes that are known to be upregulated in human multiple myeloma. Moreover, gene expression profiling revealed that MafB-expressing HS/PCs were more similar to B cells and tumour plasma cells than to any other subset, including wild-type HS/PCs. Consistent with this, genome-scale DNA methylation profiling revealed that MafB imposes an epigenetic program in HS/PCs, and that this program is preserved in mature B cells of MafB-transgenic mice, demonstrating a novel molecular mechanism involved in tumour initiation. Our findings suggest that, mechanistically, the haematopoietic progenitor population can be the target for transformation in MafB-associated plasma cell neoplasias. PMID:22903061

  18. An investigation into membrane bound redox carriers involved in energy transduction mechanism in Brevibacterium linens DSM 20158 with unsequenced genome.

    PubMed

    Shabbiri, Khadija; Botting, Catherine H; Adnan, Ahmad; Fuszard, Matthew; Naseem, Shahid; Ahmed, Safeer; Shujaat, Shahida; Syed, Quratulain; Ahmad, Waqar

    2014-04-01

    Brevibacterium linens (B. linens) DSM 20158 with an unsequenced genome can be used as a non-pathogenic model to study features it has in common with other unsequenced pathogens of the same genus on the basis of comparative proteome analysis. The most efficient way to kill a pathogen is to target its energy transduction mechanism. In the present study, we have identified the redox protein complexes involved in the electron transport chain of B. linens DSM 20158 from their clear homology with the shot-gun genome sequenced strain BL2 of B. linens by using the SDS-Polyacrylamide gel electrophoresis coupled with nano LC-MS/MS mass spectrometry. B. linens is found to have a branched electron transport chain (Respiratory chain), in which electrons can enter the respiratory chain either at NADH (Complex I) or at Complex II level or at the cytochrome level. Moreover, we are able to isolate, purify, and characterize the membrane bound Complex II (succinate dehydrogenase), Complex III (menaquinone cytochrome c reductase cytochrome c subunit, Complex IV (cytochrome c oxidase), and Complex V (ATP synthase) of B. linens strain DSM 20158. PMID:24573306

  19. Newt tail regeneration: a model for gravity-dependent morphogenesis and clues to the molecular mechanisms involved.

    NASA Astrophysics Data System (ADS)

    Radugina, Elena A.; Almeida, Eduardo; Grigoryan, Eleonora

    factors and are expressed during development, we hypothesized they may play a role newt tail regenerative morphogenesis under altered g-levels. Specifically there is increasing evidence for HSPs expression changes as a result of hyper-and microgravity. HSPs are also expressed throughout regeneration, rather than just after surgery. To test this hypothesis we performed heat shock on intact and regenerating newts and collected tail tissues. In these experiments we observed that some tails had uplifted tips while others mimicked hook-like regenerates at 1g or 2g. These findings suggest that heat shock, and HSPs induction, may be involved in the mechanism responsible for gravity effects on morphogenesis, or at least interact with them. Current work underway is focused on analyzing the expression of mRNA and localization of proteins for two members of the group, Hsp70 and Hsp90. In summary, we developed and characterized a new practical animal model in which gravity mechanostimulation at 1g, versus unloading in aquaria, causes prominent effects on newt tail regenerative morphogenesis. This model can be achieved without the use of a centrifuge, significantly simplifying its research applications. Initial results using this model suggest that induction of HSPs may be involved in gravity regulation of newt tail regenerative morphogenesis. Further research based on this simple model may help to unravel mechanisms of gravity influence relevant not only to newt tail regeneration, but also to a broad range of other biological processes in amphibian models.

  20. Direct vs. Indirect Moral Enhancement.

    PubMed

    Schaefer, G Owen

    2015-09-01

    Moral enhancement is an ostensibly laudable project. Who wouldn't want people to become more moral? Still, the project's approach is crucial. We can distinguish between two approaches for moral enhancement: direct and indirect. Direct moral enhancements aim at bringing about particular ideas, motives or behaviors. Indirect moral enhancements, by contrast, aim at making people more reliably produce the morally correct ideas, motives or behaviors without committing to the content of those ideas, motives and/or actions. I will argue, on Millian grounds, that the value of disagreement puts serious pressure on proposals for relatively widespread direct moral enhancement. A more acceptable path would be to focus instead on indirect moral enhancements while staying neutral, for the most part, on a wide range of substantive moral claims. I will outline what such indirect moral enhancement might look like, and why we should expect it to lead to general moral improvement.

  1. Indirect electroanalytical detection of phenols.

    PubMed

    Kolliopoulos, Athanasios V; Kampouris, Dimitrios K; Banks, Craig E

    2015-05-01

    A novel indirect electrochemical protocol for the electroanalytical detection of phenols is presented for the first time. This methodology is demonstrated with the indirect determination of the target analytes phenol, 2-chlorophenol, 4-chlorophenol and 2,4-dichlorophenol through an electrochemically adapted optical protocol. This electrochemical adaptation allows the determination of the above mentioned phenols without the use of any oxidising agents, as is the case in the optical method, where pyrazoline compounds (mediators) chemically react with the target phenols forming a quinoneimine product which is electrochemically active providing an indirect analytical signal to measure the target phenol(s). A range of commercially available pyrazoline substitution products, namely 4-dimethylaminoantipyrine, antipyrine, 3-methyl-1-(2-phenylethyl)-2-pyrazolin-5-one, 3-amino-1-(1-naphthylmethyl)-2-Pyrazolin-5-one, 4-amino-1,2-dimethyl-3-pentadecyl-3-pyrazolin-5-one hydrochloride, 3-amino-1-(2-amino-4-methylsulfonylphenyl)-2-pyrazolin-5-one hydrochloride and 4-aminoantipyrine are evaluated as mediators for the indirect detection of phenols. The indirect electrochemical detection of phenol, 2-chlorophenol, 4-chlorophenol and 2,4-dichlorophenol through the use of 4-aminoantipyrine as a mediator are successfully determined in drinking water samples at analytically useful levels. Finally, the comparison of the direct (no mediator) and the proposed indirect determination (with 4-aminoantipyrine) towards the analytical detection of the target phenols in drinking water is presented. The limitation of the proposed electroanalytical protocol is quantified for all the four target phenols.

  2. Metabotropic glutamate receptor 7 modulates the rewarding effects of cocaine in rats: involvement of a ventral pallidal GABAergic mechanism.

    PubMed

    Li, Xia; Li, Jie; Peng, Xiao-Qing; Spiller, Krista; Gardner, Eliot L; Xi, Zheng-Xiong

    2009-06-01

    The metabotropic glutamate receptor 7 (mGluR7) has received much attention as a potential target for the treatment of epilepsy, major depression, and anxiety. In this study, we investigated the possible involvement of mGluR7 in cocaine reward in animal models of drug addiction. Pretreatment with the selective mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082; 1-20 mg/kg, i.p.) dose-dependently inhibited cocaine-induced enhancement of electrical brain-stimulation reward and intravenous cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement conditions, but failed to alter either basal or cocaine-enhanced locomotion or oral sucrose self-administration, suggesting a specific inhibition of cocaine reward. Microinjections of AMN082 (1-5 microg/microl per side) into the nucleus accumbens (NAc) or ventral pallidum (VP), but not dorsal striatum, also inhibited cocaine self-administration in a dose-dependent manner. Intra-NAc or intra-VP co-administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP, 5 microg/microl per side), a selective mGluR7 allosteric antagonist, significantly blocked AMN082's action, suggesting an effect mediated by mGluR7 in these brain regions. In vivo microdialysis demonstrated that cocaine (10 mg/kg, i.p.) priming significantly elevated extracellular DA in the NAc or VP, while decreasing extracellular GABA in VP (but not in NAc). AMN082 pretreatment selectively blocked cocaine-induced changes in extracellular GABA, but not in DA, in both naive rats and cocaine self-administration rats. These data suggest: (1) mGluR7 is critically involved in cocaine's acute reinforcement; (2) GABA-, but not DA-, dependent mechanisms in the ventral striatopallidal pathway appear to underlie AMN082's actions; and (3) AMN082 or other mGluR7-selective agonists may be useful in the treatment of cocaine addiction.

  3. Insulin-mimetic signaling by the sulfonylurea glimepiride and phosphoinositolglycans involves distinct mechanisms for redistribution of lipid raft components.

    PubMed

    Müller, G; Jung, C; Wied, S; Welte, S; Frick, W

    2001-12-01

    (CIR) is not required for glimepiride-induced glucose transport, IRS-1/2 tyrosine phosphorylation, and redistribution of GPI proteins and NRTK. The data suggest that CIR is involved in concentrating signaling molecules at DIGs vs detergent-insoluble non-DIGs areas. These inhibitory interactions are relieved in response to putative physiological (PIG) or pharmacological (sulfonylurea) stimuli via different molecular mechanisms (dependent on or independent of CIR, respectively) thereby inducing IR-independent positive cross-talk to metabolic insulin signaling.

  4. Mechanisms involved in the antinociception caused by ethanolic extract obtained from the leaves of Melissa officinalis (lemon balm) in mice.

    PubMed

    Guginski, Giselle; Luiz, Ana Paula; Silva, Morgana Duarte; Massaro, Murilo; Martins, Daniel Fernandes; Chaves, Juliana; Mattos, Robson Willain; Silveira, Damaris; Ferreira, Vânia M M; Calixto, João Batista; Santos, Adair R S

    2009-07-01

    The present study examined the antinociceptive effect of the ethanolic extract from Melissa officinalis L. and of the rosmarinic acid in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. The extract (3-1000 mg/kg), given orally (p.o.) 1 h prior to testing, produced dose-dependent inhibition of acetic acid-induced visceral pain, with ID50 value of 241.9 mg/kg. In the formalin test, the extract (30-1000 mg/kg, p.o.) also caused significant inhibition of both, the early (neurogenic pain) and the late (inflammatory pain), phases of formalin-induced licking. The extract (10-1000 mg/kg, p.o.) also caused significant and dose-dependent inhibition of glutamate-induced pain, with ID50 value of 198.5 mg/kg. Furthermore, the rosmarinic acid (0.3-3 mg/kg), given p.o. 1 h prior, produced dose-related inhibition of glutamate-induced pain, with ID50 value of 2.64 mg/kg. The antinociception caused by the extract (100 mg/kg, p.o.) in the glutamate test was significantly attenuated by intraperitoneal (i.p.) treatment of mice with atropine (1 mg/kg), mecamylamine (2 mg/kg) or l-arginine (40 mg/kg). In contrast, the extract (100 mg/kg, p.o.) antinociception was not affected by i.p. treatment with naloxone (1 mg/kg) or D-arginine (40 mg/kg). It was also not associated with non-specific effects, such as muscle relaxation or sedation. Collectively, the present results suggest that the extract produced dose-related antinociception in several models of chemical pain through mechanisms that involved cholinergic systems (i.e. through muscarinic and nicotinic acetylcholine receptors) and the L-arginine-nitric oxide pathway. In addition, the rosmarinic acid contained in this plant appears to contribute for the antinociceptive property of the extract. Moreover, the antinociceptive action demonstrated in the present study supports, at least partly, the ethnomedical uses of this plant. PMID:19358864

  5. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states.

