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Sample records for activation state insights

  1. Sport for All? Insight into Stratification and Compensation Mechanisms of Sporting Activity in the 27 European Union Member States

    ERIC Educational Resources Information Center

    Van Tuyckom, Charlotte; Scheerder, Jeroen

    2010-01-01

    Physical activity is an important public health issue and the benefits of an active lifestyle in relation to well-being and health have been strongly emphasised in recent years in Europe, as well as in most parts of the world. However, previous research has shown that physical activity within Europe and its member states is stratified. The present…

  2. Novel Molecular Insights into Classical and Alternative Activation States of Microglia as Revealed by Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-based Proteomics*

    PubMed Central

    Bell-Temin, Harris; Culver-Cochran, Ashley E.; Chaput, Dale; Carlson, Christina M.; Kuehl, Melanie; Burkhardt, Brant R.; Bickford, Paula C.; Liu, Bin; Stevens, Stanley M.

    2015-01-01

    Microglia, the resident immune cells of the brain, have been shown to display a complex spectrum of roles that span from neurotrophic to neurotoxic depending on their activation status. Microglia can be classified into four stages of activation, M1, which most closely matches the classical (pro-inflammatory) activation stage, and the alternative activation stages M2a, M2b, and M2c. The alternative activation stages have not yet been comprehensively analyzed through unbiased, global-scale protein expression profiling. In this study, BV2 mouse immortalized microglial cells were stimulated with agonists specific for each of the four stages and total protein expression for 4644 protein groups was quantified using SILAC-based proteomic analysis. After validating induction of the various stages through a targeted cytokine assay and Western blotting of activation states, the data revealed novel insights into the similarities and differences between the various states. The data identify several protein groups whose expression in the anti-inflammatory, pro-healing activation states are altered presumably to curtail inflammatory activation through differential protein expression, in the M2a state including CD74, LYN, SQST1, TLR2, and CD14. The differential expression of these proteins promotes healing, limits phagocytosis, and limits activation of reactive nitrogen species through toll-like receptor cascades. The M2c state appears to center around the down-regulation of a key member in the formation of actin-rich phagosomes, SLP-76. In addition, the proteomic data identified a novel activation marker, DAB2, which is involved in clathrin-mediated endocytosis and is significantly different between M2a and either M1 or M2b states. Western blot analysis of mouse primary microglia stimulated with the various agonists of the classical and alternative activation states revealed a similar trend of DAB2 expression compared with BV2 cells. PMID:26424600

  3. Novel Molecular Insights into Classical and Alternative Activation States of Microglia as Revealed by Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-based Proteomics.

    PubMed

    Bell-Temin, Harris; Culver-Cochran, Ashley E; Chaput, Dale; Carlson, Christina M; Kuehl, Melanie; Burkhardt, Brant R; Bickford, Paula C; Liu, Bin; Stevens, Stanley M

    2015-12-01

    Microglia, the resident immune cells of the brain, have been shown to display a complex spectrum of roles that span from neurotrophic to neurotoxic depending on their activation status. Microglia can be classified into four stages of activation, M1, which most closely matches the classical (pro-inflammatory) activation stage, and the alternative activation stages M2a, M2b, and M2c. The alternative activation stages have not yet been comprehensively analyzed through unbiased, global-scale protein expression profiling. In this study, BV2 mouse immortalized microglial cells were stimulated with agonists specific for each of the four stages and total protein expression for 4644 protein groups was quantified using SILAC-based proteomic analysis. After validating induction of the various stages through a targeted cytokine assay and Western blotting of activation states, the data revealed novel insights into the similarities and differences between the various states. The data identify several protein groups whose expression in the anti-inflammatory, pro-healing activation states are altered presumably to curtail inflammatory activation through differential protein expression, in the M2a state including CD74, LYN, SQST1, TLR2, and CD14. The differential expression of these proteins promotes healing, limits phagocytosis, and limits activation of reactive nitrogen species through toll-like receptor cascades. The M2c state appears to center around the down-regulation of a key member in the formation of actin-rich phagosomes, SLP-76. In addition, the proteomic data identified a novel activation marker, DAB2, which is involved in clathrin-mediated endocytosis and is significantly different between M2a and either M1 or M2b states. Western blot analysis of mouse primary microglia stimulated with the various agonists of the classical and alternative activation states revealed a similar trend of DAB2 expression compared with BV2 cells.

  4. Dihydrogen activation by sulfido-bridged dinuclear Ru/Ge complexes: insight into the [NiFe] hydrogenase unready state.

    PubMed

    Matsumoto, Tsuyoshi; Itakura, Naohisa; Nakaya, Yukiko; Tatsumi, Kazuyuki

    2011-01-21

    A S/SH bridged hetero-dinuclear Ru/Ge complex cation reacted with H(2) to afford the μ-S/μ-H complex. The reaction was considerably slower compared to that of the μ-S/μ-OH complex. Thus, the μ-S/μ-SH and μ-S/μ-OH complexes might provide models for the unready and ready states, respectively, of [NiFe] hydrogenase. PMID:21072402

  5. Impaired insight into illness and cognitive insight in schizophrenia spectrum disorders: Resting state functional connectivity

    PubMed Central

    Gerretsen, Philip; Menon, Mahesh; Mamo, David C.; Fervaha, Gagan; Remington, Gary; Pollock, Bruce G.; Graff-Guerrero, Ariel

    2015-01-01

    Background Impaired insight into illness (clinical insight) in schizophrenia has negative effects on treatment adherence and clinical outcomes. Schizophrenia is described as a disorder of disrupted brain connectivity. In line with this concept, resting state networks (RSNs) appear differentially affected in persons with schizophrenia. Therefore, impaired clinical, or the related construct of cognitive insight (which posits that impaired clinical insight is a function of metacognitive deficits), may reflect alterations in RSN functional connectivity (fc). Based on our previous research, which showed that impaired insight into illness was associated with increased left hemisphere volume relative to right, we hypothesized that impaired clinical insight would be associated with increased connectivity in the DMN with specific left hemisphere brain regions. Methods Resting state MRI scans were acquired for participants with schizophrenia or schizoaffective disorder (n = 20). Seed-to-voxel and ROI-to-ROI fc analyses were performed using the CONN-fMRI fc toolbox v13 for established RSNs. Clinical and cognitive insight were measured with the Schedule for the Assessment of Insight—Expanded Version and Beck Cognitive Insight Scale, respectively, and included as the regressors in fc analyses. Results As hypothesized, impaired clinical insight was associated with increased connectivity in the default mode network (DMN) with the left angular gyrus, and also in the self-referential network (SRN) with the left insula. Cognitive insight was associated with increased connectivity in the dorsal attention network (DAN) with the right inferior frontal cortex (IFC) and left anterior cingulate cortex (ACC). Conclusion Increased connectivity in DMN and SRN with the left angular gyrus and insula, respectively, may represent neural correlates of impaired clinical insight in schizophrenia spectrum disorders, and is consistent with the literature attributing impaired insight to left

  6. Insight Across the Different Mood States of Bipolar Disorder.

    PubMed

    de Assis da Silva, Rafael; Mograbi, Daniel C; Silveira, Luciana Angélica Silva; Nunes, Ana Letícia Santos; Novis, Fernanda Demôro; Landeira-Fernandez, J; Cheniaux, Elie

    2015-09-01

    In bipolar disorder, levels of insight vary as a function of the mood state and appear to influence pharmacology compliance, quality of life, the presence of suicidal ideations, and aggressive behavior. To establish a comparison among different mood states in bipolar with regard to level of insight. Forty-eight patients were evaluated in different affective states (i.e., euthymia, mania, depression, and mixed state). Identifying information, sociodemographic data, and clinical records were recorded. The following scales were applied: Hamilton Depression Scale, Young Mania Rating Scale, Positive and Negative Syndrome Scale positive symptoms subscale, and Global Assessment of Functioning and Clinical Global Impressions Scale for use in bipolar disorder. Insight was evaluated using items 11 and 17 of the Young Mania Rating Scale and Hamilton Depression Scale, respectively. Insight in bipolar disorder was found to be more compromised during manic phases and mixed episodes than during periods of depression or euthymia. The factors associated with lower levels of insight were the following: shorter illness duration, older age, and greater severity in mania; the female gender and older age in depression; and shorter illness duration and more severe depressive symptoms in mixed episodes. In the same individual, levels of insight vary as a function of the affective state over the course of bipolar disorder and appear to be influenced by several clinical variables.

  7. Accelerated Learning Options: A Promising Strategy for States. Policy Insights

    ERIC Educational Resources Information Center

    Michelau, Demaree

    2006-01-01

    This issue of Policy Insights draws on findings from WICHE's report Accelerated Learning Options: Moving the Needle on Access and Success, to lay out some of the important policy issues that decision makers might consider when adopting new state policy related to accelerated learning or modifying policies already in existence. The publication…

  8. X-ray-induced catalytic active-site reduction of a multicopper oxidase: structural insights into the proton-relay mechanism and O2-reduction states.

    PubMed

    Serrano-Posada, Hugo; Centeno-Leija, Sara; Rojas-Trejo, Sonia Patricia; Rodríguez-Almazán, Claudia; Stojanoff, Vivian; Rudiño-Piñera, Enrique

    2015-12-01

    During X-ray data collection from a multicopper oxidase (MCO) crystal, electrons and protons are mainly released into the system by the radiolysis of water molecules, leading to the X-ray-induced reduction of O2 to 2H2O at the trinuclear copper cluster (TNC) of the enzyme. In this work, 12 crystallographic structures of Thermus thermophilus HB27 multicopper oxidase (Tth-MCO) in holo, apo and Hg-bound forms and with different X-ray absorbed doses have been determined. In holo Tth-MCO structures with four Cu atoms, the proton-donor residue Glu451 involved in O2 reduction was found in a double conformation: Glu451a (∼7 Å from the TNC) and Glu451b (∼4.5 Å from the TNC). A positive peak of electron density above 3.5σ in an Fo - Fc map for Glu451a O(ℇ2) indicates the presence of a carboxyl functional group at the side chain, while its significant absence in Glu451b strongly suggests a carboxylate functional group. In contrast, for apo Tth-MCO and in Hg-bound structures neither the positive peak nor double conformations were observed. Together, these observations provide the first structural evidence for a proton-relay mechanism in the MCO family and also support previous studies indicating that Asp106 does not provide protons for this mechanism. In addition, eight composite structures (Tth-MCO-C1-8) with different X-ray-absorbed doses allowed the observation of different O2-reduction states, and a total depletion of T2Cu at doses higher than 0.2 MGy showed the high susceptibility of this Cu atom to radiation damage, highlighting the importance of taking radiation effects into account in biochemical interpretations of an MCO structure.

  9. Neural Activity When People Solve Verbal Problems with Insight

    PubMed Central

    2004-01-01

    People sometimes solve problems with a unique process called insight, accompanied by an “Aha!” experience. It has long been unclear whether different cognitive and neural processes lead to insight versus noninsight solutions, or if solutions differ only in subsequent subjective feeling. Recent behavioral studies indicate distinct patterns of performance and suggest differential hemispheric involvement for insight and noninsight solutions. Subjects solved verbal problems, and after each correct solution indicated whether they solved with or without insight. We observed two objective neural correlates of insight. Functional magnetic resonance imaging (Experiment 1) revealed increased activity in the right hemisphere anterior superior temporal gyrus for insight relative to noninsight solutions. The same region was active during initial solving efforts. Scalp electroencephalogram recordings (Experiment 2) revealed a sudden burst of high-frequency (gamma-band) neural activity in the same area beginning 0.3 s prior to insight solutions. This right anterior temporal area is associated with making connections across distantly related information during comprehension. Although all problem solving relies on a largely shared cortical network, the sudden flash of insight occurs when solvers engage distinct neural and cognitive processes that allow them to see connections that previously eluded them. PMID:15094802

  10. Insights into Mechanism of Glucokinase Activation

    PubMed Central

    Liu, Shenping; Ammirati, Mark J.; Song, Xi; Knafels, John D.; Zhang, Jeff; Greasley, Samantha E.; Pfefferkorn, Jeffrey A.; Qiu, Xiayang

    2012-01-01

    Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and mutations that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKAs) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion, but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK-glucose complex in a wide open conformation. To assess conformations of GK in solution, we also carried out small angle x-ray scattering experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared with wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKAs with reduced hypoglycemic risk. PMID:22298776

  11. Forecasting the solar activity cycle: new insights

    NASA Astrophysics Data System (ADS)

    Nandy, Dibyendu; Karak, Bidya Binay

    2013-07-01

    Having advance knowledge of solar activity is important because the Sun's magnetic output governs space weather and impacts technologies reliant on space. However, the irregular nature of the solar cycle makes solar activity predictions a challenging task. This is best achieved through appropriately constrained solar dynamo simulations and as such the first step towards predictions is to understand the underlying physics of the solar dynamo mechanism. In Babcock-Leighton type dynamo models, the poloidal field is generated near the solar surface whereas the toroidal field is generated in the solar interior. Therefore a finite time is necessary for the coupling of the spatially segregated source layers of the dynamo. This time delay introduces a memory in the dynamo mechanism which allows forecasting of future solar activity. Here we discuss how this forecasting ability of the solar cycle is affected by downward turbulent pumping of magnetic flux. With significant turbulent pumping the memory of the dynamo is severely degraded and thus long term prediction of the solar cycle is not possible; only a short term prediction of the next cycle peak may be possible based on observational data assimilation at the previous cycle minimum.

  12. Orbitofrontal activation restores insight lost after cocaine use.

    PubMed

    Lucantonio, Federica; Takahashi, Yuji K; Hoffman, Alexander F; Chang, Chun Yun; Bali-Chaudhary, Sheena; Shaham, Yavin; Lupica, Carl R; Schoenbaum, Geoffrey

    2014-08-01

    Addiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

  13. Insights into the "free state" enzyme reaction kinetics in nanoconfinement.

    PubMed

    Wang, Chen; Ye, De-Kai; Wang, Yun-Yi; Lu, Tao; Xia, Xing-Hua

    2013-04-21

    The investigation of enzyme reaction kinetics in nanoconfined spaces mimicking the conditions in living systems is of great significance. Here, a nanofluidics chip integrated with an electrochemical detector has been designed for studying "free state" enzyme reaction kinetics in nanoconfinement. The nanofluidics chip is fabricated using the UV-ablation technique developed in our group. The enzyme and substrate solutions are simultaneously supplied from two single streams into a nanochannel through a Y-shaped junction. The laminar flow forms in the front of the nanochannel, then the two liquids fully mix at their downstream where a homogeneous enzyme reaction occurs. The "free state" enzyme reaction kinetics in nanoconfinement can thus be investigated in this laminar flow based nanofluidics device. For demonstration, glucose oxidase (GOx) is chosen as the model enzyme, which catalyzes the oxidation of beta-d-glucose. The reaction product hydrogen peroxide (H2O2) can be electrochemically detected by a microelectrode aligning to the end of nanochannel. The steady-state electrochemical current responding to various glucose concentrations is used to evaluate the activity of the "free state" GOx under nanoconfinement conditions. The effect of liquid flow rate, enzyme concentration, and nanoconfinement on reaction kinetics has been studied in detail. Results show that the "free state" GOx activity increases significantly compared to the immobilized enzyme and bath system, and the GOx reaction rate in the nanochannel is two-fold faster than that in bulk solution, demonstrating the importance of "free state" and spatial confinement for the enzyme reaction kinetics. The present approach provides an effective method for exploiting the "free state" enzyme activity in nanospatial confinement.

  14. An allolactose trapped at the lacZ β-galactosidase active site with its galactosyl moiety in a (4)H3 conformation provides insights into the formation, conformation, and stabilization of the transition state.

    PubMed

    Wheatley, Robert W; Huber, Reuben E

    2015-12-01

    When lactose was incubated with G794A-β-galactosidase (a variant with a "closed" active site loop that binds transition state analogs well) an allolactose was trapped with its Gal moiety in a (4)H3 conformation, similar to the oxocarbenium ion-like conformation expected of the transition state. The numerous interactions formed between the (4)H3 structure and β-galactosidase indicate that this structure is representative of the transition state. This conformation is also very similar to that of d-galactono-1,5-lactone, a good transition state analog. Evidence indicates that substrates take up the (4)H3 conformation during migration from the shallow to the deep mode. Steric forces utilizing His418 and other residues are important for positioning the O1 leaving group into a quasi-axial position. An electrostatic interaction between the O5 of the distorted Gal and Tyr503 as well as C-H-π bonds with Trp568 are also significant. Computational studies of the energy of sugar ring distortion show that the β-galactosidase reaction itinerary is driven by energetic considerations in utilization of a (4)H3 transition state with a novel (4)C1-(4)H3-(4)C1 conformation itinerary. To our knowledge, this is the first X-ray crystallographic structural demonstration that the transition state of a natural substrate of a glycosidase has a (4)H3 conformation.

  15. An allolactose trapped at the lacZ β-galactosidase active site with its galactosyl moiety in a (4)H3 conformation provides insights into the formation, conformation, and stabilization of the transition state.

    PubMed

    Wheatley, Robert W; Huber, Reuben E

    2015-12-01

    When lactose was incubated with G794A-β-galactosidase (a variant with a "closed" active site loop that binds transition state analogs well) an allolactose was trapped with its Gal moiety in a (4)H3 conformation, similar to the oxocarbenium ion-like conformation expected of the transition state. The numerous interactions formed between the (4)H3 structure and β-galactosidase indicate that this structure is representative of the transition state. This conformation is also very similar to that of d-galactono-1,5-lactone, a good transition state analog. Evidence indicates that substrates take up the (4)H3 conformation during migration from the shallow to the deep mode. Steric forces utilizing His418 and other residues are important for positioning the O1 leaving group into a quasi-axial position. An electrostatic interaction between the O5 of the distorted Gal and Tyr503 as well as C-H-π bonds with Trp568 are also significant. Computational studies of the energy of sugar ring distortion show that the β-galactosidase reaction itinerary is driven by energetic considerations in utilization of a (4)H3 transition state with a novel (4)C1-(4)H3-(4)C1 conformation itinerary. To our knowledge, this is the first X-ray crystallographic structural demonstration that the transition state of a natural substrate of a glycosidase has a (4)H3 conformation. PMID:26291713

  16. Building structure-activity insights through patent mining.

    PubMed

    Tu, Meihua; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel; Filipski, Kevin J

    2012-11-01

    One gap in current patent-mining practice is the lack of tools to build SAR knowledge. Here, we report a novel technique that enabled us to derive useful SAR information from the exemplified structures of a series of patents. In our approach, exemplified chemical structures were extracted from patent documents. They were grouped into structural series based on similarity and binding mode, after which the R-group table was generated. By analyzing R-group usages over time, we were able to build insights into SAR of a structural series, even though the biological activities were not available.

  17. MAPK-Activated Protein Kinases (MKs): Novel Insights and Challenges.

    PubMed

    Gaestel, Matthias

    2015-01-01

    Downstream of MAPKs, such as classical/atypical ERKs and p38 MAPKs, but not of JNKs, signaling is often mediated by protein kinases which are phosphorylated and activated by MAPKs and, therefore, designated MAPK-activated protein kinases (MAPKAPKs). Recently, novel insights into the specificity of the assembly of MAPK/MAPKAPK hetero-dimeric protein kinase signaling complexes have been gained. In addition, new functional aspects of MKs have been described and established functions have been challenged. This short review will summarize recent developments including the linear motif (LM) in MKs, the ERK-independent activation of RSK, the RSK-independent effects of some RSK-inhibitors and the challenged role of MK5/PRAK in tumor suppression. PMID:26779481

  18. Insights on activation enthalpy for non-Schmid slip in body-centered cubic metals

    DOE PAGES

    Hale, Lucas M.; Lim, Hojun; Zimmerman, Jonathan A.; Battaile, Corbett C.; Weinberger, Christopher R.

    2014-12-18

    We use insights gained from atomistic simulation to develop an activation enthalpy model for dislocation slip in body-centered cubic iron. Furthermore, using a classical potential that predicts dislocation core stabilities consistent with ab initio predictions, we quantify the non-Schmid stress-dependent effects of slip. The kink-pair activation enthalpy is evaluated and a model is identified as a function of the general stress state. Thus, our model enlarges the applicability of the classic Kocks activation enthalpy model to materials with non-Schmid behavior.

  19. Mechanistic Insights into Glucan Phosphatase Activity against Polyglucan Substrates*

    PubMed Central

    Meekins, David A.; Raththagala, Madushi; Auger, Kyle D.; Turner, Benjamin D.; Santelia, Diana; Kötting, Oliver; Gentry, Matthew S.; Vander Kooi, Craig W.

    2015-01-01

    Glucan phosphatases are central to the regulation of starch and glycogen metabolism. Plants contain two known glucan phosphatases, Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2), which dephosphorylate starch. Starch is water-insoluble and reversible phosphorylation solubilizes its outer surface allowing processive degradation. Vertebrates contain a single known glucan phosphatase, laforin, that dephosphorylates glycogen. In the absence of laforin, water-soluble glycogen becomes insoluble, leading to the neurodegenerative disorder Lafora Disease. Because of their essential role in starch and glycogen metabolism glucan phosphatases are of significant interest, yet a comparative analysis of their activities against diverse glucan substrates has not been established. We identify active site residues required for specific glucan dephosphorylation, defining a glucan phosphatase signature motif (CζAGΨGR) in the active site loop. We further explore the basis for phosphate position-specific activity of these enzymes and determine that their diverse phosphate position-specific activity is governed by the phosphatase domain. In addition, we find key differences in glucan phosphatase activity toward soluble and insoluble polyglucan substrates, resulting from the participation of ancillary glucan-binding domains. Together, these data provide fundamental insights into the specific activity of glucan phosphatases against diverse polyglucan substrates. PMID:26231210

  20. Update: Influenza Activity - United States.

    PubMed

    Smith, Sophie; Blanton, Lenee; Kniss, Krista; Mustaquim, Desiree; Steffens, Craig; Reed, Carrie; Bramley, Anna; Flannery, Brendan; Fry, Alicia M; Grohskopf, Lisa A; Bresee, Joseph; Wallis, Teresa; Garten, Rebecca; Xu, Xiyan; Elal, Anwar Isa Abd; Gubareva, Larisa; Barnes, John; Wentworth, David E; Burns, Erin; Katz, Jacqueline; Jernigan, Daniel; Brammer, Lynnette

    2015-12-11

    CDC collects, compiles, and analyzes data on influenza activity year-round in the United States. The influenza season generally begins in the fall and continues through the winter and spring months; however, the timing and severity of circulating influenza viruses can vary by geographic location and season. Influenza activity in the United States remained low through October and November in 2015. Influenza A viruses have been most frequently identified, with influenza A (H3) viruses predominating. This report summarizes U.S. influenza activity for the period October 4-November 28, 2015. PMID:26656182

  1. Atomistic insights into rhodopsin activation from a dynamic model.

    PubMed

    Tikhonova, Irina G; Best, Robert B; Engel, Stanislav; Gershengorn, Marvin C; Hummer, Gerhard; Costanzi, Stefano

    2008-08-01

    Rhodopsin, the light sensitive receptor responsible for blue-green vision, serves as a prototypical G protein-coupled receptor (GPCR). Upon light absorption, it undergoes a series of conformational changes that lead to the active form, metarhodopsin II (META II), initiating a signaling cascade through binding to the G protein transducin (G(t)). Here, we first develop a structural model of META II by applying experimental distance restraints to the structure of lumi-rhodopsin (LUMI), an earlier intermediate. The restraints are imposed by using a combination of biased molecular dynamics simulations and perturbations to an elastic network model. We characterize the motions of the transmembrane helices in the LUMI-to-META II transition and the rearrangement of interhelical hydrogen bonds. We then simulate rhodopsin activation in a dynamic model to study the path leading from LUMI to our META II model for wild-type rhodopsin and a series of mutants. The simulations show a strong correlation between the transition dynamics and the pharmacological phenotypes of the mutants. These results help identify the molecular mechanisms of activation in both wild type and mutant rhodopsin. While static models can provide insights into the mechanisms of ligand recognition and predict ligand affinity, a dynamic model of activation could be applicable to study the pharmacology of other GPCRs and their ligands, offering a key to predictions of basal activity and ligand efficacy.

  2. Understanding the transition states of phosphodiester bond cleavage: insights from heavy atom isotope effects.

    PubMed

    Cassano, Adam G; Anderson, Vernon E; Harris, Michael E

    2004-01-01

    The nucleotides of DNA and RNA are joined by phosphodiester linkages whose synthesis and hydrolysis are catalyzed by numerous essential enzymes. Two prominent mechanisms have been proposed for RNA and protein enzyme catalyzed cleavage of phosphodiester bonds in RNA: (a) intramolecular nucleophilic attack by the 2'-hydroxyl group adjacent to the reactive phosphate; and (b) intermolecular nucleophilic attack by hydroxide, or other oxyanion. The general features of these two mechanisms have been established by physical organic chemical analyses; however, a more detailed understanding of the transition states of these reactions is emerging from recent kinetic isotope effect (KIE) studies. The recent data show interesting differences between the chemical mechanisms and transition state structures of the inter- and intramolecular reactions, as well as provide information on the impact of metal ion, acid, and base catalysis on these mechanisms. Importantly, recent nonenzymatic model studies show that interactions with divalent metal ions, an important feature of many phosphodiesterase active sites, can influence both the mechanism and transition state structure of nonenzymatic phosphodiester cleavage. Such detailed investigations are important because they mimic catalytic strategies employed by both RNA and protein phosphodiesterases, and so set the stage for explorations of enzyme-catalyzed transition states. Application of KIE analyses for this class of enzymes is just beginning, and several important technical challenges remain to be overcome. Nonetheless, such studies hold great promise since they will provide novel insights into the role of metal ions and other active site interactions.

  3. Insights.

    ERIC Educational Resources Information Center

    Bogner, Donna, Ed.

    1988-01-01

    Describes two methods to teach radioactive decay to secondary students with wide ranging abilities. Activities are designed to follow classroom discussions of atomic structure, transmutation, half life, and nuclear decay. Includes "The Tasmanian Empire: A Radioactive Dating Activity" and an exercise to teach concepts of half life without using…

  4. Initial insights into structure-activity relationships of avian defensins.

    PubMed

    Derache, Chrystelle; Meudal, Hervé; Aucagne, Vincent; Mark, Kevin J; Cadène, Martine; Delmas, Agnès F; Lalmanach, Anne-Christine; Landon, Céline

    2012-03-01

    Numerous β-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian β-defensins, and this study was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both L- and D-proteins clearly indicates that there is no chiral partner. Therefore, the bacterial membrane is in all likelihood the primary target. Moreover, this work indicates that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural three-stranded antiparallel β-sheet characteristic of β-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of the avian β-defensin family was analyzed. Well conserved residues were highlighted, and the potential strategic role of the lysine 31 residue of AvBD2 was emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity. PMID:22205704

  5. On the time to steady state: insights from numerical modeling

    NASA Astrophysics Data System (ADS)

    Goren, L.; Willett, S.; McCoy, S. W.; Perron, J.

    2013-12-01

    How fast do fluvial landscapes approach steady state after an application of tectonic or climatic perturbation? While theory and some numerical models predict that the celerity of the advective wave (knickpoint) controls the response time for perturbations, experiments and other landscape evolution models demonstrate that the time to steady state is much longer than the theoretically predicted response time. We posit that the longevity of transient features and the time to steady state are controlled by the stability of the topology and geometry of channel networks. Evolution of a channel network occurs by a combination of discrete capture events and continuous migration of water divides, processes, which are difficult to represent accurately in landscape evolution models. We therefore address the question of the time to steady state using the DAC landscape evolution model that solves accurately for the location of water divides, using a combination of analytical solution for hillslopes and low-order channels together with a numerical solution for higher order channels. DAC also includes an explicit capture criterion. We have tested fundamental predictions from DAC and show that modeled networks reproduce natural network characteristics such as the Hack's exponent and coefficient and the fractal dimension. We define two steady-state criteria: a topographic steady state, defined by global, pointwise steady elevation, and a topological steady state defined as the state in which no further reorganization of the drainage network takes place. Analyzing block uplift simulations, we find that the time to achieve either topographic or topological steady state exceeds by an order of magnitude the theoretical response time of the fluvial network. The longevity of the transient state is the result of the area feedback, by which, migration of a divide changes the local contributing area. This change propagates downstream as a slope adjustment, forcing further divide migrations

  6. Insights into the different catalytic activities of Clostridium neurotoxins.

    PubMed

    Chen, Sheng; Karalewitz, Andrew P A; Barbieri, Joseph T

    2012-05-01

    The clostridial neurotoxins are among the most potent protein toxins for humans and are responsible for botulism, a flaccid paralysis elicited by the botulinum toxins (BoNT), and spastic paralysis elicited by tetanus toxin (TeNT). Seven serotypes of botulinum neurotoxins (A-G) and tetanus toxin showed different toxicities and cleave their substrates with different efficiencies. However, the molecular basis of their different catalytic activities with respect to their substrates is not clear. BoNT/B light chain (LC/B) and TeNT light chain (LC/T) cleave vesicle-associated membrane protein 2 (VAMP2) at the same scissile bond but possess different catalytic activities and substrate requirements, which make them the best candidates for studying the mechanisms of their different catalytic activities. The recognition of five major P sites of VAMP2 (P7, P6, P1, P1', and P2') and fine alignment of sites P2 and P3 and sites P2 and P4 by LC/B and LC/T, respectively, contributed to their substrate recognition and catalysis. Significantly, we found that the S1 pocket mutation LC/T(K(168)E) increased the rate of native VAMP2 cleavage so that it approached the rate of LC/B, which explains the molecular basis for the lower k(cat) that LC/T possesses for VAMP2 cleavage relative to that of LC/B. This analysis explains the molecular basis underlying the VAMP2 recognition and cleavage by LC/B and LC/T and provides insight that may extend the pharmacologic utility of these neurological reagents.

  7. New insight into the physical state of galaxies and quasars

    NASA Technical Reports Server (NTRS)

    Green, R. F.

    1981-01-01

    Data from the International Ultraviolet Explorer satellite have revolutionized many concepts in extragalactic astronomy. These include the physical processes at work in the emitting gas characteristic of active objects, the nature of the continuum source itself in those objects, and the constituent hot stellar and gaseous components of normal galaxies. Several problems of extragalactic research investigated with IUE were reviewed.

  8. Markov state models provide insights into dynamic modulation of protein function.

    PubMed

    Shukla, Diwakar; Hernández, Carlos X; Weber, Jeffrey K; Pande, Vijay S

    2015-02-17

    CONSPECTUS: Protein function is inextricably linked to protein dynamics. As we move from a static structural picture to a dynamic ensemble view of protein structure and function, novel computational paradigms are required for observing and understanding conformational dynamics of proteins and its functional implications. In principle, molecular dynamics simulations can provide the time evolution of atomistic models of proteins, but the long time scales associated with functional dynamics make it difficult to observe rare dynamical transitions. The issue of extracting essential functional components of protein dynamics from noisy simulation data presents another set of challenges in obtaining an unbiased understanding of protein motions. Therefore, a methodology that provides a statistical framework for efficient sampling and a human-readable view of the key aspects of functional dynamics from data analysis is required. The Markov state model (MSM), which has recently become popular worldwide for studying protein dynamics, is an example of such a framework. In this Account, we review the use of Markov state models for efficient sampling of the hierarchy of time scales associated with protein dynamics, automatic identification of key conformational states, and the degrees of freedom associated with slow dynamical processes. Applications of MSMs for studying long time scale phenomena such as activation mechanisms of cellular signaling proteins has yielded novel insights into protein function. In particular, from MSMs built using large-scale simulations of GPCRs and kinases, we have shown that complex conformational changes in proteins can be described in terms of structural changes in key structural motifs or "molecular switches" within the protein, the transitions between functionally active and inactive states of proteins proceed via multiple pathways, and ligand or substrate binding modulates the flux through these pathways. Finally, MSMs also provide a theoretical

  9. Markov State Models Provide Insights into Dynamic Modulation of Protein Function

    PubMed Central

    2015-01-01

    Conspectus Protein function is inextricably linked to protein dynamics. As we move from a static structural picture to a dynamic ensemble view of protein structure and function, novel computational paradigms are required for observing and understanding conformational dynamics of proteins and its functional implications. In principle, molecular dynamics simulations can provide the time evolution of atomistic models of proteins, but the long time scales associated with functional dynamics make it difficult to observe rare dynamical transitions. The issue of extracting essential functional components of protein dynamics from noisy simulation data presents another set of challenges in obtaining an unbiased understanding of protein motions. Therefore, a methodology that provides a statistical framework for efficient sampling and a human-readable view of the key aspects of functional dynamics from data analysis is required. The Markov state model (MSM), which has recently become popular worldwide for studying protein dynamics, is an example of such a framework. In this Account, we review the use of Markov state models for efficient sampling of the hierarchy of time scales associated with protein dynamics, automatic identification of key conformational states, and the degrees of freedom associated with slow dynamical processes. Applications of MSMs for studying long time scale phenomena such as activation mechanisms of cellular signaling proteins has yielded novel insights into protein function. In particular, from MSMs built using large-scale simulations of GPCRs and kinases, we have shown that complex conformational changes in proteins can be described in terms of structural changes in key structural motifs or “molecular switches” within the protein, the transitions between functionally active and inactive states of proteins proceed via multiple pathways, and ligand or substrate binding modulates the flux through these pathways. Finally, MSMs also provide a

  10. Building Capacity for Tracking Human Capital Development and Its Mobility across State Lines. Policy Insights

    ERIC Educational Resources Information Center

    Prescott, Brian T.

    2014-01-01

    This issue of "Policy Insights" provides a review of the past five years of the cost and value of higher education, which have gained increased policymaker, consumer, and media attention. The Western Interstate Commission for Higher Education (WICHE) has worked with four of its member states (Hawai'i, Idaho, Oregon, and Washington) to…

  11. Meditation promotes insightful problem-solving by keeping people in a mindful and alert conscious state.

    PubMed

    Ren, Jun; Huang, Zhihui; Luo, Jing; Wei, Gaoxia; Ying, Xiaoping; Ding, Zhiguang; Wu, Yibin; Luo, Fei

    2011-10-01

    Although previous studies have shown that sleep can inspire insight, it is still unclear whether meditation can promote insight. Meditation differs from other types of passive rest such as relaxation and sleep because it requires full consciousness and mindfulness of targets such as one's breathing. Forty-eight university students without meditation experience were recruited to learn a simple meditation technique. They were given a list of 10 insight problems to solve (the pre-test session). In this study, we focused on the unsolved problems and examined if they could be successfully solved after a 20 min rest interval with or without meditation. Results showed that relative to the control group that listened to Chinese or English words and made a language judgment, the groups who learned meditation successfully solved significantly more failed problems from the pre-test session, providing direct evidence for the role of meditation in promoting insight. Further analysis showed that maintaining a mindful and alert state during meditation (raising a hand to report every 10 deep breaths compared to every 100 deep breaths) resulted in more insight regarding the failed items from the pre-test session. This implies that it was watchfulness in meditation, rather than relaxation, that actually contributed to insight. Consistently, in the meditation session or control task, the percentage of alpha waves-a brain index of mental relaxation-was negatively correlated with insight. These results suggest a meditation-based insight-promoting mechanism different from that involved in passive rest such as relaxation and sleep.

  12. Constitutive Activation of G Protein-Coupled Receptors and Diseases: Insights into Mechanisms of Activation and Therapeutics

    PubMed Central

    Tao, Ya-Xiong

    2008-01-01

    The existence of constitutive activity for G protein-coupled receptors (GPCRs) was first described in 1980s. In 1991, the first naturally occurring constitutively active mutations in GPCRs that cause diseases were reported in rhodopsin. Since then, numerous constitutively active mutations that cause human diseases were reported in several additional receptors. More recently, loss of constitutive activity was postulated to also cause diseases. Animal models expressing some of these mutants confirmed the roles of these mutations in the pathogenesis of the diseases. Detailed functional studies of these naturally occurring mutations, combined with homology modeling using rhodopsin crystal structure as the template, lead to important insights into the mechanism of activation in the absence of crystal structure of GPCRs in active state. Search for inverse agonists on these receptors will be critical for correcting the diseases cause by activating mutations in GPCRs. Theoretically, these inverse agonists are better therapeutics than neutral antagonists in treating genetic diseases caused by constitutively activating mutations in GPCRs. PMID:18768149

  13. Design Insights for Tuning the Electrocatalytic Activity of Perovskite Oxides for the Oxygen Evolution Reaction

    SciTech Connect

    Malkhandi, S; Trinh, P; Manohar, AK; Manivannan, A; Balasubramanian, M; Prakash, GKS; Narayanan, SR

    2015-04-16

    Rechargeable metal-air batteries and water electrolyzers based on aqueous alkaline electrolytes hold the potential to be sustainable solutions to address the challenge of storing large amounts of electrical energy generated from solar and wind resources. For these batteries and electrolyzers to be economically viable, it is essential to have efficient, durable, and inexpensive electrocatalysts for the oxygen evolution reaction. In this article, we describe new insights for predicting and tuning the activity of inexpensive transition metal oxides for designing efficient and inexpensive electrocatalysts. We have focused on understanding the factors determining the electrocatalytic activity for oxygen evolution in a strong alkaline medium. To this end, we have conducted a systematic investigation of nanophase calcium-doped lanthanum cobalt manganese oxide, an example of a mixed metal oxide that can be tuned for its electrocatalytic activity by varying the transition metal composition. Using X-ray absorption spectroscopy (XANES), X-ray photoelectron spectroscopy (XPS), electrochemical polarization experiments, and analysis of mechanisms, we have identified the key determinants of electrocatalytic activity. We have found that the Tafel slopes are determined by the oxidation states and the bond energy of the surface intermediates of Mn-OH and Co-OH bonds while the catalytic activity increased with the average d-electron occupancy of the sigma* orbital of the M-OH bond. We anticipate that such understanding will be very useful in predicting the behavior of other transition metal oxide catalysts.

  14. Hydrogen activation by frustrated lewis pairs: insights from computational studies.

    PubMed

    Rokob, Tibor András; Pápai, Imre

    2013-01-01

    Sterically encumbered Lewis acid-base pairs, the so-called frustrated Lewis pairs, can split dihydrogen heterolytically and act as transition metal free catalysts for the hydrogenation of unsaturated compounds. Here we review the results from our quantum chemical calculations aimed at the understanding of this remarkable class of reactions and we put them into the context of related works from other research groups. The thermodynamics of the H2 splitting reaction is discussed first; the role of acid-base properties, intramolecular cooperativity, and other factors is assessed, employing an energy partitioning scheme and also in the light of the latest experimental findings. The mechanism of hydrogen cleavage is then examined, and an overview about the applicability of our reactivity model involving synergistic electron transfers between H2 and preorganized Lewis acid/base centers is given. Finally, insights about catalytic cycles in FLP-mediated hydrogenations are summarized, pinpointing the diversity of the involved elementary steps and their possible sequences.

  15. Structural and mechanistic insights into Mps1 kinase activation

    SciTech Connect

    Wang, Wei; Yang, Yuting; Gao, Yuefeng; Xu, Quanbin; Wang, Feng; Zhu, Songcheng; Old, William; Resing, Katheryn; Ahn, Natalie; Lei, Ming; Liu, Xuedong

    2010-11-05

    Mps1 is one of the several essential kinases whose activation is required for robust mitotic spindle checkpoint signalling. The activity of Mps1 is tightly regulated and increases dramatically during mitosis or in response to spindle damage. To understand the molecular mechanism underlying Mps1 regulation, we determined the crystal structure of the kinase domain of Mps1. The 2.7-{angstrom}-resolution crystal structure shows that the Mps1 kinase domain adopts a unique inactive conformation. Intramolecular interactions between the key Glu residue in the {alpha}C helix of the N-terminal lobe and the backbone amides in the catalytic loop lock the kinase in the inactive conformation. Autophosphorylation appears to be a priming event for kinase activation. We identified Mps1 autophosphorylation sites in the activation and the P+1 loops. Whereas activation loop autophosphorylation enhances kinase activity, autophosphorylation at the P+1 loop (T686) is associated with the active kinase. Mutation of T686 autophosphorylation site impairs both autophosphorylation and transphosphorylation. Furthermore, we demonstrated that phosphorylation of T676 may be a priming event for phosphorylation at T686. Finally, we identified two critical lysine residues in the loop between helices {alpha}EF and {alpha}F that are essential for substrate recruitment and maintaining high levels of kinase activity. Our studies reveal critical biochemical mechanisms for Mps1 kinase regulation.

  16. Improved prediction of RNA tertiary structure with insights into native state dynamics.

    PubMed

    Bida, John Paul; Maher, L James

    2012-03-01

    The importance of RNA tertiary structure is evident from the growing number of published high resolution NMR and X-ray crystallographic structures of RNA molecules. These structures provide insights into function and create a knowledge base that is leveraged by programs such as Assemble, ModeRNA, RNABuilder, NAST, FARNA, Mc-Sym, RNA2D3D, and iFoldRNA for tertiary structure prediction and design. While these methods sample native-like RNA structures during simulations, all struggle to capture the native RNA conformation after scoring. We propose RSIM, an improved RNA fragment assembly method that preserves RNA global secondary structure while sampling conformations. This approach enhances the quality of predicted RNA tertiary structure, provides insights into the native state dynamics, and generates a powerful visualization of the RNA conformational space. RSIM is available for download from http://www.github.com/jpbida/rsim.