    PubMed

    Levy, Bruno; Desebbe, Olivier; Montemont, Chantal; Gibot, Sebastien

    2008-10-01

    During septic shock, muscle produces lactate by way of an exaggerated NaK-adenosine triphosphatase (ATPase)-stimulated aerobic glycolysis associated with epinephrine stimulation possibly through beta2 adrenoreceptor involvement. It therefore seems logical that a proportion of hyperlactatemia in low cardiac output states would be also related to this mechanism. Thus, in low-flow and normal-to-high-flow models of shock, we investigate (1) whether muscle produces lactate and (2) whether muscle lactate production is linked to beta2 adrenergic stimulation and Na+K+-ATPase. We locally modulated the adrenergic pathway and Na+K+-ATPase activity in male Wistar rats' skeletal muscle using microdialysis with nonselective and selective beta blockers and ouabain in different models of rodent shock (endotoxin, peritonitis, and hemorrhage). Blood flow at the probe site was evaluated by ethanol clearance. We measured the difference between muscle lactate and blood lactate concentration, with a positive gradient indicating muscle lactate or pyruvate production. Epinephrine levels were elevated in all shock groups. All models were associated with hypotension and marked hyperlactatemia. Muscle lactate concentrations were consistently higher than arterial levels, with a mean gradient of 2.5+/-0.3 in endotoxic shock, 2.1+/-0.2 mM in peritonitis group, and 0.9+/-0.2 mM in hemorrhagic shock (P<0.05 for all groups). Muscle pyruvate concentrations were also always higher than arterial levels, with a mean gradient of 260+/-40 microM in endotoxic shock, 210+/-30 microM in peritonitis group, and 90+/-10 microM in hemorrhagic shock (P<0.05 for all groups). Despite a decrease in blood flow, lactate formation was decreased by all the pharmacological agents studied irrespective of shock mechanism. This demonstrates that lactate production during shock states is related, at least in part, to increased NaK-ATPase activity under beta2 stimulation. In shock state associated with a reduced or

  6. Arachnoid cell involvement in the mechanism of coagulation-initiated inflammation in the subarachnoid space after subarachnoid hemorrhage*

    PubMed Central

    Xin, Zhao-liang; Wu, Xiao-kang; Xu, Jian-rong; Li, Xi

    2010-01-01

    the first 3 d, had increased by Day 4. The content of sIL-2r peaked 7.53 ng/ml on Day 7 and then reduced gradually. Conclusions: (1) Basic HLA-DR expression is present in arachnoid cells. (2) After stimulation by bloody CSF, arachnoid cells have the potential to serve as antigen presenting cells (APCs) and the ability to activate T-lymphocytes, indicating that arachnoid cells are involved in the mechanism of coagulation-initiated inflammation in the subarachnoid space after SAH. PMID:20593517

  7. Mechanisms involved in the antinociception caused by ethanolic extract obtained from the leaves of Melissa officinalis (lemon balm) in mice.

    PubMed

    Guginski, Giselle; Luiz, Ana Paula; Silva, Morgana Duarte; Massaro, Murilo; Martins, Daniel Fernandes; Chaves, Juliana; Mattos, Robson Willain; Silveira, Damaris; Ferreira, Vânia M M; Calixto, João Batista; Santos, Adair R S

    2009-07-01

    The present study examined the antinociceptive effect of the ethanolic extract from Melissa officinalis L. and of the rosmarinic acid in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. The extract (3-1000 mg/kg), given orally (p.o.) 1 h prior to testing, produced dose-dependent inhibition of acetic acid-induced visceral pain, with ID50 value of 241.9 mg/kg. In the formalin test, the extract (30-1000 mg/kg, p.o.) also caused significant inhibition of both, the early (neurogenic pain) and the late (inflammatory pain), phases of formalin-induced licking. The extract (10-1000 mg/kg, p.o.) also caused significant and dose-dependent inhibition of glutamate-induced pain, with ID50 value of 198.5 mg/kg. Furthermore, the rosmarinic acid (0.3-3 mg/kg), given p.o. 1 h prior, produced dose-related inhibition of glutamate-induced pain, with ID50 value of 2.64 mg/kg. The antinociception caused by the extract (100 mg/kg, p.o.) in the glutamate test was significantly attenuated by intraperitoneal (i.p.) treatment of mice with atropine (1 mg/kg), mecamylamine (2 mg/kg) or l-arginine (40 mg/kg). In contrast, the extract (100 mg/kg, p.o.) antinociception was not affected by i.p. treatment with naloxone (1 mg/kg) or D-arginine (40 mg/kg). It was also not associated with non-specific effects, such as muscle relaxation or sedation. Collectively, the present results suggest that the extract produced dose-related antinociception in several models of chemical pain through mechanisms that involved cholinergic systems (i.e. through muscarinic and nicotinic acetylcholine receptors) and the L-arginine-nitric oxide pathway. In addition, the rosmarinic acid contained in this plant appears to contribute for the antinociceptive property of the extract. Moreover, the antinociceptive action demonstrated in the present study supports, at least partly, the ethnomedical uses of this plant.

  8. Mechanisms Involved in the Anti-Inflammatory Action of a Polysulfated Fraction from Gracilaria cornea in Rats

    PubMed Central

    Coura, Chistiane Oliveira; Souza, Ricardo Basto; Rodrigues, José Ariévilo Gurgel; Vanderlei, Edfranck de Sousa Oliveira; de Araújo, Ianna Wivianne Fernandes; Ribeiro, Natássia Albuquerque; Frota, Annyta Fernandes; Ribeiro, Kátia Alves; Chaves, Hellíada Vasconcelos; Pereira, Karuza Maria Alves; da Cunha, Rodrigo Maranguape Silva; Bezerra, Mirna Marques; Benevides, Norma Maria Barros

    2015-01-01

    The anti-inflammatory mechanisms of the sulfated polysaccharidic fraction obtained from red marine alga Gracilaria cornea (Gc-FI) were investigated using a paw edema model induced in rats by different inflammatory agents (carrageenan, dextran, serotonin, bradykinin, compound 48/80 or L-arginine). Gc-FI at the doses of 3, 9 or 27 mg/kg, subcutaneously - s.c., significantly inhibited rat paw edema induced by carrageenan and dextran, as confirmed by myeloperoxidase and Evans’ blue assessments, respectively. Gc-FI (9 mg/kg, s.c.) inhibited rat paw edema induced by histamine, compound 48/80 and L-arginine. Additionally, Gc-FI (9 mg/kg, s.c.) inhibited Cg-induced edema in animals with intact mast cells but did not inhibit that with degranulated mast cells by compound 48/80, revealing a protective role on mast cell membranes. Gc-FI down-regulated the IL-1β, TNF-α and COX-2 mRNA and protein levels compared with those of the carrageenan group, based on qRT-PCR and immunohistochemistry analyses. After inhibition with ZnPP IX, a specific heme oxygenase-1 (HO-1) inhibitor, the anti-inflammatory effect of Gc-FI was not observed in Cg-induced paw edema, suggesting that the anti-inflammatory effect of Gc-FI is, in part, dependent on the integrity of the HO-1 pathway. Gc-FI can target a combination of multiple points involved in inflammatory phenomena. PMID:25807556

  9. Mast cells phagocyte Candida albicans and produce nitric oxide by mechanisms involving TLR2 and Dectin-1.

    PubMed

    Pinke, Karen Henriette; Lima, Heliton Gustavo de; Cunha, Fernando Queiroz; Lara, Vanessa Soares

    2016-02-01

    Candida albicans (C. albicans) is a fungus commonly found in the human mucosa, which may cause superficial and systemic infections, especially in immunosuppression. Until now, the main actors in the defense against this fungus are the epithelial cells, neutrophils, macrophages/monocytes and dendritic cells. However, mast cells are strategically located to play a first line of anti-Candida defense and it has appropriate mechanisms to do it. As with other cells, the recognition of C. albicans occurs meanly via TLR2 and Dectin-1. We assess the TLR2/Dectin-1 involvement in phagocytosis and production of nitric oxide (NO) and reactive oxygen species (ROS) by mast cells challenged with C. albicans. Bone marrow-derived mast cells (MC) from wild type (Wt) or knockout (TLR2-/-) mice C57BL/6 were subjected to in vitro Dectin-1 blockade. After challenged with FITC-labeled C. albicans or zymosan, phagocytosis was analyzed by microscopy. The intracellular production of NO and ROS was measured by DAF-FM diacetate and CellROX Deep/Red Reagent kits. The nitrite formation and hydrogen peroxide release were analyzed by Griess reaction and Amplex Red Hydrogen Peroxide/Peroxidase Assay Kit. Wt/MC phagocytose C. albicans with production of intracellular NO, but not ROS. Moreover, increased levels of nitrite were also observed. The absence and/or blockade of TLR2/Dectin-1 caused significant decreased in C. albicans phagocytosis and NO production. Our results showed that mast cells are able to phagocytose and produce NO against C. albicans via TLR2/Dectin-1. Therefore, mast cells could be important during the course of Candida infection and as a therapeutic target.

  10. Antimanic-like activity of candesartan in mice: Possible involvement of antioxidant, anti-inflammatory and neurotrophic mechanisms.

    PubMed

    de Souza Gomes, Júlia Ariana; de Souza, Greicy Coelho; Berk, Michael; Cavalcante, Lígia Menezes; de Sousa, Francisca Cléa F; Budni, Josiane; de Lucena, David Freitas; Quevedo, João; Carvalho, André F; Macêdo, Danielle

    2015-11-01

    Activation of the brain angiotensin II type 1 receptor (AT1R) triggers pro-oxidant and pro-inflammatory mechanisms which are involved in the neurobiology of bipolar disorder (BD). Candesartan (CDS) is an AT1 receptor antagonist with potential neuroprotective properties. Herein we investigated CDS effects against oxidative, neurotrophic inflammatory and cognitive effects of amphetamine (AMPH)-induced mania. In the reversal protocol adult mice were given AMPH 2 mg/kg i.p. or saline and between days 8 and 14 received CDS 0.1, 0.3 or 1 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention treatment, mice were pretreated with CDS, Li or saline prior to AMPH. Locomotor activity and working memory performance were assessed. Glutathione (GSH), thiobarbituric acid-reactive substance (TBARS) and TNF-α levels were evaluated in the hippocampus (HC) and cerebellar vermis (CV). Brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase 3-beta (GSK-3beta) levels were measured in the HC. CDS and Li prevented and reversed the AMPH-induced increases in locomotor activity. Only CDS prevented and reversed AMPH-induced working memory deficits. CDS prevented AMPH-induced alterations in GSH (HC and CV), TBARS (HC and CV), TNF-α (HC and CV) and BDNF (HC) levels. Li prevented alterations in BDNF and phospho-Ser9-GSK3beta. CDS reversed AMPH-induced alterations in GSH (HC and CV), TBARS (HC), TNF-α (CV) and BDNF levels. Li reversed AMPH-induced alterations in TNF-α (HC and CV) and BDNF (HC) levels. CDS is effective in reversing and preventing AMPH-induced behavioral and biochemical alterations, providing a rationale for the design of clinical trials investigating CDS׳s possible therapeutic effects.

  11. Mechanisms involved in carbachol-induced Ca2+ sensitization of contractile elements in rat proximal and distal colon

    PubMed Central

    Takeuchi, Tadayoshi; Kushida, Masahiko; Hirayama, Nobue; Kitayama, Muneyoshi; Fujita, Akikazu; Hata, Fumiaki

    2004-01-01

    Mechanisms involved in Ca2+ sensitization of contractile elements induced by the activation of muscarinic receptors in membrane-permeabilized preparations of the rat proximal and distal colon were studied. In α-toxin-permeabilized preparations from the rat proximal and distal colon, Ca2+ induced a rapid phasic and subsequent tonic component. After Ca2+-induced contraction reached a plateau, guanosine 5′-triphosphate (GTP) and carbachol (CCh) in the presence of GTP further contracted preparations of both the proximal and distal colon (Ca2+ sensitization). Y-27632, a rho-kinase inhibitor, inhibited GTP plus CCh-induced Ca2+ sensitization more significantly in the proximal colon than in the distal colon. Y-27632 at 10 μM had no effect on Ca2+-induced contraction or slightly inhibited phorbol-12,13-dibutyrate-induced Ca2+ sensitization in either proximal or distal colon. Chelerythrine, a protein kinase C inhibitor, inhibited GTP plus CCh-induced Ca2+ sensitization in the distal colon, but not in the proximal colon. The component of Ca2+ sensitization that persisted after the chelerythrine treatment was completely inhibited by Y-27632. In β-escin-permeabilized preparations of the proximal colon, C3 exoenzyme completely inhibited GTP plus CCh-induced Ca2+ sensitization, but PKC(19–31) did not. In the distal colon, C3 exoenzyme abolished GTP-induced Ca2+ sensitization. It inhibited CCh-induced sensitization by 50 % and the remaining component was inhibited by PKC(19–31). These results suggest that both protein kinase C and rho pathways in parallel mediate the Ca2+ sensitization coupled to activation of muscarinic receptors in the rat distal colon, whereas the rho pathway alone mediates this action in the proximal colon. PMID:15159278

  12. Mechanisms involved in the anti-inflammatory action of a polysulfated fraction from Gracilaria cornea in rats.

    PubMed

    Coura, Chistiane Oliveira; Souza, Ricardo Basto; Rodrigues, José Ariévilo Gurgel; Vanderlei, Edfranck de Sousa Oliveira; de Araújo, Ianna Wivianne Fernandes; Ribeiro, Natássia Albuquerque; Frota, Annyta Fernandes; Ribeiro, Kátia Alves; Chaves, Hellíada Vasconcelos; Pereira, Karuza Maria Alves; da Cunha, Rodrigo Maranguape Silva; Bezerra, Mirna Marques; Benevides, Norma Maria Barros

    2015-01-01

    The anti-inflammatory mechanisms of the sulfated polysaccharidic fraction obtained from red marine alga Gracilaria cornea (Gc-FI) were investigated using a paw edema model induced in rats by different inflammatory agents (carrageenan, dextran, serotonin, bradykinin, compound 48/80 or L-arginine). Gc-FI at the doses of 3, 9 or 27 mg/kg, subcutaneously--s.c., significantly inhibited rat paw edema induced by carrageenan and dextran, as confirmed by myeloperoxidase and Evans' blue assessments, respectively. Gc-FI (9 mg/kg, s.c.) inhibited rat paw edema induced by histamine, compound 48/80 and L-arginine. Additionally, Gc-FI (9 mg/kg, s.c.) inhibited Cg-induced edema in animals with intact mast cells but did not inhibit that with degranulated mast cells by compound 48/80, revealing a protective role on mast cell membranes. Gc-FI down-regulated the IL-1β, TNF-α and COX-2 mRNA and protein levels compared with those of the carrageenan group, based on qRT-PCR and immunohistochemistry analyses. After inhibition with ZnPP IX, a specific heme oxygenase-1 (HO-1) inhibitor, the anti-inflammatory effect of Gc-FI was not observed in Cg-induced paw edema, suggesting that the anti-inflammatory effect of Gc-FI is, in part, dependent on the integrity of the HO-1 pathway. Gc-FI can target a combination of multiple points involved in inflammatory phenomena.

  13. The Ang II-induced growth of vascular smooth muscle cells involves a phospholipase D-mediated signaling mechanism.

    PubMed

    Freeman, E J

    2000-02-15

    Angiotensin (Ang) II acts as a mitogen in vascular smooth muscle cells (VSMC) via the activation of multiple signaling cascades, including phospholipase C, tyrosine kinase, and mitogen-activated protein kinase pathways. However, increasing evidence supports signal-activated phospholipases A(2) and D (PLD) as additional mechanisms. Stimulation of PLD results in phosphatidic acid (PA) formation, and PA has been linked to cell growth. However, the direct involvement of PA or its metabolite diacylglycerol (DAG) in Ang II-induced growth is unclear. PLD activity was measured in cultured rat VSMC prelabeled with [(3)H]oleic acid, while the incorporation of [(3)H]thymidine was used to monitor growth. We have previously reported the Ang II-dependent, AT(1)-coupled stimulation of PLD and growth in VSMC. Here, we show that Ang II (100 nM) and exogenous PLD (0.1-100 units/mL; Streptomyces chromofuscus) stimulated thymidine incorporation (43-208% above control). PA (100 nM-1 microM) also increased thymidine incorporation to 135% of control. Propranolol (100 nM-10 microM), which inhibits PA phosphohydrolase, blocked the growth stimulated by Ang II, PLD, or PA by as much as 95%, an effect not shared by other beta-adrenergic antagonists. Propranolol also increased the production of PA in the presence of Ang II by 320% and reduced DAG and arachidonic acid (AA) accumulation. The DAG lipase inhibitor RHC-80267 (1-10 microM) increased Ang II-induced DAG production, while attenuating thymidine incorporation and release of AA. Thus, it appears that activation of PLD, formation of PA, conversion of PA to DAG, and metabolism of DAG comprise an important signaling cascade in Ang II-induced growth of VSMC.

  14. A Functional Selectivity Mechanism at the Serotonin-2A GPCR Involves Ligand-Dependent Conformations of Intracellular Loop 2

    PubMed Central

    2014-01-01

    With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT2AR) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT2AR is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT2AR agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT2AR interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. The findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5-HT2AR activation. PMID:25314362

  15. Direct and Indirect Influence of Non-Native Neighbours on Pollination and Fruit Production of a Native Plant

    PubMed Central

    Montero-Castaño, Ana; Vilà, Montserrat

    2015-01-01

    Background Entomophilous non-native plants can directly affect the pollination and reproductive success of native plant species and also indirectly, by altering the composition and abundance of floral resources in the invaded community. Separating direct from indirect effects is critical for understanding the mechanisms underlying the impacts of non-native species on recipient communities. Objectives Our aims are: (a) to explore both the direct effect of the non-native Hedysarum coronarium and its indirect effect, mediated by the alteration of floral diversity, on the pollinator visitation rate and fructification of the native Leopoldia comosa and (b) to distinguish whether the effects of the non-native species were due to its floral display or to its vegetative interactions. Methods We conducted field observations within a flower removal experimental setup (i.e. non-native species present, absent and with its inflorescences removed) at the neighbourhood scale. Results Our study illustrates the complexity of mechanisms involved in the impacts of non-native species on native species. Overall, Hedysarum increased pollinator visitation rates to Leopoldia target plants as a result of direct and indirect effects acting in the same direction. Due to its floral display, Hedysarum exerted a direct magnet effect attracting visits to native target plants, especially those made by the honeybee. Indirectly, Hedysarum also increased the visitation rate of native target plants. Due to the competition for resources mediated by its vegetative parts, it decreased floral diversity in the neighbourhoods, which was negatively related to the visitation rate to native target plants. Hedysarum overall also increased the fructification of Leopoldia target plants, even though such an increase was the result of other indirect effects compensating for the observed negative indirect effect mediated by the decrease of floral diversity. PMID:26110630

  16. In vitro particulate matter exposure causes direct and lung-mediated indirect effects on cardiomyocyte function

    PubMed Central

    Gorr, Matthew W.; Youtz, Dane J.; Eichenseer, Clayton M.; Smith, Korbin E.; Nelin, Timothy D.; Cormet-Boyaka, Estelle

    2015-01-01

    Particulate matter (PM) exposure induces a pathological response from both the lungs and the cardiovascular system. PM is capable of both manifestation into the lung epithelium and entrance into the bloodstream. Therefore, PM has the capacity for both direct and lung-mediated indirect effects on the heart. In the present studies, we exposed isolated rat cardiomyocytes to ultrafine particulate matter (diesel exhaust particles, DEP) and examined their contractile function and calcium handling ability. In another set of experiments, lung epithelial cells (16HBE14o- or Calu-3) were cultured on permeable supports that allowed access to both the basal (serosal) and apical (mucosal) media; the basal media was used to culture cardiomyocytes to model the indirect, lung-mediated effects of PM on the heart. Both the direct and indirect treatments caused a reduction in contractility as evidenced by reduced percent sarcomere shortening and reduced calcium handling ability measured in field-stimulated cardiomyocytes. Treatment of cardiomyocytes with various anti-oxidants before culture with DEP was able to partially prevent the contractile dysfunction. The basal media from lung epithelial cells treated with PM contained several inflammatory cytokines, and we found that monocyte chemotactic protein-1 was a key trigger for cardiomyocyte dysfunction. These results indicate the presence of both direct and indirect effects of PM on cardiomyocyte function in vitro. Future work will focus on elucidating the mechanisms involved in these separate pathways using in vivo models of air pollution exposure. PMID:25957217