  17. Sodium channel activation mechanisms. Insights from deuterium oxide substitution

    SciTech Connect

    Alicata, D.A.; Rayner, M.D.; Starkus, J.G. )

    1990-04-01

    Schauf and Bullock, using Myxicola giant axons, demonstrated that solvent substitution with deuterium oxide (D2O) significantly affects both sodium channel activation and inactivation kinetics without corresponding changes in gating current or tail current rates. They concluded that (a) no significant component of gating current derives from the final channel opening step, and (b) channels must deactivate (during tail currents) by a different pathway from that used in channel opening. By contrast, Oxford found in squid axons that when a depolarizing pulse is interrupted by a brief (approximately 100 microseconds) return to holding potential, subsequent reactivation (secondary activation) is very rapid and shows almost monoexponential kinetics. Increasing the interpulse interval resulted in secondary activation rate returning towards control, sigmoid (primary activation) kinetics. He concluded that channels open and close (deactivate) via the same pathway. We have repeated both sets of observations in crayfish axons, confirming the results obtained in both previous studies, despite the apparently contradictory conclusions reached by these authors. On the other hand, we find that secondary activation after a brief interpulse interval (50 microseconds) is insensitive to D2O, although reactivation after longer interpulse intervals (approximately 400 microseconds) returns towards a D2O sensitivity similar to that of primary activation. We conclude that D2O-sensitive primary activation and D2O-insensitive tail current deactivation involve separate pathways. However, D2O-insensitive secondary activation involves reversal of the D2O-insensitive deactivation step. These conclusions are consistent with parallel gate models, provided that one gating particle has a substantially reduced effective valence.

  18. Unraveling the actions of AMP-activated protein kinase in metabolic diseases: Systemic to molecular insights.

    PubMed

    Weikel, Karen A; Ruderman, Neil B; Cacicedo, José M

    2016-05-01

    AMP-activated protein kinase (AMPK) plays a critical role both in sensing and regulating cellular energy state. In experimental animals, its activation has been shown to reduce the risk of obesity and diabetes-related co-morbidities such as insulin resistance, the metabolic syndrome and atherosclerotic cardiovascular disease. However, in humans, AMPK activation alone often does not completely resolve these conditions. Thus, an improved understanding of AMPK action and regulation in metabolic and other diseases is needed. Herein, we provide a brief description of the enzymatic regulation of AMPK and review its role in maintaining energy homeostasis. We then discuss tissue-specific actions of AMPK that become distorted during such conditions as obesity, type 2 diabetes and certain cancers. Finally, we explore recent findings regarding the interactions of AMPK with mammalian target of rapamycin complex 1 and the lysosome and discuss how changes in these relationships during overnutrition may lead to AMPK dysfunction. A more thorough understanding of AMPK's molecular interactions during diseases of overnutrition may provide key insights for the development of AMPK-based combinatorial treatments for metabolic disease. PMID:27085772

  19. Valsalva maneuver: Insights into baroreflex modulation of human sympathetic activity

    NASA Technical Reports Server (NTRS)

    Smith, Michael L.; Eckberg, Dwain L.; Fritsch, Janice M.; Beightol, Larry A.; Ellenbogen, Kenneth A.

    1991-01-01

    Valsalva's maneuver, voluntary forced expiration against a closed glottis, is a well-characterized research tool, used to assess the integrity of human autonomic cardiovascular control. Valsalva straining provokes a stereotyped succession of alternating positive and negative arterial pressure and heart rate changes mediated in part by arterial baroreceptors. Arterial pressure changes result primarily from fluctuating levels of venous return to the heart and changes of sympathetic nerve activity. Muscle sympathetic activity was measured directly in nine volunteers to explore quantitatively the relation between arterial pressure and human sympathetic outflow during pressure transients provoked by controlled graded Valsalva maneuvers. Our results underscore several properties of sympathetic regulation during Valsalva straining. First, muscle sympathetic nerve activity changes as a mirror image of changes in arterial pressure. Second, the magnitude of sympathetic augmentation during Valsalva straining predicts phase 4 arterial pressure elevations. Third, post-Valsalva sympathetic inhibition persists beyond the return of arterial and right atrial pressures to baseline levels which reflects an alteration of the normal relation between arterial pressure and muscle sympathetic activity. Therefore, Valsalva straining may have some utility for investigating changes of reflex control of sympathetic activity after space flight; however, measurement of beat-to-beat arterial pressure is essential for this use. The utility of this technique in microgravity can not be determined from these data. Further investigations are necessary to determine whether these relations are affected by the expansion of intrathoracic blood volume associated with microgravity.

  20. Ecological Insights from Pelagic Habitats Acquired Using Active Acoustic Techniques

    NASA Astrophysics Data System (ADS)

    Benoit-Bird, Kelly J.; Lawson, Gareth L.

    2016-01-01

    Marine pelagic ecosystems present fascinating opportunities for ecological investigation but pose important methodological challenges for sampling. Active acoustic techniques involve producing sound and receiving signals from organisms and other water column sources, offering the benefit of high spatial and temporal resolution and, via integration into different platforms, the ability to make measurements spanning a range of spatial and temporal scales. As a consequence, a variety of questions concerning the ecology of pelagic systems lend themselves to active acoustics, ranging from organism-level investigations and physiological responses to the environment to ecosystem-level studies and climate. As technologies and data analysis methods have matured, the use of acoustics in ecological studies has grown rapidly. We explore the continued role of active acoustics in addressing questions concerning life in the ocean, highlight creative applications to key ecological themes ranging from physiology and behavior to biogeography and climate, and discuss emerging avenues where acoustics can help determine how pelagic ecosystems function.

  1. Ecological Insights from Pelagic Habitats Acquired Using Active Acoustic Techniques.

    PubMed

    Benoit-Bird, Kelly J; Lawson, Gareth L

    2016-01-01

    Marine pelagic ecosystems present fascinating opportunities for ecological investigation but pose important methodological challenges for sampling. Active acoustic techniques involve producing sound and receiving signals from organisms and other water column sources, offering the benefit of high spatial and temporal resolution and, via integration into different platforms, the ability to make measurements spanning a range of spatial and temporal scales. As a consequence, a variety of questions concerning the ecology of pelagic systems lend themselves to active acoustics, ranging from organism-level investigations and physiological responses to the environment to ecosystem-level studies and climate. As technologies and data analysis methods have matured, the use of acoustics in ecological studies has grown rapidly. We explore the continued role of active acoustics in addressing questions concerning life in the ocean, highlight creative applications to key ecological themes ranging from physiology and behavior to biogeography and climate, and discuss emerging avenues where acoustics can help determine how pelagic ecosystems function.

  2. Ecological Insights from Pelagic Habitats Acquired Using Active Acoustic Techniques.

    PubMed

    Benoit-Bird, Kelly J; Lawson, Gareth L

    2016-01-01

    Marine pelagic ecosystems present fascinating opportunities for ecological investigation but pose important methodological challenges for sampling. Active acoustic techniques involve producing sound and receiving signals from organisms and other water column sources, offering the benefit of high spatial and temporal resolution and, via integration into different platforms, the ability to make measurements spanning a range of spatial and temporal scales. As a consequence, a variety of questions concerning the ecology of pelagic systems lend themselves to active acoustics, ranging from organism-level investigations and physiological responses to the environment to ecosystem-level studies and climate. As technologies and data analysis methods have matured, the use of acoustics in ecological studies has grown rapidly. We explore the continued role of active acoustics in addressing questions concerning life in the ocean, highlight creative applications to key ecological themes ranging from physiology and behavior to biogeography and climate, and discuss emerging avenues where acoustics can help determine how pelagic ecosystems function. PMID:26515810

  3. 'Waking activity': the neglected state of infancy.

    PubMed

    Becker, P T; Thoman, E B

    1982-08-01

    The significance of the waking activity state was investigated using naturalistic observations of 20 infants at 2, 3, 4 and 5 weeks of age. Sleep and wake states were recorded at 10-s intervals throughout a 7-h day, along with co-occurring behaviors of the mother. The infant's behavioral state was classified as 'waking activity' when the eyes were open but unfocused, and there was diffuse motor activity. Thus the infant was not alert, drowsy, dazed, or crying. Infants showed individual consistency in amount of waking activity over weeks, although this state composed only 4.4% of the total observation. The mean amount of waking activity over weeks was related to an index of stability in state organization, as measured by the consistency of state profiles over weeks. Profile consistency was assessed by an ANOVA for each infant's data. Separate stability indexes were derived for that portion of the day when the infants were alone, and for that portion when they were with their mothers. Infants with higher levels of waking activity had lower state stability scores in each context. The results indicate that waking activity is a behavioral state which reflects overall state control and is therefore significant for an understanding of brain-behavior relationships.

  4. Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase

    PubMed Central

    Klein, Tobias; Vajpai, Navratna; Phillips, Jonathan J.; Davies, Gareth; Holdgate, Geoffrey A.; Phillips, Chris; Tucker, Julie A.; Norman, Richard A.; Scott, Andrew D.; Higazi, Daniel R.; Lowe, David; Thompson, Gary S.; Breeze, Alexander L.

    2015-01-01

    Protein tyrosine kinases differ widely in their propensity to undergo rearrangements of the N-terminal Asp–Phe–Gly (DFG) motif of the activation loop, with some, including FGFR1 kinase, appearing refractory to this so-called ‘DFG flip'. Recent inhibitor-bound structures have unexpectedly revealed FGFR1 for the first time in a ‘DFG-out' state. Here we use conformationally selective inhibitors as chemical probes for interrogation of the structural and dynamic features that appear to govern the DFG flip in FGFR1. Our detailed structural and biophysical insights identify contributions from altered dynamics in distal elements, including the αH helix, towards the outstanding stability of the DFG-out complex with the inhibitor ponatinib. We conclude that the αC-β4 loop and ‘molecular brake' regions together impose a high energy barrier for this conformational rearrangement, and that this may have significance for maintaining autoinhibition in the non-phosphorylated basal state of FGFR1. PMID:26203596

  5. Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase

    NASA Astrophysics Data System (ADS)

    Klein, Tobias; Vajpai, Navratna; Phillips, Jonathan J.; Davies, Gareth; Holdgate, Geoffrey A.; Phillips, Chris; Tucker, Julie A.; Norman, Richard A.; Scott, Andrew D.; Higazi, Daniel R.; Lowe, David; Thompson, Gary S.; Breeze, Alexander L.

    2015-07-01

    Protein tyrosine kinases differ widely in their propensity to undergo rearrangements of the N-terminal Asp-Phe-Gly (DFG) motif of the activation loop, with some, including FGFR1 kinase, appearing refractory to this so-called `DFG flip'. Recent inhibitor-bound structures have unexpectedly revealed FGFR1 for the first time in a `DFG-out' state. Here we use conformationally selective inhibitors as chemical probes for interrogation of the structural and dynamic features that appear to govern the DFG flip in FGFR1. Our detailed structural and biophysical insights identify contributions from altered dynamics in distal elements, including the αH helix, towards the outstanding stability of the DFG-out complex with the inhibitor ponatinib. We conclude that the αC-β4 loop and `molecular brake' regions together impose a high energy barrier for this conformational rearrangement, and that this may have significance for maintaining autoinhibition in the non-phosphorylated basal state of FGFR1.

  6. Insights into animal and plant lectins with antimicrobial activities.

    PubMed

    Dias, Renata de Oliveira; Machado, Leandro Dos Santos; Migliolo, Ludovico; Franco, Octavio Luiz

    2015-01-05

    Lectins are multivalent proteins with the ability to recognize and bind diverse carbohydrate structures. The glyco -binding and diverse molecular structures observed in these protein classes make them a large and heterogeneous group with a wide range of biological activities in microorganisms, animals and plants. Lectins from plants and animals are commonly used in direct defense against pathogens and in immune regulation. This review focuses on sources of animal and plant lectins, describing their functional classification and tridimensional structures, relating these properties with biotechnological purposes, including antimicrobial activities. In summary, this work focuses on structural-functional elucidation of diverse lectin groups, shedding some light on host-pathogen interactions; it also examines their emergence as biotechnological tools through gene manipulation and development of new drugs.

  7. Insight in the Chemistry of Laser-Activated Dental Bleaching

    PubMed Central

    De Moor, Roeland Jozef Gentil; Meire, Maarten August; De Coster, Peter Jozef; Walsh, Laurence James

    2015-01-01

    The use of optical radiation for the activation of bleaching products has not yet been completely elucidated. Laser light is suggested to enhance the oxidizing effect of hydrogen peroxide. Different methods of enhancing hydrogen peroxide based bleaching are possible. They can be classified into six groups: alkaline pH environment, thermal enhancement and photothermal effect, photooxidation effect and direct photobleaching, photolysis effect and photodissociation, Fenton reaction and photocatalysis, and photodynamic effect. PMID:25874251

  8. Insight in the chemistry of laser-activated dental bleaching.

    PubMed

    De Moor, Roeland Jozef Gentil; Verheyen, Jeroen; Diachuk, Andrii; Verheyen, Peter; Meire, Maarten August; De Coster, Peter Jozef; Keulemans, Filip; De Bruyne, Mieke; Walsh, Laurence James

    2015-01-01

    The use of optical radiation for the activation of bleaching products has not yet been completely elucidated. Laser light is suggested to enhance the oxidizing effect of hydrogen peroxide. Different methods of enhancing hydrogen peroxide based bleaching are possible. They can be classified into six groups: alkaline pH environment, thermal enhancement and photothermal effect, photooxidation effect and direct photobleaching, photolysis effect and photodissociation, Fenton reaction and photocatalysis, and photodynamic effect.

  9. Proteomics reliability for micropollutants degradation insight into activated sludge systems.

    PubMed

    Buttiglieri, Gianluigi; Collado, Neus; Casas, Nuria; Comas, Joaquim; Rodriguez-Roda, Ignasi

    2015-01-01

    Little information is available on pharmaceutical trace compounds degradation pathways in wastewater. The potential of the proteomics approach has been evaluated to extract information on activated sludge microbial metabolism in degrading a trace concentration of a pharmaceutical compound (ibuprofen). Ibuprofen is one of the most consumed pharmaceuticals, measured in wastewater at very high concentrations and, despite its high removal rates, found in different environmental compartments. Aerated and completely mixed activated sludge batch tests were spiked with ibuprofen at 10 and 1,000 μg L(-1). Ibuprofen concentrations were determined in the liquid phase: 100% removal was observed and the kinetics were estimated. The solid phase was sampled for proteomics purposes. The first objective was to apply proteomics to evaluate protein profile variations in a complex matrix such as activated sludge. The second objective was to determine, at different ibuprofen concentrations, which proteins followed pre-defined trends. No newly expressed proteins were found. Nonetheless, the obtained results suggest that proteomics itself is a promising methodology to be applied in this field. Statistical and comparative studies analyses provided, in fact, useful information on biological reproducibility and permitted us to detect 62 proteins following coherent and plausible expected trends in terms of presence and intensity change. PMID:26360747

  10. Proteomics reliability for micropollutants degradation insight into activated sludge systems.

    PubMed

    Buttiglieri, Gianluigi; Collado, Neus; Casas, Nuria; Comas, Joaquim; Rodriguez-Roda, Ignasi

    2015-01-01

    Little information is available on pharmaceutical trace compounds degradation pathways in wastewater. The potential of the proteomics approach has been evaluated to extract information on activated sludge microbial metabolism in degrading a trace concentration of a pharmaceutical compound (ibuprofen). Ibuprofen is one of the most consumed pharmaceuticals, measured in wastewater at very high concentrations and, despite its high removal rates, found in different environmental compartments. Aerated and completely mixed activated sludge batch tests were spiked with ibuprofen at 10 and 1,000 μg L(-1). Ibuprofen concentrations were determined in the liquid phase: 100% removal was observed and the kinetics were estimated. The solid phase was sampled for proteomics purposes. The first objective was to apply proteomics to evaluate protein profile variations in a complex matrix such as activated sludge. The second objective was to determine, at different ibuprofen concentrations, which proteins followed pre-defined trends. No newly expressed proteins were found. Nonetheless, the obtained results suggest that proteomics itself is a promising methodology to be applied in this field. Statistical and comparative studies analyses provided, in fact, useful information on biological reproducibility and permitted us to detect 62 proteins following coherent and plausible expected trends in terms of presence and intensity change.

  11. Structural insights into μ-opioid receptor activation

    PubMed Central

    Huang, Weijiao; Manglik, Aashish; Venkatakrishnan, A. J.; Laeremans, Toon; Feinberg, Evan N.; Sanborn, Adrian L.; Kato, Hideaki E.; Livingston, Kathryn E.; Thorsen, Thor S.; Kling, Ralf; Granier, Sébastien; Gmeiner, Peter; Husbands, Stephen M.; Traynor, John R.; Weis, William I.; Steyaert, Jan; Dror, Ron O.; Kobilka, Brian K.

    2015-01-01

    Summary Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To understand the structural basis for μOR activation, we obtained a 2.1 Å X-ray crystal structure of the μOR bound to the morphinan agonist BU72 and stabilized by a G protein-mimetic camelid-antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2 adrenergic receptor (β2AR) and the M2 muscarinic receptor (M2R). Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three GPCRs. PMID:26245379

  12. Structural insights into µ-opioid receptor activation.

    PubMed

    Huang, Weijiao; Manglik, Aashish; Venkatakrishnan, A J; Laeremans, Toon; Feinberg, Evan N; Sanborn, Adrian L; Kato, Hideaki E; Livingston, Kathryn E; Thorsen, Thor S; Kling, Ralf C; Granier, Sébastien; Gmeiner, Peter; Husbands, Stephen M; Traynor, John R; Weis, William I; Steyaert, Jan; Dror, Ron O; Kobilka, Brian K

    2015-08-20

    Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2-adrenergic receptor (β2AR) and the M2 muscarinic receptor. Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors. PMID:26245379

  13. Molecular structure of amyloid fibrils: insights from solid-state NMR.

    PubMed

    Tycko, Robert

    2006-02-01

    Solid-state nuclear magnetic resonance (NMR) measurements have made major contributions to our understanding of the molecular structures of amyloid fibrils, including fibrils formed by the beta-amyloid peptide associated with Alzheimer's disease, by proteins associated with fungal prions, and by a variety of other polypeptides. Because solid-state NMR techniques can be used to determine interatomic distances (both intramolecular and intermolecular), place constraints on backbone and side-chain torsion angles, and identify tertiary and quaternary contacts, full molecular models for amyloid fibrils can be developed from solid-state NMR data, especially when supplemented by lower-resolution structural constraints from electron microscopy and other sources. In addition, solid-state NMR data can be used as experimental tests of various proposals and hypotheses regarding the mechanisms of amyloid formation, the nature of intermediate structures, and the common structural features within amyloid fibrils. This review introduces the basic experimental and conceptual principles behind solid-state NMR methods that are applicable to amyloid fibrils, reviews the information about amyloid structures that has been obtained to date with these methods, and discusses how solid-state NMR data provide insights into the molecular interactions that stabilize amyloid structures, the generic propensity of polypeptide chains to form amyloid fibrils, and a number of related issues that are of current interest in the amyloid field.

  14. Uniformity and nonuniformity of neural activities correlated to different insight problem solving.

    PubMed

    Zhao, Q; Li, Y; Shang, X; Zhou, Z; Han, L

    2014-06-13

    Previous studies on the neural basis of insight reflected weak consistency except for the anterior cingulate cortex. The present work adopted the semantic and homophonic punny riddle to explore the uniformity and nonuniformity of neural activities correlated to different insight problem solving. Results showed that in the early period of insight solving, the semantic and homophonic punny riddles induced a common N350-500 over the central scalp. However, during -400 to 0 ms before the riddles were solved, the semantic punny riddles induced a positive event-related potential (ERP) deflection over the temporal cortex for retrieving the extensive semantic information, while the homophonic punny riddles induced a positive ERP deflection over the temporal cortex and a negative one in the left frontal cortex which might reflect the semantic and phonological information processing respectively. Our study indicated that different insight problem solving should have the same cognitive process of detecting cognitive conflicts, but have different ways to solve the conflicts.

  15. Degassing Dynamics at Stromboli Volcano: Insights From Infrasonic Activity

    NASA Astrophysics Data System (ADS)

    Marchetti, E.; Ripepe, M.; Ulivieri, G.; Delle Donne, D.

    2006-12-01

    Infrasound at Stromboli consists on transients related to explosions and on small amplitude intermittent pulses associated with "active" over-pressurized degassing of the magma column. Degassing of a magmatic system is generally understood as a quasi-steady "non-explosive" passive mechanism, when the slow exsolution process allows the continuous compensation of the gas pressure. In contrast infrasound indicates that degassing can occur also in over-pressurized condition, associated to the bursting of small gas pockets at the magma free-surface. This intermittent release of gas induces in the atmosphere small (< 0.1 x105 Pa at the source) infrasonic pulses and occurs almost regularly every ~1-2 s. The permanent small aperture 5-elements infrasonic array at Stromboli is monitoring both explosions and degassing providing position, over-pressure and occurrence of the source and revealing the complex and complete behavior of the magma column. Log-linear amplitude distribution of infrasonic data shows 2 different trends of decay suggesting that degassing and explosions are driven by a different gas dynamics. Moreover, infrasound location indicates that over-pressurized degassing is active only in one vent at once. Location of the puffing is stable in a single vent over hours-to-days periods, or it can shift from vent to vent with smooth or abrupt transitions. The stability in the position of the puffing within the crater terrace is suggesting that the over-pressurized gas bubble flow is following only one preferential segment of the feeding conduits at once. The stable location of the bursting bubbles, however, may change from time to time and without any apparent evidence or trigger mechanisms, leading to a sharp change in the rising path of gas bubbles. This gas bubble behavior seems to be consistent with experimental and numerical studies on the flow of particles and drops at pipe bifurcations. Over-pressurized gas bursting could reflect higher gas flux regimes in the

  16. A periodically active pulsar giving insight into magnetospheric physics.

    PubMed

    Kramer, M; Lyne, A G; O'Brien, J T; Jordan, C A; Lorimer, D R

    2006-04-28

    PSR B1931+24 (J1933+2421) behaves as an ordinary isolated radio pulsar during active phases that are 5 to 10 days long. However, when the radio emission ceases, it switches off in less than 10 seconds and remains undetectable for the next 25 to 35 days, then switches on again. This pattern repeats quasi-periodically. The origin of this behavior is unclear. Even more remarkably, the pulsar rotation slows down 50% faster when it is on than when it is off. This indicates a massive increase in magnetospheric currents when the pulsar switches on, proving that pulsar wind plays a substantial role in pulsar spin-down. This allows us, for the first time, to estimate the magnetospheric currents in a pulsar magnetosphere during the occurrence of radio emission.

  17. An Insightful Steady-State Performance of a Squirrel Cage Induction Generator Enhanced with STATCOM

    NASA Astrophysics Data System (ADS)

    Ojo, Olorunfemi; Khayamy, Mehdy; Bule, Mehari

    2014-06-01

    This paper presents the regulation of the terminal voltage and reactive power of a grid-connected squirrel cage induction generator. A shunt connected voltage source inverter (VSI) with a capacitor in the DC side operating as a Static Compensator (STATCOM) and a shunt capacitor are used for regulating the generator terminal voltage and limit the reactive power demand from the grid. Simulation results for steady-state operation for a wide variation of speed in the super-synchronous region are presented as well as the dynamic stability of the system. Closed-form steady-state characteristics equations for the system are used to determine key variables and to demonstrate how the operation of the system depends on various parameters. This characteristics curve which contains all of the equations of the system provides the all in one insightful view to the inherent characteristics of the system and the effect of the parameter variation on the terminal voltage plane.

  18. Small Molecule Activation by Constrained Phosphorus Compounds: Insights from Theory.

    PubMed

    Pal, Amrita; Vanka, Kumar

    2016-01-19

    An exciting new development in main group chemistry has been the use of a constrained, "flat", phosphorus-based complex to mediate in reactions such as the dehydrogenation of ammonia borane (AB), and the activation of the N-H bond in primary amines. Its importance is based on the fact that it shows that main group compounds, when properly designed, can be as effective as transition metal complexes for doing significant chemical transformations. What the current computational study, employing density functional theory (DFT), reveals is that a common, general mechanism exists that accounts for the behavior of the flat phosphorus compound in the different reactions that have been experimentally reported to date. This mechanism, which involves the mediation by a base as a proton transfer agent, is simpler and energetically more favorable than the previous mechanisms that have been proposed for the same reactions in the literature. It is likely that the knowledge gained from the current work about the chemical behavior of this phosphorus compound can be utilized to design new constrained phosphorus-based compounds. PMID:26700074

  19. Diversity of Active States in TMT Opsins

    PubMed Central

    Sakai, Kazumi; Yamashita, Takahiro; Imamoto, Yasushi; Shichida, Yoshinori

    2015-01-01

    Opn3/TMT opsins belong to one of the opsin groups with vertebrate visual and non-visual opsins, and are widely distributed in eyes, brains and other internal organs in various vertebrates and invertebrates. Vertebrate Opn3/TMT opsins are further classified into four groups on the basis of their amino acid identities. However, there is limited information about molecular properties of these groups, due to the difficulty in preparing the recombinant proteins. Here, we successfully expressed recombinant proteins of TMT1 and TMT2 opsins of medaka fish (Oryzias latipes) in cultured cells and characterized their molecular properties. Spectroscopic and biochemical studies demonstrated that TMT1 and TMT2 opsins functioned as blue light-sensitive Gi/Go-coupled receptors, but exhibited spectral properties and photo-convertibility of the active state different from each other. TMT1 opsin forms a visible light-absorbing active state containing all-trans-retinal, which can be photo-converted to 7-cis- and 9-cis-retinal states in addition to the original 11-cis-retinal state. In contrast, the active state of TMT2 opsin is a UV light-absorbing state having all-trans-retinal and does not photo-convert to any other state, including the original 11-cis-retinal state. Thus, TMT opsins are diversified so as to form a different type of active state, which may be responsible for their different functions. PMID:26491964

  20. Mechanistic insights into metal ion activation and operator recognition by the ferric uptake regulator

    NASA Astrophysics Data System (ADS)

    Deng, Zengqin; Wang, Qing; Liu, Zhao; Zhang, Manfeng; Machado, Ana Carolina Dantas; Chiu, Tsu-Pei; Feng, Chong; Zhang, Qi; Yu, Lin; Qi, Lei; Zheng, Jiangge; Wang, Xu; Huo, Xinmei; Qi, Xiaoxuan; Li, Xiaorong; Wu, Wei; Rohs, Remo; Li, Ying; Chen, Zhongzhou

    2015-07-01

    Ferric uptake regulator (Fur) plays a key role in the iron homeostasis of prokaryotes, such as bacterial pathogens, but the molecular mechanisms and structural basis of Fur-DNA binding remain incompletely understood. Here, we report high-resolution structures of Magnetospirillum gryphiswaldense MSR-1 Fur in four different states: apo-Fur, holo-Fur, the Fur-feoAB1 operator complex and the Fur-Pseudomonas aeruginosa Fur box complex. Apo-Fur is a transition metal ion-independent dimer whose binding induces profound conformational changes and confers DNA-binding ability. Structural characterization, mutagenesis, biochemistry and in vivo data reveal that Fur recognizes DNA by using a combination of base readout through direct contacts in the major groove and shape readout through recognition of the minor-groove electrostatic potential by lysine. The resulting conformational plasticity enables Fur binding to diverse substrates. Our results provide insights into metal ion activation and substrate recognition by Fur that suggest pathways to engineer magnetotactic bacteria and antipathogenic drugs.

  1. Mechanistic insights into metal ion activation and operator recognition by the ferric uptake regulator

    PubMed Central

    Deng, Zengqin; Wang, Qing; Liu, Zhao; Zhang, Manfeng; Machado, Ana Carolina Dantas; Chiu, Tsu-Pei; Feng, Chong; Zhang, Qi; Yu, Lin; Qi, Lei; Zheng, Jiangge; Wang, Xu; Huo, XinMei; Qi, Xiaoxuan; Li, Xiaorong; Wu, Wei; Rohs, Remo; Li, Ying; Chen, Zhongzhou

    2015-01-01

    Ferric uptake regulator (Fur) plays a key role in the iron homeostasis of prokaryotes, such as bacterial pathogens, but the molecular mechanisms and structural basis of Fur–DNA binding remain incompletely understood. Here, we report high-resolution structures of Magnetospirillum gryphiswaldense MSR-1 Fur in four different states: apo-Fur, holo-Fur, the Fur–feoAB1 operator complex and the Fur–Pseudomonas aeruginosa Fur box complex. Apo-Fur is a transition metal ion-independent dimer whose binding induces profound conformational changes and confers DNA-binding ability. Structural characterization, mutagenesis, biochemistry and in vivo data reveal that Fur recognizes DNA by using a combination of base readout through direct contacts in the major groove and shape readout through recognition of the minor-groove electrostatic potential by lysine. The resulting conformational plasticity enables Fur binding to diverse substrates. Our results provide insights into metal ion activation and substrate recognition by Fur that suggest pathways to engineer magnetotactic bacteria and antipathogenic drugs. PMID:26134419

  2. Political contexts and maternal health policy: insights from a comparison of south Indian states.

    PubMed

    Smith, Stephanie L

    2014-01-01

    Nearly 300,000 women die from pregnancy-related complications each year. One-fifth of these deaths occur in India. Maternal survival rose on India's national policy agenda in the mid-2000s, but responsibility for health policy and implementation in the federal system is largely devolved to the state level where priority for the issue and maternal health outcomes vary. This study investigates sources of variation in maternal health policy and implementation sub-nationally in India. The study is guided by four analytical categories drawn from policy process literature: constitutional, governing and social structures; political contexts; actors and ideas. The experiences of two south Indian states-Tamil Nadu a leader and Karnataka a relatively slow mover-are examined. Process-tracing, a case study methodology that helps to identify roles of complex historical events in causal processes, was employed to investigate the research question in each state. The study is informed by interviews with public health policy experts and service delivery professionals, observation of implementation sites and archival document analysis. Historical legacies-Tamil Nadu's non-Brahmin social movement and Karnataka's developmental disparities combined with decentralization-shape the states' political contexts, affecting variation in maternal health policy and implementation. Competition to advance consistent political priorities across regimes in Tamil Nadu offers fertile ground for policy entrepreneurship and strong public health system administration facilitates progress. Inconsistent political priorities and relatively weak public health system administration frustrate progress in Karnataka. These variations offer insights to the ways in which sub-national political and administrative contexts shape health policy and implementation. PMID:24444838

  3. Political contexts and maternal health policy: insights from a comparison of south Indian states.

    PubMed

    Smith, Stephanie L

    2014-01-01

    Nearly 300,000 women die from pregnancy-related complications each year. One-fifth of these deaths occur in India. Maternal survival rose on India's national policy agenda in the mid-2000s, but responsibility for health policy and implementation in the federal system is largely devolved to the state level where priority for the issue and maternal health outcomes vary. This study investigates sources of variation in maternal health policy and implementation sub-nationally in India. The study is guided by four analytical categories drawn from policy process literature: constitutional, governing and social structures; political contexts; actors and ideas. The experiences of two south Indian states-Tamil Nadu a leader and Karnataka a relatively slow mover-are examined. Process-tracing, a case study methodology that helps to identify roles of complex historical events in causal processes, was employed to investigate the research question in each state. The study is informed by interviews with public health policy experts and service delivery professionals, observation of implementation sites and archival document analysis. Historical legacies-Tamil Nadu's non-Brahmin social movement and Karnataka's developmental disparities combined with decentralization-shape the states' political contexts, affecting variation in maternal health policy and implementation. Competition to advance consistent political priorities across regimes in Tamil Nadu offers fertile ground for policy entrepreneurship and strong public health system administration facilitates progress. Inconsistent political priorities and relatively weak public health system administration frustrate progress in Karnataka. These variations offer insights to the ways in which sub-national political and administrative contexts shape health policy and implementation.

  4. Toward understanding the active SETI debate: Insights from risk communication and perception

    NASA Astrophysics Data System (ADS)

    Korbitz, Adam

    2014-12-01

    Insights from the robust field of risk communication and perception have to date been almost totally absent from the policy debate regarding the relative risks and merits of Active SETI or Messaging to Extraterrestrial Intelligence (METI). For many years, the practice (or proposed practice) of Active SETI has generated a vigorous and sometimes heated policy debate within the scientific community. There have also been some negative reactions in the media toward the activities of those engaged in Active SETI. Risk communication is a scientific approach to communication regarding situations involving potentially sensitive or controversial situations in which there may be high public concern and low public trust. The discipline has found wide acceptance and utility in fields such as public health, industrial regulation and environmental protection. Insights from the scientific field of risk communication (such as omission bias, loss aversion, the availability heuristic, probability neglect, and the general human preference for voluntary over involuntary risks) may help those who have participated in either side of the debate over Active SETI to better understand why the debate has taken on this posture. Principles of risk communication and risk perception may also help those engaged in Active SETI to communicate more effectively with other scientists, the public, with the media, and with policy makers regarding their activities and to better understand and respond to concerns expressed regarding the activity.

  5. Uniformity and nonuniformity of neural activities correlated to different insight problem solving.

    PubMed

    Zhao, Q; Li, Y; Shang, X; Zhou, Z; Han, L

    2014-06-13

    Previous studies on the neural basis of insight reflected weak consistency except for the anterior cingulate cortex. The present work adopted the semantic and homophonic punny riddle to explore the uniformity and nonuniformity of neural activities correlated to different insight problem solving. Results showed that in the early period of insight solving, the semantic and homophonic punny riddles induced a common N350-500 over the central scalp. However, during -400 to 0 ms before the riddles were solved, the semantic punny riddles induced a positive event-related potential (ERP) deflection over the temporal cortex for retrieving the extensive semantic information, while the homophonic punny riddles induced a positive ERP deflection over the temporal cortex and a negative one in the left frontal cortex which might reflect the semantic and phonological information processing respectively. Our study indicated that different insight problem solving should have the same cognitive process of detecting cognitive conflicts, but have different ways to solve the conflicts. PMID:24759773

  6. The role of alpha-rhythm states in perceptual learning: insights from experiments and computational models

    PubMed Central

    Sigala, Rodrigo; Haufe, Sebastian; Roy, Dipanjan; Dinse, Hubert R.; Ritter, Petra

    2014-01-01

    During the past two decades growing evidence indicates that brain oscillations in the alpha band (~10 Hz) not only reflect an “idle” state of cortical activity, but also take a more active role in the generation of complex cognitive functions. A recent study shows that more than 60% of the observed inter-subject variability in perceptual learning can be ascribed to ongoing alpha activity. This evidence indicates a significant role of alpha oscillations for perceptual learning and hence motivates to explore the potential underlying mechanisms. Hence, it is the purpose of this review to highlight existent evidence that ascribes intrinsic alpha oscillations a role in shaping our ability to learn. In the review, we disentangle the alpha rhythm into different neural signatures that control information processing within individual functional building blocks of perceptual learning. We further highlight computational studies that shed light on potential mechanisms regarding how alpha oscillations may modulate information transfer and connectivity changes relevant for learning. To enable testing of those model based hypotheses, we emphasize the need for multidisciplinary approaches combining assessment of behavior and multi-scale neuronal activity, active modulation of ongoing brain states and computational modeling to reveal the mathematical principles of the complex neuronal interactions. In particular we highlight the relevance of multi-scale modeling frameworks such as the one currently being developed by “The Virtual Brain” project. PMID:24772077

  7. Metabolic restructuring during energy-limited states: insights from Artemia franciscana embryos and other animals.

    PubMed

    Hand, Steven C; Menze, Michael A; Borcar, Apu; Patil, Yuvraj; Covi, Joseph A; Reynolds, Julie A; Toner, Mehmet

    2011-05-01

    Many life history stages of animals that experience environmental insults enter developmental arrested states that are characterized by reduced cellular proliferation, with or without a concurrent reduction in overall metabolism. In the case of the most profound metabolic arrest reported in invertebrates, i.e., anaerobic quiescence in Artemia franciscana embryos, acidification of the intracellular milieu is a major factor governing catabolic and anabolic downregulation. Release of ions from intracellular compartments is the source for approximately 50% of the proton equivalents needed for the 1.5 unit acidification that is observed. Recovery from the metabolic arrest requires re-sequestration of the protons with a vacuolar-type ATPase (V-ATPase). The remarkable facet of this mechanism is the ability of embryonic cells to survive the dissipation of intracellular ion gradients. Across many diapause-like states, the metabolic reduction and subsequent matching of energy demand is accomplished by shifting energy metabolism from oxidative phosphorylation to aerobic glycolysis. Molecular pathways that are activated to induce these resilient hypometabolic states include stimulation of the AMP-activated protein kinase (AMPK) and insulin signaling via suite of daf (dauer formation) genes for diapause-like states in nematodes and insects. Contributing factors for other metabolically depressed states involve hypoxia-inducible factor-1 and downregulation of the pyruvate dehydrogenase complex. Metabolic similarities between natural states of stasis and some cancer phenotypes are noteworthy. Reduction of flux through oxidative phosphorylation helps prevent cell death in certain cancer types, similar to the way it increases viability of dauer stages in Caenorhabditis elegans. Mechanisms that underlie natural stasis are being used to pre-condition mammalian cells prior to cell biostabilization and storage.

  8. X-ray Raman Scattering at Extreme Conditions: Insights to Local Structure, Oxidation and Spin state

    NASA Astrophysics Data System (ADS)

    Wilke, M.; Sternemann, C.; Sahle, C.; Spiekermann, G.; Nyrow, A.; Weis, C.; Cerantola, V.; Schmidt, C.; Yavas, H.

    2015-12-01

    In the last decades, X-ray spectroscopic techniques using very intense synchrotron radiation (SR) have become indispensable tools for studying geomaterials. Due to the rather low absorption of hard X-rays, SR opens up the possibility to perform measurements in high-pressure, high temperature cells. The range of elements accessible by X-ray absorption spectroscopy (XAFS) techniques in these cells is limited by the absorption of X-rays due to the sample environment, i.e. the diamond windows. The indirect measurement of XAFS spectra by inelastic X-ray Raman scattering (XRS) provides a workaround to access absorption edges at low energies (e.g. low Z elements). Therefore, XRS enables measurements that are similar to electron energy loss spectroscopy but offer to measure at in-situ conditions and not just in vacuum. Measurements of the O K-edge of H2O from ambient to supercritical PT-conditions (up to 600°C @ 134 MPa; 400°C @ 371 MPa) were used to trace structural changes of the hydrogen-bonded network, which controls many physical and chemical properties of H2O [1]. The Fe M3,2-edge measured by XRS were used to characterize the oxidation state and local structure in crystalline compounds and glasses [2]. Furthermore, the M3,2 yields detailed insight to the crystal-field splitting and electronic spin state. In a reconnaissance study, the pressure-induced high-spin to low-spin transition of Fe in FeS between 6 and 8 GPa was measured. By multiplet calculations of the spectra for octahedral Fe2+, a difference in crystal field splitting between the two states of ca. 1.7 eV was estimated [3]. Finally, we successfully assessed the electronic structure of Fe in siderite by measurements of M and L-edge up to 50 GPa, covering the spin transition between 40 and 45 GPa. [1] Sahle et al. (2013) PNAS, doi: 10.1073/pnas.1220301110.. [2] Nyrow et al. (2014) Contrib Mineral Petrol 167, 1012. [3] Nyrow et al. (2014) Appl Phys Lett 104, 262408.

  9. Antimicrobial activity of human α-defensin 6 analogs: insights into the physico-chemical reasons behind weak bactericidal activity of HD6 in vitro.

    PubMed

    Mathew, Basil; Nagaraj, Ramakrishnan

    2015-11-01

    Human α-defensin 6 (HD6), unlike other mammalian defensins, does not exhibit bactericidal activity, particularly against aerobic bacteria. Monomeric HD6 has a tertiary structure similar to other α-defensins in the crystalline state. However, the physico-chemical reasons behind the lack of antibacterial activity of HD6 are yet to be established unequivocally. In this study, we have investigated the antimicrobial activity of HD6 analogs. A linear analog of HD6, in which the distribution of arginine residues was similar to active α-defensins, shows broad-spectrum antimicrobial activity, indicating that atypical distribution of arginine residues contributes to the inactivity of HD6. Peptides spanning the N-terminal cationic segment were active against a wide range of organisms. Antimicrobial potency of these shorter analogs was further enhanced when myristic acid was conjugated at the N-terminus. Cytoplasmic localization of the analogs without fatty acylation was observed to be necessary for bacterial killing, while they exhibited fungicidal activity by permeabilizing Candida albicans membranes. Myristoylated analogs and the linear full-length arginine analog exhibited activity by permeabilizing bacterial and fungal membranes. Our study provides insights into the lack of bactericidal activity of HD6 against aerobic bacteria. PMID:26400692

  10. Evolutionary History of Assassin Bugs (Insecta: Hemiptera: Reduviidae): Insights from Divergence Dating and Ancestral State Reconstruction

    PubMed Central

    Hwang, Wei Song; Weirauch, Christiane

    2012-01-01

    Assassin bugs are one of the most successful clades of predatory animals based on their species numbers (∼6,800 spp.) and wide distribution in terrestrial ecosystems. Various novel prey capture strategies and remarkable prey specializations contribute to their appeal as a model to study evolutionary pathways involved in predation. Here, we reconstruct the most comprehensive reduviid phylogeny (178 taxa, 18 subfamilies) to date based on molecular data (5 markers). This phylogeny tests current hypotheses on reduviid relationships emphasizing the polyphyletic Reduviinae and the blood-feeding, disease-vectoring Triatominae, and allows us, for the first time in assassin bugs, to reconstruct ancestral states of prey associations and microhabitats. Using a fossil-calibrated molecular tree, we estimated divergence times for key events in the evolutionary history of Reduviidae. Our results indicate that the polyphyletic Reduviinae fall into 11–14 separate clades. Triatominae are paraphyletic with respect to the reduviine genus Opisthacidius in the maximum likelihood analyses; this result is in contrast to prior hypotheses that found Triatominae to be monophyletic or polyphyletic and may be due to the more comprehensive taxon and character sampling in this study. The evolution of blood-feeding may thus have occurred once or twice independently among predatory assassin bugs. All prey specialists evolved from generalist ancestors, with multiple evolutionary origins of termite and ant specializations. A bark-associated life style on tree trunks is ancestral for most of the lineages of Higher Reduviidae; living on foliage has evolved at least six times independently. Reduviidae originated in the Middle Jurassic (178 Ma), but significant lineage diversification only began in the Late Cretaceous (97 Ma). The integration of molecular phylogenetics with fossil and life history data as presented in this paper provides insights into the evolutionary history of reduviids and clears

  11. Evolutionary history of assassin bugs (insecta: hemiptera: Reduviidae): insights from divergence dating and ancestral state reconstruction.