  17. Indirect comparisons of therapeutic interventions

    PubMed Central

    Schöttker, Ben; Lühmann, Dagmar; Boulkhemair, Dalila; Raspe, Heiner

    2009-01-01

    Health political background The comparison of the effectiveness of health technologies is not only laid down in German law (Social Code Book V, § 139 and § 35b) but also constitutes a central element of clinical guidelines and decision making in health care. Tools supporting decision making (e. g. Health Technology Assessments (HTA)) are therefore in need of a valid methodological repertoire for these comparisons. Scientific background Randomised controlled head-to-head trials which directly compare the effects of different therapies are considered the gold standard methodological approach for the comparison of the efficacy of interventions. Because this type of trial is rarely found, comparisons of efficacy often need to rely on indirect comparisons whose validity is being controversially debated. Research questions Research questions for the current assessment are: Which (statistical) methods for indirect comparisons of therapeutic interventions do exist, how often are they applied and how valid are their results in comparison to the results of head-to-head trials? Methods In a systematic literature research all medical databases of the German Institute of Medical Documentation and Information (DIMDI) are searched for methodological papers as well as applications of indirect comparisons in systematic reviews. Results of the literature analysis are summarized qualitatively for the characterisation of methods and quantitatively for the frequency of their application. The validity of the results from indirect comparisons is checked by comparing them to the results from the gold standard – a direct comparison. Data sets from systematic reviews which use both direct and indirect comparisons are tested for consistency by of the z-statistic. Results 29 methodological papers and 106 applications of indirect methods in systematic reviews are being analysed. Four methods for indirect comparisons can be identified: Unadjusted indirect comparisons include, independent of

  18. Low prosocial attachment, involvement with drug-using peers, and adolescent drug use: a longitudinal examination of mediational mechanisms.

    PubMed

    Henry, Kimberly L

    2008-06-01

    The process of disengagement from prosocial entities (e.g., family and school) and either simultaneous or subsequent engagement with antisocial entities (e.g., friends who use drugs) is a critical contributor to adolescent drug use and delinquency. This study provides a series of formal mediation tests to demonstrate the relationship between poor family attachment, poor school attachment, involvement with friends who use drugs, and a student's own use of drugs. Results indicate that poor family attachment exerts its effect on drug use through poor school attachment and involvement with friends who use drugs. In addition, poor school attachment exerts its effect on drug use through involvement with friends who use drugs. The results of this study corroborate theories that suggest disengagement from prosocial entities is associated with involvement with antisocial entities and eventual involvement in drug use. Implications for prevention strategies are discussed.

  19. A Ca2+-induced Ca2+ Release Mechanism Involved in Asynchronous Exocytosis at Frog Motor Nerve Terminals

    PubMed Central

    Narita, K.; Akita, T.; Osanai, M.; Shirasaki, T.; Kijima, H.; Kuba, K.

    1998-01-01

    The extent to which Ca2+-induced Ca2+ release (CICR) affects transmitter release is unknown. Continuous nerve stimulation (20–50 Hz) caused slow transient increases in miniature end-plate potential (MEPP) frequency (MEPP-hump) and intracellular free Ca2+ ([Ca2+]i) in presynaptic terminals (Ca2+-hump) in frog skeletal muscles over a period of minutes in a low Ca2+, high Mg2+ solution. Mn2+ quenched Indo-1 and Fura-2 fluorescence, thus indicating that stimulation was accompanied by opening of voltage-dependent Ca2+ channels. MEPP-hump depended on extracellular Ca2+ (0.05–0.2 mM) and stimulation frequency. Both the Ca2+- and MEPP-humps were blocked by 8-(N,N-diethylamino)octyl3,4,5-trimethoxybenzoate hydrochloride (TMB-8), ryanodine, and thapsigargin, but enhanced by CN−. Thus, Ca2+-hump is generated by the activation of CICR via ryanodine receptors by Ca2+ entry, producing MEPP-hump. A short interruption of tetanus (<1 min) during MEPP-hump quickly reduced MEPP frequency to a level attained under the effect of TMB-8 or thapsigargin, while resuming tetanus swiftly raised MEPP frequency to the previous or higher level. Thus, the steady/equilibrium condition balancing CICR and Ca2+ clearance occurs in nerve terminals with slow changes toward a greater activation of CICR (priming) during the rising phase of MEPP-hump and toward a smaller activation during the decay phase. A short pause applied after the end of MEPP- or Ca2+-hump affected little MEPP frequency or [Ca2+]i, but caused a quick increase (faster than MEPP- or Ca2+-hump) after the pause, whose magnitude increased with an increase in pause duration (<1 min), suggesting that Ca2+ entry-dependent inactivation, but not depriming process, explains the decay of the humps. The depriming process was seen by giving a much longer pause (>1 min). Thus, ryanodine receptors in frog motor nerve terminals are endowed with Ca2+ entry-dependent slow priming and fast inactivation mechanisms, as well as Ca2+ entry

  20. Mechanisms involved in the early increase of serotonin contraction evoked by endotoxin in rat middle cerebral arteries

    PubMed Central

    Hernanz, Raquel; Alonso, María J; Briones, Ana M; Vila, Elisabet; Simonsen, Ulf; Salaices, Mercedes

    2003-01-01

    The present study investigated the mechanisms involved in the increased 5-hydroxytryptamine (5-HT) vasoconstriction observed in rat middle cerebral arteries exposed in vitro to lipopolysaccharide (LPS, 10 μg ml−1) for 1–5 h. Functional, immunohistochemical and Western blot analysis and superoxide anion measurements by ethidium fluorescence were performed. LPS exposure increased 5-HT (10 μM) vasoconstriction only during the first 4 h. In contrast to control tissue, indomethacin (10 μM), the COX-2 inhibitor NS 398 (10 μM), the TXA2/PGH2 receptor antagonist SQ 29,548 (1 μM) and the TXA2 synthase inhibitor furegrelate (1 μM) reduced 5-HT contraction of LPS-treated arteries from hour one. The iNOS inhibitor aminoguanidine (0.1 mM) increased 5-HT contraction from hour three of LPS incubation. The superoxide anion scavenger superoxide dismutase (SOD, 100 U ml−1) and the H2O2 scavenger catalase (1000 U ml−1), as well as the respective inhibitors of NAD(P)H oxidase and xanthine oxidase, apocynin (0.3 mM) and allopurinol (0.3 mM), reduced 5-HT contraction after LPS incubation. LPS induced an increase in superoxide anion levels that was abolished by PEG-SOD. Subthreshold concentrations of the TXA2 analogue U 46619, xanthine/xanthine oxidase and H2O2 potentiated, whereas those of sodium nitroprusside inhibited, the 5-HT contraction. COX-2 expression was increased at 1 and 5 h of LPS incubation, while that of iNOS, Cu/Zn-SOD and Mn-SOD was only increased after 5 h. All the three vascular layers expressed COX-2 and Cu/Zn-SOD. iNOS expression was detected in the endothelium and adventitia after LPS. In conclusion, increased production of TXA2 from COX-2, superoxide anion and H2O2 enhanced vasoconstriction to 5-HT during the first few hours of LPS exposure; iNOS and SOD expression counteracted that increase at 5 h. These changes can contribute to the disturbance of cerebral blood flow in endotoxic shock. PMID:14534151

  1. Thermodynamic analysis of ionizable groups involved in the catalytic mechanism of human matrix metalloproteinase 7 (MMP-7).

    PubMed

    Takeharu, Hitoshi; Yasukawa, Kiyoshi; Inouye, Kuniyo

    2011-12-01

    Human matrix metalloproteinase 7 (MMP-7) exhibits a broad bell-shaped pH-dependence with the acidic and alkaline pK(e) (pK(e1) and pK(e2)) values of about 4 and 10. In this study, we estimated the ionizable groups involved in its catalytic mechanism by thermodynamic analysis. pK(a) of side chains of L-Asp, L-Glu, L-His, L-Cys, L-Tyr, L-Lys, and L-Arg at 25-45°C were determined by the pH titration of amino-acid solutions, from which their enthalpy changes, ∆H°, of deprotonation were calculated. pK(e1) and pK(e2) of MMP-7 at 15-45°C were determined in the hydrolysis of (7-methoxycoumarin-4-yl)acetyl-L-Pro-L-Leu-Gly-L-Leu-[N(3)-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl]-L-Ala-L-Arg-NH(2), from which ∆H(o) for pK(e1) and pK(e2) was calculated. The ∆H(o) for pK(e1) (-20.6±6.1kJmol(-1)) was similar to that for L-Glu (-23.6±5.8kJmol(-1)), and the ∆H(o) for pK(e2) (89.9±4.0kJmol(-1)) was similar to those for L-Arg (87.6±5.5kJmol(-1)) and L-Lys (70.4±4.4kJmol(-1)). The mutation of the active-site residue Glu198 into Ala completely abolished the activity, suggesting that Glu198 is the ionizable group for pK(e1). On the other hand, no arginine or lysine residues are found in the active site of MMP-7. We proposed a possibility that a protein-bound water is the ionizable group for pK(e2).

  2. Indirect pulp capping: a survey.

    PubMed

    Kaplowitz, G J

    1992-01-01

    This study addresses the acceptance of the clinical practice of indirect pulp capping. State and regional dental boards and postgraduate dental education programs throughout the United States were surveyed. Results indicate that no clear consensus exists for the acceptance of this clinical procedure.

  3. Water Rockets and Indirect Measurement.

    ERIC Educational Resources Information Center

    Inman, Duane

    1997-01-01

    Describes an activity that teaches a number of scientific concepts including indirect measurement, Newton's third law of motion, manipulating and controlling variables, and the scientific method of inquiry. Uses process skills such as observation, inference, prediction, mensuration, and communication as well as problem solving and higher-order…

  4. Indirect methods in nuclear astrophysics

    NASA Astrophysics Data System (ADS)

    Bertulani, C. A.; Shubhchintak; Mukhamedzhanov, A.; Kadyrov, A. S.; Kruppa, A.; Pang, D. Y.

    2016-04-01

    We discuss recent developments in indirect methods used in nuclear astrophysics to determine the capture cross sections and subsequent rates of various stellar burning processes, when it is difficult to perform the corresponding direct measurements. We discuss in brief, the basic concepts of Asymptotic Normalization Coefficients, the Trojan Horse Method, the Coulomb Dissociation Method, (d,p), and charge-exchange reactions.

  5. 19 CFR 10.816 - Indirect materials.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Indirect materials. 10.816 Section 10.816 Customs... Rules of Origin § 10.816 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  6. 19 CFR 10.776 - Indirect materials.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Indirect materials. 10.776 Section 10.776 Customs... Rules of Origin § 10.776 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  7. 19 CFR 10.816 - Indirect materials.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Indirect materials. 10.816 Section 10.816 Customs... Rules of Origin § 10.816 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  8. 19 CFR 10.776 - Indirect materials.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 1 2013-04-01 2013-04-01 false Indirect materials. 10.776 Section 10.776 Customs... Rules of Origin § 10.776 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  9. 19 CFR 10.776 - Indirect materials.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Indirect materials. 10.776 Section 10.776 Customs... Rules of Origin § 10.776 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  10. 19 CFR 10.879 - Indirect materials.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Indirect materials. 10.879 Section 10.879 Customs... of Origin § 10.879 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  11. 19 CFR 10.816 - Indirect materials.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Indirect materials. 10.816 Section 10.816 Customs... Rules of Origin § 10.816 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  12. 19 CFR 10.776 - Indirect materials.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Indirect materials. 10.776 Section 10.776 Customs... Rules of Origin § 10.776 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  13. 19 CFR 10.879 - Indirect materials.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Indirect materials. 10.879 Section 10.879 Customs... of Origin § 10.879 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  14. 19 CFR 10.879 - Indirect materials.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Indirect materials. 10.879 Section 10.879 Customs... of Origin § 10.879 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  15. 19 CFR 10.816 - Indirect materials.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Indirect materials. 10.816 Section 10.816 Customs... Rules of Origin § 10.816 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  16. 19 CFR 10.776 - Indirect materials.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Indirect materials. 10.776 Section 10.776 Customs... Rules of Origin § 10.776 Indirect materials. Indirect materials are to be disregarded in determining..., except that the cost of such indirect materials may be included in meeting the value-content...

  17. The Minicommunity Design to Assess Indirect Effects of Vaccination

    PubMed Central

    Halloran, M. Elizabeth

    2013-01-01

    We propose the minicommunity design to estimate indirect effects of vaccination. Establishing indirect effects of vaccination in unvaccinated subpopulations could have important implications for global vaccine policies. In the minicommunity design, the household or other small transmission unit serves as the cluster in which to estimate indirect effects of vaccination, similar to studies in larger communities to estimate indirect, total, and overall effects. Examples from the literature include studies in small transmission units to estimate indirect effects of pertussis, pneumococcal, influenza, and cholera vaccines. We characterize the minicommunity design by several methodologic considerations, including the assignment mechanism, ascertainment, the role of transmission outside the transmission unit, and the relation of the size of the transmission unit to number of people vaccinated. The minicommunity study for indirect effects is contrasted with studies to estimate vaccine effects on infectiousness and protective effects under conditions of household exposure within small transmission units. The minicommunity design can be easily implemented in individually randomized studies by enrolling and following-up members of households of the randomized individuals. The methodology for the minicommunity design for estimating indirect effects of vaccination deserves much future research. PMID:23599908

  18. Involvement of protein kinase C in the mechanism of action of Escherichia coli heat-stable enterotoxin (STa) in a human colonic carcinoma cell line, COLO-205

    SciTech Connect

    Gupta, Dyuti Datta; Saha, Subhrajit; Chakrabarti, Manoj K. . E-mail: mkc_niced@yahoo.co.in

    2005-08-01

    The present study was undertaken to determine the involvement of calcium-protein kinase C pathway in the mechanism of action of Escherichia coli heat stable enterotoxin (STa) apart from STa-induced activation of guanylate cyclase in human colonic carcinoma cell line COLO-205, which was used as a model cultured cell line to study the mechanism of action of E. coli STa. In response to E. coli STa, protein kinase C (PKC) activity was increased in a time-dependent manner with its physical translocation from cytosol to membrane. Inhibition of the PKC activity in membrane fraction and inhibition of its physical translocation in response to IP{sub 3}-mediated calcium release inhibitor dantrolene suggested the involvement of intracellular store depletion in the regulation of PKC activity. Among different PKC isoforms, predominant involvement of calcium-dependent protein kinase C (PKC{alpha}) was specified using isotype-specific pseudosubstrate, which showed pronounce enzyme activity. Inhibition of enzyme activity by PKC{alpha}-specific inhibitor Goe6976 and immunoblott study employing isotype-specific antibody further demonstrated the involvement of calcium-dependent isoform of PKC in the mechanism of action of E. coli STa. Moreover, inhibition of guanylate cyclase activity by PKC{alpha}-specific inhibitor Goe6976 suggested the involvement of PKC{alpha} in the regulation of guanylate cyclase activity.

  19. Mechanisms involved in the spontaneous occurrence of diploid-triploid chimerism in the mink (Mustela vison) and chicken (Gallus domesticus).

    PubMed

    Fechheimer, N S; Isakova, G K; Belyaev, D K

    1983-01-01

    Diploid-triploid chimeras have been observed both in man and in a number of laboratory and livestock animals. The mechanism(s) of their origin remains enigmatic. One approach is to calculate for each proposed mechanism the expected frequencies of zygotes bearing different gonosomic complements in the two cell lines. Observed samples are then compared with the expectations. The mechanisms that have been considered include: (1) fertilization of a blastomere, (2) absorption of the second polar body into a blastomere, (3) fertilization of the first polar body, (4) independent fertilization of both nuclei in binucleated oocytes, (5) fertilization of the second polar body as well as the egg, and (6) fusion of two eggs. The sample of minks comprised three preimplantation embryos, nine postimplantation embryos, and three neonatal pups, with gonosomic complements of 7 XX/XXX, 3 XX/XXY, 4XY/XXY, and 1 XY/XYY; the chicks comprised 13 embryos at 1 day of incubation, 1 embryo at 4 days, and one adult bird, with gonosomic complements of 5 ZZ/ZZZ, 1 ZZ/ZZW, 1 ZW/ZZZ, 3 ZW/ZZW, and 5 ZW/ZWW. If it is assumed that within each species all, or most, of the 2n/3n chimeras arise from the same mechanism, then the occurrence of a type that has an expected frequency of zero for a given proposed mechanism effectively eliminates that mechanism as a source. All of the chicks could have resulted from only one mechanism, viz., independent fertilization of both nuclei in binucleated oocytes. The sample of minks could have resulted from the same mechanism or from fertilization of a blastomere of a two-cell, 2n embryo. PMID:6578004

  20. Invasive prey indirectly increase predation on their native competitors.

    PubMed

    Castorani, Max C N; Hovel, Kevin A

    2015-07-01

    Ecological theory predicts that invasive prey can interact with native prey directly by competing for shared resources or indirectly by changing the abundance or behavior of shared native predators. However, both the study and management of invasive prey have historically overlooked indirect effects. In southern California estuaries, introduction of the Asian nest mussel Arcuatula senhousia has been linked to profound changes in native bivalve assemblages, but the mechanisms of these interactions remain unclear. We performed three field experiments to assess the mechanisms of competition between Arcuatula and native bivalves, and evaluated the potential for Arcuatula to indirectly mediate native predator-prey dynamics. We found that Arcuatula reduces the diversity, abundance, and size of native bivalve recruits by preemptively exploiting space in surface sediments. When paired with native shallow-dwelling clams (Chione undatella and Laevicardium substriatum), Arcuatula reduces adult survival through overgrowth competition. However, Arcuatula also attracts native predators, causing apparent competition by indirectly increasing predation of native clams, especially for poorly defended species. Therefore, invasive prey can indirectly increase predation rates on native competitors by changing the behavior of shared native predators, but the magnitude of apparent competition strongly depends on the vulnerability of natives to predation. Interestingly, our results indicate that the vulnerability of invasive prey to predation can greatly exacerbate impacts on their native competitors. Our findings suggest that consideration of both direct and indirect effects of invasive prey, as well as native predator-prey relationships, should lead to more effective invasive species management.

  1. Spatially indirect excitons in coupled quantum wells

    SciTech Connect

    Lai, Chih-Wei Eddy

    2004-03-01

    Microscopic quantum phenomena such as interference or phase coherence between different quantum states are rarely manifest in macroscopic systems due to a lack of significant correlation between different states. An exciton system is one candidate for observation of possible quantum collective effects. In the dilute limit, excitons in semiconductors behave as bosons and are expected to undergo Bose-Einstein condensation (BEC) at a temperature several orders of magnitude higher than for atomic BEC because of their light mass. Furthermore, well-developed modern semiconductor technologies offer flexible manipulations of an exciton system. Realization of BEC in solid-state systems can thus provide new opportunities for macroscopic quantum coherence research. In semiconductor coupled quantum wells (CQW) under across-well static electric field, excitons exist as separately confined electron-hole pairs. These spatially indirect excitons exhibit a radiative recombination time much longer than their thermal relaxation time a unique feature in direct band gap semiconductor based structures. Their mutual repulsive dipole interaction further stabilizes the exciton system at low temperature and screens in-plane disorder more effectively. All these features make indirect excitons in CQW a promising system to search for quantum collective effects. Properties of indirect excitons in CQW have been analyzed and investigated extensively. The experimental results based on time-integrated or time-resolved spatially-resolved photoluminescence (PL) spectroscopy and imaging are reported in two categories. (i) Generic indirect exciton systems: general properties of indirect excitons such as the dependence of exciton energy and lifetime on electric fields and densities were examined. (ii) Quasi-two-dimensional confined exciton systems: highly statistically degenerate exciton systems containing more than tens of thousands of excitons within areas as small as (10 micrometer){sup 2} were

  2. Three-person game facilitates indirect reciprocity under image scoring.

    PubMed

    Suzuki, Shinsuke; Akiyama, Eizo

    2007-11-01

    Reputation building plays an important role in the evolution of reciprocal altruism when the same individuals do not interact repeatedly because, by referring to reputation, a reciprocator can know which partners are cooperative and can reciprocate with a cooperator. This reciprocity based on reputation is called indirect reciprocity. Previous studies of indirect reciprocity have focused only on two-person games in which only two individuals participate in a single interaction, and have claimed that indirectly reciprocal cooperation cannot be established under image scoring reputation criterion where the reputation of an individual who has cooperated (defected) becomes good (bad). In this study, we specifically examine three-person games, and reveal that indirectly reciprocal cooperation can be formed and maintained stably, even under image scoring, by a nucleus shield mechanism. In the nucleus shield, reciprocators are a shield that keeps out unconditional defectors, whereas unconditional cooperators are the backbone of cooperation that retains a good reputation among the population.