    PubMed

    Hwang, Wei Song; Weirauch, Christiane

    2012-01-01

    Assassin bugs are one of the most successful clades of predatory animals based on their species numbers (∼6,800 spp.) and wide distribution in terrestrial ecosystems. Various novel prey capture strategies and remarkable prey specializations contribute to their appeal as a model to study evolutionary pathways involved in predation. Here, we reconstruct the most comprehensive reduviid phylogeny (178 taxa, 18 subfamilies) to date based on molecular data (5 markers). This phylogeny tests current hypotheses on reduviid relationships emphasizing the polyphyletic Reduviinae and the blood-feeding, disease-vectoring Triatominae, and allows us, for the first time in assassin bugs, to reconstruct ancestral states of prey associations and microhabitats. Using a fossil-calibrated molecular tree, we estimated divergence times for key events in the evolutionary history of Reduviidae. Our results indicate that the polyphyletic Reduviinae fall into 11-14 separate clades. Triatominae are paraphyletic with respect to the reduviine genus Opisthacidius in the maximum likelihood analyses; this result is in contrast to prior hypotheses that found Triatominae to be monophyletic or polyphyletic and may be due to the more comprehensive taxon and character sampling in this study. The evolution of blood-feeding may thus have occurred once or twice independently among predatory assassin bugs. All prey specialists evolved from generalist ancestors, with multiple evolutionary origins of termite and ant specializations. A bark-associated life style on tree trunks is ancestral for most of the lineages of Higher Reduviidae; living on foliage has evolved at least six times independently. Reduviidae originated in the Middle Jurassic (178 Ma), but significant lineage diversification only began in the Late Cretaceous (97 Ma). The integration of molecular phylogenetics with fossil and life history data as presented in this paper provides insights into the evolutionary history of reduviids and clears

  12. ACTIVE STATE OF MUSCLE IN IODOACETATE RIGOR

    PubMed Central

    Mauriello, George E.; Sandow, Alexander

    1959-01-01

    Frog sartorius muscles, equilibrated to 2 x 10-4 M iodoacetic acid-Ringer's solution and activated by a series of twitches or a long tetanus, perform a rigor response consisting in general of a contractile change which plateaus and is then automatically reversed. Isotonic rigor shortening obeys a force-velocity relation which, with certain differences in value of the constants, accords with Hill's equation for this relation. Changes in rigidity during either isotonic or isometric rigor response show that the capacity of the rigor muscle to bear a load increases more abruptly than the corresponding onset of the ordinarily recorded response, briefly plateaus, and then decays. A quick release of about 1 mm. applied at any instant of isometric rigor output causes the tension to drop instantaneously to zero and then redevelop, the rate of redevelopment varying as does the intensity of the load-bearing capacity. These results demonstrate that rigor mechanical responses result from interaction of a passive, undamped series elastic component, and a contractile component with active state properties like those of normal contraction. Adenosinetriphosphate is known to break down in association with development of the rigor active state. This is discussed in relation to the apparent absence of ATP splitting in normal activation of the contractile component. PMID:13654738

  13. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 2 2011-07-01 2010-07-01 true State-level activities. 300.704 Section 300.704... Allotments, Grants, and Use of Funds § 300.704 State-level activities. (a) State administration. (1) For the... under that Part. (b) Other State-level activities. (1) States may reserve a portion of their...

  14. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 2 2014-07-01 2013-07-01 true State-level activities. 300.704 Section 300.704... Allotments, Grants, and Use of Funds § 300.704 State-level activities. (a) State administration. (1) For the... under that Part. (b) Other State-level activities. (1) States may reserve a portion of their...

  15. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 2 2013-07-01 2013-07-01 false State-level activities. 300.704 Section 300.704... Allotments, Grants, and Use of Funds § 300.704 State-level activities. (a) State administration. (1) For the... under that Part. (b) Other State-level activities. (1) States may reserve a portion of their...

  16. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 2 2012-07-01 2012-07-01 false State-level activities. 300.704 Section 300.704... Allotments, Grants, and Use of Funds § 300.704 State-level activities. (a) State administration. (1) For the... under that Part. (b) Other State-level activities. (1) States may reserve a portion of their...

  17. Further insight into mechanisms of solid-state interactions in UMo/Al system

    NASA Astrophysics Data System (ADS)

    Mazaudier, F.; Proye, C.; Hodaj, F.

    2008-07-01

    In this paper, the solid-state interactions between metastable γ-UMo alloys (containing 5, 7 and 10 wt%Mo) and Al, at temperatures ranging from 440 to 600 °C and for ageing times up to 10 h, are studied using the diffusion couple technique and nuclear fuel plate annealing. The reaction product consists of three main zones, two of them presenting a periodic layered morphology. The growth kinetics is limited by solid-state diffusion and Al is the most mobile species. Both growth kinetics and its global energy of activation are similar to that found for the U/Al binary system. The diffusion path is determined and phase equilibrium relations are deduced for the Mo-poor part of the U-Mo-Al metastable ternary phase diagram.

  18. Structural insights into Ca2+-activated long-range allosteric channel gating of RyR1

    PubMed Central

    Wei, Risheng; Wang, Xue; Zhang, Yan; Mukherjee, Saptarshi; Zhang, Lei; Chen, Qiang; Huang, Xinrui; Jing, Shan; Liu, Congcong; Li, Shuang; Wang, Guangyu; Xu, Yaofang; Zhu, Sujie; Williams, Alan J; Sun, Fei; Yin, Chang-Cheng

    2016-01-01

    Ryanodine receptors (RyRs) are a class of giant ion channels with molecular mass over 2.2 mega-Daltons. These channels mediate calcium signaling in a variety of cells. Since more than 80% of the RyR protein is folded into the cytoplasmic assembly and the remaining residues form the transmembrane domain, it has been hypothesized that the activation and regulation of RyR channels occur through an as yet uncharacterized long-range allosteric mechanism. Here we report the characterization of a Ca2+-activated open-state RyR1 structure by cryo-electron microscopy. The structure has an overall resolution of 4.9 Å and a resolution of 4.2 Å for the core region. In comparison with the previously determined apo/closed-state structure, we observed long-range allosteric gating of the channel upon Ca2+ activation. In-depth structural analyses elucidated a novel channel-gating mechanism and a novel ion selectivity mechanism of RyR1. Our work not only provides structural insights into the molecular mechanisms of channel gating and regulation of RyRs, but also sheds light on structural basis for channel-gating and ion selectivity mechanisms for the six-transmembrane-helix cation channel family. PMID:27573175

  19. Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1.

    PubMed

    Wei, Risheng; Wang, Xue; Zhang, Yan; Mukherjee, Saptarshi; Zhang, Lei; Chen, Qiang; Huang, Xinrui; Jing, Shan; Liu, Congcong; Li, Shuang; Wang, Guangyu; Xu, Yaofang; Zhu, Sujie; Williams, Alan J; Sun, Fei; Yin, Chang-Cheng

    2016-09-01

    Ryanodine receptors (RyRs) are a class of giant ion channels with molecular mass over 2.2 mega-Daltons. These channels mediate calcium signaling in a variety of cells. Since more than 80% of the RyR protein is folded into the cytoplasmic assembly and the remaining residues form the transmembrane domain, it has been hypothesized that the activation and regulation of RyR channels occur through an as yet uncharacterized long-range allosteric mechanism. Here we report the characterization of a Ca(2+)-activated open-state RyR1 structure by cryo-electron microscopy. The structure has an overall resolution of 4.9 Å and a resolution of 4.2 Å for the core region. In comparison with the previously determined apo/closed-state structure, we observed long-range allosteric gating of the channel upon Ca(2+) activation. In-depth structural analyses elucidated a novel channel-gating mechanism and a novel ion selectivity mechanism of RyR1. Our work not only provides structural insights into the molecular mechanisms of channel gating and regulation of RyRs, but also sheds light on structural basis for channel-gating and ion selectivity mechanisms for the six-transmembrane-helix cation channel family.

  20. Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1.

    PubMed

    Wei, Risheng; Wang, Xue; Zhang, Yan; Mukherjee, Saptarshi; Zhang, Lei; Chen, Qiang; Huang, Xinrui; Jing, Shan; Liu, Congcong; Li, Shuang; Wang, Guangyu; Xu, Yaofang; Zhu, Sujie; Williams, Alan J; Sun, Fei; Yin, Chang-Cheng

    2016-09-01

    Ryanodine receptors (RyRs) are a class of giant ion channels with molecular mass over 2.2 mega-Daltons. These channels mediate calcium signaling in a variety of cells. Since more than 80% of the RyR protein is folded into the cytoplasmic assembly and the remaining residues form the transmembrane domain, it has been hypothesized that the activation and regulation of RyR channels occur through an as yet uncharacterized long-range allosteric mechanism. Here we report the characterization of a Ca(2+)-activated open-state RyR1 structure by cryo-electron microscopy. The structure has an overall resolution of 4.9 Å and a resolution of 4.2 Å for the core region. In comparison with the previously determined apo/closed-state structure, we observed long-range allosteric gating of the channel upon Ca(2+) activation. In-depth structural analyses elucidated a novel channel-gating mechanism and a novel ion selectivity mechanism of RyR1. Our work not only provides structural insights into the molecular mechanisms of channel gating and regulation of RyRs, but also sheds light on structural basis for channel-gating and ion selectivity mechanisms for the six-transmembrane-helix cation channel family. PMID:27573175

  1. Population activities of the United States government.

    PubMed

    Miles Re, J

    1971-08-01

    The editor's comment in this issue of the journal cites 5 overlapping phases in the evolution of population and family planning programs in the United States. The phases are 1) collecting census data and vital statistics, 1790-, 2) family planning assistance to developing nations, 1963, 3) family planning assistance to the U.S. "disadvantaged," 1964-, 4) overpopulation as a national concern, 1969-, and 5) the multiple action phase, 197? (phase including diverse steps to limit population growth and occurring after basic attitudes toward human reproduction have changed). The issue of the journal focuses on total population size and rates of population increase rather than on the distribution of population, and on federal action rather than on the activities of state and local governments. The editor's comment is followed by an extensive discussion of population activities of the United States government, especially since 1963. Topics discussed include demographic data, international programs, research, federally subsidized family planning services, medical care programs, educational and international programs, national growth policy, and the roles of the legislative and executive branches of government. A directory listing federal agencies with substantial and identifiable programs concerned with population and family planning is appended.

  2. Body position alters human resting-state: Insights from multi-postural magnetoencephalography.

    PubMed

    Thibault, Robert T; Lifshitz, Michael; Raz, Amir

    2016-09-01

    Neuroimaging researchers tacitly assume that body-position scantily affects neural activity. However, whereas participants in most psychological experiments sit upright, many modern neuroimaging techniques (e.g., fMRI) require participants to lie supine. Sparse findings from electroencephalography and positron emission tomography suggest that body position influences cognitive processes and neural activity. Here we leverage multi-postural magnetoencephalography (MEG) to further unravel how physical stance alters baseline brain activity. We present resting-state MEG data from 12 healthy participants in three orthostatic conditions (i.e., lying supine, reclined at 45°, and sitting upright). Our findings demonstrate that upright, compared to reclined or supine, posture increases left-hemisphere high-frequency oscillatory activity over common speech areas. This proof-of-concept experiment establishes the feasibility of using MEG to examine the influence of posture on brain dynamics. We highlight the advantages and methodological challenges inherent to this approach and lay the foundation for future studies to further investigate this important, albeit little-acknowledged, procedural caveat. PMID:26409469

  3. Body position alters human resting-state: Insights from multi-postural magnetoencephalography.

    PubMed

    Thibault, Robert T; Lifshitz, Michael; Raz, Amir

    2016-09-01

    Neuroimaging researchers tacitly assume that body-position scantily affects neural activity. However, whereas participants in most psychological experiments sit upright, many modern neuroimaging techniques (e.g., fMRI) require participants to lie supine. Sparse findings from electroencephalography and positron emission tomography suggest that body position influences cognitive processes and neural activity. Here we leverage multi-postural magnetoencephalography (MEG) to further unravel how physical stance alters baseline brain activity. We present resting-state MEG data from 12 healthy participants in three orthostatic conditions (i.e., lying supine, reclined at 45°, and sitting upright). Our findings demonstrate that upright, compared to reclined or supine, posture increases left-hemisphere high-frequency oscillatory activity over common speech areas. This proof-of-concept experiment establishes the feasibility of using MEG to examine the influence of posture on brain dynamics. We highlight the advantages and methodological challenges inherent to this approach and lay the foundation for future studies to further investigate this important, albeit little-acknowledged, procedural caveat.

  4. Musical training induces functional plasticity in perceptual and motor networks: insights from resting-state FMRI.

    PubMed

    Luo, Cheng; Guo, Zhi-wei; Lai, Yong-xiu; Liao, Wei; Liu, Qiang; Kendrick, Keith M; Yao, De-zhong; Li, Hong

    2012-01-01

    A number of previous studies have examined music-related plasticity in terms of multi-sensory and motor integration but little is known about the functional and effective connectivity patterns of spontaneous intrinsic activity in these systems during the resting state in musicians. Using functional connectivity and Granger causal analysis, functional and effective connectivity among the motor and multi-sensory (visual, auditory and somatosensory) cortices were evaluated using resting-state functional magnetic resonance imaging (fMRI) in musicians and non-musicians. The results revealed that functional connectivity was significantly increased in the motor and multi-sensory cortices of musicians. Moreover, the Granger causality results demonstrated a significant increase outflow-inflow degree in the auditory cortex with the strongest causal outflow pattern of effective connectivity being found in musicians. These resting state fMRI findings indicate enhanced functional integration among the lower-level perceptual and motor networks in musicians, and may reflect functional consolidation (plasticity) resulting from long-term musical training, involving both multi-sensory and motor functional integration.

  5. An active solid state ring laser gyroscope

    SciTech Connect

    Valle, T.J.

    1992-01-01

    The properties of an active, solid state ring laser gyroscope were investigated. Two laser diode pumped monolithic nonplanar ring oscillators (NPRO), forced to lase in opposite directions, formed the NPRO-Gyro. It was unique in being an active ring laser gyroscope with a homogeneously broadened gain medium. This work examined sources of technical and fundamental noise. Associated calculations accounted for aspects of the NPRO-Gyro performance, suggested design improvements, and outlined limitations. The work brought out the need to stabilize the NPRO environment in order to achieve performance goals. Two Nd:YAG NPROs were mounted within an environment short term stabilized to microdegrees Celsius. The Allan variance of the NPRO-Gyro beat note was 500 Hz for a one second time delay. Unequal treatment of the NPROs appeared as noise on the beat frequency, therefore reducing its rotation sensitivity. The sensitivity to rotation was limited by technical noise sources.

  6. Uncovering Camouflage: Amygdala Activation Predicts Long-Term Memory of Induced Perceptual Insight

    PubMed Central

    Ludmer, Rachel; Dudai, Yadin; Rubin, Nava

    2012-01-01

    What brain mechanisms underlie learning of new knowledge from single events? We studied encoding in long-term memory of a unique type of one-shot experience, induced perceptual insight. While undergoing an fMRI brain scan, participants viewed degraded images of real-world pictures where the underlying objects were hard to recognize (‘camouflage’), followed by brief exposures to the original images (‘solution’), which led to induced insight (“Aha!”). A week later, participants’ memory was tested; a solution image was classified as ‘remembered’ if detailed perceptual knowledge was elicited from the camouflage image alone. During encoding, subsequently remembered images enjoyed higher activity in mid-level visual cortex and medial frontal cortex, but most pronouncedly in the amygdala, whose activity could be used to predict which solutions will remain in long-term memory. Our findings extend the known roles of amygdala in memory to include promoting of long-term memory of the sudden reorganization of internal representations. PMID:21382558

  7. Edge states in confined active fluids

    NASA Astrophysics Data System (ADS)

    Souslov, Anton; Vitelli, Vincenzo

    Recently, topologically protected edge modes have been proposed and realized in both mechanical and acoustic metamaterials. In one class of such metamaterials, Time-Reversal Symmetry is broken, and, to achieve this TRS breaking in mechanical and acoustic systems, an external energy input must be used. For example, motors provide a driving force that uses energy and, thus, explicitly break TRS. As a result, motors have been used as an essential component in the design of topological metamaterials. By contrast, we explore the design of topological metamaterials that use a class of far-from-equilibrium liquids, called polar active liquids, that spontaneously break TRS. We thus envision the confinement of a polar active liquid to a prescribed geometry in order to realize topological order with broken time-reversal symmetry. We address the design of the requisite geometries, for example a regular honeycomb lattice composed of annular channels, in which the active liquid may be confined. We also consider the physical character of the active liquid that, when introduced into the prescribed geometry, will spontaneously form the flow pattern of a metamaterial with topologically protected edge states. Finally, we comment on potential experimental realizations of such metamaterials.

  8. Structural insights into the inhibited states of the Mer receptor tyrosine kinase

    PubMed Central

    Huang, Xudong; Finerty, Patrick; Walker, John R.; Butler-Cole, Christine; Vedadi, Masoud; Schapira, Matthieu; Parker, Sirlester A.; Turk, Benjamin E.; Thompson, Debra A.; Dhe-Paganon, Sirano

    2009-01-01

    The mammalian ortholog of the retroviral oncogene v-Eyk, and a receptor tyrosine kinase upstream of antiapoptotic and transforming signals, Mer (MerTK) is a mediator of the phagocytic process, being involved in retinal and immune cell clearance and platelet aggregation. Mer knockout mice are viable and are protected from epinephrine-induced pulmonary thromboembolism and ferric chloride-induced thrombosis. Mer overexpression, on the other hand, is associated with numerous carcinomas. Although Mer adaptor proteins and signaling pathways have been identified, it remains unclear how Mer initiates phagocytosis. When bound to its nucleotide cofactor, the high-resolution structure of Mer shows an autoinhibited αC-Glu-out conformation with insertion of an activation loop residue into the active site. Mer complexed with compound-52 (C52: 2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropylpurine), a ligand identified from a focused library, retains its DFG-Asp-in and αC-Glu-out conformation, but acquires other conformational changes. The αC helix and DFGL region is closer to the hinge region and the ethanolamine moiety of C52 binds in the groove formed between Leu593 and Val601 of the P-loop, causing a compression of the active site pocket. These conformational states reveal the mechanisms of autoinhibition, the pathophysiological basis of disease-causing mutations, and a platform for the development of chemical probes. PMID:19028587

  9. The Contribution of Extracurricular Activities to Adolescent Friendships: New Insights through Social Network Analysis

    PubMed Central

    Schaefer, David R.; Simpkins, Sandra D.; Vest, Andrea E.; Price, Chara D.

    2011-01-01

    Extracurricular activities are settings that are theorized to help adolescents maintain existing friendships and develop new friendships. The overarching goal of the current investigation was to examine whether co-participating in school-based extracurricular activities supported adolescents’ school-based friendships. We utilized social network methods and data from the National Longitudinal Study of Adolescent Health to examine whether dyadic friendship ties were more likely to exist among activity co-participants while controlling for alternative friendship processes, namely dyadic homophily (e.g., demographic and behavioral similarities) and network-level processes (e.g., triadic closure). Results provide strong evidence that activities were associated with current friendships and promoted the formation of new friendships. These associations varied based on school level (i.e., middle versus high school) and activity type (i.e., sports, academic, arts). Results of this study provide new insight into the complex relations between activities and friendship that can inform theories of their developmental outcomes. PMID:21639618

  10. Role of Id proteins in B lymphocyte activation: new insights from knockout mouse studies.

    PubMed

    Sugai, Manabu; Gonda, Hiroyuki; Nambu, Yukiko; Yokota, Yoshifumi; Shimizu, Akira

    2004-09-01

    Id (inhibitor of differentiation) proteins play important roles in cell differentiation, cell cycle control, and apoptosis. They act as negative regulators of basic helix-loop-helix-type transcription factors, which positively regulate differentiation of various cell types. Id proteins work to block B lymphocyte (B cell) maturation at an early differentiation step, as demonstrated by gain-of-function studies. In recent years a series of gene-targeted mice lacking different Ids have been generated. Analyses of these gene-targeted mice provide information useful for understanding the physiological roles of Ids in B cell biology. Id3 is required for proper B cell functions and acts by controlling the cell cycle. Upon B cell activation, Id2 acts as a negative regulator to prevent potentially harmful effects brought about by excessive immunological reactions; one of its special roles is to maintain low serum concentrations of immunoglobulin E (IgE). The Id2 protein does this by antagonizing E2A and Pax5 activities, both of which are required for proper B cell activation. This review presents several new insights into B cell differentiation and activation programs and the physiological role of Id proteins in B cell activation. PMID:15184986

  11. Structural Insights into the Tetrameric State of Aspartate-β-semialdehyde Dehydrogenases from Fungal Species

    PubMed Central

    Li, Qinqin; Mu, Zhixia; Zhao, Rong; Dahal, Gopal; Viola, Ronald E.; Liu, Tao; Jin, Qi; Cui, Sheng

    2016-01-01

    Aspartate-β-semialdehyde dehydrogenase (ASADH) catalyzes the second reaction in the aspartate pathway, a pathway required for the biosynthesis of one fifth of the essential amino acids in plants and microorganisms. Microarray analysis of a fungal pathogen T. rubrum responsible for most human dermatophytoses identified the upregulation of ASADH (trASADH) expression when the fungus is exposed to human skin, underscoring its potential as a drug target. Here we report the crystal structure of trASADH, revealing a tetrameric ASADH with a GAPDH-like fold. The tetramerization of trASADH was confirmed by sedimentation and SAXS experiments. Native PAGE demonstrated that this ASADH tetramerization is apparently universal in fungal species, unlike the functional dimer that is observed in all bacterial ASADHs. The helical subdomain in dimeric bacteria ASADH is replaced by the cover loop in archaeal/fungal ASADHs, presenting the determinant for this altered oligomerization. Mutations that disrupt the tetramerization of trASADH also abolish the catalytic activity, suggesting that the tetrameric state is required to produce the active fungal enzyme form. Our findings provide a basis to categorize ASADHs into dimeric and tetrameric enzymes, adopting a different orientation for NADP binding and offer a structural framework for designing drugs that can specifically target the fungal pathogens. PMID:26869335

  12. Active State Model for Autonomous Systems

    NASA Technical Reports Server (NTRS)

    Park, Han; Chien, Steve; Zak, Michail; James, Mark; Mackey, Ryan; Fisher, Forest

    2003-01-01

    The concept of the active state model (ASM) is an architecture for the development of advanced integrated fault-detection-and-isolation (FDI) systems for robotic land vehicles, pilotless aircraft, exploratory spacecraft, or other complex engineering systems that will be capable of autonomous operation. An FDI system based on the ASM concept would not only provide traditional diagnostic capabilities, but also integrate the FDI system under a unified framework and provide mechanism for sharing of information between FDI subsystems to fully assess the overall health of the system. The ASM concept begins with definitions borrowed from psychology, wherein a system is regarded as active when it possesses self-image, self-awareness, and an ability to make decisions itself, such that it is able to perform purposeful motions and other transitions with some degree of autonomy from the environment. For an engineering system, self-image would manifest itself as the ability to determine nominal values of sensor data by use of a mathematical model of itself, and selfawareness would manifest itself as the ability to relate sensor data to their nominal values. The ASM for such a system may start with the closed-loop control dynamics that describe the evolution of state variables. As soon as this model was supplemented with nominal values of sensor data, it would possess self-image. The ability to process the current sensor data and compare them with the nominal values would represent self-awareness. On the basis of self-image and self-awareness, the ASM provides the capability for self-identification, detection of abnormalities, and self-diagnosis.

  13. Scrutinizing the Noninnocence of Quinone Ligands in Ruthenium Complexes: Insights from Structural, Electronic, Energy, and Effective Oxidation State Analyses.

    PubMed

    Skara, Gabriella; Gimferrer, Marti; De Proft, Frank; Salvador, Pedro; Pinter, Balazs

    2016-03-01

    The most relevant manifestations of ligand noninnocence of quinone and bipyridine derivatives are thoroughly scrutinized and discussed through an extensive and systematic set of octahedral ruthenium complexes, [(en)2RuL](z), in four oxidation states (z = +3, +2, +1, and 0). The characteristic structural deformation of ligands upon coordination/noninnocence is put into context with the underlying electronic structure of the complexes and its change upon reduction. In addition, by means of decomposing the corresponding reductions into electron transfer and structural relaxation subprocesses, the energetic contribution of these structural deformations to the redox energetics is revealed. The change of molecular electron density upon metal- and ligand-centered reductions is also visualized and shown to provide novel insights into the corresponding redox processes. Moreover, the charge distribution of the π-subspace is straightforwardly examined and used as indicator of ligand noninnocence in the distinct oxidation states of the complexes. The aromatization/dearomatization processes of ligand backbones are also monitored using magnetic (NICS) and electronic (PDI) indicators of aromaticity, and the consequences to noninnocent behavior are discussed. Finally, the recently developed effective oxidation state (EOS) analysis is utilized, on the one hand, to test its applicability for complexes containing noninnocent ligands, and, on the other hand, to provide new insights into the magnitude of state mixings in the investigated complexes. The effect of ligand substitution, nature of donor atom, ligand frame modification on these manifestations, and measures is discussed in an intuitive and pedagogical manner. PMID:26866981

  14. The nature of inherent bactericidal activity: insights from the nanotopology of three species of dragonfly

    NASA Astrophysics Data System (ADS)

    Mainwaring, David E.; Nguyen, Song Ha; Webb, Hayden; Jakubov, Timur; Tobin, Mark; Lamb, Robert N.; Wu, Alex H.-F.; Marchant, Richard; Crawford, Russell J.; Ivanova, Elena P.

    2016-03-01

    While insect wings are widely recognised as multi-functional, recent work showed that this extends to extensive bactericidal activity brought about by cell deformation and lysis on the wing nanotopology. We now quantitatively show that subtle changes to this topography result in substantial changes in bactericidal activity that are able to span an order of magnitude. Notably, the chemical composition of the lipid nanopillars was seen by XPS and synchrotron FTIR microspectroscopy to be similar across these activity differences. Modelling the interaction between bacterial cells and the wing surface lipids of 3 species of dragonflies, that inhabit similar environments, but with distinctly different behavioural repertoires, provided the relationship between surface structure and antibacterial functionality. In doing so, these principal behavioural patterns correlated with the demands for antimicrobial efficiency dictated by differences in their foraging strategies. This work now reveals a new feature in the design elegance of natural multi-functional surfaces as well providing insights into the bactericidal mechanism underlying inherently antimicrobial materials, while suggesting that nanotopology is related to the evolutionary development of a species through the demands of its behavioural repertoire. The underlying relationship between the processes of wetting, adhesion and capillarity of the lipid nanopillars and bactericidal efficiency suggests new prospects for purely mechano-responsive antibacterial surfaces.While insect wings are widely recognised as multi-functional, recent work showed that this extends to extensive bactericidal activity brought about by cell deformation and lysis on the wing nanotopology. We now quantitatively show that subtle changes to this topography result in substantial changes in bactericidal activity that are able to span an order of magnitude. Notably, the chemical composition of the lipid nanopillars was seen by XPS and synchrotron

  15. Insights into properties of activated carbons prepared from different raw precursors by pyrophosphoric acid activation.

    PubMed

    Gao, Yuan; Yue, Qinyan; Gao, Baoyu

    2016-03-01

    Low-cost activated carbons (ACs) were prepared from four kinds of solid wastes: petroleum coke, Enteromorpha prolifera, lignin from papermaking black liquid and hair, by pyrophosphoric acid (H4P2O7) activation. Thermo-gravimetric analysis of the pyrolysis of H4P2O7-precursor mixtures implied that H4P2O7 had different influences on the pyrolysis behavior of the four raw materials. N2 adsorption/desorption isotherms, scanning electron microscopy, Fourier transform infrared spectroscopy and adsorption capacities for dyes were used to characterize the prepared activated carbons. AC derived from E. prolifera exhibited the highest surface area (1094m(2)/g) and maximum monolayer adsorption capacity for malachite green (1250mg/g). Kinetic studies showed that the experimental data were in agreement with the pseudo-second-order model. The adsorption isotherms were well described by the Langmuir isotherm model, indicating the adsorption of dye onto the ACs proceeded by monolayers. PMID:26969070

  16. Short-term meditation modulates brain activity of insight evoked with solution cue.

    PubMed

    Ding, Xiaoqian; Tang, Yi-Yuan; Cao, Chen; Deng, Yuqin; Wang, Yan; Xin, Xiu; Posner, Michael I

    2015-01-01

    Meditation has been shown to improve creativity in some situation. However, little is known about the brain systems underling insight into a problem when the person fails to solve the problem. Here, we examined the neural correlation using Chinese Remote Association Test, as a measure of creativity. We provide a solution following the failure of the participant to provide one. We examine how meditation in comparison with relaxation influences the reaction of the participant to a correct solution. The event-related functional magnetic resonance imaging showed greater activity, mainly distributed in the right cingulate gyrus (CG), insula, putamen, inferior frontal gyrus (IFG), and the bilateral middle frontal gyrus (MFG), the inferior parietal lobule (IPL) and the superior temporal gyrus (STG). This pattern of activation was greater following 5 h of meditation training than the same amount of relaxation. Based on prior research, we speculate on the function of this pattern of brain activity: (i) CG may be involved in detecting conflict and breaking mental set, (ii) MFG/IFG may play an important role in restructuring of the problem representation, (iii) insula, IPL and STG may be associated with error detection, problem understanding or general attentive control and (iv) putamen may be activated by 'Aha' feeling.

  17. The Active Site of Oligogalacturonate Lyase Provides Unique Insights into Cytoplasmic Oligogalacturonate β-Elimination*

    PubMed Central

    Abbott, D. Wade; Gilbert, Harry J.; Boraston, Alisdair B.

    2010-01-01

    Oligogalacturonate lyases (OGLs; now also classified as pectate lyase family 22) are cytoplasmic enzymes found in pectinolytic members of Enterobacteriaceae, such as the enteropathogen Yersinia enterocolitica. OGLs utilize a β-elimination mechanism to preferentially catalyze the conversion of saturated and unsaturated digalacturonate into monogalacturonate and the 4,5-unsaturated monogalacturonate-like molecule, 5-keto-4-deoxyuronate. To provide mechanistic insights into the specificity of this enzyme activity, we have characterized the OGL from Y. enterocolitica, YeOGL, on oligogalacturonides and determined its three-dimensional x-ray structure to 1.65 Å. The model contains a Mn2+ atom in the active site, which is coordinated by three histidines, one glutamine, and an acetate ion. The acetate mimics the binding of the uronate group of galactourono-configured substrates. These findings, in combination with enzyme kinetics and metal supplementation assays, provide a framework for modeling the active site architecture of OGL. This enzyme appears to contain a histidine for the abstraction of the α-proton in the −1 subsite, a residue that is highly conserved throughout the OGL family and represents a unique catalytic base among pectic active lyases. In addition, we present a hypothesis for an emerging relationship observed between the cellular distribution of pectate lyase folding and the distinct metal coordination chemistries of pectate lyases. PMID:20851883

  18. Faster than their prey: new insights into the rapid movements of active carnivorous plants traps.

    PubMed

    Poppinga, Simon; Masselter, Tom; Speck, Thomas

    2013-07-01

    Plants move in very different ways and for different reasons, but some active carnivorous plants perform extraordinary motion: Their snap-, catapult- and suction traps perform very fast and spectacular motions to catch their prey after receiving mechanical stimuli. Numerous investigations have led to deeper insights into the physiology and biomechanics of these trapping devices, but they are far from being fully understood. We review concisely how plant movements are classified and how they follow principles that bring together speed, actuation and architecture of the moving organ. In particular, we describe and discuss how carnivorous plants manage to execute fast motion. We address open questions and assess the prospects for future studies investigating potential universal mechanisms that could be the basis of key characteristic features in plant movement such as stimulus transduction, post-stimulatory mechanical answers, and organ formation.

  19. Making Personalized Health Care Even More Personalized: Insights From Activities of the IOM Genomics Roundtable

    PubMed Central

    David, Sean P.; Johnson, Samuel G.; Berger, Adam C.; Feero, W. Gregory; Terry, Sharon F.; Green, Larry A.; Phillips, Robert L.; Ginsburg, Geoffrey S.

    2015-01-01

    Genomic research has generated much new knowledge into mechanisms of human disease, with the potential to catalyze novel drug discovery and development, prenatal and neonatal screening, clinical pharmacogenomics, more sensitive risk prediction, and enhanced diagnostics. Genomic medicine, however, has been limited by critical evidence gaps, especially those related to clinical utility and applicability to diverse populations. Genomic medicine may have the greatest impact on health care if it is integrated into primary care, where most health care is received and where evidence supports the value of personalized medicine grounded in continuous healing relationships. Redesigned primary care is the most relevant setting for clinically useful genomic medicine research. Taking insights gained from the activities of the Institute of Medicine (IOM) Roundtable on Translating Genomic-Based Research for Health, we apply lessons learned from the patient-centered medical home national experience to implement genomic medicine in a patient-centered, learning health care system. PMID:26195686

  20. How has magmatism in the northwest United States affected the lithosphere? Insights from Sp Receiver Functions

    NASA Astrophysics Data System (ADS)

    Hopper, E.; Ford, H. A.; Fischer, K. M.; Lekic, V.; Fouch, M. J.

    2012-12-01

    The origins of the age-progressive hot spot track of the eastern Snake River Plain (ESRP) and the age-progressive magmatic wave of the Newberry Trend in the High Lava Plains (HLP) are much debated. Constraining lithospheric structure and its relationship to magmatism in this region can provide new insights. We employ Sp receiver functions to image the base of the lithosphere. Data was collected from stations within a ~1500km x ~900km area centered on the ESRP, comprising both permanent network stations (e.g. US, IW) and many temporary arrays, including the High Lava Plains seismic array and EarthScope's USArray Transportable Array. We first obtained Sp receiver functions for individual waveforms using an extended-time multi-taper deconvolution method. We then migrated into a 3D volume using common-conversion point stacking and a spline function representation of phase Fresnel zones assuming mantle velocities from Obrebski et al. (2011) and the crustal model of Lowry and Perez-Gussinye (2011). In some areas, we detect a mantle Sp arrival indicating a decrease in velocity with depth in the 55-100 km depth range, which is consistent with the transition from high velocity lithosphere to low velocity asthenosphere in the tomography. To the southeast of Newberry volcano beneath the HLP, a particularly strong and clear negative Sp phase increases in depth from ~55 km beneath the youngest magmatism to ~65 km beneath 9-11 Ma eruptive centers. The depth of this phase is roughly consistent with the pressures of last equilibration of asthenospherically derived magmatic samples [Till et al, 2012]. Continuing to the southeast beneath the Owyhee Plateau, where there are 14-16 Ma silicic calderas associated with the onset of the SRP magmatic trend, a significantly weaker negative Sp phase is found at depths of 80-90 km. Image quality is poorer beneath the eastern SRP, where magmatic ages are 12 Ma and younger, due to sparser path coverage east of the High Lava Plains array

  1. State and Local Bar Associations Law-Related Education Activities.

    ERIC Educational Resources Information Center

    American Bar Association, Chicago, IL. Special Committee on Youth Education for Citizenship.

    This document is a listing of the law-related education activities of state and local bar associations grouped by state. Under each state, the state association and often one or more local association are listed. Information on each association includes committees relating to law related education, a listing of law related education activities,…

  2. New Insights in 4f(12)5d(1) Excited States of Tm(2+) through Excited State Excitation Spectroscopy.

    PubMed

    de Jong, Mathijs; Biner, Daniel; Krämer, Karl W; Barandiarán, Zoila; Seijo, Luis; Meijerink, Andries

    2016-07-21

    Optical excitation of ions or molecules typically leads to an expansion of the equilibrium bond lengths in the excited electronic state. However, for 4f(n-1)5d(1) excited states in lanthanide ions both expansion and contraction relative to the 4f(n) ground state have been reported, depending on the crystal field and nature of the 5d state. To probe the equilibrium distance offset between different 4f(n-1)5d(1) excited states, we report excited state excitation (ESE) spectra for Tm(2+) doped in CsCaBr3 and CsCaCl3 using two-color excited state excitation spectroscopy. The ESE spectra reveal sharp lines at low energies, confirming a similar distance offset for 4f(n-1)5d(t2g)(1) states. At higher energies, broader bands are observed, which indicate the presence of excited states with a different offset. On the basis of ab initio embedded-cluster calculations, the broad bands are assigned to two-photon d-d absorption from the excited state. In this work, we demonstrate that ESE is a powerful spectroscopic tool, giving access to information which cannot be obtained through regular one-photon spectroscopy. PMID:27347766

  3. New Insights in 4f(12)5d(1) Excited States of Tm(2+) through Excited State Excitation Spectroscopy.

    PubMed

    de Jong, Mathijs; Biner, Daniel; Krämer, Karl W; Barandiarán, Zoila; Seijo, Luis; Meijerink, Andries

    2016-07-21

    Optical excitation of ions or molecules typically leads to an expansion of the equilibrium bond lengths in the excited electronic state. However, for 4f(n-1)5d(1) excited states in lanthanide ions both expansion and contraction relative to the 4f(n) ground state have been reported, depending on the crystal field and nature of the 5d state. To probe the equilibrium distance offset between different 4f(n-1)5d(1) excited states, we report excited state excitation (ESE) spectra for Tm(2+) doped in CsCaBr3 and CsCaCl3 using two-color excited state excitation spectroscopy. The ESE spectra reveal sharp lines at low energies, confirming a similar distance offset for 4f(n-1)5d(t2g)(1) states. At higher energies, broader bands are observed, which indicate the presence of excited states with a different offset. On the basis of ab initio embedded-cluster calculations, the broad bands are assigned to two-photon d-d absorption from the excited state. In this work, we demonstrate that ESE is a powerful spectroscopic tool, giving access to information which cannot be obtained through regular one-photon spectroscopy.

  4. Mechanistic insights into the first Lygus-active β-pore forming protein.

    PubMed

    Jerga, Agoston; Chen, Danqi; Zhang, Chunfen; Fu, Jinping; Kouadio, Jean-Louis K; Wang, Yanfei; Duff, Stephen M G; Howard, Jennifer E; Rydel, Timothy J; Evdokimov, Artem G; Ramaseshadri, Parthasarathy; Evans, Adam; Bolognesi, Renata; Park, Yoonseong; Haas, Jeffrey A

    2016-06-15

    The cotton pests Lygus hesperus and Lygus lineolaris can be controlled by expressing Cry51Aa2.834_16 in cotton. Insecticidal activity of pore-forming proteins is generally associated with damage to the midgut epithelium due to pores, and their biological specificity results from a set of key determinants including proteolytic activation and receptor binding. We conducted mechanistic studies to gain insight into how the first Lygus-active β-pore forming protein variant functions. Biophysical characterization revealed that the full-length Cry51Aa2.834_16 was a stable dimer in solution, and when exposed to Lygus saliva or to trypsin, the protein underwent proteolytic cleavage at the C-terminus of each of the subunits, resulting in dissociation of the dimer to two separate monomers. The monomer showed tight binding to a specific protein in Lygus brush border membranes, and also formed a membrane-associated oligomeric complex both in vitro and in vivo. Chemically cross-linking the β-hairpin to the Cry51Aa2.834_16 body rendered the protein inactive, but still competent to compete for binding sites with the native protein in vivo. Our study suggests that disassociation of the Cry51Aa2.834_16 dimer into monomeric units with unoccupied head-region and sterically unhindered β-hairpin is required for brush border membrane binding, oligomerization, and the subsequent steps leading to insect mortality. PMID:27001423

  5. The nature of inherent bactericidal activity: insights from the nanotopology of three species of dragonfly.

    PubMed

    Mainwaring, David E; Nguyen, Song Ha; Webb, Hayden; Jakubov, Timur; Tobin, Mark; Lamb, Robert N; Wu, Alex H-F; Marchant, Richard; Crawford, Russell J; Ivanova, Elena P

    2016-03-28

    While insect wings are widely recognised as multi-functional, recent work showed that this extends to extensive bactericidal activity brought about by cell deformation and lysis on the wing nanotopology. We now quantitatively show that subtle changes to this topography result in substantial changes in bactericidal activity that are able to span an order of magnitude. Notably, the chemical composition of the lipid nanopillars was seen by XPS and synchrotron FTIR microspectroscopy to be similar across these activity differences. Modelling the interaction between bacterial cells and the wing surface lipids of 3 species of dragonflies, that inhabit similar environments, but with distinctly different behavioural repertoires, provided the relationship between surface structure and antibacterial functionality. In doing so, these principal behavioural patterns correlated with the demands for antimicrobial efficiency dictated by differences in their foraging strategies. This work now reveals a new feature in the design elegance of natural multi-functional surfaces as well providing insights into the bactericidal mechanism underlying inherently antimicrobial materials, while suggesting that nanotopology is related to the evolutionary development of a species through the demands of its behavioural repertoire. The underlying relationship between the processes of wetting, adhesion and capillarity of the lipid nanopillars and bactericidal efficiency suggests new prospects for purely mechano-responsive antibacterial surfaces. PMID:26935293

  6. Insights into GATA-1 Mediated Gene Activation versus Repression via Genome-wide Chromatin Occupancy Analysis

    PubMed Central

    Yu, Ming; Riva, Laura; Xie, Huafeng; Schindler, Yocheved; Moran, Tyler B.; Cheng, Yong; Yu, Duonan; Hardison, Ross; Weiss, Mitchell J; Orkin, Stuart H.; Bernstein, Bradley E.; Fraenkel, Ernest; Cantor, Alan B.

    2009-01-01

    Summary The transcription factor GATA-1 is required for terminal erythroid maturation and functions as an activator or repressor depending on gene context. Yet its in vivo site selectivity and ability to distinguish between activated versus repressed genes remain incompletely understood. In this study, we performed GATA-1 ChIP-seq in erythroid cells and compared it to GATA-1 induced gene expression changes. Bound and differentially expressed genes contain a greater number of GATA binding motifs, a higher frequency of palindromic GATA sites, and closer occupancy to the transcriptional start site versus non-differentially expressed genes. Moreover, we show that the transcription factor Zbtb7a occupies GATA-1 bound regions of some direct GATA-1 target genes, that the presence of SCL/TAL1 helps distinguish transcriptional activation versus repression, and that Polycomb Repressive Complex 2 (PRC2) is involved in epigenetic silencing of a subset of GATA-1 repressed genes. These data provide insights into GATA-1 mediated gene regulation in vivo. PMID:19941827

  7. Trait and State Attributes of Insight in First Episodes of Early-Onset Schizophrenia and Other Psychoses: A 2-Year Longitudinal Study

    PubMed Central

    Parellada, Mara; Boada, Leticia; Fraguas, David; Reig, Santiago; Castro-Fornieles, Josefina; Moreno, Dolores; Gonzalez-Pinto, Ana; Otero, Soraya; Rapado-Castro, Marta; Graell, Montserrat; Baeza, Inmaculada; Arango, Celso

    2011-01-01

    Background: Increasing evidence supports the important role of illness state and individual characteristics in insight. Methods: Insight, as measured with the Scale to Assess Unawareness of Mental Disorder, over the first 2 years of early-onset first-episode psychosis and its correlations with clinical, socio-demographic, cognitive, and structural brain variables are studied. Results: (1) insight at 2 years is poorer in schizophrenia spectrum disorders (SSDs) than in subjects with other psychoses; (2) the more severe the psychosis, the worse the insight. In SSD, depressive symptoms, poorer baseline executive functioning, lower IQ, longer duration of untreated psychosis (DUP), and poorer premorbid infancy adjustment are associated with poorer insight; frontal and parietal gray matter (GM) reductions at baseline correlate with worse insight into having psychotic symptoms at 2 years; (3) insight into having a mental disorder (Scale to Assess Unawareness of Mental Disorder [SUMD]1) at 1 year, DUP, and baseline IQ are the most consistent variables explaining different aspects of insight at 2 years in SSD patients. IQ and SUMD1 at 1 year, together with left frontal and parietal GM volumes, explain 80% of the variance of insight into having specific psychotic symptoms in SSD patients (adjusted R2 = 0.795, F = 15.576, P < .001). Conclusion: Insight is a complex phenomenon that depends both on severity of psychopathology and also on disease and subject characteristics, such as past adjustment, IQ, DUP, cognitive functioning, frontal and parietal GM volumes, and age, gender, and ethnicity. PMID:20884756

  8. Unchaining the beast; insights from structural and evolutionary studies on TGFβ secretion, sequestration, and activation

    PubMed Central

    Robertson, Ian B; Rifkin, Daniel B

    2013-01-01

    TGFβ is secreted in a latent state and must be “activated” by molecules that facilitate its release from a latent complex and allow binding to high affinity cell surface receptors. Numerous molecules have been implicated as potential mediators of this activation process, but only a limited number of these activators have been demonstrated to play a role in TGFβ mobilization in vivo. Here we review the process of TGFβ secretion and activation using evolutionary data, sequence conservation and structural information to examine the molecular mechanisms by which TGFβ is secreted, sequestered and released. This allows the separation of more ancient TGFβ activators from those factors that emerged more recently, and helps to define a potential hierarchy of activation mechanisms. PMID:23849989

  9. Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation.

    PubMed

    Keller, Nadine; Mares, Jirí; Zerbe, Oliver; Grütter, Markus G

    2009-03-11

    Caspases are proteases with an active-site cysteine and aspartate specificity in their substrates. They are involved in apoptotic cell death and inflammation, and dysfunction of these enzymes is directly linked to a variety of diseases. Caspase-8 initiates an apoptotic pathway triggered by external stimuli. It was previously characterized in its active inhibitor bound state by crystallography. Here we present the solution structure of the monomeric unprocessed catalytic domain of the caspase-8 zymogen, procaspase-8, showing for the first time the position of the linker and flexibility of the active site forming loops. Biophysical studies of carefully designed mutants allowed disentangling dimerization and processing, and we could demonstrate lack of activity of monomeric uncleaved procaspase-8 and of a processed but dimerization-incompetent mutant. The data provide experimental support in so-far unprecedented detail, and reveal why caspase-8 (and most likely other initiator caspases) needs the dimerization platform during activation.

  10. Insights into partially folded or unfolded States of metalloproteins from nuclear magnetic resonance.

    PubMed

    Turano, Paola

    2004-12-13

    Nuclear magnetic resonance (NMR) provides detailed insights into the conformational features of unfolded and partially folded proteins. In the case of metalloproteins, special attention should be devoted to the characterization of the properties of the metal binding sites, and specific approaches need to be developed depending on the nature of the metal ion and its coordination environment. At the same time, metal-based NMR parameters may help in getting a better picture of the average structural properties of the metalloprotein. A critical evaluation of the limits of applicability of paramagnetic effects for solution structure determination in partially folded or unfolded proteins is presented. The coupling between NMR characterization of structure and dynamic of the polypeptide chain and of the metal environment provides insights into the stabilizing role of metal ions in metalloproteins. The overall approach is illustrated for some case examples of increasing flexibility obtained far from native conditions for cytochrome c and superoxide dismutase, two metalloproteins that have been extensively studied in our lab and whose misfolded forms may be relevant for important biological processes.

  11. State Equations for Active Circuits with Memristors

    NASA Astrophysics Data System (ADS)

    Hasler, Martin

    2013-01-01

    Nonlinear dynamic circuits including memristors are considered. Graph-theoretical criteria are given as sufficient conditions for the existence of global state equations, with the capacitor and memristor charges as state variables (for convenience we do not consider inductors here). They are based on earlier work on circuits without memristors. Global state equations in these charges fail to exist when the charges are dependent or when singular points are present, socalled impasse points. The values of state variables at initial time uniquely determine a solution. Therefore, even for numerical circuit analysis that in general does not use state equations, the determination of a set of state variables is important, and to know whether, with the "canonical candidates" for states, global state equations exist, is the first and most important step. The graph-theoretical criteria are easy to check directly for simple circuits. We give a few simple examples that illustrate the various cases. Larger circuits have to be examined by combinatorial algorithms.

  12. Structural Insights into the Anti-HIV Activity of the Oscillatoria agardhii Agglutinin Homolog Lectin Family*

    PubMed Central

    Koharudin, Leonardus M. I.; Kollipara, Sireesha; Aiken, Christopher; Gronenborn, Angela M.

    2012-01-01

    Oscillatoria agardhii agglutinin homolog (OAAH) proteins belong to a recently discovered lectin family. All members contain a sequence repeat of ∼66 amino acids, with the number of repeats varying among different family members. Apart from data for the founding member OAA, neither three-dimensional structures, information about carbohydrate binding specificities, nor antiviral activity data have been available up to now for any other members of the OAAH family. To elucidate the structural basis for the antiviral mechanism of OAAHs, we determined the crystal structures of Pseudomonas fluorescens and Myxococcus xanthus lectins. Both proteins exhibit the same fold, resembling the founding family member, OAA, with minor differences in loop conformations. Carbohydrate binding studies by NMR and x-ray structures of glycan-lectin complexes reveal that the number of sugar binding sites corresponds to the number of sequence repeats in each protein. As for OAA, tight and specific binding to α3,α6-mannopentaose was observed. All the OAAH proteins described here exhibit potent anti-HIV activity at comparable levels. Altogether, our results provide structural details of the protein-carbohydrate interaction for this novel lectin family and insights into the molecular basis of their HIV inactivation properties. PMID:22865886

  13. Structural insights into Cydia pomonella pheromone binding protein 2 mediated prediction of potentially active semiochemicals

    PubMed Central

    Tian, Zhen; Liu, Jiyuan; Zhang, Yalin

    2016-01-01

    Given the advantages of behavioral disruption application in pest control and the damage of Cydia pomonella, due progresses have not been made in searching active semiochemicals for codling moth. In this research, 31 candidate semiochemicals were ranked for their binding potential to Cydia pomonella pheromone binding protein 2 (CpomPBP2) by simulated docking, and this sorted result was confirmed by competitive binding assay. This high predicting accuracy of virtual screening led to the construction of a rapid and viable method for semiochemicals searching. By reference to binding mode analyses, hydrogen bond and hydrophobic interaction were suggested to be two key factors in determining ligand affinity, so is the length of molecule chain. So it is concluded that semiochemicals of appropriate chain length with hydroxyl group or carbonyl group at one head tended to be favored by CpomPBP2. Residues involved in binding with each ligand were pointed out as well, which were verified by computational alanine scanning mutagenesis. Progress made in the present study helps establish an efficient method for predicting potentially active compounds and prepares for the application of high-throughput virtual screening in searching semiochemicals by taking insights into binding mode analyses. PMID:26928635

  14. Excited state decay of cyclometalated polypyridine ruthenium complexes: insight from theory and experiment.

    PubMed

    Kreitner, Christoph; Heinze, Katja

    2016-09-21

    Deactivation pathways of the triplet metal-to-ligand charge transfer ((3)MLCT) excited state of cyclometalated polypyridine ruthenium complexes with [RuN5C](+) coordination are discussed on the basis of the available experimental data and a series of density functional theory calculations. Three different complex classes are considered, namely with [Ru(N^N)2(N^C)](+), [Ru(N^N^N)(N^C^N)](+) and [Ru(N^N^N)(N^N^C)](+) coordination modes. Excited state deactivation in these complex types proceeds via five distinct decay channels. Vibronic coupling of the (3)MLCT state to high-energy oscillators of the singlet ground state ((1)GS) allows tunneling to the ground state followed by vibrational relaxation (path A). A ligand field excited state ((3)MC) is thermally accessible via a (3)MLCT →(3)MC transition state with the (3)MC state being strongly coupled to the (1)GS surface via a low-energy minimum energy crossing point (path B). Furthermore, a (3)MLCT →(1)GS surface crossing point directly couples the triplet and singlet potential energy surfaces (path C). Charge transfer states either with higher singlet character or with different orbital parentage and intrinsic symmetry restrictions are thermally populated which promote non-radiative decay via tunneling to the (1)GS state (path D). Finally, the excited state can decay via phosphorescence (path E). The dominant deactivation pathways differ for the three individual complex classes. The implications of these findings for isoelectronic iridium(iii) or iron(ii) complexes are discussed. Ultimately, strategies for optimizing the emission efficiencies of cyclometalated polypyridine complexes of d(6)-metal ions, especially Ru(II), are suggested. PMID:27334798

  15. Excited state decay of cyclometalated polypyridine ruthenium complexes: insight from theory and experiment.

    PubMed

    Kreitner, Christoph; Heinze, Katja

    2016-09-21

    Deactivation pathways of the triplet metal-to-ligand charge transfer ((3)MLCT) excited state of cyclometalated polypyridine ruthenium complexes with [RuN5C](+) coordination are discussed on the basis of the available experimental data and a series of density functional theory calculations. Three different complex classes are considered, namely with [Ru(N^N)2(N^C)](+), [Ru(N^N^N)(N^C^N)](+) and [Ru(N^N^N)(N^N^C)](+) coordination modes. Excited state deactivation in these complex types proceeds via five distinct decay channels. Vibronic coupling of the (3)MLCT state to high-energy oscillators of the singlet ground state ((1)GS) allows tunneling to the ground state followed by vibrational relaxation (path A). A ligand field excited state ((3)MC) is thermally accessible via a (3)MLCT →(3)MC transition state with the (3)MC state being strongly coupled to the (1)GS surface via a low-energy minimum energy crossing point (path B). Furthermore, a (3)MLCT →(1)GS surface crossing point directly couples the triplet and singlet potential energy surfaces (path C). Charge transfer states either with higher singlet character or with different orbital parentage and intrinsic symmetry restrictions are thermally populated which promote non-radiative decay via tunneling to the (1)GS state (path D). Finally, the excited state can decay via phosphorescence (path E). The dominant deactivation pathways differ for the three individual complex classes. The implications of these findings for isoelectronic iridium(iii) or iron(ii) complexes are discussed. Ultimately, strategies for optimizing the emission efficiencies of cyclometalated polypyridine complexes of d(6)-metal ions, especially Ru(II), are suggested.

  16. Insights into the structural nature of the transition state in the Kir channel gating pathway.

    PubMed

    Fowler, Philip W; Bollepalli, Murali K; Rapedius, Markus; Nematian-Ardestani, Ehsan; Shang, Lijun; Sansom, Mark Sp; Tucker, Stephen J; Baukrowitz, Thomas

    2014-01-01

    In a previous study we identified an extensive gating network within the inwardly rectifying Kir1.1 (ROMK) channel by combining systematic scanning mutagenesis and functional analysis with structural models of the channel in the closed, pre-open and open states. This extensive network appeared to stabilize the open and pre-open states, but the network fragmented upon channel closure. In this study we have analyzed the gating kinetics of different mutations within key parts of this gating network. These results suggest that the structure of the transition state (TS), which connects the pre-open and closed states of the channel, more closely resembles the structure of the pre-open state. Furthermore, the G-loop, which occurs at the center of this extensive gating network, appears to become unstructured in the TS because mutations within this region have a 'catalytic' effect upon the channel gating kinetics. PMID:25483285

  17. Insights into the structural nature of the transition state in the Kir channel gating pathway

    PubMed Central

    Fowler, Philip W; Bollepalli, Murali K; Rapedius, Markus; Nematian-Ardestani, Ehsan; Shang, Lijun; Sansom, Mark SP; Tucker, Stephen J; Baukrowitz, Thomas

    2014-01-01

    In a previous study we identified an extensive gating network within the inwardly rectifying Kir1.1 (ROMK) channel by combining systematic scanning mutagenesis and functional analysis with structural models of the channel in the closed, pre-open and open states. This extensive network appeared to stabilize the open and pre-open states, but the network fragmented upon channel closure. In this study we have analyzed the gating kinetics of different mutations within key parts of this gating network. These results suggest that the structure of the transition state (TS), which connects the pre-open and closed states of the channel, more closely resembles the structure of the pre-open state. Furthermore, the G-loop, which occurs at the center of this extensive gating network, appears to become unstructured in the TS because mutations within this region have a ‘catalytic’ effect upon the channel gating kinetics. PMID:25483285

  18. State-Level Activities: A Plan for Action.

    ERIC Educational Resources Information Center

    Lamborn, Robert L.

    A variety of specific activities that have been successfully undertaken by the Council for American Private Education (CAPE) are suggested for state members. The activities are related to developing private school communications within states and developing working relationships with local, metropolitan, and state governments and their agencies.…

  19. Legal restrictions and complications of abortion: insights from data on complication rates in the United States.

    PubMed

    Rolnick, Joshua A; Vorhies, John S

    2012-08-01

    Although US federal law requires all American states to permit abortion within their borders, states retain authority to impose restrictions.We used hospital discharge data to study the rates of major abortion complications in 23 states from 2001 to 2008 and their relationship to two laws: (i) restrictions on Medicaid – the state insurance programs for the poor – funding, and (ii) mandatory delays before abortion. Of 131 000 000 discharges in the data set, 10 980 involved an abortion complication. The national rate for complications was 1.90 per 1000 abortions (95 per cent CI: 1.57–2.23). Eleven states required mandatory delays and 12 restricted funding for Medicaid participants. After controlling for socioeconomic characteristics and the pregnancy complication rate, legal restrictions were associated with lower complication rates: mandatory delays (OR 0.79(0.65–0.95)) and restricted Medicaid funding (OR 0.74 (0.61–0.90)). This result may reflect the fact that states without restrictions perform a higher percentage of second-trimester abortions. This study is the first to assess the association between legal restrictions on abortion and complication rates.

  20. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders.

    PubMed

    Wakabayashi, Aoi; Ulirsch, Jacob C; Ludwig, Leif S; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I; Sankaran, Vijay G

    2016-04-19

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptionalcis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.

  1. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders.

    PubMed

    Wakabayashi, Aoi; Ulirsch, Jacob C; Ludwig, Leif S; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I; Sankaran, Vijay G

    2016-04-19

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptionalcis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders. PMID:27044088

  2. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

    PubMed Central

    Wakabayashi, Aoi; Ulirsch, Jacob C.; Ludwig, Leif S.; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I.; Sankaran, Vijay G.

    2016-01-01

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders. PMID:27044088

  3. Validity Evidence for the State Mindfulness Scale for Physical Activity

    ERIC Educational Resources Information Center

    Cox, Anne E.; Ullrich-French, Sarah; French, Brian F.

    2016-01-01

    Being attentive to and aware of one's experiences in the present moment with qualities of acceptance and openness reflects the state of mindfulness. Positive associations exist between state mindfulness and state autonomous motivation for everyday activities. Though this suggests that state mindfulness links with adaptive motivational experiences,…

  4. An insight into non-emissive excited states in conjugated polymers

    PubMed Central

    Hu, Zhongjian; Willard, Adam P.; Ono, Robert J.; Bielawski, Christopher W.; Rossky, Peter J.; Vanden Bout, David A.

    2015-01-01

    Conjugated polymers in the solid state usually exhibit low fluorescence quantum yields, which limit their applications in many areas such as light-emitting diodes. Despite considerable research efforts, the underlying mechanism still remains controversial and elusive. Here, the nature and properties of excited states in the archetypal polythiophene are investigated via aggregates suspended in solvents with different dielectric constants (ɛ). In relatively polar solvents (ɛ>∼ 3), the aggregates exhibit a low fluorescence quantum yield (QY) of 2–5%, similar to bulk films, however, in relatively nonpolar solvents (ɛ<∼ 3) they demonstrate much higher fluorescence QY up to 20–30%. A series of mixed quantum-classical atomistic simulations illustrate that dielectric induced stabilization of nonradiative charge-transfer (CT) type states can lead to similar drastic reduction in fluorescence QY as seen experimentally. Fluorescence lifetime measurement reveals that the CT-type states exist as a competitive channel of the formation of emissive exciton-type states. PMID:26391514

  5. Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

    PubMed Central

    Yang, Hongchun; Howard, Martin; Dean, Caroline

    2016-01-01

    Establishment and maintenance of gene expression states is central to development and differentiation. Transcriptional and epigenetic mechanisms interconnect in poorly understood ways to determine these states. We explore these mechanisms through dissection of the regulation of Arabidopsis thaliana FLOWERING LOCUS C (FLC). FLC can be present in a transcriptionally active state marked by H3K36me3 or a silent state marked by H3K27me3. Here, we investigate the trans factors modifying these opposing histone states and find a physical coupling in vivo between the H3K36 methyltransferase, SDG8, and the H3K27me3 demethylase, ELF6. Previous modeling has predicted this coupling would exist as it facilitates bistability of opposing histone states. We also find association of SDG8 with the transcription machinery, namely RNA polymerase II and the PAF1 complex. Delivery of the active histone modifications is therefore likely to be through transcription at the locus. SDG8 and ELF6 were found to influence the localization of each other on FLC chromatin, showing the functional importance of the interaction. In addition, both influenced accumulation of the associated H3K27me3 and H3K36me3 histone modifications at FLC. We propose the physical coupling of activation and derepression activities coordinates transcriptional activity and prevents ectopic silencing. PMID:27482092

  6. Insights into the conformation of aminofluorene-deoxyguanine adduct in a DNA polymerase active site.

    PubMed

    Vaidyanathan, Vaidyanathan G; Liang, Fengting; Beard, William A; Shock, David D; Wilson, Samuel H; Cho, Bongsup P

    2013-08-01

    The active site conformation of the mutagenic fluoroaminofluorene-deoxyguanine adduct (dG-FAF, N-(2'-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene) has been investigated in the presence of Klenow fragment of Escherichia coli DNA polymerase I (Kfexo(-)) and DNA polymerase β (pol β) using (19)F NMR, insertion assay, and surface plasmon resonance. In a single nucleotide gap, the dG-FAF adduct adopts both a major-groove- oriented and base-displaced stacked conformation, and this heterogeneity is retained upon binding pol β. The addition of a non-hydrolysable 2'-deoxycytosine-5'-[(α,β)-methyleno]triphosphate (dCMPcPP) nucleotide analog to the binary complex results in an increase of the major groove conformation of the adduct at the expense of the stacked conformation. Similar results were obtained with the addition of an incorrect dAMPcPP analog but with formation of the minor groove binding conformer. In contrast, dG-FAF adduct at the replication fork for the Kfexo(-) complex adopts a mix of the major and minor groove conformers with minimal effect upon the addition of non-hydrolysable nucleotides. For pol β, the insertion of dCTP was preferred opposite the dG-FAF adduct in a single nucleotide gap assay consistent with (19)F NMR data. Surface plasmon resonance binding kinetics revealed that pol β binds tightly with DNA in the presence of correct dCTP, but the adduct weakens binding with no nucleotide specificity. These results provide molecular insights into the DNA binding characteristics of FAF in the active site of DNA polymerases and the role of DNA structure and sequence on its coding potential.

  7. Career Readiness in the United States 2015. ACT Insights in Education and Work

    ERIC Educational Resources Information Center

    LeFebvre, Mary

    2015-01-01

    ACT has conducted over 20,000 job analyses for occupations across a diverse array of industries and occupations since 1993. This report highlights the levels of career readiness for various subgroups of ACT Work Keys® examinees in the United States and provides career readiness benchmarks for selected ACT WorkKeys cognitive skills by career…

  8. Request Strategies in Professional E-Mail Correspondence: Insights from the United States Workplace

    ERIC Educational Resources Information Center

    Leopold, Lisa

    2015-01-01

    Despite growing interest in the rhetorical features of e-mail correspondence, this is the first study to examine the request strategies in e-mails written by native English-speaking professionals from a variety of industries in the United States. This study uses Blum-Kulka, House, and Kasper's (1989) speech act framework to analyze the request…

  9. What State Policymakers Should Know about Federal Higher Education Policy. Policy Insights

    ERIC Educational Resources Information Center

    Longanecker, David A.

    2006-01-01

    Despite the mantra that education is primarily a state responsibility, the federal government is an important and influential player when it comes to providing higher education to the nation's students. The federal government invests roughly $25 billion annually in higher education excluding loans that are ultimately repaid, military benefits that…

  10. Seismic amplification within the Seattle Basin, Washington State: Insights from SHIPS seismic tomography experiments

    USGS Publications Warehouse

    Snelson, C.M.; Brocher, T.M.; Miller, K.C.; Pratt, T.L.; Trehu, A.M.

    2007-01-01

    Recent observations indicate that the Seattle sedimentary basin, underlying Seattle and other urban centers in the Puget Lowland, Washington, amplifies long-period (1-5 sec) weak ground motions by factors of 10 or more. We computed east-trending P- and S-wave velocity models across the Seattle basin from Seismic Hazard Investigations of Puget Sound (SHIPS) experiments to better characterize the seismic hazard the basin poses. The 3D tomographic models, which resolve features to a depth of 10 km, for the first time define the P- and S-wave velocity structure of the eastern end of the basin. The basin, which contains sedimentary rocks of Eocene to Holocene, is broadly symmetric in east-west section and reaches a maximum thickness of 6 km along our profile beneath north Seattle. A comparison of our velocity model with coincident amplification curves for weak ground motions produced by the 1999 Chi-Chi earthquake suggests that the distribution of Quaternary deposits and reduced velocity gradients in the upper part of the basement east of Seattle have significance in forecasting variations in seismic-wave amplification across the basin. Specifically, eastward increases in the amplification of 0.2- to 5-Hz energy correlate with locally thicker unconsolidated deposits and a change from Crescent Formation basement to pre-Tertiary Cascadia basement. These models define the extent of the Seattle basin, the Seattle fault, and the geometry of the basement contact, giving insight into the tectonic evolution of the Seattle basin and its influence on ground shaking.

  11. Direct observation of frictional contacts: New insights for state-dependent properties

    USGS Publications Warehouse

    Dieterich, J.H.; Kilgore, B.D.

    1994-01-01

    Rocks and many other materials display a rather complicated, but characteristic, dependence of friction on sliding history. These effects are well-described by empirical rate- and state-dependent constitutive formulations which have been utilized for analysis of fault slip and earthquake processes. We present a procedure for direct quantitative microscopic observation of frictional contacts during slip. The observations reveal that frictional state dependence represents an increase of contact area with contact age. Transient changes of sliding resistance correlate with changes in contact area and arise from shifts of contact population age. Displacement-dependent replacement of contact populations is shown to cause the diagnostic evolution of friction over a characteristic sliding distance that occurs whenever slip begins or sliding conditions change. ?? 1994 Birkha??user Verlag.

  12. Solid-state NMR in macromolecular systems: insights on how molecular entities move.

    PubMed

    Hansen, Michael Ryan; Graf, Robert; Spiess, Hans Wolfgang

    2013-09-17

    The function of synthetic and natural macromolecularsystems critically depends on the packing and dynamics of the individual components of a given system. Not only can solid-state NMR provide structural information with atomic resolution, but it can also provide a way to characterize the amplitude and time scales of motions over broad ranges of length and time. These movements include molecular dynamics, rotational and translational motions of the building blocks, and also the motion of the functional species themselves, such as protons or ions. This Account examines solid-state NMR methods for correlating dynamics and function in a variety of chemical systems. In the early days, scientists thought that the rotationalmotions reflected the geometry of the moving entities. They described these phenomena as jumps about well-defined axes, such as phenyl flips, even in amorphous polymers. Later, they realized that conformational transitions in macromolecules happen in a much more complex way. Because the individual entities do not rotate around well-defined axes, they require much less space. Only recently researchers have appreciated the relative importance of large angle fluctuations of polymers over rotational jumps. Researchers have long considered that cooperative motions might be at work, yet only recently they have clearly detected these motions by NMR in macromolecular and supramolecular systems. In correlations of dynamics and function, local motions do not always provide the mechanism of long-range transport. This idea holds true in ion conduction but also applies to chain transport in polymer melts and semicrystalline polymers. Similar chain motions and ion transport likewise occur in functional biopolymers, systems where solid-state NMR studies are also performed. In polymer science, researchers have appreciated the unique information on molecular dynamics available from advanced solid-state NMR at times, where their colleagues in the biomacromolecular

  13. From REM sleep behaviour disorder to status dissociatus: insights into the maze of states of being.

    PubMed

    Vetrugno, Roberto; Montagna, Pasquale

    2011-12-01

    Sleep is a coordinated process involving more or less simultaneous changes in sensory, motor, autonomic, hormonal, and cerebral processes. On the other hand, none of the changes occurring with sleep are invariably coupled to sleep. EEG synchrony, heat loss, sleep-related hormone secretion, and even REM-related motoneuron paralysis may occur independent of the parent state. In REM sleep behaviour disorder (RBD) the muscle tone of wakefulness intrudes into REM sleep, allowing the release of dream-enacting behaviours. Status dissociatus (SD) is a condition in which brain and mind are in disarray along the boundaries of sleep and wakefulness. The existence of such dissociated behaviours shows that they have separate neuronal control systems and indicates that the whole organization of sleep is an emergent property of the collective neuronal systems to synchronize. Insults to the brain can drastically alter the circuitries responsible for maintaining the integrity of wakefulness, NREM sleep, and REM sleep. As a consequence, the basic states of existence can become admixed and interchanged with striking disturbances of consciousness, brain electrophysiology, and the behavioural and polygraphic expression of sleep and wakefulness. The evolution of RBD into SD may result from a disarray of (brainstem) structures that orchestrate the whole brain wake-sleep conditions, but with preserved discrete systems and dissociable strategies to still place navigation in wake and sleep. Advances in the fields of genetics, neuroimaging, and behavioural neurology will expand the understanding of the mechanisms underlying the organization of the states of being along with their somatic/behavioural manifestations.

  14. An insight into the biophysical characterization of different states of cefotaxime hydrolyzing β-lactamase 15 (CTX-M-15).

    PubMed

    Rehman, Md Tabish; Faheem, Mohd; Khan, Asad U

    2015-01-01

    Cefotaxime hydrolyzing β-lactamase-15 (CTX-M-15) is encoded by blaCTX-M-15 gene present on plasmid of various Gram-negative bacteria, such as E. coli, E. cloacae, K. pneumoniae, etc. The widespread dissemination of CTX-M-15 harboring bacteria in hospital as well as community settings is a universal threat as they are resistant to various clinically significant antibiotics. In order to gain an insight into the folding mechanism of CTX-M-15, we carried out pH-induced denaturation study by monitoring Trp fluorescence, far-UV circular dichroism (CD), and ANS fluorescence. We found that the pH-induced denaturation of CTX-M-15 was a three-step process with the accumulation of two stable folding intermediates (XI at pH 2.5 and XII at pH 1.5) in the folding pathway. The intermediates were further characterized by far-UV and near-UV CD analysis, Trp fluorescence, ANS fluorescence, three-dimensional fluorescence, acrylamide quenching, dynamic light scattering, and thermal denaturation studies. We found that XI state lacked tertiary structure but retained most of the secondary structure, its Trp residues were partially exposed to the solvent and its hydrophobic patches were highly accessible to ANS. On the other hand, a complete disruption of tertiary structure along with more than 50% loss in secondary structure was observed in XII state. We conclude that the XI state of CTX-M-15 at pH 2.5 had all the characteristics of a molten globule (MG) state, while its XII state at pH 1.5 was more similar to pre-molten globule (PMG) state. ANS fluorescence also showed that the binding of ANS in XII state was lower than that in the XI state. We propose that the accumulation of MG- and PMG-states was due to separation (at pH 2.5) and then unfolding (at pH 1.5) of the αβα-fold of CTX-M-15, respectively. PMID:24650131

  15. Functional insights into modulation of BKCa channel activity to alter myometrial contractility

    PubMed Central

    Lorca, Ramón A.; Prabagaran, Monali; England, Sarah K.

    2014-01-01

    The large-conductance voltage- and Ca2+-activated K+ channel (BKCa) is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits), association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function. PMID:25132821

  16. On the dynamical state of galaxy clusters: insights from cosmological simulations II.

    NASA Astrophysics Data System (ADS)

    Cui, Weiguang; Power, Chris; Borgani, Stefano; Knebe, Alexander; Lewis, Geraint F.; Murante, Giuseppe; Poole, Gregory B.

    2016-10-01

    Using a suite of cosmology simulations of a sample of >120 galaxy clusters with log (MDM, vir) ≤ 14.5. We compare clusters that form in purely dark matter run and their counterparts in hydro runs and investigate 4 independent parameters, that are normally used to classify dynamical state. We find that the virial ratio η in hydro-dynamical runs is ˜10 per cent lower than in the DM run, and there is no clear separation between the relaxed and unrelaxed clusters for any parameter. Further, using the velocity dispersion deviation parameter ζ, which is defined as the ratio between cluster velocity dispersion σ and the theoretical prediction σ _t = √{G M_{total}/R}, we find that there is a linear correlation between the virial ratio η and this ζ parameter. We propose to use this ζ parameter, which can be easily derived from observed galaxy clusters, as a substitute of the η parameter to quantify the cluster dynamical state.

  17. Non-sulfate sulfur in fine aerosols across the United States: Insight for organosulfate prevalence

    NASA Astrophysics Data System (ADS)

    Shakya, Kabindra M.; Peltier, Richard E.

    2015-01-01

    We investigated the discrepancies in long-term sulfur measurements from 2000 to 2012 by two separate speciation methods, X-ray fluorescence (XRF) spectroscopy and ion chromatography (IC) across the United States (334 sites). Overall, there was a good correlation between sulfur measurements by XRF spectroscopy and IC (R ≥ 0.90 for most of the sites). However, the inorganic sulfate measured by ion chromatography was not sufficient to account for all the sulfur measured by XRF spectroscopy at many of the sites. Discrepancies were observed with the high ratios of sulfur measured by XRF spectroscopy to that by IC. Such high ratios also exhibited seasonal variation, and differed across land use types; significant differences occurred at locations classified as forest, agriculture, and mobile, but not in locations classified as commercial, desert, industrial, and residential. On average, the excess, or non-sulfate, sulfur (unmeasured organic sulfur or other inorganic species of sulfur) was variable and observed as high as ∼13% of organic carbon and ∼2% of PM2.5. The contribution of such assumed organosulfur was larger in the eastern region than other geographical locations in the United States. Besides the temporal and spatial trends, the additional sulfur was found to be related to other factors such as aerosol acidity and emission sources. The results suggest that these unmeasured sulfur species could have significant contribution to aerosol burden, and the understanding of these could help to control PM2.5 levels and to assess other effects of sulfur aerosols.

  18. Amyloidogenic behavior of different intermediate state of stem bromelain: A biophysical insight.

    PubMed

    Zaman, Masihuz; Ehtram, Aquib; Chaturvedi, Sumit Kumar; Nusrat, Saima; Khan, Rizwan Hasan

    2016-10-01

    Stem bromelain, a cysteine proteases from Ananas comosus is a widely accepted therapeutic drug with broad medicinal application. It exists as intermediate states at pH 2.0 and 10.0, where it encountered in gastrointestinal tract during adsorption (acidic pH) and in gut epithelium (alkaline pH), respectively. In this study, we monitored the thermal aggregation/amyloid formation of SB at different pH intermediate states. Thermal treatment of stem bromelain at pH 10.0 favors the fibrillation in which the extent of aggregation increases with increase in protein concentration. However, no fibril formation in stem bromelain at pH 2.0 was found at all the concentration used at pH 10.0. The fibril formation was confirmed by various techniques such as turbidity measurements, Rayleigh light scattering, dye binding assays and far UV circular dichroism. The Dynamic light scattering confirmed the formation of aggregates by measuring the hydrodynamic radii pattern. Moreover, microscopic techniques were performed to analyze the morphology of fibrils. The aggregation behavior may be due to variation in number of charged amino acid residues. The less negative charge developed at pH 10.0 may be responsible for aggregation. This work helps to overcome the aggregation related problems of stem bromelain during formulations in pharmaceutical industry.

  19. Amyloidogenic behavior of different intermediate state of stem bromelain: A biophysical insight.

    PubMed

    Zaman, Masihuz; Ehtram, Aquib; Chaturvedi, Sumit Kumar; Nusrat, Saima; Khan, Rizwan Hasan

    2016-10-01

    Stem bromelain, a cysteine proteases from Ananas comosus is a widely accepted therapeutic drug with broad medicinal application. It exists as intermediate states at pH 2.0 and 10.0, where it encountered in gastrointestinal tract during adsorption (acidic pH) and in gut epithelium (alkaline pH), respectively. In this study, we monitored the thermal aggregation/amyloid formation of SB at different pH intermediate states. Thermal treatment of stem bromelain at pH 10.0 favors the fibrillation in which the extent of aggregation increases with increase in protein concentration. However, no fibril formation in stem bromelain at pH 2.0 was found at all the concentration used at pH 10.0. The fibril formation was confirmed by various techniques such as turbidity measurements, Rayleigh light scattering, dye binding assays and far UV circular dichroism. The Dynamic light scattering confirmed the formation of aggregates by measuring the hydrodynamic radii pattern. Moreover, microscopic techniques were performed to analyze the morphology of fibrils. The aggregation behavior may be due to variation in number of charged amino acid residues. The less negative charge developed at pH 10.0 may be responsible for aggregation. This work helps to overcome the aggregation related problems of stem bromelain during formulations in pharmaceutical industry. PMID:27259642

  20. Non-sulfate sulfur in fine aerosols across the United States: Insight for organosulfate prevalence

    PubMed Central

    Shakya, Kabindra M.; Peltier, Richard E.

    2014-01-01

    We investigated the discrepancies in long-term sulfur measurements from 2000 to 2012 by two separate speciation methods, X-ray fluorescence (XRF) spectroscopy and ion chromatography (IC) across the United States (334 sites). Overall, there was a good correlation between sulfur measurements by XRF spectroscopy and IC (R ≥ 0.90 for most of the sites). However, the inorganic sulfate measured by ion chromatography was not sufficient to account for all the sulfur measured by XRF spectroscopy at many of the sites. Discrepancies were observed with the high ratios of sulfur measured by XRF spectroscopy to that by IC. Such high ratios also exhibited seasonal variation, and differed across land use types; significant differences occurred at locations classified as forest, agriculture, and mobile, but not in locations classified as commercial, desert, industrial, and residential. On average, the excess, or non-sulfate, sulfur (unmeasured organic sulfur or other inorganic species of sulfur) was variable and observed as high as ~13% of organic carbon and ~2% of PM2.5. The contribution of such assumed organosulfur was larger in the eastern region than other geographical locations in the United States. Besides the temporal and spatial trends, the additional sulfur was found to be related to other factors such as aerosol acidity and emission sources. The results suggest that these unmeasured sulfur species could have significant contribution to aerosol burden, and the understanding of these could help to control PM2.5 levels and to assess other effects of sulfur aerosols. PMID:25620874

  1. The peptide-receptive transition state of MHC-1 molecules: Insight from structure and molecular dynamics

    SciTech Connect

    Robinson H.; Mage, M.; Dolan, M.; Wang, R.; Boyd, L.; Revilleza, M.; Natarajan, K.; Myers, N.; Hansen, T.; Margulies, D.

    2012-05-01

    MHC class I (MHC-I) proteins of the adaptive immune system require antigenic peptides for maintenance of mature conformation and immune function via specific recognition by MHC-I-restricted CD8(+) T lymphocytes. New MHC-I molecules in the endoplasmic reticulum are held by chaperones in a peptide-receptive (PR) transition state pending release by tightly binding peptides. In this study, we show, by crystallographic, docking, and molecular dynamics methods, dramatic movement of a hinged unit containing a conserved 3(10) helix that flips from an exposed 'open' position in the PR transition state to a 'closed' position with buried hydrophobic side chains in the peptide-loaded mature molecule. Crystallography of hinged unit residues 46-53 of murine H-2L(d) MHC-I H chain, complexed with mAb 64-3-7, demonstrates solvent exposure of these residues in the PR conformation. Docking and molecular dynamics predict how this segment moves to help form the A and B pockets crucial for the tight peptide binding needed for stability of the mature peptide-loaded conformation, chaperone dissociation, and Ag presentation.

  2. Change-of-state determination to recognize mobility activities using a BlackBerry smartphone.

    PubMed

    Wu, Hui Hsien; Lemaire, Edward D; Baddour, Natalie

    2011-01-01

    A Wearable Mobility Monitoring System (WMMS) can be a useful tool for rehabilitation decision-making. This paper presents preliminary design and evaluation of a WMMS proof-of-concept system. Software was developed for the BlackBerry 9550, using the integrated three axes accelerometer, GPS, video camera, and timer to identify mobility changes-of-state (CoS) between static activities, walking-related activities, taking an elevator, bathroom activities, working in the kitchen, and meal preparation (five able-bodied subjects). This pilot project provides insight into new algorithms and features that recognize CoS and activities in real-time. Following features extraction from the sensor data, two decision trees were used to distinguish the CoS and activities. Real-time CoS identification triggered BlackBerry video recording for improved mobility context analysis during post-processing. PMID:22255522

  3. Molecular Structure of Aggregated Amyloid-β: Insights from Solid State Nuclear Magnetic Resonance

    PubMed Central

    Tycko, Robert

    2016-01-01

    Amyloid-β (Aβ) peptides aggregate to form polymorphic amyloid fibrils and a variety of intermediate assemblies, including oligomers and protofibrils, both in vitro and in human brain tissue. Since the beginning of the 21st century, considerable progress has been made on characterization of the molecular structures of Aβ aggregates. Full molecular structural models that are based primarily on data from solid state nuclear magnetic resonance measurements have been developed for several in vitro Aβ fibrils and one metastable protofibril. Partial structural characterization of other aggregation intermediates has been achieved. One full structural model for fibrils derived from brain tissue has also been reported. Future work is likely to focus on additional structures from brain tissue and on further clarification of nonfibrillar Aβ aggregates. PMID:27481836

  4. The Impact of Seawater Saturation State on Early Skeletal Development in Larval Corals: Insights into Scleractinian Biomineralization

    NASA Astrophysics Data System (ADS)

    Cohen, A. L.; McCorkle, D. C.; de Putron, S.

    2007-12-01

    Understanding the response of coral calcification to changes in seawater saturation state (ocean acidification) could provide important insights into the fundamental processes of scleractinian biomineralization. In particular, larval calcification, which involves initiation of skeletogenesis by a previously non-calcifying planktonic planula, offers a unique opportunity to examine the role and limitations of biological control over an essentially physicochemical process. Larvae of the brooding Atlantic coral Favia fragum were settled in unmodified seawater onto clay tiles within 12h of spawning, and placed into non-through flow 30 L aquaria prior to initiation of calcification. Seawater chemistry was pre-adjusted via HCl addition and continuous bubbling with laboratory air, yielding four aragonite saturation states: Omega(aragonite) = 3.71 (unmodified), 2.4, 1.04, and 0.22. The aquaria were held at 25 °C on a 12h/12h light/dark cycle, and sets of tiles harvested at 1, 5 and 8 days post-spawning. Accretion of aragonite (confirmed by Raman spectroscopy) in all treatments indicates that the settled larvae were able to elevate the saturation state of aquarium seawater sequestered within their calcifying space. However, external aqueous carbonate chemistry had a striking effect on larval mortality, on the nature and timing of basal plate formation, on skeletal growth rates (based on the length and cross-sectional area of septa), and on the structure and organization of aragonite crystals within the septa (imaged using SEM). Larval survival rates at the two lower saturation states was only 40% of that in the control and Omega = 2.35 treatments, and skeletal growth decreased by 30 % (relative to the control) in seawater with saturation state comparable to that predicted for the mid-latitude surface ocean by 2100 AD. SEM imaging of the larval skeletons revealed significant differences in the morphology of aragonite crystals accreted under different conditions. In stark

  5. Detecting concept relations in clinical text: insights from a state-of-the-art model.

    PubMed

    Zhu, Xiaodan; Cherry, Colin; Kiritchenko, Svetlana; Martin, Joel; de Bruijn, Berry

    2013-04-01

    This paper addresses an information-extraction problem that aims to identify semantic relations among medical concepts (problems, tests, and treatments) in clinical text. The objectives of the paper are twofold. First, we extend an earlier one-page description (appearing as a part of [5]) of a top-ranked model in the 2010 I2B2 NLP Challenge to a necessary level of details, with the belief that feature design is the most crucial factor to the success of our system and hence deserves a more detailed discussion. We present a precise quantification of the contributions of a wide variety of knowledge sources. In addition, we show the end-to-end results obtained on the noisy output of a top-ranked concept detector, which could help construct a more complete view of the state of the art in the real-world scenario. As the second major objective, we reformulate our models into a composite-kernel framework and present the best result, according to our knowledge, on the same dataset.