  3. Intracellular mechanisms involved in copper-gonadotropin-releasing hormone (Cu-GnRH) complex-induced cAMP/PKA signaling in female rat anterior pituitary cells in vitro.

    PubMed

    Gajewska, Alina; Zielinska-Gorska, Marlena; Wolinska-Witort, Ewa; Siawrys, Gabriela; Baran, Marta; Kotarba, Grzegorz; Biernacka, Katarzyna

    2016-01-01

    The copper-gonadotropin-releasing hormone molecule (Cu-GnRH) is a GnRH analog, which preserves its amino acid sequence, but which contains a Cu(2+) ion stably bound to the nitrogen atoms including that of the imidazole ring of Histidine(2). A previous report indicated that Cu-GnRH was able to activate cAMP/PKA signaling in anterior pituitary cells in vitro, but raised the question of which intracellular mechanism(s) mediated the Cu-GnRH-induced cAMP synthesis in gonadotropes. To investigate this mechanism, in the present study, female rat anterior pituitary cells in vitro were pretreated with 0.1 μM antide, a GnRH antagonist; 0.1 μM cetrorelix, a GnRH receptor antagonist; 0.1 μM PACAP6-38, a PAC-1 receptor antagonist; 2 μM GF109203X, a protein kinase C inhibitor; 50 mM PMA, a protein kinase C activator; the protein kinase A inhibitors H89 (30 μM) and KT5720 (60 nM); factors affecting intracellular calcium activity: 2.5 mM EGTA; 2 μM thapsigargin; 5 μM A23187, a Ca(2+) ionophore; or 10 μg/ml cycloheximide, a protein synthesis inhibitor. After one of the above pretreatments, cells were incubated in the presence of 0.1 μM Cu-GnRH for 0.5, 1, and 3 h. Radioimmunoassay analysis of cAMP confirmed the functional link between Cu-GnRH stimulation and cAMP/PKA signal transduction in rat anterior pituitary cells, demonstrating increased intracellular cAMP, which was reduced in the presence of specific PKA inhibitors. The stimulatory effect of Cu-GnRH on cAMP production was partly dependent on GnRH receptor activation. In addition, an indirect and Ca(2+)-dependent mechanism might be involved in intracellular adenylate cyclase stimulation. Neither activation of protein kinase C nor new protein synthesis was involved in the Cu-GnRH-induced increase of cAMP in the rat anterior pituitary primary cultures. Presented data indicate that conformational changes of GnRH molecule resulting from cooper ion coordination affect specific pharmacological properties of Cu

  4. Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

    PubMed Central

    Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

    2015-01-01

    Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

  5. A Fast Response Mechanism for Insulin Storage in Crystals May Involve a Novel Mode of Kink Generation

    NASA Astrophysics Data System (ADS)

    Vekilov, Peter

    2010-03-01

    Crystals, likely rhombohedral, of Zn-insulin hexamers form in the islets of Langerhans in the pancreases of many mammals. The suggested function of crystal formation is to protect the insulin from proteases and increase the degree of conversion of soluble proinsulin. To accomplish this, crystal growth should be fast and adaptable to rate fluctuations in the conversion reaction. Zn-insulin crystals grow layer-by-layer. Each layer spreads by the attachment of molecules to kinks located at the layers' edges, also called steps. The kinks are thought to be generated either by thermal fluctuations, as postulated by Gibbs, or by one-dimensional nucleation of new crystalline rows. The kink density determines the rate at which steps advance, and these two kink-generation mechanisms lead to weak near-linear responses of the growth rate to concentration variations. We demonstrate for the crystallization of Zn-insulin a novel mechanism of kink generation, whereby 2D clusters of several insulin molecules pre-formed on the terraces between steps associate to the steps. This mechanism results in several-fold higher kink density, faster rate of crystallization, and a high sensitivity of the kinetics to small increases of the solute concentration. If the found mechanism operates during insulin crystallization in vivo, it could be a part of the biological regulation of insulin production and function. For other crystallizing materials in biological and non-biological systems, this mechanism provides an understanding of the often seen non-linear acceleration of the kinetics.

  6. Biochemical mechanisms involved in the endotoxin-induced type II cell hyperplasia in F344 rat lung

    SciTech Connect

    Tesfaigzi, J.; Johnson, N.F.; Lechner, J.F.

    1994-11-01

    Proliferative lesions and pulmonary epithelial neoplasms induced in the rat by plutonium inhalation have been shown to be of type II cell origin. Defining the gene changes responsible for the development of the type II proliferative lesions would help to elucidate the genetic events involved in the expansion of initiated type II cells into fully transformed tumor cells. One problem in identifying these gene alterations is dissociating changes in gene expression linked to cell replication or repair from those involved in tumor initiation and progression. The long-term goals of these investigations are to first develop and characterize a model of transient type II cell hyperplasia. Second, changes in gene expression associated with remodeling epithelium will be compared to gene changes exhibited by the {sup 239}Pu-induced hyperplastic lesions.

  7. Hypertonicity sensing in organum vasculosum lamina terminalis neurons: a mechanical process involving TRPV1 but not TRPV4.

    PubMed

    Ciura, Sorana; Liedtke, Wolfgang; Bourque, Charles W

    2011-10-12

    Primary osmosensory neurons in the mouse organum vasculosum lamina terminalis (OVLT) transduce hypertonicity via the activation of nonselective cation channels that cause membrane depolarization and increased action potential discharge, and this effect is absent in mice lacking expression of the transient receptor potential vanilloid 1 (Trpv1) gene (Ciura and Bourque, 2006). However other experiments have indicated that channels encoded by Trpv4 also contribute to central osmosensation in mice (Liedtke and Friedman, 2003; Mizuno et al., 2003). At present, the mechanism by which hypertonicity modulates cation channels in OVLT neurons is unknown, and it remains unclear whether Trpv1 and Trpv4 both contribute to this process. Here, we show that physical shrinking is necessary and sufficient to mediate hypertonicity sensing in OVLT neurons isolated from adult mice. Steps coupling progressive decreases in cell volume to increased neuronal activity were quantitatively equivalent whether shrinking was evoked by osmotic pressure or mechanical aspiration. Finally, modulation of OVLT neurons by tonicity or mechanical stimulation was unaffected by deletion of trpv4 but was abolished in cells lacking Trpv1 or wild-type neurons treated with the TRPV1 antagonist SB366791. Thus, hypertonicity sensing is a mechanical process requiring Trpv1, but not Trpv4. PMID:21994383

  8. Pathophysiological Mechanisms Involved in Vasomotor Disturbances in Complex Regional Pain Syndrome and Implications for Therapy: A Review.

    PubMed

    Kortekaas, Minke C; Niehof, Sjoerd P; Stolker, Robert J; Huygen, Frank J P M

    2016-09-01

    Complex regional pain syndrome (CRPS) is characterized by continuous pain, disproportional to the initial trauma. It usually spreads to the distal parts of the affected limb. Besides continuing pain, a mix of sensory, sudo- and vasomotor disturbances, motor dysfunction, and trophic changes is responsible for physical complaints. Vasomotor disturbance is characterized by changes in skin temperature and color. In CRPS patients with a cold extremity, a decrease in blood flow can cause decreased tissue saturation and tissue acidosis, resulting in ischemic pain. The pathophysiology of vasomotor disturbances is not completely understood. Temperature asymmetry is generally assumed as a result of disturbance in the sympathetic nervous system. Vasodilating drugs and sympathetic blockade have been cornerstones of therapy in cold CRPS for years. However, only a limited part of these patients improve on this kind of therapies. Research has shown a pivotal role for inflammation in the pathophysiology of CRPS. Inflammation can result in endothelial dysfunction. Endothelial function plays an important role in the local regulation of vascular tone. Endothelial dysfunction could be another mechanism responsible for the vasomotor disturbances in cold CRPS. An important goal in the treatment of cold-type CRPS is the restoration of a normal blood flow. Consequently it is important to distinguish the underlying pathophysiological mechanisms of vasomotor disturbances. A disturbance of the sympathetic nervous system may require another type of treatment than inflammation-induced endothelial dysfunction. Diagnostic tools to distinguish these underlying pathophysiological mechanisms of vasomotor disturbances would enable a mechanism-based treatment and improve clinical outcome.

  9. A chromatin modifying enzyme, SDG8, is involved in morphological, gene expression, and epigenetic responses to mechanical stimulation.

    PubMed

    Cazzonelli, Christopher I; Nisar, Nazia; Roberts, Andrea C; Murray, Kevin D; Borevitz, Justin O; Pogson, Barry J

    2014-01-01

    Thigmomorphogenesis is viewed as being a response process of acclimation to short repetitive bursts of mechanical stimulation or touch. The underlying molecular mechanisms that coordinate changes in how touch signals lead to long-term morphological changes are enigmatic. Touch responsive gene expression is rapid and transient, and no transcription factor or DNA regulatory motif has been reported that could confer a genome wide mechanical stimulus. We report here on a chromatin modifying enzyme, SDG8/ASHH2, which can regulate the expression of many touch responsive genes identified in Arabidopsis. SDG8 is required for the permissive expression of touch induced genes; and the loss of function of sdg8 perturbs the maximum levels of induction on selected touch gene targets. SDG8 is required to maintain permissive H3K4 trimethylation marks surrounding the Arabidopsis touch-inducible gene TOUCH 3 (TCH3), which encodes a calmodulin-like protein (CML12). The gene neighboring was also slightly down regulated, revealing a new target for SDG8 mediated chromatin modification. Finally, sdg8 mutants show perturbed morphological response to wind-agitated mechanical stimuli, implicating an epigenetic memory-forming process in the acclimation response of thigmomorphogenesis. PMID:25374573

  10. A chromatin modifying enzyme, SDG8, is involved in morphological, gene expression, and epigenetic responses to mechanical stimulation

    PubMed Central

    Cazzonelli, Christopher I.; Nisar, Nazia; Roberts, Andrea C.; Murray, Kevin D.; Borevitz, Justin O.; Pogson, Barry J.