  6. Eldercare in the transnational setting: insights from Bangladeshi transnational families in the United States.

    PubMed

    Amin, Iftekhar; Ingman, Stan

    2014-09-01

    Little is known about the emotional impact of caregiving for elderly parents on migrant child in the transnational setting. To address this gap in the literature, this study examines the stressors, mediators, and outcomes of eldercare in the transnational context. Data were collected from 21 Bangladeshi immigrant men and women living in the United States who had living parents in Bangladesh over 60 years old. Despite the geographic distance, the migrants provide care to their parents such as emotional support, financial assistance, and arranging for care. While the health status of the care recipients contributed to primary objective stressors, none of the transnational caregivers' narratives reflected the presence of any subjective stressors such as role overload, role captivity, and relational deprivation. Distance and depending on others for hands-on caregiving resulted in feelings of loss of control over the caregiving process. Caregivers experienced a range of emotions from guilt, excessive worrying, and distress over the unpredictability and uncertainty of their circumstances. Kin networks, communicative technologies, and a cultural norm of filial piety contributed to mediating stress. The findings underscore the importance of supportive institutional policies such as visa and travel policies, employment leave, and counseling services for caregivers who provide care for their elderly parents transnationally.

  7. Intermediate states in the binding process of folic acid to folate receptor α: insights by molecular dynamics and metadynamics.

    PubMed

    Della-Longa, Stefano; Arcovito, Alessandro

    2015-01-01

    Folate receptor α (FRα) is a cell surface, glycophosphatidylinositol-anchored protein which has focussed attention as a therapeutic target and as a marker for the diagnosis of cancer. It has a high affinity for the dietary supplemented folic acid (FOL), carrying out endocytic transport across the cell membrane and delivering the folate at the acidic pH of the endosome. Starting from the recently reported X-ray structure at pH 7, 100 ns classical molecular dynamics simulations have been carried out on the FRα-FOL complex; moreover, the ligand dissociation process has been studied by metadynamics, a recently reported method for the analysis of free-energy surfaces (FES), providing clues on the intermediate states and their energy terms. Multiple dissociation runs were considered to enhance the configurational sampling; a final clustering of conformations within the averaged FES provides the representative structures of several intermediate states, within an overall barrier for ligand escape of about 75 kJ/mol. Escaping of FOL to solvent occurs while only minor changes affect the FRα conformation of the binding pocket. During dissociation, the FOL molecule translates and rotates around a turning point located in proximity of the receptor surface. FOL at this transition state assumes an "L" shaped conformation, with the pteridin ring oriented to optimize stacking within W102 and W140 residues, and the negatively charged glutamate tail, outside the receptor, interacting with the positively charged R103 and R106 residues, that contrary to the bound state, are solvent exposed. We show that metadynamics method can provide useful insights at the atomistic level on the effects of point-mutations affecting functionality, thus being a very promising tool for any study related to folate-targeted drug delivery or cancer therapies involving folate uptake.

  8. Tritium activities in the United States

    SciTech Connect

    Anderson, J.L.; LaMarche, P.

    1995-07-01

    There have been many significant changes in the status of tritium activities in the US since the 4th Tritium Conference in October, 1991. The replacement Tritium Facility (RTF) at Savannah River Site and the Weapons Engineering Tritium Facility (WETF) at the Los Alamos National Laboratory are now operational with tritium. The Tokamak Fusion Test Reactor (TFTR) has initiated a highly successful experimental campaign studying DT plasmas, and has produced more than 10 Megawatts (MW) of fusion power in a D-T plasma. Sandia National Laboratory has ceased tritium operations at the Tritium Research Laboratory (TRL) and many of the activities previously performed there have been transferred to Los Alamos and Savannah River. The tritium laboratory at Lawrence Livermore National Laboratory has reduced the tritium inventory to <5 grams. The Tritium Systems Test Assembly (TSTA) at Los Alamos continues to be at the forefront of tritium technology and safety development for the fusion energy program.

  9. A Structural Snapshot of CYP2B4 in Complex with Paroxetine Provides Insights into Ligand Binding and Clusters of Conformational States

    PubMed Central

    Kufareva, Irina; Pascual, Jaime; Zhang, Qinghai; Stout, C. David; Halpert, James R.

    2013-01-01

    An X-ray crystal structure of CYP2B4 in complex with the drug paroxetine [(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine] was solved at 2.14 Å resolution. The structure revealed a conformation intermediate to that of the recently solved complex with amlodipine and that of the more compact complex with 4-(4-chlorophenyl)imidazole in terms of the placement of the F-G cassette. Moreover, comparison of the new structure with 15 previously solved structures of CYP2B4 revealed some new insights into the determinants of active-site size and shape. The 2B4-paroxetine structure is nearly superimposable on a previously solved closed structure in a ligand-free state. Despite the overall conformational similarity among multiple closed structures, the active-site cavity volume of the paroxetine complex is enlarged. Further analysis of the accessible space and binding pocket near the heme reveals a new subchamber that resulted from the movement of secondary structural elements and rearrangements of active-site side chains. Overall, the results from the comparison of all 16 structures of CYP2B4 demonstrate a cluster of protein conformations that were observed in the presence or absence of various ligands. PMID:23633618

  10. Structure of the eastern Seattle fault zone, Washington state: New insights from seismic reflection data

    USGS Publications Warehouse

    Liberty, L.M.; Pratt, T.L.

    2008-01-01

    We identify and characterize the active Seattle fault zone (SFZ) east of Lake Washington with newly acquired seismic reflection data. Our results focus on structures observed in the upper 1 km below the cities of Bellevue, Sammamish, Newcastle, and Fall City, Washington. The SFZ appears as a broad zone of faulting and folding at the southern boundary of the Seattle basin and north edge of the Seattle uplift. We interpret the Seattle fault as a thrust fault that accommodates north-south shortening by forming a fault-propagation fold with a forelimb breakthrough. The blind tip of the main fault forms a synclinal growth fold (deformation front) that extends at least 8 km east of Vasa Park (west side of Lake Sammamish) and defines the south edge of the Seattle basin. South of the deformation front is the forelimb break-through fault, which was exposed in a trench at Vasa Park. The Newcastle Hills anticline, a broad anticline forming the north part of the Seattle uplift east of Lake Washington, is interpreted to lie between the main blind strand of the Seattle fault and a backthrust. Our profiles, on the northern limb of this anticline, consistently image north-dipping strata. A structural model for the SFZ east of Lake Washington is consistent with about 8 km of slip on the upper part of the Seattle fault, but the amount of motion is only loosely constrained.

  11. Targeting CDK6 in cancer: State of the art and new insights

    PubMed Central

    Tadesse, Solomon; Yu, Mingfeng; Kumarasiri, Malika; Le, Bich Thuy; Wang, Shudong

    2015-01-01

    Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed. PMID:26315616

  12. Molecular Insight in Structure and Activity of Highly Efficient, Low-Ir Ir-Ni Oxide Catalysts for Electrochemical Water Splitting (OER).

    PubMed

    Reier, Tobias; Pawolek, Zarina; Cherevko, Serhiy; Bruns, Michael; Jones, Travis; Teschner, Detre; Selve, Sören; Bergmann, Arno; Nong, Hong Nhan; Schlögl, Robert; Mayrhofer, Karl J J; Strasser, Peter

    2015-10-14

    Mixed bimetallic oxides offer great opportunities for a systematic tuning of electrocatalytic activity and stability. Here, we demonstrate the power of this strategy using well-defined thermally prepared Ir-Ni mixed oxide thin film catalysts for the electrochemical oxygen evolution reaction (OER) under highly corrosive conditions such as in acidic proton exchange membrane (PEM) electrolyzers and photoelectrochemical cells (PEC). Variation of the Ir to Ni ratio resulted in a volcano type OER activity curve with an unprecedented 20-fold improvement in Ir mass-based activity over pure Ir oxide. In situ spectroscopic probing of metal dissolution indicated that, against common views, activity and stability are not directly anticorrelated. To uncover activity and stability controlling parameters, the Ir-Ni mixed thin oxide film catalysts were characterized by a wide array of spectroscopic, microscopic, scattering, and electrochemical techniques in conjunction with DFT theoretical computations. By means of an intuitive model for the formation of the catalytically active state of the bimetallic Ir-Ni oxide surface, we identify the coverage of reactive surface hydroxyl groups as a suitable descriptor for the OER activity and relate it to controllable synthetic parameters. Overall, our study highlights a novel, highly active oxygen evolution catalyst; moreover, it provides novel important insights into the structure and performance of bimetallic oxide OER electrocatalysts in corrosive acidic environments.

  13. Some insights about the activity of the Ceboruco Volcano (Nayarit, Mexico) from recent seismic low-frequency activity

    NASA Astrophysics Data System (ADS)

    Rodríguez Uribe, María Carolina; Núñez-Cornú, Francisco Javier; Nava Pichardo, Fidencio Alejandro; Suárez-Plascencia, Carlos

    2013-10-01

    The Ceboruco stratovolcano (2,280 m.a.s.l.) is located in Nayarit, Mexico, at the western end of the Mexican volcanic belt, near several population centers and by the side of a strategic highway. During the last 1,000 years it has had, on the average, one eruption every 125 years. It last eruptive activity began in 1870, and during the following 5 years it presented superficial activity including vapor emissions, ash falls, and rhyodacitic lava flows along the southeast side. A data set consisting of 139 low-frequency volcanic-type earthquakes, recorded from March 2003 to July 2008 at the CEBN triaxial short period digital station on the southwestern side of the volcano, was classified according to waveform and spectral characteristics into four families: short duration, extended coda, bobbin, and modulated amplitude. Approximate hypocentral locations indicate that there is no particular location for events of any family, but rather that all events occur at different points within the volcano. The presence of ongoing volcanic-earthquake activity together with the ongoing vapor emissions indicate that the Ceboruco volcano continues to be active, and the higher occurrence rates of short-duration events, as compared with those for the other families, could indicate an increase in the stress in the volcanic edifice. This apparent stress increase, together with the fact that the last eruption occurred 143 years ago, tell us that the Ceboruco may be approaching a critical state, and may represent a hazard to the surrounding communities and economic activities.

  14. VIP+ interneurons control neocortical activity across brain states.

    PubMed

    Jackson, Jesse; Ayzenshtat, Inbal; Karnani, Mahesh M; Yuste, Rafael

    2016-06-01

    GABAergic interneurons are positioned to powerfully influence the dynamics of neural activity, yet the interneuron-mediated circuit mechanisms that control spontaneous and evoked neocortical activity remains elusive. Vasoactive intestinal peptide (VIP+) interneurons are a specialized cell class which synapse specifically on other interneurons, potentially serving to facilitate increases in cortical activity. In this study, using in vivo Ca(2+) imaging, we describe the interaction between local network activity and VIP+ cells and determine their role in modulating neocortical activity in mouse visual cortex. VIP+ cells were active across brain states including locomotion, nonlocomotion, visual stimulation, and under anesthesia. VIP+ activity correlated most clearly with the mean level of population activity of nearby excitatory neurons during all brain states, suggesting VIP+ cells enable high-excitability states in the cortex. The pharmacogenetic blockade of VIP+ cell output reduced network activity during locomotion, nonlocomotion, anesthesia, and visual stimulation, suggesting VIP+ cells exert a state-independent facilitation of neural activity in the cortex. Collectively, our findings demonstrate that VIP+ neurons have a causal role in the generation of high-activity regimes during spontaneous and stimulus evoked neocortical activity. PMID:26961109

  15. State opportunities for action: Update of states' combined heat and power activities

    SciTech Connect

    Brown, Elizabeth; Elliott, R. Neal

    2003-10-01

    This report updates the review of state policies with regard to CHP that the American Council for and Energy Efficient Economy completed in 2002. It describes the current activities of states with programs during the initial survey and also reviews new programs offered by the states.

  16. 34 CFR 403.70 - How must funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... State Leadership Activities? 403.70 Section 403.70 Education Regulations of the Offices of the... the Basic Programs? State Programs and State Leadership Activities § 403.70 How must funds be used under the State Programs and State Leadership Activities? A State shall use funds reserved under...

  17. 34 CFR 403.70 - How must funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... State Leadership Activities? 403.70 Section 403.70 Education Regulations of the Offices of the... the Basic Programs? State Programs and State Leadership Activities § 403.70 How must funds be used under the State Programs and State Leadership Activities? A State shall use funds reserved under...

  18. 34 CFR 403.70 - How must funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... State Leadership Activities? 403.70 Section 403.70 Education Regulations of the Offices of the... the Basic Programs? State Programs and State Leadership Activities § 403.70 How must funds be used under the State Programs and State Leadership Activities? A State shall use funds reserved under...

  19. 34 CFR 403.70 - How must funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... State Leadership Activities? 403.70 Section 403.70 Education Regulations of the Offices of the... the Basic Programs? State Programs and State Leadership Activities § 403.70 How must funds be used under the State Programs and State Leadership Activities? A State shall use funds reserved under...

  20. 34 CFR 403.70 - How must funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... State Leadership Activities? 403.70 Section 403.70 Education Regulations of the Offices of the... the Basic Programs? State Programs and State Leadership Activities § 403.70 How must funds be used under the State Programs and State Leadership Activities? A State shall use funds reserved under...

  1. Active Solid State Dosimetry for Lunar EVA

    NASA Technical Reports Server (NTRS)

    Wrbanek, John D.; Fralick, Gustave C.; Wrbanek, Susan Y.; Chen, Liang-Yu.

    2006-01-01

    The primary threat to astronauts from space radiation is high-energy charged particles, such as electrons, protons, alpha and heavier particles, originating from galactic cosmic radiation (GCR), solar particle events (SPEs) and trapped radiation belts in Earth orbit. There is also the added threat of secondary neutrons generated as the space radiation interacts with atmosphere, soil and structural materials.[1] For Lunar exploration missions, the habitats and transfer vehicles are expected to provide shielding from standard background radiation. Unfortunately, the Lunar Extravehicular Activity (EVA) suit is not expected to afford such shielding. Astronauts need to be aware of potentially hazardous conditions in their immediate area on EVA before a health and hardware risk arises. These conditions would include fluctuations of the local radiation field due to changes in the space radiation field and unknown variations in the local surface composition. Should undue exposure occur, knowledge of the dynamic intensity conditions during the exposure will allow more precise diagnostic assessment of the potential health risk to the exposed individual.[2

  2. Intrinsic Brain Activity in Altered States of Consciousness

    PubMed Central

    Boly, M.; Phillips, C.; Tshibanda, L.; Vanhaudenhuyse, A.; Schabus, M.; Dang-Vu, T.T.; Moonen, G.; Hustinx, R.; Maquet, P.; Laureys, S.

    2010-01-01

    Spontaneous brain activity has recently received increasing interest in the neuroimaging community. However, the value of resting-state studies to a better understanding of brain–behavior relationships has been challenged. That altered states of consciousness are a privileged way to study the relationships between spontaneous brain activity and behavior is proposed, and common resting-state brain activity features observed in various states of altered consciousness are reviewed. Early positron emission tomography studies showed that states of extremely low or high brain activity are often associated with unconsciousness. However, this relationship is not absolute, and the precise link between global brain metabolism and awareness remains yet difficult to assert. In contrast, voxel-based analyses identified a systematic impairment of associative frontoparieto–cingulate areas in altered states of consciousness, such as sleep, anesthesia, coma, vegetative state, epileptic loss of consciousness, and somnambulism. In parallel, recent functional magnetic resonance imaging studies have identified structured patterns of slow neuronal oscillations in the resting human brain. Similar coherent blood oxygen level–dependent (BOLD) systemwide patterns can also be found, in particular in the default-mode network, in several states of unconsciousness, such as coma, anesthesia, and slow-wave sleep. The latter results suggest that slow coherent spontaneous BOLD fluctuations cannot be exclusively a reflection of conscious mental activity, but may reflect default brain connectivity shaping brain areas of most likely interactions in a way that transcends levels of consciousness, and whose functional significance remains largely in the dark. PMID:18591474

  3. [Nonequilibrium state of electrochemically activated water and its biological activity].

    PubMed

    Petrushanko, I Iu; Lobyshev, V I

    2001-01-01

    Changes in the physicochemical parameters (pH, redox potential and electroconductivity) of catholyte and anolyte produced by membrane electrolysis of distilled water and dilute (c < 10(-3) M) sodium chloride solutions were studied. The relaxation of these parameters after electrolysis and the influence of catholyte and anolyte on the growth of roots of Tradescantia viridis grafts, the development of duckweed, and the motive activity of infusoria Spirostomum ambiguum were investigated. It was found that the anolyte of distilled water stimulated development of these biological objects. The direction of shift of physicochemical parameters of catholyte and anolyte from equilibrium values and the type of their biological activity (stimulation or inhibition) depend on salt concentration in initial solution. Barbotage of initial distilled water with argon or nitrogen leads to a greater decrease in the redox potential of catholyte during electrolysis. The physicochemical parameters relax to equilibrium values, and the biological activity of catholite and anolyte decreases with time and practically disappears by the end of the day. It was found that the oxidation of reducing agent by atmospheric oxygen is not the sole cause of the relaxation of catalyte redox potential. The increase in the ionic strength of catholite and anolyte by the addition of concentrated sodium chloride after electrolysis decreases the rate of redox potential relaxation several times. The redox potential can be maintained for long periods by freezing.

  4. Observing single enzyme molecules interconvert between activity states upon heating.

    PubMed

    Rojek, Marcin J; Walt, David R

    2014-01-01

    In this paper, we demonstrate that single enzyme molecules of β-galactosidase interconvert between different activity states upon exposure to short pulses of heat. We show that these changes in activity are the result of different enzyme conformations. Hundreds of single β-galactosidase molecules are trapped in femtoliter reaction chambers and the individual enzymes are subjected to short heating pulses. When heating pulses are introduced into the system, the enzyme molecules switch between different activity states. Furthermore, we observe that the changes in activity are random and do not correlate with the enzyme's original activity. This study demonstrates that different stable conformations play an important role in the static heterogeneity reported previously, resulting in distinct long-lived activity states of enzyme molecules in a population.

  5. Synaptic plasticity modulates autonomous transitions between waking and sleep states: insights from a Morris-Lecar model.

    PubMed

    Ciszak, Marzena; Bellesi, Michele

    2011-12-01

    The transitions between waking and sleep states are characterized by considerable changes in neuronal firing. During waking, neurons fire tonically at irregular intervals and a desynchronized activity is observed at the electroencephalogram. This activity becomes synchronized with slow wave sleep onset when neurons start to oscillate between periods of firing (up-states) and periods of silence (down-states). Recently, it has been proposed that the connections between neurons undergo potentiation during waking, whereas they weaken during slow wave sleep. Here, we propose a dynamical model to describe basic features of the autonomous transitions between such states. We consider a network of coupled neurons in which the strength of the interactions is modulated by synaptic long term potentiation and depression, according to the spike time-dependent plasticity rule (STDP). The model shows that the enhancement of synaptic strength between neurons occurring in waking increases the propensity of the network to synchronize and, conversely, desynchronization appears when the strength of the connections become weaker. Both transitions appear spontaneously, but the transition from sleep to waking required a slight modification of the STDP rule with the introduction of a mechanism which becomes active during sleep and changes the proportion between potentiation and depression in accordance with biological data. At the neuron level, transitions from desynchronization to synchronization and vice versa can be described as a bifurcation between two different states, whose dynamical regime is modulated by synaptic strengths, thus suggesting that transition from a state to an another can be determined by quantitative differences between potentiation and depression.

  6. Synaptic plasticity modulates autonomous transitions between waking and sleep states: Insights from a Morris-Lecar model

    NASA Astrophysics Data System (ADS)

    Ciszak, Marzena; Bellesi, Michele

    2011-12-01

    The transitions between waking and sleep states are characterized by considerable changes in neuronal firing. During waking, neurons fire tonically at irregular intervals and a desynchronized activity is observed at the electroencephalogram. This activity becomes synchronized with slow wave sleep onset when neurons start to oscillate between periods of firing (up-states) and periods of silence (down-states). Recently, it has been proposed that the connections between neurons undergo potentiation during waking, whereas they weaken during slow wave sleep. Here, we propose a dynamical model to describe basic features of the autonomous transitions between such states. We consider a network of coupled neurons in which the strength of the interactions is modulated by synaptic long term potentiation and depression, according to the spike time-dependent plasticity rule (STDP). The model shows that the enhancement of synaptic strength between neurons occurring in waking increases the propensity of the network to synchronize and, conversely, desynchronization appears when the strength of the connections become weaker. Both transitions appear spontaneously, but the transition from sleep to waking required a slight modification of the STDP rule with the introduction of a mechanism which becomes active during sleep and changes the proportion between potentiation and depression in accordance with biological data. At the neuron level, transitions from desynchronization to synchronization and vice versa can be described as a bifurcation between two different states, whose dynamical regime is modulated by synaptic strengths, thus suggesting that transition from a state to an another can be determined by quantitative differences between potentiation and depression.

  7. Provision of recreational activities in hospices in the United States.

    PubMed

    DeMong, S A

    1997-01-01

    Quality of life issues encompass the philosophies of both hospice and recreation participation. This study examines the status of recreational activities provision in hospices in the United States. The offering, frequency of offering, and location of offering of 39 recreational activities in a random sample of hospices in the United States were surveyed. The functional levels of participating patients were also recorded. Reading to patients at bedside daily was determined to be the most frequently provided recreational activity. Recreational activities are being offered in 40% of the larger U.S. hospices on a varying schedule in different locations. PMID:9305025

  8. Are Auditory Hallucinations Related to the Brain's Resting State Activity? A 'Neurophenomenal Resting State Hypothesis'

    PubMed Central

    2014-01-01

    While several hypotheses about the neural mechanisms underlying auditory verbal hallucinations (AVH) have been suggested, the exact role of the recently highlighted intrinsic resting state activity of the brain remains unclear. Based on recent findings, we therefore developed what we call the 'resting state hypotheses' of AVH. Our hypothesis suggest that AVH may be traced back to abnormally elevated resting state activity in auditory cortex itself, abnormal modulation of the auditory cortex by anterior cortical midline regions as part of the default-mode network, and neural confusion between auditory cortical resting state changes and stimulus-induced activity. We discuss evidence in favour of our 'resting state hypothesis' and show its correspondence with phenomenal, i.e., subjective-experiential features as explored in phenomenological accounts. Therefore I speak of a 'neurophenomenal resting state hypothesis' of auditory hallucinations in schizophrenia. PMID:25598821

  9. Mechanistic insight into the hydrazine decomposition on Rh(111): effect of reaction intermediate on catalytic activity.

    PubMed

    Deng, Zhigang; Lu, Xiaoqing; Wen, Zengqiang; Wei, Shuxian; Liu, Yunjie; Fu, Dianling; Zhao, Lianming; Guo, Wenyue

    2013-10-14

    Periodic density functional theory (DFT) calculations have been performed to systematically investigate the effect of reaction intermediate on catalytic activity for hydrazine (N2H4) decomposition on Rh(111). Reaction mechanisms via intramolecular and NH2-assisted N2H4 decompositions are comparatively analyzed, including adsorption configuration, reaction energy and barrier of elementary step, and reaction network. Our results show that the most favorable N2H4 decomposition pathway starts with the initial N-N bond scission to the NH2 intermediate, followed by stepwise H stripping from adsorbed N2Hx (x = 1-4) species, and finally forms the N2 and NH3 products. Comparatively, the stepwise intramolecular dehydrogenation via N2H4→ N2H3→ N2H2→ N2H → N2, and N2H4→ NH2→ NH → N with or without NH2 promotion effect, are unfavorable due to higher energy barriers encountered. Energy barrier analysis, reaction rate constants, and electronic structures are used to identify the crucial competitive route. The promotion effect of the NH2 intermediate is structurally reflected in the weakening of the N-H bond and strengthening of the N-N bond in N2Hx in the coadsorption system; it results intrinsically from the less structural deformation of the adsorbate, and weakening of the interaction between dehydrogenated fragment and departing H in transition state. Our results highlight the crucial effect of reaction intermediate on catalytic activity and provide a theoretical approach to analyze the effect. PMID:23990024

  10. Mechanistic insight into the hydrazine decomposition on Rh(111): effect of reaction intermediate on catalytic activity.

    PubMed

    Deng, Zhigang; Lu, Xiaoqing; Wen, Zengqiang; Wei, Shuxian; Liu, Yunjie; Fu, Dianling; Zhao, Lianming; Guo, Wenyue

    2013-10-14

    Periodic density functional theory (DFT) calculations have been performed to systematically investigate the effect of reaction intermediate on catalytic activity for hydrazine (N2H4) decomposition on Rh(111). Reaction mechanisms via intramolecular and NH2-assisted N2H4 decompositions are comparatively analyzed, including adsorption configuration, reaction energy and barrier of elementary step, and reaction network. Our results show that the most favorable N2H4 decomposition pathway starts with the initial N-N bond scission to the NH2 intermediate, followed by stepwise H stripping from adsorbed N2Hx (x = 1-4) species, and finally forms the N2 and NH3 products. Comparatively, the stepwise intramolecular dehydrogenation via N2H4→ N2H3→ N2H2→ N2H → N2, and N2H4→ NH2→ NH → N with or without NH2 promotion effect, are unfavorable due to higher energy barriers encountered. Energy barrier analysis, reaction rate constants, and electronic structures are used to identify the crucial competitive route. The promotion effect of the NH2 intermediate is structurally reflected in the weakening of the N-H bond and strengthening of the N-N bond in N2Hx in the coadsorption system; it results intrinsically from the less structural deformation of the adsorbate, and weakening of the interaction between dehydrogenated fragment and departing H in transition state. Our results highlight the crucial effect of reaction intermediate on catalytic activity and provide a theoretical approach to analyze the effect.

  11. Education Finance Legislative Activity and Trends at the State Level.

    ERIC Educational Resources Information Center

    Crampton, Faith E.

    1999-01-01

    Reviews 1997 school finance legislation, comparing legislative activity levels from 1994 to 1997. In 1997, 32 states passed legislation pertaining to capital-outlay funding, tax bases, and taxation for education funding. Half passed legislation for state aid, technology, special-purpose education, budgeting/fiscal management, and school personnel…

  12. 34 CFR 300.812 - Reservation for State activities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 2 2010-07-01 2010-07-01 false Reservation for State activities. 300.812 Section 300.812 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION ASSISTANCE TO STATES FOR THE EDUCATION...

  13. 34 CFR 300.812 - Reservation for State activities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 2 2014-07-01 2013-07-01 true Reservation for State activities. 300.812 Section 300.812 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION ASSISTANCE TO STATES FOR THE EDUCATION...

  14. 34 CFR 300.812 - Reservation for State activities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 2 2011-07-01 2010-07-01 true Reservation for State activities. 300.812 Section 300.812 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION ASSISTANCE TO STATES FOR THE EDUCATION...

  15. 34 CFR 300.812 - Reservation for State activities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 2 2013-07-01 2013-07-01 false Reservation for State activities. 300.812 Section 300.812 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION ASSISTANCE TO STATES FOR THE EDUCATION...

  16. Monitoring Affect States during Effortful Problem Solving Activities

    ERIC Educational Resources Information Center

    D'Mello, Sidney K.; Lehman, Blair; Person, Natalie

    2010-01-01

    We explored the affective states that students experienced during effortful problem solving activities. We conducted a study where 41 students solved difficult analytical reasoning problems from the Law School Admission Test. Students viewed videos of their faces and screen captures and judged their emotions from a set of 14 states (basic…

  17. Ethanol Electro-Oxidation on Ternary Platinum–Rhodium–Tin Nanocatalysts: Insights in the Atomic 3D Structure of the Active Catalytic Phase

    SciTech Connect

    Erini, Nina; Loukrakpam, Rameshwori; Petkov, Valeri; Baranova, Elena A.; Yang, Ruizhi; Teschner, Detre; Huang, Yunhui; Brankovic, Stanko R.; Strasser, Peter

    2014-04-25

    Novel insights in the synthesis–structure–catalytic activity relationships of nanostructured trimetallic Pt–Rh–Sn electrocatalysts for the electrocatalytic oxidation of ethanol are reported. In particular, we identify a novel single-phase Rh-doped Pt–Sn Niggliite mineral phase as the source of catalytically active sites for ethanol oxidation; we discuss its morphology, composition, chemical surface state, and the detailed 3D atomic arrangement using high-energy (HE-XRD), atomic pair distribution function (PDF) analysis, and X-ray photoelectron spectroscopy (XPS). The intrinsic ethanol oxidation activity of the active Niggliite phase exceeded those of earlier reports, lending support to the notion that the atomic-scale neighborhood of Pt, Rh, and Sn is conducive to the emergence of active surface catalytic sites under reaction conditions. In situ mechanistic Fourier transform infrared (in situ FTIR) analysis confirms an active 12 electron oxidation reaction channel to CO2 at electrode potentials as low as 450 mV/RHE, demonstrating the favorable efficiency of the PtRhSn Niggliite phase for C–C bond splitting.

  18. Proofs that Develop Insight

    ERIC Educational Resources Information Center

    Weber, Keith

    2010-01-01

    Many mathematics educators have noted that mathematicians do not only read proofs to gain conviction but also to obtain insight. The goal of this article is to discuss what this insight is from mathematicians' perspective. Based on interviews with nine research-active mathematicians, two sources of insight are discussed. The first is reading a…

  19. Heterogeneity of dopamine neuron activity across traits and states

    PubMed Central

    Marinelli, Michela; McCutcheon, James E.

    2014-01-01

    Midbrain dopamine neurons fire irregularly, with interspersed clusters of high-frequency spikes, commonly called ‘bursts’. In this review we examine such heterogeneity in activity, and provide insight into how it can participate in psychiatric conditions such as drug addiction. We first describe several techniques used to evaluate dopamine neuron activity, and comment on the different measures that each provides. We next describe the activity of dopamine neurons in ‘basal’ conditions. Specifically, we discuss how the use of anesthesia and reduced preparations may alter aspects of dopamine cell activity, and how there is heterogeneity across species and regions. We also describe how dopamine cell firing changes throughout the peri-adolescent period and how dopamine neuron activity differs across the population. In the final section, we discuss how dopamine neuron activity changes in response to life events. First, we focus attention on drugs of abuse. Drugs themselves change firing activity through a variety of mechanisms, with effects on firing while drug is present differing from those seen after drug discontinuation. We then review how stimuli that are rewarding, aversive, or salient can evoke changes in firing rate and discharge pattern of dopamine neurons, and provide behavioral relevance of dopamine signaling. Finally, we discuss how stress can modulate dopamine neuron firing and how this may contribute to the role that stressful experiences play in psychiatric disorders such as addiction and depression. PMID:25084048

  20. Aircraft: United States Air Force Child Care Program Activity Guide.

    ERIC Educational Resources Information Center

    Boggs, Juanita; Brant, Linda

    General information about United States' aircraft is provided in this program activity guide for teachers and caregivers in Air Force preschools and day care centers. The guide includes basic information for teachers and caregivers, basic understandings, suggested teaching methods and group activities, vocabulary, ideas for interest centers, and…

  1. The Very Young and Education: 1974 State Activity.

    ERIC Educational Resources Information Center

    Hayas, Denise Kale; Ross, Doris M.

    This booklet contains more than 100 brief descriptions of early childhood projects, activities, studies, and legislation obtained from newsletters, bulletins, and the Education Commission of the States' (ECS) 1974 Annual Survey. Only legislation and activities that have been validated or newly reported are included. Bills which failed or were…

  2. Improving Administrative Activities of State Vocational Education Agencies.

    ERIC Educational Resources Information Center

    Koble, Daniel E., Jr., Ed.; Coker, Robert U., Ed.

    The 1973 seminar focused on improving administrative activities of State vocational education agencies, and emphasis was given to the processes and innovative concepts related to the maintenance and improvement of administrative activities. Guidelines and position papers were presented in the following areas: (1) The Role of Vocational Education…

  3. Hydroxylation of p-substituted phenols by tyrosinase: Further insight into the mechanism of tyrosinase activity

    SciTech Connect

    Munoz-Munoz, Jose Luis; Berna, Jose; Garcia-Molina, Maria del Mar; Garcia-Molina, Francisco; Garcia-Ruiz, Pedro Antonio; Varon, Ramon [Departamento de Quimica-Fisica, Escuela de Ingenieros Industriales de Albacete, Universidad de Castilla la Mancha, Avda. Espana s and others

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer The action the copper complexes and tyrosinase on phenols is equivalent. Black-Right-Pointing-Pointer Isotope effect showed that nucleophilic attack to copper atom may be the slower step. Black-Right-Pointing-Pointer The value of {rho} (Hammett constant) supports an electrophilic aromatic substitution. Black-Right-Pointing-Pointer Data obtained in steady state pH 7 conditions support the mechanism of Scheme 1SM. -- Abstract: A study of the monophenolase activity of tyrosinase by measuring the steady state rate with a group of p-substituted monophenols provides the following kinetic information: k{sub cat}{sup m} and the Michaelis constant, K{sub M}{sup m}. Analysis of these data taking into account chemical shifts of the carbon atom supporting the hydroxyl group ({delta}) and {sigma}{sub p}{sup +}, enables a mechanism to be proposed for the transformation of monophenols into o-diphenols, in which the first step is a nucleophilic attack on the copper atom on the form E{sub ox} (attack of the oxygen of the hydroxyl group of C-1 on the copper atom) followed by an electrophilic attack (attack of the hydroperoxide group on the ortho position with respect to the hydroxyl group of the benzene ring, electrophilic aromatic substitution with a reaction constant {rho} of -1.75). These steps show the same dependency on the electronic effect of the substituent groups in C-4. Furthermore, a study of a solvent deuterium isotope effect on the oxidation of monophenols by tyrosinase points to an appreciable isotopic effect. In a proton inventory study with a series of p-substituted phenols, the representation of k{sub cat}{sup f{sub n}}/k{sub cat}{sup f{sub 0}} against n (atom fractions of deuterium), where k{sub cat}{sup f{sub n}} is the catalytic constant for a molar fraction of deuterium (n) and k{sub cat}{sup f{sub 0}} is the corresponding kinetic parameter in a water solution, was linear for all substrates. These results indicate that

  4. On the way of classifying new states of active matter

    NASA Astrophysics Data System (ADS)

    Menzel, Andreas M.

    2016-07-01

    With ongoing research into the collective behavior of self-propelled particles, new states of active matter are revealed. Some of them are entirely based on the non-equilibrium character and do not have an immediate equilibrium counterpart. In their recent work, Romanczuk et al (2016 New J. Phys. 18 063015) concentrate on the characterization of smectic-like states of active matter. A new type, referred to by the authors as smectic P, is described. In this state, the active particles form stacked layers and self-propel along them. Identifying and classifying states and phases of non-equilibrium matter, including the transitions between them, is an up-to-date effort that will certainly extend for a longer period into the future.

  5. Mild activation of CeO2-supported gold nanoclusters and insight into the catalytic behavior in CO oxidation.

    PubMed

    Li, Weili; Ge, Qingjie; Ma, Xiangang; Chen, Yuxiang; Zhu, Manzhou; Xu, Hengyong; Jin, Rongchao

    2016-01-28

    We report a new activation method and insight into the catalytic behavior of a CeO2-supported, atomically precise Au144(SR)60 nanocluster catalyst (where thiolate -SR = -SCH2CH2Ph) for CO oxidation. An important finding is that the activation of the catalyst is closely related to the production of active oxygen species on CeO2, rather than ligand removal of the Au144(SR)60 clusters. A mild O2 pretreatment (at 80 °C) can activate the catalyst, and the addition of reductive gases (CO or H2) can enhance the activation effects of O2 pretreatment via a redox cycle in which CO could reduce the surface of CeO2 to produce oxygen vacancies-which then adsorb and activate O2 to produce more active oxygen species. The CO/O2 pulse experiments confirm that CO is adsorbed on the cluster catalyst even with ligands on, and active oxygen species present on the surface of the pretreated catalyst reacts with CO pulses to generate CO2. The Au144(SR)60/CeO2 exhibits high CO oxidation activity at 80 °C without the removal of thiolate ligands. The surface lattice-oxygen of the support CeO2 possibly participates in the oxidation of CO over the Au144(SR)60/CeO2 catalyst.

  6. Mild activation of CeO2-supported gold nanoclusters and insight into the catalytic behavior in CO oxidation.

    PubMed

    Li, Weili; Ge, Qingjie; Ma, Xiangang; Chen, Yuxiang; Zhu, Manzhou; Xu, Hengyong; Jin, Rongchao

    2016-01-28

    We report a new activation method and insight into the catalytic behavior of a CeO2-supported, atomically precise Au144(SR)60 nanocluster catalyst (where thiolate -SR = -SCH2CH2Ph) for CO oxidation. An important finding is that the activation of the catalyst is closely related to the production of active oxygen species on CeO2, rather than ligand removal of the Au144(SR)60 clusters. A mild O2 pretreatment (at 80 °C) can activate the catalyst, and the addition of reductive gases (CO or H2) can enhance the activation effects of O2 pretreatment via a redox cycle in which CO could reduce the surface of CeO2 to produce oxygen vacancies-which then adsorb and activate O2 to produce more active oxygen species. The CO/O2 pulse experiments confirm that CO is adsorbed on the cluster catalyst even with ligands on, and active oxygen species present on the surface of the pretreated catalyst reacts with CO pulses to generate CO2. The Au144(SR)60/CeO2 exhibits high CO oxidation activity at 80 °C without the removal of thiolate ligands. The surface lattice-oxygen of the support CeO2 possibly participates in the oxidation of CO over the Au144(SR)60/CeO2 catalyst. PMID:26750474

  7. Biomarker insights into microbial activity in the serpentinite-hosted ecosystem of the Semail Ophiolite, Oman

    NASA Astrophysics Data System (ADS)

    Newman, S. A.; Lincoln, S. A.; Shock, E.; Kelemen, P. B.; Summons, R. E.

    2012-12-01

    Serpentinization is a process in which ultramafic and mafic rocks undergo exothermic reactions when exposed to water. The products of these reactions, including methane, hydrogen, and hydrogen sulfide, can sustain microbially dominated ecosystems [1,2,3]. Here, we report the lipid biomarker record of microbial activity in carbonate veins of the Semail Ophiolite, a site currently undergoing serpentinization [4]. The ophiolite, located in the Oman Mountains in the Sultanate of Oman, was obducted onto the Arabian continental margin during the closure of the southern Tethys Ocean (~70 Ma) [5]. We detected bacterial and archaeal glycerol dialkyl glycerol tetraether (GDGT) lipids in Semail carbonates. In addition to archaeal isoprenoidal GDGTs with 0-3 cyclopentane moieties, we detected crenarchaeol, an iGDGT containing 4 cyclopentane and 1 cyclohexane moiety. Crenarchaeol biosynthesis is currently understood to be limited to thaumarchaea, representatives of which have been found to fix inorganic carbon in culture. We also analyzed isoprenoidal diether lipids, potentially derived from methanogenic euryarchaea, as well as non-isoprenoidal diether and monoether lipids that may be indicative of methane cycling bacteria. The stable carbon isotopic composition of these compounds is potentially useful in determining both their origin and the origin of methane detected in ophiolite fluids. We compare our results to those found at the Lost City Hydrothermal Field, a similar microbially-dominated ecosystem fueled by serpentinization processes [3]. Modern serpentinite-hosted ecosystems such as this can serve as analogs for environments in which ultramafic and mafic rocks were prevalent (e.g. early Earth and other early terrestrial planets). Additionally, an analysis of modern serpentinite systems can help assess conditions promoting active carbon sequestration in ultramafic rocks [6]. References [1] Russell et al. (2010). Geobiology 8: 355-371. [2] Kelley et al. (2005). Science

  8. Insights into the Interferon Regulatory Factor Activation from the Crystal Structure of Dimeric IRF5

    SciTech Connect

    Chen, W.; Lam, S; Srinath, H; Jiang, Z; Correia, J; Schiffer, C; Fitzgerald, K; Lin, K; Royer, Jr., W

    2008-01-01

    The interferon regulatory factors (IRFs) are involved in the innate immune response and are activated by phosphorylation. The structure of a pseudophosphorylated IRF5 activation domain now reveals structural changes in the activated form that would turn an autoinhibitory region into a dimerization interface. In vivo analysis supports the relevance of such a dimer to transcriptional activation.

  9. Pressure is not a state function for generic active fluids

    NASA Astrophysics Data System (ADS)

    Solon, A. P.; Fily, Y.; Baskaran, A.; Cates, M. E.; Kafri, Y.; Kardar, M.; Tailleur, J.

    2015-08-01

    Pressure is the mechanical force per unit area that a confined system exerts on its container. In thermal equilibrium, it depends only on bulk properties--such as density and temperature--through an equation of state. Here we show that in a wide class of active systems the pressure depends on the precise interactions between the active particles and the confining walls. In general, therefore, active fluids have no equation of state. Their mechanical pressure exhibits anomalous properties that defy the familiar thermodynamic reasoning that holds in equilibrium. The pressure remains a function of state, however, in some specific and well-studied active models that tacitly restrict the character of the particle-wall and/or particle-particle interactions.

  10. Mechanistic insight into size-dependent activity and durability in Pt/CNT catalyzed hydrolytic dehydrogenation of ammonia borane.

    PubMed

    Chen, Wenyao; Ji, Jian; Feng, Xiang; Duan, Xuezhi; Qian, Gang; Li, Ping; Zhou, Xinggui; Chen, De; Yuan, Weikang

    2014-12-01

    We report a size-dependent activity in Pt/CNT catalyzed hydrolytic dehydrogenation of ammonia borane. Kinetic study and model calculations revealed that Pt(111) facet is the dominating catalytically active surface. There is an optimized Pt particle size of ca. 1.8 nm. Meanwhile, the catalyst durability was found to be highly sensitive to the Pt particle size. The smaller Pt particles appear to have lower durability, which could be related to more significant adsorption of B-containing species on Pt surfaces as well as easier changes in Pt particle size and shape. The insights reported here may pave the way for the rational design of highly active and durable Pt catalysts for hydrogen generation. PMID:25405630

  11. State Activities and Programs for the Homeless: A Review of Six States.

    ERIC Educational Resources Information Center

    Burt, Martha R.; Cohen, Barbara

    This report describes the activities and policies for the homeless of six states both before and after implementation of the Federal Stewart B. McKinney Homeless Assistance Act of 1987. The states covered are California, Connecticut, Georgia, New Mexico, Ohio, and Wisconsin. The following chapters are included: (1) "Introduction"; (2) "State…

  12. Translation-rotation states of H2 in C60: New insights from a perturbation-theory treatment.

    PubMed

    Felker, Peter M; Bačić, Zlatko

    2016-08-28

    We report an investigation of the translation-rotation (TR) level structure of H2 entrapped in C60, in the rigid-monomer approximation, by means of a low-order perturbation theory (PT). We focus in particular on the degree to which PT can accurately account for that level structure, by comparison with the variational quantum five-dimensional calculations. To apply PT to the system, the interaction potential of H2@C60 is decomposed into a sum over bipolar spherical tensors. A zeroth-order Hamiltonian, Hˆ0, is then constructed as the sum of the TR kinetic-energy operator and the one term in the tensor decomposition of the potential that depends solely on the radial displacement of the H2 center of mass (c.m.) from the cage center. The remaining terms in the potential are treated as perturbations. The eigenstates of Hˆ0, constructed to also account for the coupling of the angular momentum of the H2 c.m. about the cage center with the rotational angular momentum of the H2 about the c.m., are taken as the PT zeroth-order states. This zeroth-order level structure is shown to be an excellent approximation to the true one except for two types of TR-level splittings present in the latter. We then show that first-order PT accounts very well for these splittings, with respect to both their patterns and magnitudes. This allows one to connect specific features of the level structure with specific features of the potential-energy surface, and provides important new physical insight into the characteristics of the TR level structure. PMID:27586925

  13. Translation-rotation states of H2 in C60: New insights from a perturbation-theory treatment

    NASA Astrophysics Data System (ADS)

    Felker, Peter M.; Bačić, Zlatko

    2016-08-01

    We report an investigation of the translation-rotation (TR) level structure of H2 entrapped in C60, in the rigid-monomer approximation, by means of a low-order perturbation theory (PT). We focus in particular on the degree to which PT can accurately account for that level structure, by comparison with the variational quantum five-dimensional calculations. To apply PT to the system, the interaction potential of H2@C60 is decomposed into a sum over bipolar spherical tensors. A zeroth-order Hamiltonian, Hˆ 0, is then constructed as the sum of the TR kinetic-energy operator and the one term in the tensor decomposition of the potential that depends solely on the radial displacement of the H2 center of mass (c.m.) from the cage center. The remaining terms in the potential are treated as perturbations. The eigenstates of Hˆ 0, constructed to also account for the coupling of the angular momentum of the H2 c.m. about the cage center with the rotational angular momentum of the H2 about the c.m., are taken as the PT zeroth-order states. This zeroth-order level structure is shown to be an excellent approximation to the true one except for two types of TR-level splittings present in the latter. We then show that first-order PT accounts very well for these splittings, with respect to both their patterns and magnitudes. This allows one to connect specific features of the level structure with specific features of the potential-energy surface, and provides important new physical insight into the characteristics of the TR level structure.

  14. Using community insight to understand physical activity adoption in overweight and obese African American and Hispanic women: a qualitative study.

    PubMed

    Mama, Scherezade K; McCurdy, Sheryl A; Evans, Alexandra E; Thompson, Deborah I; Diamond, Pamela M; Lee, Rebecca E

    2015-06-01

    Ecologic models suggest that multiple levels of influencing factors are important for determining physical activity participation and include individual, social, and environmental factors. The purpose of this qualitative study was to use an ecologic framework to gain a deeper understanding of the underlying behavioral mechanisms that influence physical activity adoption among ethnic minority women. Eighteen African American and Hispanic women completed a 1-hour in-depth interview. Verbatim interview transcripts were analyzed for emergent themes using a constant comparison approach. Women were middle-aged (age M = 43.9 ± 7.3 years), obese (body mass index M = 35.0 ± 8.9 kg/m(2)), and of high socioeconomic status (88.9% completed some college or more, 41.2% reported income >$82,600/year). Participants discussed individual factors, including the need for confidence, motivation and time, and emphasized the importance of environmental factors, including their physical neighborhood environments and safety of and accessibility to physical activity resources. Women talked about caretaking for others and social support and how these influenced physical activity behavior. The findings from this study highlight the multilevel, interactive complexities that influence physical activity, emphasizing the need for a more sophisticated, ecologic approach for increasing physical activity adoption and maintenance among ethnic minority women. Community insight gleaned from this study may be used to better understand determinants of physical activity and develop multilevel solutions and programs guided by an ecologic framework to increase physical activity in ethnic minority women. PMID:25504569

  15. Using community insight to understand physical activity adoption in overweight and obese African American and Hispanic women: a qualitative study.

    PubMed

    Mama, Scherezade K; McCurdy, Sheryl A; Evans, Alexandra E; Thompson, Deborah I; Diamond, Pamela M; Lee, Rebecca E

    2015-06-01

    Ecologic models suggest that multiple levels of influencing factors are important for determining physical activity participation and include individual, social, and environmental factors. The purpose of this qualitative study was to use an ecologic framework to gain a deeper understanding of the underlying behavioral mechanisms that influence physical activity adoption among ethnic minority women. Eighteen African American and Hispanic women completed a 1-hour in-depth interview. Verbatim interview transcripts were analyzed for emergent themes using a constant comparison approach. Women were middle-aged (age M = 43.9 ± 7.3 years), obese (body mass index M = 35.0 ± 8.9 kg/m(2)), and of high socioeconomic status (88.9% completed some college or more, 41.2% reported income >$82,600/year). Participants discussed individual factors, including the need for confidence, motivation and time, and emphasized the importance of environmental factors, including their physical neighborhood environments and safety of and accessibility to physical activity resources. Women talked about caretaking for others and social support and how these influenced physical activity behavior. The findings from this study highlight the multilevel, interactive complexities that influence physical activity, emphasizing the need for a more sophisticated, ecologic approach for increasing physical activity adoption and maintenance among ethnic minority women. Community insight gleaned from this study may be used to better understand determinants of physical activity and develop multilevel solutions and programs guided by an ecologic framework to increase physical activity in ethnic minority women.

  16. Affordability and Student Success: Recapping 2014 Higher Education Legislative Activity in the West. Policy Insights

    ERIC Educational Resources Information Center

    Krueger, Carl

    2014-01-01

    After reaching a low point in 2012, state investment in higher education increased for the second year in a row in 2014--something that had not happened since the Great Recession of 2008 began. With greater stability in some, though certainly not all, state budgets, many Western legislatures in 2014 looked for new ways to contain college costs for…

  17. State Legislation Related to Increasing Physical Activity: 2006-2012

    PubMed Central

    Eyler, Amy A.; Budd, Elizabeth; Camberos, Gabriela J.; Yan, Yan; Brownson, Ross C.

    2016-01-01

    Background Strategies to improve physical activity prevalence often include policy and environmental changes. State-level policies can be influential in supporting access and opportunities for physical activity in schools and communities. The purpose of this study was to explore the prevalence of state legislation related to physical activity and identify the correlates of enactment of this legislation. Methods An online legislative database was used to collect bills from 50 states in the U.S. from 2006-2012 for ten topics related to physical activity. Bills were coded for content and compiled into a database with state-level variables (e.g., obesity prevalence). With enactment status as the outcome, bivariate and multivariate analyses were conducted. Results Of the 1542 bills related to physical activity introduced, 30% (N=460) were enacted. Bills on public transportation and trails were more likely to be enacted than those without these topics. Primary sponsorship by the Republican Party, bipartisan sponsorship, and mention of specific funding amounts were also correlates of enactment. Conclusion Policy surveillance of bills and correlates of enactment are important for understanding patterns in legislative support for physical activity. This information can be used to prioritize advocacy efforts and identify ways for research to better inform policy. PMID:26104603

  18. NMR structures and interactions of temporin-1Tl and temporin-1Tb with lipopolysaccharide micelles: mechanistic insights into outer membrane permeabilization and synergistic activity.

    PubMed

    Bhunia, Anirban; Saravanan, Rathi; Mohanram, Harini; Mangoni, Maria L; Bhattacharjya, Surajit

    2011-07-01

    Temporins are a group of closely related short antimicrobial peptides from frog skin. Lipopolysaccharide (LPS), the major constituent of the outer membrane of gram-negative bacteria, plays important roles in the activity of temporins. Earlier studies have found that LPS induces oligomerization of temporin-1Tb (TB) thus preventing its translocation across the outer membrane and, as a result, reduces its activity on gram-negative bacteria. On the other hand, temporin-1Tl (TL) exhibits higher activity, presumably because of lack of such oligomerization. A synergistic mechanism was proposed, involving TL and TB in overcoming the LPS-mediated barrier. Here, to gain insights into interactions of TL and TB within LPS, we investigated the structures and interactions of TL, TB, and TL+TB in LPS micelles, using NMR and fluorescence spectroscopy. In the context of LPS, TL assumes a novel antiparallel dimeric helical structure sustained by intimate packing between aromatic-aromatic and aromatic-aliphatic residues. By contrast, independent TB has populations of helical and aggregated conformations in LPS. The LPS-induced aggregated states of TB are largely destabilized in the presence of TL. Saturation transfer difference NMR studies have delineated residues of TL and TB in close contact with LPS and enhanced interactions of these two peptides with LPS, when combined together. Fluorescence resonance energy transfer and (31)P NMR have pointed out the proximity of TL and TB in LPS and conformational changes of LPS, respectively. Importantly, these results provide the first structural insights into the mode of action and synergism of antimicrobial peptides at the level of the LPS-outer membrane. PMID:21586570

  19. Physical activity promotion: a local and state health department perspective.

    PubMed

    Simon, Paul; Gonzalez, Eloisa; Ginsburg, David; Abrams, Jennifer; Fielding, Jonathan

    2009-10-01

    Local and state health departments are well-positioned to serve as catalysts for the institutional and community changes needed to increase physical activity across the population. Efforts should focus on evidence-based strategies, including promotion of high-quality physical education in schools, social support networks and structured programs for physical activity in communities, and organizational practices, policies, and programs that promote physical activity in the workplace. Health departments must also focus on land use and transportation practices and policies in communities where the built environment creates major impediments to physical activity, particularly in economically disadvantaged communities disproportionately burdened by chronic disease. PMID:19540872

  20. Pressure-induced activity loss in solid state catalase.

    PubMed

    Wurster, D E; Ternik, R L

    1995-02-01

    The pressure-induced reductions in the activities of a number of enzymes in the solution state, and more recently in the solid state, have been reported. To further investigate the effect of pressure on proteins in the solid state, the enzyme catalase was used as a model. Compacts containing 150.0 +/- 0.2 mg of catalase powder were prepared on instrumented laboratory presses using various compaction pressures between 0 and 669 MPa. After compaction, a spectrophotometric assay was utilized to determine the pseudo-first-order rate constants for the catalase-catalyzed decomposition of hydrogen peroxide. These rate constants were used to calculate the change in catalase activity. Results indicated a loss in catalase activity of up to 30% at compaction pressures of 251 MPa or greater. While the mechanism which produces the loss of enzyme activity is not clear, a strong linear correlation between enzyme activity and compaction pressure was seen over the range of pressures (0-251 MPa) where the decrease in activity occurred. In addition, compact densities were calculated and correlated to enzyme activity values. This correlation did not appear to be as strong. PMID:7738799

  1. New Insights into Active Site Conformation Dynamics of E. coli PNP Revealed by Combined H/D Exchange Approach and Molecular Dynamics Simulations

    NASA Astrophysics Data System (ADS)

    Kazazić, Saša; Bertoša, Branimir; Luić, Marija; Mikleušević, Goran; Tarnowski, Krzysztof; Dadlez, Michal; Narczyk, Marta; Bzowska, Agnieszka

    2016-01-01

    The biologically active form of purine nucleoside phosphorylase (PNP) from Escherichia coli (EC 2.4.2.1) is a homohexamer unit, assembled as a trimer of dimers. Upon binding of phosphate, neighboring monomers adopt different active site conformations, described as open and closed. To get insight into the functions of the two distinctive active site conformations, virtually inactive Arg24Ala mutant is complexed with phosphate; all active sites are found to be in the open conformation. To understand how the sites of neighboring monomers communicate with each other, we have combined H/D exchange (H/DX) experiments with molecular dynamics (MD) simulations. Both methods point to the mobility of the enzyme, associated with a few flexible regions situated at the surface and within the dimer interface. Although H/DX provides an average extent of deuterium uptake for all six hexamer active sites, it was able to indicate the dynamic mechanism of cross-talk between monomers, allostery. Using this technique, it was found that phosphate binding to the wild type (WT) causes arrest of the molecular motion in backbone fragments that are flexible in a ligand-free state. This was not the case for the Arg24Ala mutant. Upon nucleoside substrate/inhibitor binding, some release of the phosphate-induced arrest is observed for the WT, whereas the opposite effects occur for the Arg24Ala mutant. MD simulations confirmed that phosphate is bound tightly in the closed active sites of the WT; conversely, in the open conformation of the active site of the WT phosphate is bound loosely moving towards the exit of the active site. In Arg24Ala mutant binary complex Pi is bound loosely, too.

  2. Limits of state activity in the interstate water market

    SciTech Connect

    Rodgers, A.B.

    1986-01-01

    In an effort to ensure future water supplies, many western states are becoming participants in the market for water. As market participants, states gain a proprietary interest in their water resources which more effectively secures their right to the water than mere regulation or claims of ownership under the public trust doctrine. As the author points out, however, the constitution imposes numerous limitations on state water market activity. The privileges and immunities clause, the commerce clause, the property clause, as well as the equal protection clause of the fourteenth amendment, all influence the manner in which states may behave. Most significantly, the author explains, these clauses prevent states from using their power as water market participants as a disguise for economic protectionism.

  3. Insights into the activation mechanism of class I HDAC complexes by inositol phosphates

    PubMed Central

    Watson, Peter J.; Millard, Christopher J.; Riley, Andrew M.; Robertson, Naomi S.; Wright, Lyndsey C.; Godage, Himali Y.; Cowley, Shaun M.; Jamieson, Andrew G.; Potter, Barry V. L.; Schwabe, John W. R.

    2016-01-01

    Histone deacetylases (HDACs) 1, 2 and 3 form the catalytic subunit of several large transcriptional repression complexes. Unexpectedly, the enzymatic activity of HDACs in these complexes has been shown to be regulated by inositol phosphates, which bind in a pocket sandwiched between the HDAC and co-repressor proteins. However, the actual mechanism of activation remains poorly understood. Here we have elucidated the stereochemical requirements for binding and activation by inositol phosphates, demonstrating that activation requires three adjacent phosphate groups and that other positions on the inositol ring can tolerate bulky substituents. We also demonstrate that there is allosteric communication between the inositol-binding site and the active site. The crystal structure of the HDAC1:MTA1 complex bound to a novel peptide-based inhibitor and to inositol hexaphosphate suggests a molecular basis of substrate recognition, and an entropically driven allosteric mechanism of activation. PMID:27109927

  4. A new insight into the nature of seasonal variations in coordinate time series of GPS sites located near active faults

    NASA Astrophysics Data System (ADS)

    Trofimenko, Sergey V.; Bykov, Victor G.; Shestakov, Nikolay V.; Grib, Nikolay N.; Takahashi, Hiroaki

    2016-09-01

    This study provides new insights into the nature of seasonal variations in coordinate time series of GPS sites located near active faults and methods of their modeling. Monthly averaged coordinate time series were analyzed for several pairs of collocated GPS sites situated near the active fault intersection area, in close proximity to the central part of the northern boundary of the Amurian plate and the vicinity of the San Andreas Fault zone. It is concluded that the observed seasonal variations are best described by a breather function which is one of the solutions of the well-known sine-Gordon equation. The obtained results suggest that, in this case, the source of seasonal variations may be caused by the appearance of solitary strain waves in the fault intersection system, which may be qualitatively treated as standing waves of compression-extension of the geological medium. Based on statistical testing, the limits of applicability of the suggested model have been established.

  5. Pathway activation profiling reveals new insights into age-related macular degeneration and provides avenues for therapeutic interventions.

    PubMed

    Makarev, Evgeny; Cantor, Charles; Zhavoronkov, Alex; Buzdin, Anton; Aliper, Alexander; Csoka, Anotonei Benjamin

    2014-12-01

    Age-related macular degeneration (AMD) is a major cause of blindness in older people and is caused by loss of the central region of the retinal pigment epithelium (RPE). Conventional methods of gene expression analysis have yielded important insights into AMD pathogenesis, but the precise molecular pathway alterations are still poorly understood. Therefore we developed a new software program, "AMD Medicine", and discovered differential pathway activation profiles in samples of human RPE/choroid from AMD patients and controls. We identified 29 pathways in RPE-choroid AMD phenotypes: 27 pathways were activated in AMD compared to controls, and 2 pathways were activated in controls compared to AMD. In AMD, we identified a graded activation of pathways related to wound response, complement cascade, and cell survival. Also, there was downregulation of two pathways responsible for apoptosis. Furthermore, significant activation of pro-mitotic pathways is consistent with dedifferentiation and cell proliferation events, which occur early in the pathogenesis of AMD. Significantly, we discovered new global pathway activation signatures of AMD involved in the cell-based inflammatory response: IL-2, STAT3, and ERK. The ultimate aim of our research is to achieve a better understanding of signaling pathways involved in AMD pathology, which will eventually lead to better treatments. PMID:25543336

  6. Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity.

    PubMed

    Ahmed, Afsar U; Williams, Bryan R G; Hannigan, Gregory E

    2015-01-01

    Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro-inflammatory genes that carry out specific functions such as anti-microbial activity or tissue healing. Based on the nature of inflammatory stimuli, an extensive exploitation of selective transcriptional activations of pro-inflammatory genes is performed by the host to ensure a defined inflammatory response. Inflammatory signal transductions are initiated by the recognition of inflammatory stimuli by transmembrane receptors, followed by the transmission of the signals to the nucleus for differential gene activations. The differential transcriptional activation of pro-inflammatory genes is precisely controlled by the selective binding of transcription factors to the promoters of these genes. Among a number of transcription factors identified to date, NF-κB still remains the most prominent and studied factor for its diverse range of selective transcriptional activities. Differential transcriptional activities of NF-κB are dictated by post-translational modifications, specificities in dimer formation, and variability in activation kinetics. Apart from the differential functions of transcription factors, the transcriptional activation of selective pro-inflammatory genes is also governed by chromatin structures, epigenetic markers, and other regulators as the field is continuously expanding. PMID:26569329

  7. Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity.

    PubMed

    Ahmed, Afsar U; Williams, Bryan R G; Hannigan, Gregory E

    2015-11-11

    Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro-inflammatory genes that carry out specific functions such as anti-microbial activity or tissue healing. Based on the nature of inflammatory stimuli, an extensive exploitation of selective transcriptional activations of pro-inflammatory genes is performed by the host to ensure a defined inflammatory response. Inflammatory signal transductions are initiated by the recognition of inflammatory stimuli by transmembrane receptors, followed by the transmission of the signals to the nucleus for differential gene activations. The differential transcriptional activation of pro-inflammatory genes is precisely controlled by the selective binding of transcription factors to the promoters of these genes. Among a number of transcription factors identified to date, NF-κB still remains the most prominent and studied factor for its diverse range of selective transcriptional activities. Differential transcriptional activities of NF-κB are dictated by post-translational modifications, specificities in dimer formation, and variability in activation kinetics. Apart from the differential functions of transcription factors, the transcriptional activation of selective pro-inflammatory genes is also governed by chromatin structures, epigenetic markers, and other regulators as the field is continuously expanding.

  8. Mechanistic Insight into the Reactivation of BCAII Enzyme from Denatured and Molten Globule States by Eukaryotic Ribosomes and Domain V rRNAs

    PubMed Central

    Chakraborty, Biprashekhar; Bhakta, Sayan; Sengupta, Jayati

    2016-01-01

    In all life forms, decoding of messenger-RNA into polypeptide chain is accomplished by the ribosome. Several protein chaperones are known to bind at the exit of ribosomal tunnel to ensure proper folding of the nascent chain by inhibiting their premature folding in the densely crowded environment of the cell. However, accumulating evidence suggests that ribosome may play a chaperone role in protein folding events in vitro. Ribosome-mediated folding of denatured proteins by prokaryotic ribosomes has been studied extensively. The RNA-assisted chaperone activity of the prokaryotic ribosome has been attributed to the domain V, a span of 23S rRNA at the intersubunit side of the large subunit encompassing the Peptidyl Transferase Centre. Evidently, this functional property of ribosome is unrelated to the nascent chain protein folding at the exit of the ribosomal tunnel. Here, we seek to scrutinize whether this unique function is conserved in a primitive kinetoplastid group of eukaryotic species Leishmania donovani where the ribosome structure possesses distinct additional features and appears markedly different compared to other higher eukaryotic ribosomes. Bovine Carbonic Anhydrase II (BCAII) enzyme was considered as the model protein. Our results manifest that domain V of the large subunit rRNA of Leishmania ribosomes preserves chaperone activity suggesting that ribosome-mediated protein folding is, indeed, a conserved phenomenon. Further, we aimed to investigate the mechanism underpinning the ribosome-assisted protein reactivation process. Interestingly, the surface plasmon resonance binding analyses exhibit that rRNA guides productive folding by directly interacting with molten globule-like states of the protein. In contrast, native protein shows no notable affinity to the rRNA. Thus, our study not only confirms conserved, RNA-mediated chaperoning role of ribosome but also provides crucial insight into the mechanism of the process. PMID:27099964

  9. Mechanistic Insight into the Reactivation of BCAII Enzyme from Denatured and Molten Globule States by Eukaryotic Ribosomes and Domain V rRNAs.

    PubMed

    Chakraborty, Biprashekhar; Bhakta, Sayan; Sengupta, Jayati

    2016-01-01

    In all life forms, decoding of messenger-RNA into polypeptide chain is accomplished by the ribosome. Several protein chaperones are known to bind at the exit of ribosomal tunnel to ensure proper folding of the nascent chain by inhibiting their premature folding in the densely crowded environment of the cell. However, accumulating evidence suggests that ribosome may play a chaperone role in protein folding events in vitro. Ribosome-mediated folding of denatured proteins by prokaryotic ribosomes has been studied extensively. The RNA-assisted chaperone activity of the prokaryotic ribosome has been attributed to the domain V, a span of 23S rRNA at the intersubunit side of the large subunit encompassing the Peptidyl Transferase Centre. Evidently, this functional property of ribosome is unrelated to the nascent chain protein folding at the exit of the ribosomal tunnel. Here, we seek to scrutinize whether this unique function is conserved in a primitive kinetoplastid group of eukaryotic species Leishmania donovani where the ribosome structure possesses distinct additional features and appears markedly different compared to other higher eukaryotic ribosomes. Bovine Carbonic Anhydrase II (BCAII) enzyme was considered as the model protein. Our results manifest that domain V of the large subunit rRNA of Leishmania ribosomes preserves chaperone activity suggesting that ribosome-mediated protein folding is, indeed, a conserved phenomenon. Further, we aimed to investigate the mechanism underpinning the ribosome-assisted protein reactivation process. Interestingly, the surface plasmon resonance binding analyses exhibit that rRNA guides productive folding by directly interacting with molten globule-like states of the protein. In contrast, native protein shows no notable affinity to the rRNA. Thus, our study not only confirms conserved, RNA-mediated chaperoning role of ribosome but also provides crucial insight into the mechanism of the process. PMID:27099964

  10. Mechanistic Insight into the Reactivation of BCAII Enzyme from Denatured and Molten Globule States by Eukaryotic Ribosomes and Domain V rRNAs.

    PubMed

    Chakraborty, Biprashekhar; Bhakta, Sayan; Sengupta, Jayati

    2016-01-01

    In all life forms, decoding of messenger-RNA into polypeptide chain is accomplished by the ribosome. Several protein chaperones are known to bind at the exit of ribosomal tunnel to ensure proper folding of the nascent chain by inhibiting their premature folding in the densely crowded environment of the cell. However, accumulating evidence suggests that ribosome may play a chaperone role in protein folding events in vitro. Ribosome-mediated folding of denatured proteins by prokaryotic ribosomes has been studied extensively. The RNA-assisted chaperone activity of the prokaryotic ribosome has been attributed to the domain V, a span of 23S rRNA at the intersubunit side of the large subunit encompassing the Peptidyl Transferase Centre. Evidently, this functional property of ribosome is unrelated to the nascent chain protein folding at the exit of the ribosomal tunnel. Here, we seek to scrutinize whether this unique function is conserved in a primitive kinetoplastid group of eukaryotic species Leishmania donovani where the ribosome structure possesses distinct additional features and appears markedly different compared to other higher eukaryotic ribosomes. Bovine Carbonic Anhydrase II (BCAII) enzyme was considered as the model protein. Our results manifest that domain V of the large subunit rRNA of Leishmania ribosomes preserves chaperone activity suggesting that ribosome-mediated protein folding is, indeed, a conserved phenomenon. Further, we aimed to investigate the mechanism underpinning the ribosome-assisted protein reactivation process. Interestingly, the surface plasmon resonance binding analyses exhibit that rRNA guides productive folding by directly interacting with molten globule-like states of the protein. In contrast, native protein shows no notable affinity to the rRNA. Thus, our study not only confirms conserved, RNA-mediated chaperoning role of ribosome but also provides crucial insight into the mechanism of the process.

  11. Momentary Affective States Are Associated with Momentary Volume, Prospective Trends, and Fluctuation of Daily Physical Activity

    PubMed Central

    Kanning, Martina K.; Schoebi, Dominik

    2016-01-01

    Several interventions aiming to enhance physical activity in everyday life showed mixed effects. Affective constructs are thought to potentially support health behavior change. However, little is known about within-subject associations between momentary affect and subsequent physical activity in everyday life. This study analyzed the extent to which three dimensions of affective states (valence, calmness, and energetic arousal) were associated with different components of daily activity trajectories. Sixty-five undergraduates’ students (Age: M = 24.6; SD = 3.2; females: 57%) participated in this study. Physical activity was assessed objectively through accelerometers during 24 h. Affective states assessments were conducted randomly every 45 min using an e-diary with a six-item mood scale that was especially designed for ambulatory assessment. We conducted three-level multi-level analyses to investigate the extent to which momentary affect accounted for momentary volume, prospective trends, and stability vs. fluctuation of physical activity in everyday life. All three affect dimensions were significantly associated with momentary activity volumes and prospective trends over 45 min periods. Physical activity didn’t fluctuate freely, but featured significant autocorrelation across repeated measurements, suggesting some stability of physical activity across 5-min assessments. After adjusting for the autoregressive structure in physical activity assessments, only energetic arousal remained a significant predictor. Feeling energized and awake was associated with an increased momentary volume of activity and initially smaller but gradually growing decreases in subsequent activity within the subsequent 45 min. Although not related to trends in physical activity, higher valence predicted lower stability in physical activity across subsequent 45 min, suggesting more short-term fluctuations in daily activity the more participants reported positive affective valence. The

  12. Insights into antioxidant activity of 1-adamantylthiopyridine analogs using multiple linear regression.

    PubMed

    Worachartcheewan, Apilak; Nantasenamat, Chanin; Owasirikul, Wiwat; Monnor, Teerawat; Naruepantawart, Orapan; Janyapaisarn, Sayamon; Prachayasittikul, Supaluk; Prachayasittikul, Virapong

    2014-02-12

    A data set of 1-adamantylthiopyridine analogs (1-19) with antioxidant activity, comprising of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide dismutase (SOD) activities, was used for constructing quantitative structure-activity relationship (QSAR) models. Molecular structures were geometrically optimized at B3LYP/6-31g(d) level and subjected for further molecular descriptor calculation using Dragon software. Multiple linear regression (MLR) was employed for the development of QSAR models using 3 significant descriptors (i.e. Mor29e, F04[N-N] and GATS5v) for predicting the DPPH activity and 2 essential descriptors (i.e. EEig06r and Mor06v) for predicting the SOD activity. Such molecular descriptors accounted for the effects and positions of substituent groups (R) on the 1-adamantylthiopyridine ring. The results showed that high atomic electronegativity of polar substituent group (R = CO2H) afforded high DPPH activity, while substituent with high atomic van der Waals volumes such as R = Br gave high SOD activity. Leave-one-out cross-validation (LOO-CV) and external test set were used for model validation. Correlation coefficient (QCV) and root mean squared error (RMSECV) of the LOO-CV set for predicting DPPH activity were 0.5784 and 8.3440, respectively, while QExt and RMSEExt of external test set corresponded to 0.7353 and 4.2721, respectively. Furthermore, QCV and RMSECV values of the LOO-CV set for predicting SOD activity were 0.7549 and 5.6380, respectively. The QSAR model's equation was then used in predicting the SOD activity of tested compounds and these were subsequently verified experimentally. It was observed that the experimental activity was more potent than the predicted activity. Structure-activity relationships of significant descriptors governing antioxidant activity are also discussed. The QSAR models investigated herein are anticipated to be useful in the rational design and development of novel compounds with antioxidant activity. PMID

  13. Color variations during activity states of the binary V Sge

    NASA Astrophysics Data System (ADS)

    Šimon, V.; Shugarov, S.

    2001-12-01

    Color variations in V Sge during various states of its activity in the course of 1995-1997 show that B-V gets bluer while U-B does not change significantly. Comparison of our data with the outburst observed by Herbig et al. (1965) shows that although the character of the activity in V Sge changed during the last decades (Šimon and Mattei 1999) the colors and their variations remained similar. .

  14. Informal Face-to-Face Interaction Improves Mood State Reflected in Prefrontal Cortex Activity

    PubMed Central

    Watanabe, Jun-ichiro; Atsumori, Hirokazu; Kiguchi, Masashi

    2016-01-01

    Recent progress with wearable sensors has enabled researchers to capture face-to-face interactions quantitatively and given great insight into human dynamics. One attractive field for applying such sensors is the workplace, where the relationship between the face-to-face behaviors of employees and the productivity of the organization has been investigated. One interesting result of previous studies showed that informal face-to-face interaction among employees, captured by wearable sensors that the employees wore, significantly affects their performance. However, the mechanism behind this relationship has not yet been adequately explained, though experiences at the job scene might qualitatively support the finding. We hypothesized that informal face-to-face interaction improves mood state, which in turn affects the task performance. To test this hypothesis, we evaluated the change of mood state before and after break time for two groups of participants, one that spent their breaks alone and one that spent them with other participants, by administering questionnaires and taking brain activity measurements. Recent neuroimaging studies have suggested a significant relationship between mood state and brain activity. Here, we show that face-to-face interaction during breaks significantly improved mood state, which was measured by Profiles of Mood States (POMS). We also observed that the verbal working memory (WM) task performance of participants who did not have face-to-face interaction during breaks decreased significantly. In this paper, we discuss how the change of mood state was evidenced in the prefrontal cortex (PFC) activity accompanied by WM tasks measured by near-infrared spectroscopy (NIRS). PMID:27199715

  15. The Contribution of Extracurricular Activities to Adolescent Friendships: New Insights through Social Network Analysis

    ERIC Educational Resources Information Center

    Schaefer, David R.; Simpkins, Sandra D.; Vest, Andrea E.; Price, Chara D.

    2011-01-01

    Extracurricular activities are settings that are theorized to help adolescents maintain existing friendships and develop new friendships. The overarching goal of the current investigation was to examine whether coparticipating in school-based extracurricular activities supported adolescents' school-based friendships. We used social network methods…

  16. Insights for Exercise Adherence from a Minimal Planning Intervention to Increase Physical Activity

    ERIC Educational Resources Information Center

    Chapman, Janine; Campbell, Marianne; Wilson, Carlene

    2015-01-01

    Objective: To test the impact of a minimal, online planning intervention on physical activity in Australian office workers. Method: Employees were randomized to an implementation intention intervention (n = 124) or health information control group (n = 130). Measures of physical activity, past behavior, and motivation were taken at baseline and 6…

  17. Mild activation of CeO2-supported gold nanoclusters and insight into the catalytic behavior in CO oxidation

    NASA Astrophysics Data System (ADS)

    Li, Weili; Ge, Qingjie; Ma, Xiangang; Chen, Yuxiang; Zhu, Manzhou; Xu, Hengyong; Jin, Rongchao

    2016-01-01

    We report a new activation method and insight into the catalytic behavior of a CeO2-supported, atomically precise Au144(SR)60 nanocluster catalyst (where thiolate -SR = -SCH2CH2Ph) for CO oxidation. An important finding is that the activation of the catalyst is closely related to the production of active oxygen species on CeO2, rather than ligand removal of the Au144(SR)60 clusters. A mild O2 pretreatment (at 80 °C) can activate the catalyst, and the addition of reductive gases (CO or H2) can enhance the activation effects of O2 pretreatment via a redox cycle in which CO could reduce the surface of CeO2 to produce oxygen vacancies--which then adsorb and activate O2 to produce more active oxygen species. The CO/O2 pulse experiments confirm that CO is adsorbed on the cluster catalyst even with ligands on, and active oxygen species present on the surface of the pretreated catalyst reacts with CO pulses to generate CO2. The Au144(SR)60/CeO2 exhibits high CO oxidation activity at 80 °C without the removal of thiolate ligands. The surface lattice-oxygen of the support CeO2 possibly participates in the oxidation of CO over the Au144(SR)60/CeO2 catalyst.We report a new activation method and insight into the catalytic behavior of a CeO2-supported, atomically precise Au144(SR)60 nanocluster catalyst (where thiolate -SR = -SCH2CH2Ph) for CO oxidation. An important finding is that the activation of the catalyst is closely related to the production of active oxygen species on CeO2, rather than ligand removal of the Au144(SR)60 clusters. A mild O2 pretreatment (at 80 °C) can activate the catalyst, and the addition of reductive gases (CO or H2) can enhance the activation effects of O2 pretreatment via a redox cycle in which CO could reduce the surface of CeO2 to produce oxygen vacancies--which then adsorb and activate O2 to produce more active oxygen species. The CO/O2 pulse experiments confirm that CO is adsorbed on the cluster catalyst even with ligands on, and active oxygen

  18. Insights on the role of physical activity in patients with rheumatoid arthritis.

    PubMed

    Conigliaro, Paola; Triggianese, Paola; Ippolito, Francesco; Lucchetti, Ramona; Chimenti, Maria Sole; Perricone, Roberto

    2014-11-01

    Patients with rheumatoid arthritis (RA) are physically inactive, and trials have been undertaken to examine the effect of physical activity on pain, disease activity, functional ability and quality of life (QoL) in RA. The aim of this study was to explore the relationship between physical activity and disease-activity in RA and in healthy controls. Our findings showed that fewer RA patients had a professional occupation compared with controls, but patients and controls were similar with respect to the sedentary extent of their job. Physical exercise was inversely associated with disease activity (DAS-28), stiffness visual analog scale (VAS), patient global VAS and SF-36, but not associated with Health Assessment Questionnaire (HAQ), pain VAS, fatigue VAS, global health and the Arthritis Ipact Measurement Scale (AIMS), suggesting that pain and fatigue are important barriers to physical activity. Our findings suggest that this is more pronounced in RA patients who do not participate in regular physical activity, and so physical exercise should be recommended as part of comprehensive RA care.

  19. New insights into the antioxidant activity and components in crude oat oil and soybean oil.

    PubMed

    Chen, Hao; Qiu, Shuang; Gan, Jing; Li, Zaigui; Nirasawa, Satoru; Yin, Lijun

    2016-01-01

    Developing new antioxidants and using natural examples is of current interest. This study evaluated the antioxidant activities and the ability to inhibit soybean oil oxidation of oat oil obtained with different solvents. Oat oil extract obtained by ethanol extraction gave the highest antioxidant activity with a DPPH radical (1,1-diphenyl-2-picrylhydrazyl) scavenging activity of 88.2 % and a reducing power (A 700) of 0.83. Oat oil extracted by ethanol contained the highest polyphenol and α-tocopherol content. Significant correlation was observed between the total polyphenol contents, individual phenolic acid, α-tocopherol, and DPPH radical scavenging activity. Soybean oil with 2 % added oat oil showed low malondialdehyde content (8.35 mmol mL(-1)), suggesting that the added oat oil inhibited oxidation. Oat oil showed good antioxidant activity, especially when extracted with ethanol which could also retard the oxidation of soybean oil . DPPH radical scavenging activity was the best method to evaluate the antioxidant activity and components of oat oil.

  20. Insights into mechanism of glucokinase activation: observation of multiple distinct protein conformations.

    PubMed

    Liu, Shenping; Ammirati, Mark J; Song, Xi; Knafels, John D; Zhang, Jeff; Greasley, Samantha E; Pfefferkorn, Jeffrey A; Qiu, Xiayang

    2012-04-20

    Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and mutations that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKAs) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion, but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK-glucose complex in a wide open conformation. To assess conformations of GK in solution, we also carried out small angle x-ray scattering experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared with wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKAs with reduced hypoglycemic risk.

  1. Oscillations and multiple steady states in active membrane transport models.

    PubMed

    Vieira, F M; Bisch, P M

    1994-01-01

    The dynamic behavior of some non-linear extensions of the six-state alternating access model for active membrane transport is investigated. We use stoichio-metric network analysis to study the stability of steady states. The bifurcation analysis has been done through standard numerical methods. For the usual six-state model we have proved that there is only one steady state, which is globally asymptotically stable. When we added an autocatalytic step we found self-oscillations. For the competition between a monomer cycle and a dimer cycle, with steps of dimer formation, we have also found self-oscillations. We have also studied models involving the formation of a complex with other molecules. The addition of two steps for formation of a complex of the monomer with another molecule does not alter either the number or the stability of steady states of the basic six-state model. The model which combines the formation of a complex with an autocatalytic step shows both self-oscillations and multiple steady states. The results lead us to conclude that oscillations could be produced by active membrane transport systems if the transport cycle contains a sufficiently large number of steps (six in the present case) and is coupled to at least one autocatalytic reaction,. Oscillations are also predicted when the monomer cycle is coupled to a dimer cycle. In fact, the autocatalytic reaction can be seen as a simplification of the model involving competition between monomer and dimer cycles, which seems to be a more realistic description of biological systems. A self-regulation mechanism of the pumps, related to the multiple stationary states, is expected only for a combined effect of autocatalysis and formation of complexes with other molecules. Within the six-state model this model also leads to oscillation.

  2. Data inconsistencies from states with unconventional oil and gas activity.

    PubMed

    Malone, Samantha; Kelso, Matthew; Auch, Ted; Edelstein, Karen; Ferrar, Kyle; Jalbert, Kirk

    2015-01-01

    The quality and availability of unconventional oil and gas (O&G) data in the United States have never been compared methodically state-to-state. By conducting such an assessment, this study seeks to better understand private and publicly sourced data variability and to identify data availability gaps. We developed an exploratory data-grading tool - Data Accessibility and Usability Index (DAUI) - to guide the review of O&G data quality. Between July and October 2013, we requested, collected, and assessed 5 categories of unconventional O&G data (wells drilled, violations, production, waste, and Class II disposal wells) from 10 states with active drilling activity. We based our assessment on eight data quality parameters (accessibility, usability, point location, completeness, metadata, agency responsiveness, accuracy, and cost). Using the DAUI, two authors graded the 10 states and then averaged their scores. The average score received across all states, data categories, and parameters was 67.1 out of 100, largely insufficient for proper data transparency. By state, Pennsylvania received the highest average ( = 93.5) and ranked first in all but one data category. The lowest scoring state was Texas ( = 44) largely due to its policy of charging for certain data. This article discusses the various reasons for scores received, as well as methodological limitations of the assessment metrics. We argue that the significant variability of unconventional O&G data-and its availability to the public-is a barrier to regulatory and industry transparency. The lack of transparency also impacts public education and broader participation in industry governance. This study supports the need to develop a set of data best management practices (BMPs) for state regulatory agencies and the O&G industry, and suggests potential BMPs for this purpose.

  3. Data inconsistencies from states with unconventional oil and gas activity.

    PubMed

    Malone, Samantha; Kelso, Matthew; Auch, Ted; Edelstein, Karen; Ferrar, Kyle; Jalbert, Kirk

    2015-01-01

    The quality and availability of unconventional oil and gas (O&G) data in the United States have never been compared methodically state-to-state. By conducting such an assessment, this study seeks to better understand private and publicly sourced data variability and to identify data availability gaps. We developed an exploratory data-grading tool - Data Accessibility and Usability Index (DAUI) - to guide the review of O&G data quality. Between July and October 2013, we requested, collected, and assessed 5 categories of unconventional O&G data (wells drilled, violations, production, waste, and Class II disposal wells) from 10 states with active drilling activity. We based our assessment on eight data quality parameters (accessibility, usability, point location, completeness, metadata, agency responsiveness, accuracy, and cost). Using the DAUI, two authors graded the 10 states and then averaged their scores. The average score received across all states, data categories, and parameters was 67.1 out of 100, largely insufficient for proper data transparency. By state, Pennsylvania received the highest average ( = 93.5) and ranked first in all but one data category. The lowest scoring state was Texas ( = 44) largely due to its policy of charging for certain data. This article discusses the various reasons for scores received, as well as methodological limitations of the assessment metrics. We argue that the significant variability of unconventional O&G data-and its availability to the public-is a barrier to regulatory and industry transparency. The lack of transparency also impacts public education and broader participation in industry governance. This study supports the need to develop a set of data best management practices (BMPs) for state regulatory agencies and the O&G industry, and suggests potential BMPs for this purpose. PMID:25734825

  4. Insights and clinical questions about the active surveillance of low-risk papillary thyroid microcarcinomas [Review].

    PubMed

    Ito, Yasuhiro; Oda, Hitomi; Miyauchi, Akira

    2016-04-25

    Over 20 years ago, two Japanese institutions initiated an active surveillance policy for papillary microcarcinomas (PMCs) without high-risk features (such as clinical lymph node and distant metastases) and suspected trachea or recurrent laryngeal nerve invasion. Since the most recent American Thyroid Association (ATA) guidelines adopt active surveillance as a therapy option for low-risk PMCs, the number of institutions worldwide carrying out this policy can be expected to increase. However, before adopting an active surveillance strategy, some important clinical questions must be considered. In this review, conceivable clinical questions with our answers based on the present accumulation of low-risk PMC surveillance data are presented. PMID:26632168

  5. Widely available active sites on Ni2P for electrochemical hydrogen evolution--insights from first principles calculations.