    2014-01-01

    Thigmomorphogenesis is viewed as being a response process of acclimation to short repetitive bursts of mechanical stimulation or touch. The underlying molecular mechanisms that coordinate changes in how touch signals lead to long-term morphological changes are enigmatic. Touch responsive gene expression is rapid and transient, and no transcription factor or DNA regulatory motif has been reported that could confer a genome wide mechanical stimulus. We report here on a chromatin modifying enzyme, SDG8/ASHH2, which can regulate the expression of many touch responsive genes identified in Arabidopsis. SDG8 is required for the permissive expression of touch induced genes; and the loss of function of sdg8 perturbs the maximum levels of induction on selected touch gene targets. SDG8 is required to maintain permissive H3K4 trimethylation marks surrounding the Arabidopsis touch-inducible gene TOUCH 3 (TCH3), which encodes a calmodulin-like protein (CML12). The gene neighboring was also slightly down regulated, revealing a new target for SDG8 mediated chromatin modification. Finally, sdg8 mutants show perturbed morphological response to wind-agitated mechanical stimuli, implicating an epigenetic memory-forming process in the acclimation response of thigmomorphogenesis. PMID:25374573

  11. Autophosphorylation of [alpha]CaMKII is Differentially Involved in New Learning and Unlearning Mechanisms of Memory Extinction

    ERIC Educational Resources Information Center

    Kimura, Ryoichi; Silva, Alcino J.; Ohno, Masuo

    2008-01-01

    Accumulating evidence indicates the key role of [alpha]-calcium/calmodulin-dependent protein kinase II ([alpha]CaMKII) in synaptic plasticity and learning, but it remains unclear how this kinase participates in the processing of memory extinction. Here, we investigated the mechanism by which [alpha]CaMKII may mediate extinction by using…

  12. Mechanisms involved in the inhibition of glycolysis by cyanide and antimycin A in Candida albicans and its reversal by hydrogen peroxide. A common feature in Candida species.

    PubMed

    Peña, Antonio; Sánchez, Norma Silvia; González-López, Omar; Calahorra, Martha

    2015-12-01

    In Candida albicans, cyanide and antimycin A inhibited K(+) transport, not only with ethanol-O2 as the substrate, but also with glucose. The reason for this was that they inhibited not only respiration, but also fermentation, decreasing ATP production. Measurements of oxygen levels in cell suspensions allowed identification of the electron pathways involved. NADH fluorescence levels increased in the presence of the inhibitors, indirectly indicating lower levels of NAD(+) and so pointing to glyceraldehyde-3-phosphate dehydrogenase as the limiting step responsible for the inhibition of glycolysis, which was confirmed by the levels of glycolytic intermediaries. The cyanide effect could be reversed by hydrogen peroxide, mainly due to an activity by which H2O2 can be reduced by electrons flowing from NADH through a pathway that can be inhibited by antimycin A, and appears to be a cytochrome c peroxidase. Therefore, the inhibition of glycolysis by the respiratory inhibitors seems to be due to the decreased availability of NAD(+), resulting in a decreased activity of glyceraldehyde-3-phosphate dehydrogenase. Compartmentalization of pyridine nucleotides in favor of the mitochondria can contribute to explaining the low fermentation capacity of C. albicans. Similar results were obtained with three C. albicans strains, Candida dubliniensis and, to a lower degree, Candida parapsilosis.

  13. CRP Is an Activator of Yersinia pestis Biofilm Formation that Operates via a Mechanism Involving gmhA and waaAE-coaD.

    PubMed

    Liu, Lei; Fang, Haihong; Yang, Huiying; Zhang, Yiquan; Han, Yanping; Zhou, Dongsheng; Yang, Ruifu

    2016-01-01

    gmhA encodes a phosphoheptose isomerase that catalyzes the biosynthesis of heptose, a conserved component of lipopolysaccharide (LPS). GmhA plays an important role in Yersinia pestis biofilm blockage in the flea gut. waaA, waaE, and coaD constitute a three-gene operon waaAE-coaD in Y. pestis. waaA encodes a transferase that is responsible for binding lipid-A to the core oligosaccharide of LPS. WaaA is a key determinant in Y. pestis biofilm formation, and the waaA expression is positively regulated by the two-component regulatory system PhoP/PhoQ. WaaE is involved in LPS modification and is necessary for Y. pestis biofilm production. In this study, the biofilm-related phenotypic assays indicate that the global regulator CRP stimulates Y. pestis biofilm formation in vitro and on nematodes, while it has no regulatory effect on the biosynthesis of the biofilm-signaling molecular 3',5'-cyclic diguanosine monophosphate. Further gene regulation experiments disclose that CRP does not regulate the hms genes at the transcriptional level but directly promotes the gmhA transcription and indirectly activates the waaAE-coaD transcription through directly acting on phoPQ-YPO1632. Thus, it is speculated that CRP-mediated carbon catabolite regulation of Y. pestis biofilm formation depends on the CRP-dependent carbon source metabolic pathways of the biosynthesis, modification, and transportation of biofilm exopolysaccharide. PMID:27014218

  14. Indirect Aggression, Bullying and Female Teen Victimization: A Literature Review

    ERIC Educational Resources Information Center

    Catanzaro, Mary F.

    2011-01-01

    This article assesses the literature in relation to youth bullying in the United Kingdom, Scandinavia and North America, focusing in particular on female aggression as it is expressed in adolescent peer relationships. It addresses the escalating problems of indirect aggression, especially those involving social networking interchanges such as…

  15. Indirect orbital floor fractures: a meta-analysis.

    PubMed

    Gonzalez, Mithra O; Durairaj, Vikram D

    2010-04-01

    Orbit fractures are common in the context of orbital trauma. Fractures of the orbital floor without orbital rim involvement are known as indirect orbital floor fractures, pure internal floor fractures, and orbital blowout fractures. In this paper, we have reported a meta-analysis of orbital floor fractures focusing on indications and timing of surgical repair, outcomes, and complications. PMID:20616920

  16. The mechanism of opiorphin-induced experimental priapism in rats involves activation of the polyamine synthetic pathway

    PubMed Central

    Kanika, Nirmala Devi; Tar, Moses; Tong, Yuehong; Kuppam, Dwaraka Srinivasa Rao; Melman, Arnold

    2009-01-01

    Intracorporal injection of plasmids encoding opiorphins into retired breeder rats can result in animals developing a priapic-like condition. Microarray analysis demonstrated that following intracorporal gene transfer of plasmids expressing opiorphins the most significantly upregulated gene in corporal tissue was the ornithine decarboxylase gene (ODC). Quantitative RT-PCR confirmed the upregulation of ODC, as well as other genes involved in polyamine synthesis, such as arginase-I and -II, polyamine oxidase, spermidine synthase, spermidine acetyltransferase (SAT), and S-adenosylmethionine decarboxylase. Western blot analysis demonstrated upregulation of arginase-I and -II, ODC, and SAT at the protein level. Levels of the polyamine putrescine were upregulated in animals treated with opiorphin-expressing plasmids compared with controls. A direct role for the upregulation of polyamine synthesis in the development of the priapic-like condition was supported by the observation that the ODC inhibitor 1,3-diaminopropane, when added to the drinking water of animals treated with plasmids expressing opiorphins, prevented experimental priapism. We also demonstrate that in sickle cell mice, another model of priapism, there is increased expression of the mouse opiorphin homologue in corporal tissue compared with the background strain at a life stage prior to evidence of priapism. At a life stage when there is onset of priapism, there is increased expression of the enzymes involved in polyamine synthesis (ODC and arginase-I and -II). Our results suggest that the upregulation of enzymes involved in the polyamine synthetic pathway may play a role in the development of experimental priapism and represent a target for the prevention of priapism. PMID:19657052

  17. Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis

    SciTech Connect

    Shi, Ce; Geders, Todd W.; Park, Sae Woong; Wilson, Daniel J.; Boshoff, Helena I.; Abayomi, Orishadipe; Barry, III, Clifton E.; Schnappinger, Dirk; Finzel, Barry C.; Aldrich, Courtney C.

    2011-11-16

    BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal 5'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 {angstrom} resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.

  18. Mechanism-Based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis

    PubMed Central

    Shi, Ce; Geders, Todd W.; Park, Sae Woong; Wilson, Daniel J.; Boshoff, Helena I.; Orisadipe, Abayomi; Barry, Clifton E.; Schnappinger, Dirk; Finzel, Barry C.; Aldrich, Courtney C.

    2011-01-01

    BioA catalyzes the second step of biotin biosynthesis and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal 5′-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 Å resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression and these results provide support for the designed mechanism of action. PMID:21988601

  19. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor

    PubMed Central

    Chen, Jiezhong; Raymond, Kenneth

    2006-01-01

    Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems. The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment. The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver. This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions. In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This pattern of action may explain many of the rifampicin inducing drug-drug interactions. However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex. PMID:16480505

  20. Processes of DNA methylation are involved in the mechanisms of amnesia induction and conditioned food aversion memory reconsolidation.

    PubMed

    Solntseva, S V; Filatova, T S; Nikitin, P V; Bredov, D V; Kozyrev, S A; Nikitin, V P

    2014-02-01

    We studied the role of DNA methylation in the mechanisms of amnesia in edible snails, which was induced by impairment of conditioned food aversion memory reconsolidation with NMDA glutamate receptor antagonist. The effects of DNA methyltransferase inhibitors were shown to depend on the stage of amnesia. At the early stage of amnesia (day 3 after induction), injections of methyltransferase inhibitors in combination with conditioned food stimulus (reminder) were followed by memory recovery. Application of inhibitors in the absence of the reminder was ineffective. Methyltransferase inhibitors were ineffective at the late stage of amnesia (day 10). Our results suggest that the presentation of reminding conditioned stimuli is followed by reactivation of amnesia. Methylation or demethylation of DNA in nerve cells serves as one of the key mechanisms for amnesia.

  1. Revisiting the mechanisms involved in Line Width Roughness smoothing of 193 nm photoresist patterns during HBr plasma treatment

    SciTech Connect

    Brihoum, M.; Ramos, R.; Menguelti, K.; Cunge, G.; Pargon, E.; Joubert, O.

    2013-01-07

    HBr plasma treatments are widely used in nanoscale lithographic technologies to increase the plasma etch resistance of 193 nm photoresist masks as well as to decrease their Line Width Roughness (LWR). VUV irradiation of the photoresist is known to play a major role in this process by inducing polymer chains rearrangement and finally LWR reduction. However, in the plasma environment (i.e., with radical and ion bombardment), the interaction layer formed at the resist surface perturbs this mechanism and a lower LWR reduction is achieved compared to VUV only treatment. So far the nature of the interaction layer, its formation mechanism and its relation with the resist pattern LWR were all unclear. In this paper, we show that a graphite-like layer is formed on the resist patterns by the redeposition of carbon-based species originating from the plasma dissociation of outgassed photo-etched resist moieties. We show that the presence of this layer inhibits the LWR minimization and causes an increase in the LWR when it becomes thick enough (i.e., a few nanometers). We present evidences that the difference in the mechanical properties of the graphite-like top layer which coats the resist patterns and the bulk of the resist patterns is correlated to the LWR after plasma treatment. We can conclude that the optimization of an HBr cure process relies on the minimization of the carbon redeposition while keeping a significant VUV light flux and we show that this can be achieved by using pulsed plasma processes.