    PubMed

    Hansen, Martin H; Stern, Lucas-Alexandre; Feng, Ligang; Rossmeisl, Jan; Hu, Xile

    2015-04-28

    We present insights into the mechanism and the active site for hydrogen evolution on nickel phosphide (Ni2P). Ni2P was recently discovered to be a very active non-precious hydrogen evolution catalyst. Current literature attributes the activity of Ni2P to a particular site on the (0001) facet. In the present study, using Density Functional Theory (DFT) calculations, we show that several widely available low index crystal facets on Ni2P have better properties for a high catalytic activity. DFT calculations were used to identify moderately bonding nickel bridge sites and nickel hollow sites for hydrogen adsorption and to calculate barriers for the Tafel pathway. The investigated surfaces in this study were the (101̅0), (1̅1̅20), (112̅0), (112̅1) and (0001) facets of the hexagonal Ni2P crystal. In addition to the DFT results, we present experiments on Ni2P nanowires growing along the 〈0001〉 direction, which are shown as efficient hydrogen evolution catalysts. The experimental results add these nanowires to a variety of different morphologies of Ni2P, which are all active for HER. PMID:25812670

  6. Obesity, Health, and Physical Activity: Discourses from the United States

    ERIC Educational Resources Information Center

    Zieff, Susan G.; Veri, Maria J.

    2009-01-01

    This article examines the obesity, health, and physical activity discourses of the past 35 years in the context of the United States with particular reference to five social sectors: the biomedical domain; the popular media; nonprofit foundations, centers and agencies; various national and multinational corporations; and government at all levels.…

  7. Canada and the United States. Perspective. Learning Activity Packet.

    ERIC Educational Resources Information Center

    Maine Univ., Orono. New England - Atlantic Provinces - Quebec Center.

    The similarities and differences of Canada and the United States are explored in this Learning Activity Packet (LAP). Ten learning objectives are given which encourage students to examine: 1) the misconceptions Americans and Canadians have about each other and their ways of life; 2) the effect and influence of French and English exploration and…

  8. Robust state estimation for neural networks with discontinuous activations.

    PubMed

    Liu, Xiaoyang; Cao, Jinde

    2010-12-01

    Discontinuous dynamical systems, particularly neural networks with discontinuous activation functions, arise in a number of applications and have received considerable research attention in recent years. In this paper, the robust state estimation problem is investigated for uncertain neural networks with discontinuous activations and time-varying delays, where the neuron-dependent nonlinear disturbance on the network outputs are only assumed to satisfy the local Lipschitz condition. Based on the theory of differential inclusions and nonsmooth analysis, several criteria are presented to guarantee the existence of the desired robust state estimator for the discontinuous neural networks. It is shown that the design of the state estimator for such networks can be achieved by solving some linear matrix inequalities, which are dependent on the size of the time derivative of the time-varying delays. Finally, numerical examples are given to illustrate the theoretical results.

  9. Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens

    PubMed Central

    2015-01-01

    Negamycin is a natural product with antibacterial activity against a broad range of Gram-negative pathogens. Recent revelation of its ribosomal binding site and mode of inhibition has reinvigorated efforts to identify improved analogues with clinical potential. Translation-inhibitory potency and antimicrobial activity upon modification of different moieties of negamycin were in line with its observed ribosomal binding conformation, reaffirming stringent structural requirements for activity. However, substitutions on the N6 amine were tolerated and led to N6-(3-aminopropyl)-negamycin (31f), an analogue showing 4-fold improvement in antibacterial activity against key bacterial pathogens. This represents the most potent negamycin derivative to date and may be a stepping stone toward clinical development of this novel antibacterial class. PMID:26288696

  10. Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors.

    PubMed

    Marotta, Christopher B; Rreza, Iva; Lester, Henry A; Dougherty, Dennis A

    2014-05-16

    Nicotinic acetylcholine receptors are a diverse set of ion channels that are essential to everyday brain function. Contemporary research studies selective activation of individual subtypes of receptors, with the hope of increasing our understanding of behavioral responses and neurodegenerative diseases. Here, we aim to expand current binding models to help explain the specificity seen among three activators of α4β2 receptors: sazetidine-A, cytisine, and NS9283. Through mutational analysis, we can interchange the activation profiles of the stoichiometry-selective compounds sazetidine-A and cytisine. In addition, mutations render NS9283--currently identified as a positive allosteric modulator--into an agonist. These results lead to two conclusions: (1) occupation at each primary face of an α subunit is needed to activate the channel and (2) the complementary face of the adjacent subunit dictates the binding ability of the agonist.

  11. Soil Microbial Activity Provides Insight to Carbon Cycling in Shrub Ecotones of Sub-Arctic Sweden

    NASA Astrophysics Data System (ADS)

    Marek, E.; Kashi, N. N.; Chen, J.; Hobbie, E. A.; Schwan, M. R.; Varner, R. K.

    2015-12-01

    Shrubs are expanding in Arctic and sub-Arctic regions due to rising atmospheric temperatures. Microbial activity increases as growing temperatures cause permafrost warming and subsequent thaw, leading to a greater resource of soil nutrients enabling shrub growth. Increased carbon inputs from shrubs is predicted to result in faster carbon turnover by microbial decomposition. Further understanding of microbial activity underneath shrubs could uncover how microbes and soil processes interact to promote shrub expansion and carbon cycling. To address how higher soil carbon input from shrubs influences decomposition, soil samples were taken across a heath, shrub, and forest ecotone gradient at two sites near Abikso, Sweden. Samples were analyzed for soluble carbon and nitrogen, microbial abundance, and microbial activity of chitinase, glucosidase, and phosphatase to reflect organic matter decomposition and availability of nitrogen, carbon, and phosphate respectively. Chitinase activity positively correlated with shrub cover, suggesting microbial demands for nitrogen increase with higher shrub cover. Glucosidase activity negatively correlated with shrub cover and soluble carbon, suggesting decreased microbial demand for carbon as shrub cover and carbon stores increase. Lower glucosidase activity in areas with high carbon input from shrubs implies that microbes are decomposing carbon less readily than carbon is being put into the soil. Increasing soil carbon stores in shrub covered areas can lead to shrubs becoming a net carbon sink and a negative feedback to changing climate.

  12. Platelet Lipidomic Profiling: Novel Insight into Cytosolic Phospholipase A2α Activity and Its Role in Human Platelet Activation.

    PubMed

    Duvernay, Matthew T; Matafonov, Anton; Lindsley, Craig W; Hamm, Heidi E

    2015-09-15

    With a newer, more selective and efficacious cytosolic phospholipase A2α (cPLA2α) inhibitor available, we revisited the role of cPLA2α activity in platelet activation and discovered that a component of platelet signaling, even larger than previously appreciated, relies on this enzyme. In a whole blood shear-based flow chamber assay, giripladib, a cPLA2α inhibitor, reduced platelet adhesion and accumulation on collagen. Moreover, giripladib differentially affected P-selectin expression and GPIIbIIIa activation depending on the agonist employed. While protease-activated receptor 1 (PAR1)-mediated platelet activation was unaffected by giripladib, the levels of PAR4- and GPVI-mediated platelet activation were significantly reduced. Meanwhile, the thromboxane A2 receptor antagonist SQ29548 had no effect on PAR-, GPVI-, or puriniergic receptor-mediated platelet activation, suggesting that another eicosanoid produced downstream of arachidonic acid liberation by cPLA2α was responsible for this large component of PAR4- and GPVI-mediated platelet activation. In parallel, we profiled PAR-mediated changes in glycerophospholipid (GPL) mass with and without giripladib to better understand cPLA2α-mediated lipid metabolism. Phosphatidylcholine and phosphatidylethanolamine (PE) demonstrated the largest consumption of mass during thrombin stimulation. Additionally, we confirm phosphatidylinositol as a major substrate of cPLA2α. A comparison of PAR1- and PAR4-induced metabolism revealed the consumption of more putative arachidonyl-PE species downstream of PAR1 activation. Instead of enhanced cPLA2α activity and therefore more arachidonic acid liberation downstream of PAR4, these results indicate the major role that cPLA2α activity plays in platelet function and suggest that a novel eicosanoid is produced in response to platelet activation that represents a large component of PAR4- and GPVI-mediated responses.

  13. Platelet Lipidomic Profiling: Novel Insight into Cytosolic Phospholipase A2α Activity and Its Role in Human Platelet Activation.

    PubMed

    Duvernay, Matthew T; Matafonov, Anton; Lindsley, Craig W; Hamm, Heidi E

    2015-09-15

    With a newer, more selective and efficacious cytosolic phospholipase A2α (cPLA2α) inhibitor available, we revisited the role of cPLA2α activity in platelet activation and discovered that a component of platelet signaling, even larger than previously appreciated, relies on this enzyme. In a whole blood shear-based flow chamber assay, giripladib, a cPLA2α inhibitor, reduced platelet adhesion and accumulation on collagen. Moreover, giripladib differentially affected P-selectin expression and GPIIbIIIa activation depending on the agonist employed. While protease-activated receptor 1 (PAR1)-mediated platelet activation was unaffected by giripladib, the levels of PAR4- and GPVI-mediated platelet activation were significantly reduced. Meanwhile, the thromboxane A2 receptor antagonist SQ29548 had no effect on PAR-, GPVI-, or puriniergic receptor-mediated platelet activation, suggesting that another eicosanoid produced downstream of arachidonic acid liberation by cPLA2α was responsible for this large component of PAR4- and GPVI-mediated platelet activation. In parallel, we profiled PAR-mediated changes in glycerophospholipid (GPL) mass with and without giripladib to better understand cPLA2α-mediated lipid metabolism. Phosphatidylcholine and phosphatidylethanolamine (PE) demonstrated the largest consumption of mass during thrombin stimulation. Additionally, we confirm phosphatidylinositol as a major substrate of cPLA2α. A comparison of PAR1- and PAR4-induced metabolism revealed the consumption of more putative arachidonyl-PE species downstream of PAR1 activation. Instead of enhanced cPLA2α activity and therefore more arachidonic acid liberation downstream of PAR4, these results indicate the major role that cPLA2α activity plays in platelet function and suggest that a novel eicosanoid is produced in response to platelet activation that represents a large component of PAR4- and GPVI-mediated responses. PMID:26295742

  14. Structural insights into the role of iron-histidine bond cleavage in nitric oxide-induced activation of H-NOX gas sensor proteins.

    PubMed

    Herzik, Mark A; Jonnalagadda, Rohan; Kuriyan, John; Marletta, Michael A

    2014-10-01

    Heme-nitric oxide/oxygen (H-NOX) binding domains are a recently discovered family of heme-based gas sensor proteins that are conserved across eukaryotes and bacteria. Nitric oxide (NO) binding to the heme cofactor of H-NOX proteins has been implicated as a regulatory mechanism for processes ranging from vasodilation in mammals to communal behavior in bacteria. A key molecular event during NO-dependent activation of H-NOX proteins is rupture of the heme-histidine bond and formation of a five-coordinate nitrosyl complex. Although extensive biochemical studies have provided insight into the NO activation mechanism, precise molecular-level details have remained elusive. In the present study, high-resolution crystal structures of the H-NOX protein from Shewanella oneidensis in the unligated, intermediate six-coordinate and activated five-coordinate, NO-bound states are reported. From these structures, it is evident that several structural features in the heme pocket of the unligated protein function to maintain the heme distorted from planarity. NO-induced scission of the iron-histidine bond triggers structural rearrangements in the heme pocket that permit the heme to relax toward planarity, yielding the signaling-competent NO-bound conformation. Here, we also provide characterization of a nonheme metal coordination site occupied by zinc in an H-NOX protein.

  15. Lipid-Controlled Peptide Topology and Interactions in Bilayers: Structural Insights into the Synergistic Enhancement of the Antimicrobial Activities of PGLa and Magainin 2

    PubMed Central

    Salnikov, Evgeniy S.; Bechinger, Burkhard

    2011-01-01

    To gain further insight into the antimicrobial activities of cationic linear peptides, we investigated the topology of each of two peptides, PGLa and magainin 2, in oriented phospholipid bilayers in the presence and absence of the other peptide and as a function of the membrane lipid composition. Whereas proton-decoupled 15N solid-state NMR spectroscopy indicates that magainin 2 exhibits stable in-plane alignments under all conditions investigated, PGLa adopts a number of different membrane topologies with considerable variations in tilt angle. Hydrophobic thickness is an important parameter that modulates the alignment of PGLa. In equimolar mixtures of PGLa and magainin 2, the former adopts transmembrane orientations in dimyristoyl-, but not 1-palmitoyl-2-oleoyl-, phospholipid bilayers, whereas magainin 2 remains associated with the surface in all cases. These results have important consequences for the mechanistic models explaining synergistic activities of the peptide mixtures and will be discussed. The ensemble of data suggests that the thinning of the dimyristoyl membranes caused by magainin 2 tips the topological equilibrium of PGLa toward a membrane-inserted configuration. Therefore, lipid-mediated interactions play a fundamental role in determining the topology of membrane peptides and proteins and thereby, possibly, in regulating their activities as well. PMID:21402029

  16. Structural insights into the role of iron–histidine bond cleavage in nitric oxide-induced activation of H-NOX gas sensor proteins

    PubMed Central

    Herzik, Mark A.; Jonnalagadda, Rohan; Kuriyan, John; Marletta, Michael A.

    2014-01-01

    Heme-nitric oxide/oxygen (H-NOX) binding domains are a recently discovered family of heme-based gas sensor proteins that are conserved across eukaryotes and bacteria. Nitric oxide (NO) binding to the heme cofactor of H-NOX proteins has been implicated as a regulatory mechanism for processes ranging from vasodilation in mammals to communal behavior in bacteria. A key molecular event during NO-dependent activation of H-NOX proteins is rupture of the heme–histidine bond and formation of a five-coordinate nitrosyl complex. Although extensive biochemical studies have provided insight into the NO activation mechanism, precise molecular-level details have remained elusive. In the present study, high-resolution crystal structures of the H-NOX protein from Shewanella oneidensis in the unligated, intermediate six-coordinate and activated five-coordinate, NO-bound states are reported. From these structures, it is evident that several structural features in the heme pocket of the unligated protein function to maintain the heme distorted from planarity. NO-induced scission of the iron–histidine bond triggers structural rearrangements in the heme pocket that permit the heme to relax toward planarity, yielding the signaling-competent NO-bound conformation. Here, we also provide characterization of a nonheme metal coordination site occupied by zinc in an H-NOX protein. PMID:25253889

  17. Nonequilibrium Equation of State in Suspensions of Active Colloids

    NASA Astrophysics Data System (ADS)

    Ginot, Félix; Theurkauff, Isaac; Levis, Demian; Ybert, Christophe; Bocquet, Lydéric; Berthier, Ludovic; Cottin-Bizonne, Cécile

    2015-01-01

    Active colloids constitute a novel class of materials composed of colloidal-scale particles locally converting chemical energy into motility, mimicking micro-organisms. Evolving far from equilibrium, these systems display structural organizations and dynamical properties distinct from thermalized colloidal assemblies. Harvesting the potential of this new class of systems requires the development of a conceptual framework to describe these intrinsically nonequilibrium systems. We use sedimentation experiments to probe the nonequilibrium equation of state of a bidimensional assembly of active Janus microspheres and conduct computer simulations of a model of self-propelled hard disks. Self-propulsion profoundly affects the equation of state, but these changes can be rationalized using equilibrium concepts. We show that active colloids behave, in the dilute limit, as an ideal gas with an activity-dependent effective temperature. At finite density, increasing the activity is similar to increasing adhesion between equilibrium particles. We quantify this effective adhesion and obtain a unique scaling law relating activity and effective adhesion in both experiments and simulations. Our results provide a new and efficient way to understand the emergence of novel phases of matter in active colloidal suspensions.

  18. New Insights into the Antibacterial Activity of Hydroxycoumarins against Ralstonia solanacearum.

    PubMed

    Yang, Liang; Ding, Wei; Xu, Yuquan; Wu, Dousheng; Li, Shili; Chen, Juanni; Guo, Bing

    2016-01-01

    Coumarins are important plant-derived natural products with wide-ranging bioactivities and extensive applications. In this study, we evaluated for the first time the antibacterial activity and mechanisms of action of coumarins against the phytopathogen Ralstonia solanacearum, and investigated the effect of functional group substitution. We first tested the antibacterial activity of 18 plant-derived coumarins with different substitution patterns, and found that daphnetin, esculetin, xanthotol, and umbelliferone significantly inhibited the growth of R. solanacearum. Daphnetin showed the strongest antibacterial activity, followed by esculetin and umbelliferone, with MICs of 64, 192, and 256 mg/L, respectively, better than the archetypal coumarin with 384 mg/L. We further demonstrated that the hydroxylation of coumarins at the C-6, C-7 or C-8 position significantly enhanced the antibacterial activity against R. solanacearum. Transmission electron microscope (TEM) and fluorescence microscopy images showed that hydroxycoumarins may interact with the pathogen by mechanically destroying the cell membrane and inhibiting biofilm formation. The antibiofilm effect of hydroxycoumarins may relate to the repression of flagellar genes fliA and flhC. These physiological changes in R. solanacearum caused by hydroxycoumarins can provide information for integral pathogen control. The present findings demonstrated that hydroxycoumarins have superior antibacterial activity against the phytopathogen R. solanacearum, and thus have the potential to be applied for controlling plant bacterial wilt. PMID:27070570

  19. Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking.

    PubMed

    Islam, Barira; Sharma, Charu; Adem, Abdu; Aburawi, Elhadi; Ojha, Shreesh

    2015-01-01

    Statins are hypolipidemic drugs that are effective in the treatment of hypercholesterolemia by attenuating cholesterol synthesis in the liver via competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Recently, dietary changes associated with drug therapy have garnered attention as novel drugs to mitigate or ameliorate hypercholesterolemia. The present study was undertaken to observe different dietary polyphenols that can bind to the active site of HMGR and inhibit it. Results from the 12 dietary polyphenols tested reveal that polyphenols can bind to HMGR and block the binding of nicotinamide adenine dinucleotide phosphate (NADP(+)). We observed that the rigidity of phenolic rings prevents the polyphenols from docking to the enzyme activity site. The presence of an ester linkage between the phenolic rings in (-)-epigallocatechin-3-gallate (EGCG) and the alkyl chain in curcumin allows them to orient in the active site of the HMGR and bind to the catalytic residues. EGCG and curcumin showed binding to the active site residues with a low GRID score, which may be a potential inhibitor of HMGR. Kaempferol showed binding to HMG-CoA, but with low binding affinity. These observations provide a rationale for the consistent hypolipidemic effect of EGCG and curcumin, which has been previously reported in several epidemiological and animal studies. Therefore, this study substantiates the mechanism of polyphenols on the activity of HMGR by molecular docking and provides the impetus for drug design involving further structure-function relationship studies. PMID:26357462

  20. Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking

    PubMed Central

    Islam, Barira; Sharma, Charu; Adem, Abdu; Aburawi, Elhadi; Ojha, Shreesh

    2015-01-01

    Statins are hypolipidemic drugs that are effective in the treatment of hypercholesterolemia by attenuating cholesterol synthesis in the liver via competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Recently, dietary changes associated with drug therapy have garnered attention as novel drugs to mitigate or ameliorate hypercholesterolemia. The present study was undertaken to observe different dietary polyphenols that can bind to the active site of HMGR and inhibit it. Results from the 12 dietary polyphenols tested reveal that polyphenols can bind to HMGR and block the binding of nicotinamide adenine dinucleotide phosphate (NADP+). We observed that the rigidity of phenolic rings prevents the polyphenols from docking to the enzyme activity site. The presence of an ester linkage between the phenolic rings in (–)-epigallocatechin-3-gallate (EGCG) and the alkyl chain in curcumin allows them to orient in the active site of the HMGR and bind to the catalytic residues. EGCG and curcumin showed binding to the active site residues with a low GRID score, which may be a potential inhibitor of HMGR. Kaempferol showed binding to HMG-CoA, but with low binding affinity. These observations provide a rationale for the consistent hypolipidemic effect of EGCG and curcumin, which has been previously reported in several epidemiological and animal studies. Therefore, this study substantiates the mechanism of polyphenols on the activity of HMGR by molecular docking and provides the impetus for drug design involving further structure–function relationship studies. PMID:26357462

  1. Insights from an observational assessment of park-based physical activity in Nanchang, China

    PubMed Central

    Tu, Hong; Liao, Xiong; Schuller, Kristyn; Cook, Angelie; Fan, Si; Lan, Guilian; Lu, Yuanan; Yuan, Zhaokang; Moore, Justin B.; Maddock, Jay E.

    2015-01-01

    Internationally, parks have been shown to be an important community asset for physical activity (PA), but little is known about the relationship between park usage and physical activity in China. The purpose of this study was to determine the association between park user characteristics and PA in Nanchang, China. In June 2014, 75,678 people were observed in eight parks over 12 days using SOPARC, a validated systematic observation tool. A logistic regression analysis was used to determine the association between PA and park user characteristics. Most park users were older adults (53.5%) or adults (34.6%). Overall, 55% of park users engaged in moderate-to-vigorous physical activity (MVPA). Fewer women were observed in parks than men, but were 66% more likely to be engaged in MVPA than men. Park users were more likely to be observed in MVPA between 6–9 am and when the temperature was below 30 °C. Chinese park users were more active (55%) than US studies in Tampa (30%), Chicago (49%), and Los Angeles (34%). More research is necessary to identify features of parks that are associated with greater PA so that effective interventions can be developed to promote active park use in Chinese citizens. PMID:26844171

  2. Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship.

    PubMed

    Navarro-Retamal, Carlos; Caballero, Julio

    2016-01-01

    In the last years, the interactions of flavonoids with protein kinases (PKs) have been described by using crystallographic experiments. Interestingly, different orientations have been found for one flavonoid inside different PKs and different chemical substitutions lead to different orientations of the flavonoid scaffold inside one PK. Accordingly, orientation predictions of novel analogues could help to the design of flavonoids with high PK inhibitory activities. With this in mind, we studied the binding modes of 37 flavonoids (flavones and chalcones) inside the cyclin-dependent PK CDK1 using docking experiments. We found that the compounds under study adopted two different orientations into the active site of CDK1 (orientations I and II in the manuscript). In addition, quantitative structure-activity relationship (QSAR) models using CoMFA and CoMSIA methodologies were constructed to explain the trend of the CDK1 inhibitory activities for the studied flavonoids. Template-based and docking-based alignments were used. Models developed starting from docking-based alignment were applied for describing the whole dataset and compounds with orientation I. Adequate R2 and Q2 values were obtained by each method; interestingly, only hydrophobic and hydrogen bond donor fields describe the differential potency of the flavonoids as CDK1 inhibitors for both defined alignments and subsets. Our current application of docking and QSAR together reveals important elements to be drawn for the design of novel flavonoids with increased PK inhibitory activities. PMID:27517610

  3. Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking.

    PubMed

    Islam, Barira; Sharma, Charu; Adem, Abdu; Aburawi, Elhadi; Ojha, Shreesh

    2015-01-01

    Statins are hypolipidemic drugs that are effective in the treatment of hypercholesterolemia by attenuating cholesterol synthesis in the liver via competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Recently, dietary changes associated with drug therapy have garnered attention as novel drugs to mitigate or ameliorate hypercholesterolemia. The present study was undertaken to observe different dietary polyphenols that can bind to the active site of HMGR and inhibit it. Results from the 12 dietary polyphenols tested reveal that polyphenols can bind to HMGR and block the binding of nicotinamide adenine dinucleotide phosphate (NADP(+)). We observed that the rigidity of phenolic rings prevents the polyphenols from docking to the enzyme activity site. The presence of an ester linkage between the phenolic rings in (-)-epigallocatechin-3-gallate (EGCG) and the alkyl chain in curcumin allows them to orient in the active site of the HMGR and bind to the catalytic residues. EGCG and curcumin showed binding to the active site residues with a low GRID score, which may be a potential inhibitor of HMGR. Kaempferol showed binding to HMG-CoA, but with low binding affinity. These observations provide a rationale for the consistent hypolipidemic effect of EGCG and curcumin, which has been previously reported in several epidemiological and animal studies. Therefore, this study substantiates the mechanism of polyphenols on the activity of HMGR by molecular docking and provides the impetus for drug design involving further structure-function relationship studies.

  4. Insights into Substrate Specificity and Metal Activation of Mammalian Tetrahedral Aspartyl Aminopeptidase

    SciTech Connect

    Chen, Yuanyuan; Farquhar, Erik R.; Chance, Mark R.; Palczewski, Krzysztof; Kiser, Philip D.

    2012-07-11

    Aminopeptidases are key enzymes involved in the regulation of signaling peptide activity. Here, we present a detailed biochemical and structural analysis of an evolutionary highly conserved aspartyl aminopeptidase called DNPEP. We show that this peptidase can cleave multiple physiologically relevant substrates, including angiotensins, and thus may play a key role in regulating neuron function. Using a combination of x-ray crystallography, x-ray absorption spectroscopy, and single particle electron microscopy analysis, we provide the first detailed structural analysis of DNPEP. We show that this enzyme possesses a binuclear zinc-active site in which one of the zinc ions is readily exchangeable with other divalent cations such as manganese, which strongly stimulates the enzymatic activity of the protein. The plasticity of this metal-binding site suggests a mechanism for regulation of DNPEP activity. We also demonstrate that DNPEP assembles into a functionally relevant tetrahedral complex that restricts access of peptide substrates to the active site. These structural data allow rationalization of the enzyme's preference for short peptide substrates with N-terminal acidic residues. This study provides a structural basis for understanding the physiology and bioinorganic chemistry of DNPEP and other M18 family aminopeptidases.

  5. New Insights into the Antibacterial Activity of Hydroxycoumarins against Ralstonia solanacearum.

    PubMed

    Yang, Liang; Ding, Wei; Xu, Yuquan; Wu, Dousheng; Li, Shili; Chen, Juanni; Guo, Bing

    2016-01-01

    Coumarins are important plant-derived natural products with wide-ranging bioactivities and extensive applications. In this study, we evaluated for the first time the antibacterial activity and mechanisms of action of coumarins against the phytopathogen Ralstonia solanacearum, and investigated the effect of functional group substitution. We first tested the antibacterial activity of 18 plant-derived coumarins with different substitution patterns, and found that daphnetin, esculetin, xanthotol, and umbelliferone significantly inhibited the growth of R. solanacearum. Daphnetin showed the strongest antibacterial activity, followed by esculetin and umbelliferone, with MICs of 64, 192, and 256 mg/L, respectively, better than the archetypal coumarin with 384 mg/L. We further demonstrated that the hydroxylation of coumarins at the C-6, C-7 or C-8 position significantly enhanced the antibacterial activity against R. solanacearum. Transmission electron microscope (TEM) and fluorescence microscopy images showed that hydroxycoumarins may interact with the pathogen by mechanically destroying the cell membrane and inhibiting biofilm formation. The antibiofilm effect of hydroxycoumarins may relate to the repression of flagellar genes fliA and flhC. These physiological changes in R. solanacearum caused by hydroxycoumarins can provide information for integral pathogen control. The present findings demonstrated that hydroxycoumarins have superior antibacterial activity against the phytopathogen R. solanacearum, and thus have the potential to be applied for controlling plant bacterial wilt.

  6. Dissection of reverse gyrase activities: insight into the evolution of a thermostable molecular machine†

    PubMed Central

    Valenti, Anna; Perugino, Giuseppe; D’Amaro, Anna; Cacace, Andrea; Napoli, Alessandra; Rossi, Mosè; Ciaramella, Maria

    2008-01-01

    Reverse gyrase is a peculiar DNA topoisomerase, specific of thermophilic microorganisms, which induces positive supercoiling into DNA molecules in an ATP-dependent reaction. It is a modular enzyme and comprises an N-terminal helicase-like module fused to a C-terminal topoisomerase IA-like domain. The exact molecular mechanism of this unique reaction is not understood, and a fundamental mechanistic question is how its distinct steps are coordinated. We studied the cross-talk between the components of this molecular motor and probed communication between the DNA-binding sites and the different activities (DNA relaxation, ATP hydrolysis and positive supercoiling). We show that the isolated ATPase and topoisomerase domains of reverse gyrase form specific physical interactions, retain their own DNA binding and enzymatic activities, and when combined cooperate to achieve the unique ATP-dependent positive supercoiling activity. Our results indicate a mutual effect of both domains on all individual steps of the reaction. The C-terminal domain shows ATP-independent topoisomerase activity, which is repressed by the N-terminal domain in the full-length enzyme; experiments with the isolated domains showed that the C-terminal domain has stimulatory influence on the ATPase activity of the N-terminal domain. In addition, the two domains showed a striking reciprocal thermostabilization effect. PMID:18614606

  7. Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship

    PubMed Central

    Navarro-Retamal, Carlos

    2016-01-01

    In the last years, the interactions of flavonoids with protein kinases (PKs) have been described by using crystallographic experiments. Interestingly, different orientations have been found for one flavonoid inside different PKs and different chemical substitutions lead to different orientations of the flavonoid scaffold inside one PK. Accordingly, orientation predictions of novel analogues could help to the design of flavonoids with high PK inhibitory activities. With this in mind, we studied the binding modes of 37 flavonoids (flavones and chalcones) inside the cyclin-dependent PK CDK1 using docking experiments. We found that the compounds under study adopted two different orientations into the active site of CDK1 (orientations I and II in the manuscript). In addition, quantitative structure–activity relationship (QSAR) models using CoMFA and CoMSIA methodologies were constructed to explain the trend of the CDK1 inhibitory activities for the studied flavonoids. Template-based and docking-based alignments were used. Models developed starting from docking-based alignment were applied for describing the whole dataset and compounds with orientation I. Adequate R2 and Q2 values were obtained by each method; interestingly, only hydrophobic and hydrogen bond donor fields describe the differential potency of the flavonoids as CDK1 inhibitors for both defined alignments and subsets. Our current application of docking and QSAR together reveals important elements to be drawn for the design of novel flavonoids with increased PK inhibitory activities. PMID:27517610

  8. An insight into antimicrobial activity of the freshwater bryozoan Pectinatella magnifica.

    PubMed

    Pejin, Boris; Ciric, Ana; Horvatovic, Mladen; Jurca, Tamara; Glamoclija, Jasmina; Nikolic, Milos; Sokovic, Marina

    2016-08-01

    The antimicrobial activity of five crude extracts of the freshwater bryozoan Pectinatella magnifica (Leidy, 1851) was evaluated in vitro for the first time. P. magnifica acetone extract exhibited the highest antibacterial activity (minimum inhibitory concentrations (MIC) 0.004-0.350 mg/mL and MBC 0.007-0.500 mg/mL), while its methanol extract showed the most promising antifungal activity (MIC 0.03-0.12 mg/mL and MFC 0.06-0.25 mg/mL). Furthermore, at a concentration of 0.25 MIC, the methanol extract reduced biofilm formation of the bacterial strain Pseudomonas aeruginosa PAO1 in a considerable extent (59.14%). FTIR spectra of the most active extracts indicate the presence of carbonyl compounds, long-chain alcohols and/or sterols. According to the experimental data obtained, P. magnifica methanol extract may be considered as a good resource of novel natural products with potent antibiofilm activity against the bacterium well known for its resistance. PMID:26252786

  9. Behavioral State Modulates the Activity of Brainstem Sensorimotor Neurons

    PubMed Central

    McArthur, Kimberly L.

    2011-01-01

    Sensorimotor processing must be modulated according to the animal's behavioral state. A previous study demonstrated that motion responses were strongly state dependent in birds. Vestibular eye and head responses were significantly larger and more compensatory during simulated flight, and a flight-specific vestibular tail response was also characterized. In the current study, we investigated the neural substrates for these state-dependent vestibular behaviors by recording extracellularly from neurons in the vestibular nuclear complex and comparing their spontaneous activity and sensory responses during default and simulated flight states. We show that motion-sensitive neurons in the lateral vestibular nucleus are state dependent. Some neurons increased their spontaneous firing rates during flight, though their increased excitability was not reflected in higher sensory gains. However, other neurons exhibited state-dependent gating of sensory inputs, responding to rotational stimuli only during flight. These results demonstrate that vestibular processing in the brainstem is state dependent and lay the foundation for future studies to investigate the synaptic mechanisms responsible for these modifications. PMID:22090497

  10. Structural insights into catalysis and dimerization enhanced exonuclease activity of RNase J

    PubMed Central

    Zhao, Ye; Lu, Meihua; Zhang, Hui; Hu, Jing; Zhou, Congli; Xu, Qiang; Ul Hussain Shah, Amir Miraj; Xu, Hong; Wang, Liangyan; Hua, Yuejin

    2015-01-01

    RNase J is a conserved ribonuclease that belongs to the β-CASP family of nucleases. It possesses both endo- and exo-ribonuclease activities, which play a key role in pre-rRNA maturation and mRNA decay. Here we report high-resolution crystal structures of Deinococcus radiodurans RNase J complexed with RNA or uridine 5′-monophosphate in the presence of manganese ions. Biochemical and structural studies revealed that RNase J uses zinc ions for two-metal-ion catalysis. One residue conserved among RNase J orthologues (motif B) forms specific electrostatic interactions with the scissile phosphate of the RNA that is critical for the catalysis and product stabilization. The additional manganese ion, which is coordinated by conserved residues at the dimer interface, is critical for RNase J dimerization and exonuclease activity. The structures may also shed light on the mechanism of RNase J exo- and endonucleolytic activity switch. PMID:25940620

  11. Recent insights into the biological activities and drug delivery systems of tanshinones.

    PubMed

    Cai, Yuee; Zhang, Wenji; Chen, Zirong; Shi, Zhi; He, Chengwei; Chen, Meiwan

    2016-01-01

    Tanshinones, the major lipid-soluble pharmacological constituents of the Chinese medicinal herb Tanshen (Salvia miltiorrhiza), have attracted growing scientific attention because of the prospective biomedical applications of these compounds. Numerous pharmacological activities, including anti-inflammatory, anticancer, and cardio-cerebrovascular protection activities, are exhibited by the three primary bioactive constituents among the tanshinones, ie, tanshinone I (TNI), tanshinone IIA (TNIIA), and cryptotanshinone (CPT). However, due to their poor solubility and low dissolution rate, the clinical applications of TNI, TNIIA, and CPT are limited. To solve these problems, many studies have focused on loading tanshinones into liposomes, nanoparticles, microemulsions, cyclodextrin inclusions, solid dispersions, and so on. In this review, we aim to offer an updated summary of the biological activities and drug delivery systems of tanshinones to provide a reference for these constituents in clinical applications. PMID:26792989

  12. Recent insights into the biological activities and drug delivery systems of tanshinones

    PubMed Central

    Cai, Yuee; Zhang, Wenji; Chen, Zirong; Shi, Zhi; He, Chengwei; Chen, Meiwan

    2016-01-01

    Tanshinones, the major lipid-soluble pharmacological constituents of the Chinese medicinal herb Tanshen (Salvia miltiorrhiza), have attracted growing scientific attention because of the prospective biomedical applications of these compounds. Numerous pharmacological activities, including anti-inflammatory, anticancer, and cardio-cerebrovascular protection activities, are exhibited by the three primary bioactive constituents among the tanshinones, ie, tanshinone I (TNI), tanshinone IIA (TNIIA), and cryptotanshinone (CPT). However, due to their poor solubility and low dissolution rate, the clinical applications of TNI, TNIIA, and CPT are limited. To solve these problems, many studies have focused on loading tanshinones into liposomes, nanoparticles, microemulsions, cyclodextrin inclusions, solid dispersions, and so on. In this review, we aim to offer an updated summary of the biological activities and drug delivery systems of tanshinones to provide a reference for these constituents in clinical applications. PMID:26792989

  13. New insights into the multidimensional concept of macrophage ontogeny, activation and function.

    PubMed

    Ginhoux, Florent; Schultze, Joachim L; Murray, Peter J; Ochando, Jordi; Biswas, Subhra K

    2016-01-01

    Macrophages have protective roles in immunity to pathogens, tissue development, homeostasis and repair following damage. Maladaptive immunity and inflammation provoke changes in macrophage function that are causative of disease. Despite a historical wealth of knowledge about macrophages, recent advances have revealed unknown aspects of their development and function. Following development, macrophages are activated by diverse signals. Such tissue microenvironmental signals together with epigenetic changes influence macrophage development, activation and functional diversity, with consequences in disease and homeostasis. We discuss here how recent discoveries in these areas have led to a multidimensional concept of macrophage ontogeny, activation and function. In connection with this, we also discuss how technical advances facilitate a new roadmap for the isolation and analysis of macrophages at high resolution.

  14. Insights into the interactions between enzyme and co-solvents: stability and activity of stem bromelain.

    PubMed

    Rani, Anjeeta; Venkatesu, Pannuru

    2015-02-01

    In present study, an attempt is made to elucidate the effects of various naturally occurring osmolytes and denaturants on BM at pH 7.0. The effects of the varying concentrations of glycerol, sorbitol, sucrose, trehalose, urea and guanidinium chloride (GdnHCl) on structure, stability and activity of BM are explored by fluorescence spectroscopy, circular dichroism (CD), UV-vis spectroscopy and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Our experimental observations reveal that glycerol and sorbitol are acting as stabilizers at all concentrations while sucrose and trehalose are found to be destabilizers at lower concentrations, however, acted as stabilizers at higher concentrations. On the other hand, urea and GdnHCl are denaturants except at lower concentrations. There is a direct relationship between activity and conformational stability as the activity data are found to be in accordance with conformational stability parameters (ΔGu, Tm, ΔCp) and BM profile on SDS-PAGE.

  15. New insight into the biological treatment by activated sludge: the role of adsorption process.

    PubMed

    Zhang, Xiaochun; Li, Xinrun; Zhang, Qingrui; Peng, Qiuming; Zhang, Wen; Gao, Faming

    2014-02-01

    The objective of this study was to evaluate the effect of adsorption on the biological treatment process of wastewater. In the absence of substrate in the water, activated sludge developed well in the first hour, indicating that the growth of microorganism was not directly related to substrate concentration and the dissolved organic matter in the water assays were performed, no organic matter was detected out, revealing that there was no desorption in the activated sludge adsorption process. Activated sludge batch growth experiments in the presence of different adsorption capacities indicated that specific growth rate increased as specific adsorption capacity increased. The experiment on the relationship of adsorption capacity and substrate concentration or sludge concentration was also carried out. Specific adsorption capacity increased as sludge load increased, presenting linear correlation. The experiment results showed that adsorption should be taken into account in the study of the biological treatment process of wastewater.

  16. Recent insights into the biological activities and drug delivery systems of tanshinones.

    PubMed

    Cai, Yuee; Zhang, Wenji; Chen, Zirong; Shi, Zhi; He, Chengwei; Chen, Meiwan

    2016-01-01

    Tanshinones, the major lipid-soluble pharmacological constituents of the Chinese medicinal herb Tanshen (Salvia miltiorrhiza), have attracted growing scientific attention because of the prospective biomedical applications of these compounds. Numerous pharmacological activities, including anti-inflammatory, anticancer, and cardio-cerebrovascular protection activities, are exhibited by the three primary bioactive constituents among the tanshinones, ie, tanshinone I (TNI), tanshinone IIA (TNIIA), and cryptotanshinone (CPT). However, due to their poor solubility and low dissolution rate, the clinical applications of TNI, TNIIA, and CPT are limited. To solve these problems, many studies have focused on loading tanshinones into liposomes, nanoparticles, microemulsions, cyclodextrin inclusions, solid dispersions, and so on. In this review, we aim to offer an updated summary of the biological activities and drug delivery systems of tanshinones to provide a reference for these constituents in clinical applications.

  17. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation.

    PubMed

    Próchnicki, Tomasz; Mangan, Matthew S; Latz, Eicke

    2016-01-01

    Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K (+) efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca (2+) fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation. PMID:27508077

  18. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation

    PubMed Central

    Próchnicki, Tomasz; Mangan, Matthew S.; Latz, Eicke

    2016-01-01

    Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K + efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca 2+ fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation. PMID:27508077

  19. Geomorphic signal of active faulting at the northern edge of Lut Block: Insights on the kinematic scenario of Central Iran

    NASA Astrophysics Data System (ADS)

    Calzolari, Gabriele; Della Seta, Marta; Rossetti, Federico; Nozaem, Reza; Vignaroli, Gianluca; Cosentino, Domenico; Faccenna, Claudio

    2016-01-01

    Recent works documented Neogene to Quaternary dextral strike-slip tectonics along the Kuh-e-Sarhangi and Kuh-e-Faghan intraplate strike-slip faults at the northern edge of the Lut Block of Central Iran, previously thought to be dominated by sinistral strike-slip deformation. This work focuses on the evidence of Quaternary activity of one of these fault systems, in order to provide new spatiotemporal constraints on their role in the active regional kinematic scenario. Through geomorphological and structural investigation, integrated with optically stimulated luminescence dating of three generations of alluvial fans and fluvial terraces (at ~53, ~25, and ~6 ka), this study documents (i) the topographic inheritance of the long-term (Myr) punctuated history of fault nucleation, propagation, and exhumation along the northern edge of Lut Block; (ii) the tectonic control on drainage network evolution, pediment formation, fluvial terraces, and alluvial fan architecture; (iii) the minimum Holocene age of Quaternary dextral strike-slip faulting; and (iv) the evidence of Late Quaternary fault-related uplift localized along the different fault strands. The documented spatial and temporal constraints on the active dextral strike-slip tectonics at the northern edge of Lut Block provide new insights on the kinematic model for active faulting in Central Iran, which has been reinterpreted in an escape tectonic scenario.