  2. Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: mechanisms involved and their medical implications.

    PubMed

    Sørensen, Janina Maria

    2002-06-01

    Adverse drug reactions (ADRs) and iatrogenic diseases have been identified as significant factors responsible for patient morbidity and mortality. Significant studies on drug metabolism in humans have been published during the last few years, offering a deeper comprehension of the mechanisms underlying adverse drug reactions and interactions. More understanding of these mechanisms, and of recent advances in laboratory technology, can help to evaluate potential drug interactions when drugs are prescribed concurrently. Increasing knowledge of interindividual variation in drug breakdown capacity and recent findings concerning the influence of environment, diet, nutrients, and herbal products can be used to reduce ADRs and iatrogenic diseases. Reviewed data suggest that drug treatment should be increasingly custom tailored to suit the individual patient and that appropriately co-prescribed diet and herbal remedies, could increase drug efficacy and lessen drug toxicity. This review focuses mainly on recently published research material. The cytochrome p450 enzymes, their role in metabolism, and their mechanisms of action are reviewed, and their role in drug-drug interactions are discussed. Drug-food and drug-herb interactions have garnered attention. Interdisciplinary communication among medical herbalists, medical doctors, and dietetic experts needs to be improved and encouraged. Internet resources for obtaining current information regarding drug-drug, drug-herb, and drug-nutrient interactions are provided. PMID:12165187

  3. Scaling of the anomalous Hall effect in epitaxial antiperovskite Mn3.5Dy0.5N involving multiple competing scattering mechanisms

    NASA Astrophysics Data System (ADS)

    Meng, M.; Wu, S. X.; Zhou, W. Q.; Li, S. W.

    2016-08-01

    Anomalous Hall effect (AHE) has been studied for ferrimagnetic antiperovskite Mn3.5Dy0.5N film grown by molecular-beam epitaxy. Reflective high energy electron diffraction and transmission electron microscopy demonstrate the high quality of the film. We have used a scaling involving multiple competing scattering mechanisms to distinguish variations of contributions to the AHE by heavily doped Dy. The scaling analysis revealed that the heavily doped Dy has dramatically modified the skew scattering part of the AHE in Mn4N and Mn3.5Dy0.5N has a totally different scattering mechanism from an undoped film.

  4. The Crystal Structure and Mechanism of an Unusual Oxidoreductase, GilR, Involved in Gilvocarcin V Biosynthesis

    SciTech Connect

    Noinaj, Nicholas; Bosserman, Mary A.; Schickli, M. Alexandra; Piszczek, Grzegorz; Kharel, Madan K.; Pahari, Pallab; Buchanan, Susan K.; Rohr, Jürgen

    2012-11-26

    GilR is a recently identified oxidoreductase that catalyzes the terminal step of gilvocarcin V biosynthesis and is a unique enzyme that establishes the lactone core of the polyketide-derived gilvocarcin chromophore. Gilvocarcin-type compounds form a small distinct family of anticancer agents that are involved in both photo-activated DNA-alkylation and histone H3 cross-linking. High resolution crystal structures of apoGilR and GilR in complex with its substrate pregilvocarcin V reveals that GilR belongs to the small group of a relatively new type of the vanillyl-alcohol oxidase flavoprotein family characterized by bicovalently tethered cofactors. GilR was found as a dimer, with the bicovalently attached FAD cofactor mediated through His-65 and Cys-125. Subsequent mutagenesis and functional assays indicate that Tyr-445 may be involved in reaction catalysis and in mediating the covalent attachment of FAD, whereas Tyr-448 serves as an essential residue initiating the catalysis by swinging away from the active site to accommodate binding of the 6R-configured substrate and consequently abstracting the proton of the hydroxyl residue of the substrate hemiacetal 6-OH group. These studies lay the groundwork for future enzyme engineering to broaden the substrate specificity of this bottleneck enzyme of the gilvocarcin biosynthetic pathway for the development of novel anti-cancer therapeutics.

  5. Cellular mechanisms involved in the stenosis and obliteration of the cerebral aqueduct of hyh mutant mice developing congenital hydrocephalus.

    PubMed

    Wagner, C; Batiz, L F; Rodríguez, S; Jiménez, A J; Páez, P; Tomé, M; Pérez-Fígares, J M; Rodríguez, E M

    2003-10-01

    Two phases may be recognized in the development of congenital hydrocephalus in the hyh mutant mouse. During embryonic life the detachment of the ventral ependyma is followed by a moderate hydrocephalus. During the first postnatal week the cerebral aqueduct becomes obliterated and a severe hydrocephalus develops. The aim of the present investigation was to elucidate the cellular phenomena occurring at the site of aqueduct obliteration and the probable participation of the subcommissural organ in this process. Electron microscopy, immunocytochemistry, and lectin histochemistry were used to investigate the aqueduct of normal and hydrocephalic hyh mice from embryonic day 14 (E-14) to postnatal day 7 (PN-7). In the normal hyh mouse, the aqueduct is an irregularly shaped cavity with 3 distinct regions (rostral, middle, and caudal) lined by various types of ependyma. In the hydrocephalic mouse, these 3 regions behave differently; the rostral end becomes stenosed, the middle third dilates, and the caudal end obliterates. The findings indicate that the following sequence of events lead to hydrocephalus: 1) denudation of the ventral ependyma (embryonic life); 2) denudation of dorsal ependyma and failure of the subcommissural organ to form Reissner fiber (first postnatal week); 3) obliteration of distal end of aqueduct; and 4) severe hydrocephalus. No evidence was obtained that NCAM is involved in the detachment of ependymal cells. The process of ependymal denudation would involve alterations of the surface sialoglycoproteins of the ependymal cells and the interaction of the latter with macrophages.

  6. Arabinosylated lipoarabinomannan (Ara-LAM) mediated intracellular mechanisms against tuberculosis infection: involvement of protein kinase C (PKC) mediated signaling.

    PubMed

    Das, Shibali; Bhattacharjee, Oindrila; Goswami, Avranil; Pal, Nishith K; Majumdar, Subrata

    2015-03-01

    Tuberculosis causes severe immunosuppression thereby ensuring the loss of the host protective immune responses. During Mycobacterium tuberculosis infection, the pathogen modulates TLR-2 receptor down-stream signaling, indicating the possible involvement of TLR-2 in the regulation of the host immune response. Moreover, different PKC isoforms are also involved in the course of infection. Arabinosylated lipoarabinomannan (Ara-LAM) possesses immuno-modulatory properties which induce the pro-inflammatory responses via induction of TLR-2-mediated signaling. Here, we found that pretreatment of M. tuberculosis-infected macrophages with Ara-LAM caused a significant increase in the conventional PKC expression along with their active association with TLR-2. This association activated the TLR-2 -mediated downstream signaling, facilitating the activation of MAP kinase P38. All these events culminated in the up-regulation of proinflammatory response, which was abrogated by treatment with PKC-α and P38 inhibitors. Moreover, pretreatment of macrophages with Ara-LAM abrogated the IL-10 production while restored MHC-II expression in the infected macrophages. This study demonstrates that Ara-LAM confers protection against tuberculosis via TLR-2/PKC signaling crosstalk which is responsible for the induction of host protective immune response against tuberculosis.

  7. Structures and molecular mechanisms for common 15q13.3 microduplications involving CHRNA7: benign or pathological?

    PubMed

    Szafranski, Przemyslaw; Schaaf, Christian P; Person, Richard E; Gibson, Ian B; Xia, Zhilian; Mahadevan, Sangeetha; Wiszniewska, Joanna; Bacino, Carlos A; Lalani, Seema; Potocki, Lorraine; Kang, Sung-Hae; Patel, Ankita; Cheung, Sau Wai; Probst, Frank J; Graham, Brett H; Shinawi, Marwan; Beaudet, Arthur L; Stankiewicz, Pawel

    2010-07-01

    We have investigated four approximately 1.6-Mb microduplications and 55 smaller 350-680-kb microduplications at 15q13.2-q13.3 involving the CHRNA7 gene that were detected by clinical microarray analysis. Applying high-resolution array-CGH, we mapped all 118 chromosomal breakpoints of these microduplications. We also sequenced 26 small microduplication breakpoints that were clustering at hotspots of nonallelic homologous recombination (NAHR). All four large microduplications likely arose by NAHR between BP4 and BP5 LCRs, and 54 small microduplications arose by NAHR between two CHRNA7-LCR copies. We identified two classes of approximately 1.6-Mb microduplications and five classes of small microduplications differing in duplication size, and show that they duplicate the entire CHRNA7. We propose that size differences among small microduplications result from preexisting heterogeneity of the common BP4-BP5 inversion. Clinical data and family histories of 11 patients with small microduplications involving CHRNA7 suggest that these microduplications might be associated with developmental delay/mental retardation, muscular hypotonia, and a variety of neuropsychiatric disorders. However, we conclude that these microduplications and their associated potential for increased dosage of the CHRNA7-encoded alpha 7 subunit of nicotinic acetylcholine receptors are of uncertain clinical significance at present. Nevertheless, if they prove to have a pathological effects, their high frequency could make them a common risk factor for many neurobehavioral disorders.

  8. Structures and Molecular Mechanisms for Common 15q13.3 Microduplications Involving CHRNA7: Benign or Pathological?

    PubMed Central

    Szafranski, Przemyslaw; Schaaf, Christian P.; Person, Richard E.; Gibson, Ian B.; Xia, Zhilian; Mahadevan, Sangeetha; Wiszniewska, Joanna; Bacino, Carlos A.; Lalani, Seema; Potocki, Lorraine; Kang, Sung-Hae; Patel, Ankita; Cheung, Sau Wai; Probst, Frank J.; Graham, Brett H.; Shinawi, Marwan; Beaudet, Arthur L.; Stankiewicz, Pawel

    2011-01-01

    We have investigated four ~1.6-Mb microduplications and 55 smaller 350–680-kb microduplications at 15q13.2–q13.3 involving the CHRNA7 gene that were detected by clinical microarray analysis. Applying high-resolution array-CGH, we mapped all 118 chromosomal breakpoints of these microduplications. We also sequenced 26 small microduplication breakpoints that were clustering at hotspots of nonallelic homologous recombination (NAHR). All four large microduplications likely arose by NAHR between BP4 and BP5 LCRs, and 54 small microduplications arose by NAHR between two CHRNA7-LCR copies. We identified two classes of ~1.6-Mb microduplications and five classes of small microduplications differing in dupli