  20. Immunoproteasome Activation During Early Antiviral Response in Mouse Pancreatic β-cells: New Insights into Auto-antigen Generation in Type I Diabetes?

    PubMed

    Freudenburg, Wieke; Gautam, Madhav; Chakraborty, Pradipta; James, Jared; Richards, Jennifer; Salvatori, Alison S; Baldwin, Aaron; Schriewer, Jill; Buller, R Mark L; Corbett, John A; Skowyra, Dorota

    2013-04-23

    Type 1 diabetes results from autoimmune destruction of the insulin producing pancreatic β-cells. The immunoproteasome, a version of the proteasome that collaborates with the 11S/PA28 activator to generate immunogenic peptides for presentation by MHC class I molecules, has long been implicated in the onset of the disease, but little is known about immunoproteasome function and regulation in pancreatic β-cells. Interesting insight into these issues comes from a recent analysis of the immunoproteasome expressed in pancreatic β-cells during early antiviral defenses mediated by interferon β (IFNβ), a type I IFN implicated in the induction of the diabetic state in human and animal models. Using mouse islets and the MIN6 insulinoma cell line, Freudenburg et al. found that IFNβ stimulates expression of the immunoproteasome and the 11S/PA28 activator in a manner fundamentally similar to the classic immuno-inducer IFNγ, with similar timing of mRNA accumulation and decline; similar transcriptional activation mediated primarily by the IRF1 and similar mRNA and protein levels. Furthermore, neither IFNβ nor IFNγ altered the expression of regular proteolytic subunits or prevented their incorporation into proteolytic cores. As a result, immunoproteasomes had stochastic combinations of immune and regular proteolytic sites, an arrangement that would likely increase the probability with which unique immunogenic peptides are produced. However, immunoproteasomes were activated by the 11S/PA28 only under conditions of ATP depletion. A mechanism that prevents the activation of immunoproteasome at high ATP levels has not been reported before and could have a major regulatory significance, as it could suppress the generation of immunogenic peptides as cell accumulate immunoproteasome and 11S/PA28, and activate antigen processing only when ATP levels drop. We discuss implications of these new findings on the link between early antiviral response and the onset of type 1 diabetes.

  1. Genome-wide survey of yeast mutations leading to activation of the yeast cell integrity MAPK pathway: Novel insights into diverse MAPK outcomes

    PubMed Central

    2011-01-01

    Background The yeast cell wall integrity mitogen-activated protein kinase (CWI-MAPK) pathway is the main regulator of adaptation responses to cell wall stress in yeast. Here, we adopt a genomic approach to shed light on two aspects that are only partially understood, namely, the characterization of the gene functional catalog associated with CWI pathway activation and the extent to which MAPK activation correlates with transcriptional outcomes. Results A systematic yeast mutant deletion library was screened for constitutive transcriptional activation of the CWI-related reporter gene MLP1. Monitoring phospho-Slt2/Mpk1 levels in the identified mutants revealed sixty-four deletants with high levels of phosphorylation of this MAPK, including mainly genes related to cell wall construction and morphogenesis, signaling, and those with unknown function. Phenotypic analysis of the last group of mutants suggests their involvement in cell wall homeostasis. A good correlation between levels of Slt2 phosphorylation and the magnitude of the transcriptional response was found in most cases. However, the expression of CWI pathway-related genes was enhanced in some mutants in the absence of significant Slt2 phosphorylation, despite the fact that functional MAPK signaling through the pathway was required. CWI pathway activation was associated to increased deposition of chitin in the cell wall - a known survival compensatory mechanism - in about 30% of the mutants identified. Conclusion We provide new insights into yeast genes related to the CWI pathway and into how the state of activation of the Slt2 MAPK leads to different outcomes, discovering the versatility of this kind of signaling pathways. These findings potentially have broad implications for understanding the functioning of other eukaryotic MAPKs. PMID:21810245

  2. Physical Activity and Sedentary Behavior in Breast Cancer Survivors: New Insight into Activity Patterns and Potential Intervention Targets

    PubMed Central

    Phillips, Siobhan M.; Dodd, Kevin W.; Steeves, Jeremy; McClain, James; Alfano, Catherine M.; McAuley, Edward

    2016-01-01

    Background Inactivity and sedentary behavior are related to poorer health outcomes in breast cancer survivors. However, few studies examining these behaviors in survivors have used objective measures, considered activities other than moderate-to-vigorous intensity activity (MVPA) and/or sedentary behavior (i.e. low intensity activities) or compared survivors to healthy controls. The purpose of the present study is to compare accelerometer-measured activity of various intensities (total, light, lifestyle, MVPA) and sedentary behavior between breast cancer survivors and non-cancer controls. Methods An imputation-based approach of independent sample t-tests adjusting for multiple comparisons was used to compare estimates of participation in each activity and sedentary behavior between survivors [n=398; M(SD)age=56.95 (9.11)] and block-matched non-cancer controls [n=1120; M(SD)age=54.88 (16.11)]. Potential moderating effects of body mass index (BMI), age, and education were also examined. Results Breast cancer survivors registered less daily total (282.8 v. 346.9) light (199.1 v. 259.3) and lifestyle (62.0 v. 71.7) activity minutes and more MVPA (21.6 v. 15.9) and sedentary behavior (555.7 v. 500.6) minutes than controls (p<0.001 for all). These relationships were largely consistent across BMI, age and education. On average, survivors spent an estimated 66.4% of their waking time sedentary and 31.1% in light/lifestyle activity and 2.6% in MVPA. Conclusions Breast cancer survivors are more sedentary and participate in less low intensity activity than controls. Although survivors registered more MVPA, these levels were insufficient. Future research should explore these differences and potential benefits of targeting low intensity activities and reducing sedentary time in this population. PMID:26026737

  3. Insights into cholinesterase inhibitory and antioxidant activities of five Juniperus species.

    PubMed

    Orhan, Nilufer; Orhan, Ilkay Erdogan; Ergun, Fatma

    2011-09-01

    In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory and antioxidant activities of the aqueous and ethanol extracts of the leaves, ripe fruits, and unripe fruits of Juniperus communis ssp. nana, Juniperus oxycedrus ssp. oxycedrus, Juniperus sabina, Juniperus foetidissima, and Juniperus excelsa were investigated in the present study. Cholinesterase inhibition of the extracts was screened using ELISA microplate reader. Antioxidant activity of the extracts was tested by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging, ferrous ion-chelating, and ferric-reducing antioxidant power (FRAP) assays. Total phenol and flavonoid contents of the extracts were determined spectrophotometrically. The extracts had low or no inhibition towards AChE, whereas the leaf aqueous extract of J. foetidissima showed the highest BChE inhibition (93.94 ± 0.01%). The leaf extracts usually exerted higher antioxidant activity. We herein describe the first study on anticholinesterase and antioxidant activity by the methods of ferrous ion-chelating, superoxide radical scavenging, and ferric-reducing antioxidant power (FRAP) assays of the mentioned Juniperus species.

  4. XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

    SciTech Connect

    Tainer, John; Fan, Li; Fuss, Jill O.; Cheng, Quen J.; Arvai, Andrew S.; Hammel, Michal; Roberts, Victoria A.; Cooper, Priscilla K.; Tainer, John A.

    2008-06-02

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

  5. XPD Helicase Structures And Activities: Insights Into the Cancer And Aging Phenotypes From XPD Mutations

    SciTech Connect

    Fan, L.; Fuss, J.O.; Cheng, Q.J.; Arvai, A.S.; Hammel, M.; Roberts, V.A.; Cooper, P.K.; Tainer, J.A.

    2009-05-18

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

  6. Single molecule microscopy reveals mechanistic insight into RNA polymerase II preinitiation complex assembly and transcriptional activity

    PubMed Central

    Horn, Abigail E.; Kugel, Jennifer F.; Goodrich, James A.

    2016-01-01

    Transcription by RNA polymerase II (Pol II) is a complex process that requires general transcription factors and Pol II to assemble on DNA into preinitiation complexes that can begin RNA synthesis upon binding of NTPs (nucleoside triphosphate). The pathways by which preinitiation complexes form, and how this impacts transcriptional activity are not completely clear. To address these issues, we developed a single molecule system using TIRF (total internal reflection fluorescence) microscopy and purified human transcription factors, which allows us to visualize transcriptional activity at individual template molecules. We see that stable interactions between polymerase II (Pol II) and a heteroduplex DNA template do not depend on general transcription factors; however, transcriptional activity is highly dependent upon TATA-binding protein, TFIIB and TFIIF. We also found that subsets of general transcription factors and Pol II can form stable complexes that are precursors for functional transcription complexes upon addition of the remaining factors and DNA. Ultimately we found that Pol II, TATA-binding protein, TFIIB and TFIIF can form a quaternary complex in the absence of promoter DNA, indicating that a stable network of interactions exists between these proteins independent of promoter DNA. Single molecule studies can be used to learn how different modes of preinitiation complex assembly impact transcriptional activity. PMID:27112574

  7. Moving Souls: History Offers Insights into Physical Activity that Go beyond Fitness and Fun

    ERIC Educational Resources Information Center

    Sydnor, Synthia

    2005-01-01

    This article looks at four theoretical themes that scholars insist on when studying history. The themes--social memory, liminality, community, and critique--may be useful in stimulating the direction, planning, and practice of physical activity in young adults. These particular themes were chosen because they seem to match some of the…

  8. Structural insights into the dehydroascorbate reductase activity of human omega-class glutathione transferases.

    PubMed

    Zhou, Huina; Brock, Joseph; Liu, Dan; Board, Philip G; Oakley, Aaron J

    2012-07-13

    The reduction of dehydroascorbate (DHA) to ascorbic acid (AA) is a vital cellular function. The omega-class glutathione transferases (GSTs) catalyze several reductive reactions in cellular biochemistry, including DHA reduction. In humans, two isozymes (GSTO1-1 and GSTO2-2) with significant DHA reductase (DHAR) activity are found, sharing 64% sequence identity. While the activity of GSTO2-2 is higher, it is significantly more unstable in vitro. We report the first crystal structures of human GSTO2-2, stabilized through site-directed mutagenesis and determined at 1.9 Å resolution in the presence and absence of glutathione (GSH). The structure of a human GSTO1-1 has been determined at 1.7 Å resolution in complex with the reaction product AA, which unexpectedly binds in the G-site, where the glutamyl moiety of GSH binds. The structure suggests a similar mode of ascorbate binding in GSTO2-2. This is the first time that a non-GSH-based reaction product has been observed in the G-site of any GST. AA stacks against a conserved aromatic residue, F34 (equivalent to Y34 in GSTO2-2). Mutation of Y34 to alanine in GSTO2-2 eliminates DHAR activity. From these structures and other biochemical data, we propose a mechanism of substrate binding and catalysis of DHAR activity.

  9. [Enhancing glutamate decarboxylase activity by site-directed mutagenesis: an insight from Ramachandran plot].

    PubMed

    Ke, Piyu; Huang, Jun; Hu, Sheng; Zhao, Weirui; Lü, Changjiang; Yu, Kai; Lei, Yinlin; Wang, Jinbo; Mei, Lehe

    2016-01-01

    Glutamate decarboxylase (GAD) can catalyze the decarboxylation of glutamate into γ-aminobutyrate (GABA) and is the only enzyme of GABA biosynthesis. Improving GAD activity and thermostability will be helpful for the highly efficient biosynthesis of GABA. According to the Ramachandran plot information of GAD 1407 three-dimensional structure from Lactobacillus brevis CGMCC No. 1306, we identified the unstable site K413 as the mutation target, constructed the mutant GAD by site-directed mutagenesis and measured the thermostability and activity of the wide type and mutant GAD. Mutant K413A led to a remarkably slower inactivation rate, and its half-life at 50 °C reached 105 min which was 2.1-fold higher than the wild type GAD1407. Moreover, mutant K413I exhibited 1.6-fold higher activity in comparison with the wide type GAD1407, although it had little improvement in thermostability of GAD. Ramachandran plot can be considered as a potential approach to increase GAD thermostability and activity. PMID:27443004

  10. Axonal activity-dependent myelination in development: Insights for myelin repair.

    PubMed

    Mitew, Stanislaw; Xing, Yao Lulu; Merson, Tobias D

    2016-10-01

    Recent advances in transgenic tools have allowed us to peek into the earliest stages of vertebrate development to study axon-glial communication in the control of peri-natal myelination. The emerging role of neuronal activity in regulating oligodendrocyte progenitor cell behavior during developmental myelination has opened up an exciting possibility-a role for neuronal activity in the early stages of remyelination. Recent work from our laboratory and others has also shown that contrary to previously established dogma in the field, complete remyelination up to pre-demyelination levels can be achieved in mouse models of MS by oligodendrogenic neural precursor cells that derive from the adult subventricular zone. These cells are electrically active and can be depolarized, suggesting that neuronal activity may have a modulatory role in their development and remyelination potential. In this review, we summarize recent advances in our understanding of the development of axon-glia communication and apply those same concepts to remyelination, with an emphasis on the particular roles of different sources of oligodendrocyte progenitor cells.

  11. [Enhancing glutamate decarboxylase activity by site-directed mutagenesis: an insight from Ramachandran plot].

    PubMed

    Ke, Piyu; Huang, Jun; Hu, Sheng; Zhao, Weirui; Lü, Changjiang; Yu, Kai; Lei, Yinlin; Wang, Jinbo; Mei, Lehe

    2016-01-01

    Glutamate decarboxylase (GAD) can catalyze the decarboxylation of glutamate into γ-aminobutyrate (GABA) and is the only enzyme of GABA biosynthesis. Improving GAD activity and thermostability will be helpful for the highly efficient biosynthesis of GABA. According to the Ramachandran plot information of GAD 1407 three-dimensional structure from Lactobacillus brevis CGMCC No. 1306, we identified the unstable site K413 as the mutation target, constructed the mutant GAD by site-directed mutagenesis and measured the thermostability and activity of the wide type and mutant GAD. Mutant K413A led to a remarkably slower inactivation rate, and its half-life at 50 °C reached 105 min which was 2.1-fold higher than the wild type GAD1407. Moreover, mutant K413I exhibited 1.6-fold higher activity in comparison with the wide type GAD1407, although it had little improvement in thermostability of GAD. Ramachandran plot can be considered as a potential approach to increase GAD thermostability and activity.

  12. Defining Democracy and the Terms of Engagement with the Postsocialist Polish State: Insights from HIV/AIDS

    PubMed Central

    2010-01-01

    This article explores the history of HIV activism in Poland from the socialist period through the early 1990s transformation as a means of examining the reconfiguration of rights, obligations, and responsibility as Poland redefined itself as a market democracy. Drawing on archival materials, in-depth qualitative interviews with current and former HIV activists, and participant observation at HIV prevention organizations in Warsaw, Poland, I sketch the ways in the socialist system’s failures to protect the health of its subjects led to the terms through which state-citizen engagement were defined in the postsocialist period. Uncertainties and anxieties surrounding who was responsible for protecting the health and well-being of citizens in the newly democratic Poland gave rise to a series of violent protests centered on HIV prevention and care for people living with HIV/AIDS. Resolution of these political and social crises involved defining democracy in postsocialist Poland through claims to moral authority, in alliance with the Catholic Church, and an obligation by multiple stakeholders to disseminate technical/scientific knowledge. By comparing the responses to the epidemic by diverse institutions, including the government, the Catholic Church, and the fledgling gay rights movement, this analysis reveals the ways in which democracy in postsocialist Poland tightly links science, democratic reform, and moral/religious authority, while at the same time excluding sexual minorities from engaging in political activism centered on rights to health and inclusion in the new democracy. PMID:20190876

  13. State activism and the hidden incentives behind bank acquisitions.

    PubMed

    Marquis, Christopher; Guthrie, Doug; Almandoz, Juan

    2012-01-01

    A number of studies have shown that, as a result of the ambiguity of US legal mandates, organizations have considerable latitude in how they comply with regulations. In this paper, we address how the different agendas of the federal and state governments increase ambiguities in state-firm relations and how states are interested actors in creating opportunities for firms to navigate the federal legislation. We analyze the institutional forces behind bank acquisitions within and across state lines in order to illuminate the ways that US states take advantage of federal ambiguity and are able to shape corporate practices to their benefit. We specifically examine how patterns of bank acquisitions are shaped by the crucial relationship between the federal Community Reinvestment Act (CRA) and a little-understood provision in the federal tax code that is implemented at the state level, the Low-Income Housing Tax Credit (LIHTC). The relationship is complex because, while the federal government uses the CRA to control bank acquisition activity, states promote use of the LIHTC, through which banks can address federal CRA concerns, and thereby promote bank acquisitions in their jurisdictions. Thus, our findings suggest that the implementation of social legislation at one level in a federal regulatory system undermines the mechanisms of social legislation at another level. We use archival research and in-depth interviews to examine the interaction between these institutional processes and formulate hypotheses that predict the ways in which bank acquisitions are constrained by banks' CRA ratings and the way states in turn help banks overcome their CRA constraints. Quantitative analyses of all bank acquisitions in the United States from 1990-2000 largely support these hypotheses. PMID:23017702

  14. Resting-state beta and gamma activity in Internet addiction.

    PubMed

    Choi, Jung-Seok; Park, Su Mi; Lee, Jaewon; Hwang, Jae Yeon; Jung, Hee Yeon; Choi, Sam-Wook; Kim, Dai Jin; Oh, Sohee; Lee, Jun-Young

    2013-09-01

    Internet addiction is the inability to control one's use of the Internet and is related to impulsivity. Although a few studies have examined neurophysiological activity as individuals with Internet addiction engage in cognitive processing, no information on spontaneous EEG activity in the eyes-closed resting-state is available. We investigated resting-state EEG activities in beta and gamma bands and examined their relationships with impulsivity among individuals with Internet addiction and healthy controls. Twenty-one drug-naïve patients with Internet addiction (age: 23.33 ± 3.50 years) and 20 age-, sex-, and IQ-matched healthy controls (age: 22.40 ± 2.33 years) were enrolled in this study. Severity of Internet addiction was identified by the total score on Young's Internet Addiction Test. Impulsivity was measured with the Barratt Impulsiveness Scale-11 and a stop-signal task. Resting-state EEG during eyes closed was recorded, and the absolute/relative power of beta and gamma bands was analyzed. The Internet addiction group showed high impulsivity and impaired inhibitory control. The generalized estimating equation showed that the Internet-addiction group showed lower absolute power on the beta band than did the control group (estimate = -3.370, p < 0.01). On the other hand, the Internet-addiction group showed higher absolute power on the gamma band than did the control group (estimate = 0.434, p < 0.01). These EEG activities were significantly associated with the severity of Internet addiction as well as with the extent of impulsivity. The present study suggests that resting-state fast-wave brain activity is related to the impulsivity characterizing Internet addiction. These differences may be neurobiological markers for the pathophysiology of Internet addiction.

  15. Electronic Word of Mouth on Twitter About Physical Activity in the United States: Exploratory Infodemiology Study

    PubMed Central

    Campo, Shelly; Janz, Kathleen F; Eckler, Petya; Yang, Jingzhen; Snetselaar, Linda G; Signorini, Alessio

    2013-01-01

    Background Twitter is a widely used social medium. However, its application in promoting health behaviors is understudied. Objective In order to provide insights into designing health marketing interventions to promote physical activity on Twitter, this exploratory infodemiology study applied both social cognitive theory and the path model of online word of mouth to examine the distribution of different electronic word of mouth (eWOM) characteristics among personal tweets about physical activity in the United States. Methods This study used 113 keywords to retrieve 1 million public tweets about physical activity in the United States posted between January 1 and March 31, 2011. A total of 30,000 tweets were randomly selected and sorted based on numbers generated by a random number generator. Two coders scanned the first 16,100 tweets and yielded 4672 (29.02%) tweets that they both agreed to be about physical activity and were from personal accounts. Finally, 1500 tweets were randomly selected from the 4672 tweets (32.11%) for further coding. After intercoder reliability scores reached satisfactory levels in the pilot coding (100 tweets separate from the final 1500 tweets), 2 coders coded 750 tweets each. Descriptive analyses, Mann-Whitney U tests, and Fisher exact tests were performed. Results Tweets about physical activity were dominated by neutral sentiments (1270/1500, 84.67%). Providing opinions or information regarding physical activity (1464/1500, 97.60%) and chatting about physical activity (1354/1500, 90.27%) were found to be popular on Twitter. Approximately 60% (905/1500, 60.33%) of the tweets demonstrated users’ past or current participation in physical activity or intentions to participate in physical activity. However, social support about physical activity was provided in less than 10% of the tweets (135/1500, 9.00%). Users with fewer people following their tweets (followers) (P=.02) and with fewer accounts that they followed (followings) (P=.04

  16. Mechanistic insights into an engineered riboswitch: a switching element which confers riboswitch activity.

    PubMed

    Weigand, Julia E; Schmidtke, Sina R; Will, Tristan J; Duchardt-Ferner, Elke; Hammann, Christian; Wöhnert, Jens; Suess, Beatrix

    2011-04-01

    While many different RNA aptamers have been identified that bind to a plethora of small molecules only very few are capable of acting as engineered riboswitches. Even for aptamers binding the same ligand large differences in their regulatory potential were observed. We address here the molecular basis for these differences by using a set of unrelated neomycin-binding aptamers. UV melting analyses showed that regulating aptamers are thermally stabilized to a significantly higher degree upon ligand binding than inactive ones. Regulating aptamers show high ligand-binding affinity in the low nanomolar range which is necessary but not sufficient for regulation. NMR data showed that a destabilized, open ground state accompanied by extensive structural changes upon ligand binding is important for regulation. In contrast, inactive aptamers are already pre-formed in the absence of the ligand. By a combination of genetic, biochemical and structural analyses, we identified a switching element responsible for destabilizing the ligand free state without compromising the bound form. Our results explain for the first time the molecular mechanism of an engineered riboswitch. PMID:21149263

  17. Metabolic Activation of Rhein: Insights into the Potential Toxicity Induced by Rhein-Containing Herbs.

    PubMed

    Yuan, Yuan; Zheng, Jiyue; Wang, Meiyu; Li, Yuan; Ruan, Jianqing; Zhang, Hongjian

    2016-07-20

    Rhein is a major component of the many medicinal herbs such as rhubarb. Despite wide use, intoxication cases associated with rhein-containing herbs are often reported. The present work aimed to investigate if rhein was subject to metabolic activation leading to toxicity. Upon incubations with different species of liver microsomes, three monoglucuronides were identified, corresponding to two hydroxyl glucuronides and one acyl glucuronide via the carboxyl group, respectively. Further study revealed that rhein acyl glucuronide was chemically reactive, and showed cytotoxicity toward hepatocarcinoma cells. In addition, significant species differences in glucuronidation of rhein were observed between laboratory animals and humans. Reaction phenotyping experiments demonstrated that rhein acyl glucuronide was catalyzed predominantly by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A9, and 2B7. Taken together, the present study confirmed that rhein could be metabolically activated via the formation of acyl glucuronide, especially in human. PMID:27362917

  18. Synthesis, antioxidant and cytoprotective evaluation of potential antiatherogenic phenolic hydrazones. A structure-activity relationship insight.

    PubMed

    Vanucci-Bacqué, Corinne; Carayon, Chantal; Bernis, Corinne; Camare, Caroline; Nègre-Salvayre, Anne; Bedos-Belval, Florence; Baltas, Michel

    2014-08-01

    A novel series of hydrazones derived from substituted benzaldehydes have been synthesized as potential antiatherogenic agents. Several methods were used for exploring their antioxidant and cytoprotective properties, such as their scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, the inhibition of superoxide anion (O₂(·-)) generation and the measurement of cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS). The cytoprotective efficacy was also evaluated by measuring the cell viability (monitored by the MTT assay) in the presence of cytotoxic oxidized LDL. In this report, we discuss the relationship between the chemical structure of phenolic hydrazones and their antioxidant and cytoprotective activities, for subsequent application as antiatherogenic agents. This SAR study confirms that the phenolic frame is not the only prerequisite for antioxidant activity and N-methylbenzothiazole hydrazone moiety magnifies the dual required properties in two most interesting derivatives. PMID:24924425

  19. Insights into the amplification of bacterial resistance to erythromycin in activated sludge.

    PubMed

    Guo, Mei-Ting; Yuan, Qing-Bin; Yang, Jian

    2015-10-01

    Wastewater treatment plants are significant reservoirs for antimicrobial resistance. However, little is known about wastewater treatment effects on the variation of antibiotic resistance. The shifts of bacterial resistance to erythromycin, a macrolide widely used in human medicine, on a lab-scale activated sludge system fed with real wastewater was investigated from levels of bacteria, community and genes, in this study. The resistance variation of total heterotrophic bacteria was studied during the biological treatment process, based on culture dependent method. The alterations of bacterial community resistant to erythromycin and nine typical erythromycin resistance genes were explored with molecular approaches, including high-throughput sequencing and quantitative polymerase chain reaction. The results revealed that the total heterotrophs tolerance level to erythromycin concentrations (higher than 32 mg/L) was significantly amplified during the activated sludge treatment, with the prevalence increased from 9.6% to 21.8%. High-throughput sequencing results demonstrated an obvious increase of the total heterotrophic bacterial diversity resistant to erythromycin. Proteobacteria and Bacteroidetes were the two dominant phyla in the influent and effluent of the bioreactor. However, the prevalence of Proteobacteria decreased from 76% to 59% while the total phyla number increased greatly from 18 to 29 through activated sludge treatment. The gene proportions of erm(A), mef(E) and erm(D) were greatly amplified after biological treatment. It is proposed that the transfer of antibiotic resistance genes through the variable mixtures of bacteria in the activated sludge might be the reason for the antibiotic resistance amplification. The amplified risk of antibiotic resistance in wastewater treatment needs to be paid more attention.

  20. Estimation of ground water residence times in the Critical zone: insight from U activity ratios

    NASA Astrophysics Data System (ADS)

    Chabaux, Francois; Ackerer, Julien; Lucas, Yann; viville, Daniel

    2016-04-01

    The use of radioactive disequilibria as tracers and chronometers of weathering processes and related mass transfers has been recognized since the 60'. The development, over the last two decades, of analytical methods for measuring very precisely U-series nuclides (especially, 234U, 230Th and 226Ra) in environmental samples has opened up new scientific applications in Earth Surface Sciences. Here, we propose to present the potential of U activity ratios in surface waters as chronometer of water transfers at a watershed scale. This will be illustrated from studies performed at different scales, with the analysis of U activity ratios in surface waters from small watersheds (Strengbach and Ringelbach watersheds in the Vosges Mountain, France) but also from watersheds of much more regional extension (e.g., the Upper Rhine basin or the Ganges basin). These various studies show that variations of U activity ratios in surface waters are mainly associated with 234U-238U fractionations occurring during the water transfer within the bedrock, which intensity depends on two main parameters: the petro-physical characteristics of the aquifer, principally the geometry of water-rock interfaces and the duration of the water-rock interactions. This readily explains why different U activity ratios (UAR) can be observed in the different aquifers of a continental hydrosystem and hence why UAR can be used to trace the source of river waters. For a hydrological system developed on a substratum marked by fairly homogeneous petro-physical characteristics, the main parameter controlling the UAR in waters draining such a system would be the duration of the water-rock interactions. Variations of UAR in stream or spring waters of such a system can therefore be modeled using simple reactive transport model, which allows the estimation of both the dissolution rate of the bedrock and the residence time of the waters within the aquifer.

  1. Neutron activation analysis of modern pottery: Insights for archaeological provenance research

    SciTech Connect

    Neff, H.; Arnold, D.E.; Benco, N.L.; Thieme, M.S.

    1996-12-31

    Neutron activation analysis has been employed to characterize ceramics and raw material samples from modern pottery-making communities. The original study focused on several villages in the central highlands of Guatemala. More recently, NAA data have been collected from communities in the Valley of Oaxaca, Mexico, the northern Yucatan Peninsula, and northern Morocco. The results from all four studies can now be combined to yield a comparative perspective on paste preparation effects in archaeological provenance research.

  2. A mitosis-sensing caspase activation platform? New insights into the PIDDosome.

    PubMed

    Shah, Richa B; Thompson, Ruth; Sidi, Samuel

    2016-05-01

    In contrast to the apoptosome and death-inducing signaling complex, the PIDDosome remains an orphan caspase activation platform unassigned to a specific apoptotic pathway. We found that DNA damage-induced PIDDosome formation is blocked by the mitotic checkpoint factor BUBR1 (budding uninhibited by benzimidazole-related 1), via a direct interaction that disrupts the PIDDosome core scaffold. This inhibition occurs at the kinetochore, thus physically connecting the mitotic and apoptotic machineries. PMID:27314076

  3. Insights Into the Effects of Internal Variability, External Variability, and Active Sites on Heterogeneous Ice Nucleation

    NASA Astrophysics Data System (ADS)

    Beydoun, H.; Sullivan, R. C.; Polen, M.

    2015-12-01

    Heterogeneous ice nucleation (HIN) remains one of the outstanding problems in cloud physics and atmospheric science. Experimental challenges in properly simulating HIN processes with relevant atmospheric conditions have largely contributed to the absence of a consistent and comprehensive parameterization. Here we formulate a new ice active surface site-based stochastic model of HIN with the unique feature of invoking a continuum assumption on the ice nucleation activity (contact angle) of an aerosol particle's surface. The result is a particle specific property g that defines a distribution of local surface ice nucleation rates. Upon integration this yields a full freezing probability function for an ice nucleating particle. Current cold plate droplet freezing measurements provide a great resource for studying the freezing ability of many atmospheric aerosol systems. A method based on statistical significance and critical area analysis is presented that can resolve the two-dimensional nature of the ice nucleation ability of aerosol particles: variability in active sites and freezing rates along an individual particle's surface, as well as variability between two particles of the same type in an aerosol population. When applied to published experimental data, the method demonstrates its ability to comprehensively interpret droplet freezing spectra of variable particle mass and surface area concentrations. By fitting the high concentration freezing curves to a statistically significant active site density function, the lower concentration freezing curves are successfully fitted via a process of random sampling from the statistically significant distribution. Using the new scheme, comprehensive parameterizations that can track the frozen fraction of cloud droplets in larger atmospheric models are derived.

  4. Insights into the amplification of bacterial resistance to erythromycin in activated sludge.

    PubMed

    Guo, Mei-Ting; Yuan, Qing-Bin; Yang, Jian

    2015-10-01

    Wastewater treatment plants are significant reservoirs for antimicrobial resistance. However, little is known about wastewater treatment effects on the variation of antibiotic resistance. The shifts of bacterial resistance to erythromycin, a macrolide widely used in human medicine, on a lab-scale activated sludge system fed with real wastewater was investigated from levels of bacteria, community and genes, in this study. The resistance variation of total heterotrophic bacteria was studied during the biological treatment process, based on culture dependent method. The alterations of bacterial community resistant to erythromycin and nine typical erythromycin resistance genes were explored with molecular approaches, including high-throughput sequencing and quantitative polymerase chain reaction. The results revealed that the total heterotrophs tolerance level to erythromycin concentrations (higher than 32 mg/L) was significantly amplified during the activated sludge treatment, with the prevalence increased from 9.6% to 21.8%. High-throughput sequencing results demonstrated an obvious increase of the total heterotrophic bacterial diversity resistant to erythromycin. Proteobacteria and Bacteroidetes were the two dominant phyla in the influent and effluent of the bioreactor. However, the prevalence of Proteobacteria decreased from 76% to 59% while the total phyla number increased greatly from 18 to 29 through activated sludge treatment. The gene proportions of erm(A), mef(E) and erm(D) were greatly amplified after biological treatment. It is proposed that the transfer of antibiotic resistance genes through the variable mixtures of bacteria in the activated sludge might be the reason for the antibiotic resistance amplification. The amplified risk of antibiotic resistance in wastewater treatment needs to be paid more attention. PMID:25957255

  5. Structural insight into the active site of a Bombyx mori unclassified glutathione transferase.

    PubMed

    Hossain, Md Tofazzal; Yamamoto, Kohji

    2015-01-01

    Glutathione transferases (GSTs) are major detoxification enzymes that play central roles in the defense against various environmental toxicants as well as oxidative stress. Here, we identify amino acid residues of an unclassified GST from Bombyx mori, bmGSTu-interacting glutathione (GSH). Site-directed mutagenesis of bmGSTu mutants indicated that amino acid residues Asp103, Ser162, and Ser166 contribute to catalytic activity.

  6. Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights.

    PubMed

    Grassi, Guido; Brambilla, GianMaria; Pizzalla, Daniela Prata; Seravalle, Gino

    2016-08-01

    Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients. PMID:27334011

  7. Modulation of MICAL Monooxygenase Activity by its Calponin Homology Domain: Structural and Mechanistic Insights

    PubMed Central

    Alqassim, Saif S.; Urquiza, Mauricio; Borgnia, Eitan; Nagib, Marc; Amzel, L. Mario; Bianchet, Mario A.

    2016-01-01

    MICALs (Molecule Interacting with CasL) are conserved multidomain enzymes essential for cytoskeletal reorganization in nerve development, endocytosis, and apoptosis. In these enzymes, a type-2 calponin homology (CH) domain always follows an N-terminal monooxygenase (MO) domain. Although the CH domain is required for MICAL-1 cellular localization and actin-associated function, its contribution to the modulation of MICAL activity towards actin remains unclear. Here, we present the structure of a fragment of MICAL-1 containing the MO and the CH domains—determined by X-ray crystallography and small angle scattering—as well as kinetics experiments designed to probe the contribution of the CH domain to the actin-modification activity. Our results suggest that the CH domain, which is loosely connected to the MO domain by a flexible linker and is far away from the catalytic site, couples F-actin to the enhancement of redox activity of MICALMO-CH by a cooperative mechanism involving a trans interaction between adjacently bound molecules. Binding cooperativity is also observed in other proteins regulating actin assembly/disassembly dynamics, such as ADF/Cofilins. PMID:26935886

  8. Novel Insights into Structure-Activity Relationships of N-Terminally Modified PACE4 Inhibitors.

    PubMed

    Kwiatkowska, Anna; Couture, Frédéric; Levesque, Christine; Ly, Kévin; Beauchemin, Sophie; Desjardins, Roxane; Neugebauer, Witold; Dory, Yves L; Day, Robert

    2016-02-01

    PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi-Leu (ML) peptide, an octapeptide with the sequence Ac-LLLLRVKR-NH2 . Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N-terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N-terminal extension but by the protection of both ends with the d-Leu residue and 4-amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile. PMID:26751825

  9. Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death

    PubMed Central

    Singh, Nitu; Senapati, Sanjib; Bose, Kakoli

    2016-01-01

    High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2-mediated apoptosis is poorly understood. Here, with an interdisciplinary approach that involves in silico, mutational, biochemical and biophysical probes, we dissected and characterized the E2-procasapse-8 binding interface. Our data demonstrate direct non-homotypic interaction of HPV18 E2 transactivation domain (TAD) with α2/α5 helices of procaspase-8 death effector domain-B (DED-B). The observed interaction mimics the homotypic DED-DED complexes, wherein the conserved hydrophobic motif of procaspase-8 DED-B (F122/L123) occupies a groove between α2/α3 helices of E2 TAD. This interaction possibly drives DED oligomerization leading to caspase-8 activation and subsequent cell death. Furthermore, our data establish a model for E2-induced apoptosis in HR-HPV types and provide important clues for designing E2 analogs that might modulate procaspase-8 activation and hence apoptosis. PMID:26906543

  10. Crystal structures of Ophiostoma piceae sterol esterase: structural insights into activation mechanism and product release.

    PubMed

    Gutiérrez-Fernández, Javier; Vaquero, María Eugenia; Prieto, Alicia; Barriuso, Jorge; Martínez, María Jesús; Hermoso, Juan A

    2014-09-01

    Sterol esterases are able to efficiently hydrolyze both sterol esters and triglycerides and to carry out synthesis reactions in the presence of organic solvents. Their high versatility makes them excellent candidates for biotechnological purposes. Sterol esterase from fungus Ophiostoma piceae (OPE) belongs to the family abH03.01 of the Candida rugosa lipase-like proteins. Crystal structures of OPE were solved in this study for the closed and open conformations. Enzyme activation involves a large displacement of the conserved lid, structural rearrangements of loop α16-α17, and formation of a dimer with a large opening. Three PEG molecules are placed in the active site, mimicking chains of the triglyceride substrate, demonstrating the position of the oxyanion hole and the three pockets that accommodate the sn-1, sn-2 and sn-3 fatty acids chains. One of them is an internal tunnel, connecting the active center with the outer surface of the enzyme 30 Å far from the catalytic Ser220. Based on our structural and biochemical results we propose a mechanism by which a great variety of different substrates can be hydrolyzed in OPE paving the way for the construction of new variants to improve the catalytic properties of these enzymes and their biotechnological applications. PMID:25108239

  11. Crystal structures of Ophiostoma piceae sterol esterase: structural insights into activation mechanism and product release.

    PubMed

    Gutiérrez-Fernández, Javier; Vaquero, María Eugenia; Prieto, Alicia; Barriuso, Jorge; Martínez, María Jesús; Hermoso, Juan A

    2014-09-01

    Sterol esterases are able to efficiently hydrolyze both sterol esters and triglycerides and to carry out synthesis reactions in the presence of organic solvents. Their high versatility makes them excellent candidates for biotechnological purposes. Sterol esterase from fungus Ophiostoma piceae (OPE) belongs to the family abH03.01 of the Candida rugosa lipase-like proteins. Crystal structures of OPE were solved in this study for the closed and open conformations. Enzyme activation involves a large displacement of the conserved lid, structural rearrangements of loop α16-α17, and formation of a dimer with a large opening. Three PEG molecules are placed in the active site, mimicking chains of the triglyceride substrate, demonstrating the position of the oxyanion hole and the three pockets that accommodate the sn-1, sn-2 and sn-3 fatty acids chains. One of them is an internal tunnel, connecting the active center with the outer surface of the enzyme 30 Å far from the catalytic Ser220. Based on our structural and biochemical results we propose a mechanism by which a great variety of different substrates can be hydrolyzed in OPE paving the way for the construction of new variants to improve the catalytic properties of these enzymes and their biotechnological applications.

  12. Tumulus development on lava flows: insights from observations of active tumuli and analysis of formation models

    NASA Astrophysics Data System (ADS)

    Anderson, Steven W.; Smrekar, Suzanne E.; Stofan, Ellen R.

    2012-05-01

    Here, we use observations of active flows along with detailed morphometric field measurements of more than 70 tumuli on flows at Mount Etna (Italy), Kilauea, and Hualalai (US) volcanoes to constrain a previously published model that estimates the pressure needed to form tumuli. In an attempt to discover the nature and magnitude of pressure variations within active lava flow interiors, we then consider how tumuli differ from idealized circular plates. We incorporate observations of active tumuli and find that they may grow asymmetrically yet produce a symmetrical tumulus and can form where the flow path significantly changes direction. Bending models of clamped edges provide the most reasonable head estimates for the tumuli in our study. Tumulus formation requires the proper combination of cooling and effusion rate. If cooling is too extensive and effusion rate too low, the crust will provide too much resistance to bending. If cooling is too limited and effusion rates too high, crusts will not develop or have insufficient strength to resist fracture and subsequent breakouts. We do not find it surprising that tumuli are rarely found over well-established lava tubes that typically have rigid, walls/overlying crusts that exceed 2 m in thickness and provide too much resistance to bending. Silicic flows lack tumuli because the viscosity gradients within the flow are insufficient to concentrate stress in a localized area.

  13. Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights.

    PubMed

    Grassi, Guido; Brambilla, GianMaria; Pizzalla, Daniela Prata; Seravalle, Gino

    2016-08-01

    Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients.

  14. Structural Insights into NEDD8 Activation of Cullin-RING Ligases: Conformational Control of Conjugation

    SciTech Connect

    Duda,D.; Borg, L.; Scott, D.; Hunt, H.; Hammel, M.; Schulman, B.

    2008-01-01

    Cullin-RING ligases (CRLs) comprise the largest ubiquitin E3 subclass, in which a central cullin subunit links a substrate-binding adaptor with an E2-binding RING. Covalent attachment of the ubiquitin-like protein NEDD8 to a conserved C-terminal domain (ctd) lysine stimulates CRL ubiquitination activity and prevents binding of the inhibitor CAND1. Here we report striking conformational rearrangements in the crystal structure of NEDD8{approx}Cul5ctd-Rbx1 and SAXS analysis of NEDD8{approx}Cul1ctd-Rbx1 relative to their unmodified counterparts. In NEDD8ylated CRL structures, the cullin WHB and Rbx1 RING subdomains are dramatically reoriented, eliminating a CAND1-binding site and imparting multiple potential catalytic geometries to an associated E2. Biochemical analyses indicate that the structural malleability is important for both CRL NEDD8ylation and subsequent ubiquitination activities. Thus, our results point to a conformational control of CRL activity, with ligation of NEDD8 shifting equilibria to disfavor inactive CAND1-bound closed architectures, and favor dynamic, open forms that promote polyubiquitination.

  15. Aurone synthase is a catechol oxidase with hydroxylase activity and provides insights into the mechanism of plant polyphenol oxidases.

    PubMed

    Molitor, Christian; Mauracher, Stephan Gerhard; Rompel, Annette

    2016-03-29

    Tyrosinases and catechol oxidases belong to the family of polyphenol oxidases (PPOs). Tyrosinases catalyze theo-hydroxylation and oxidation of phenolic compounds, whereas catechol oxidases were so far defined to lack the hydroxylation activity and catalyze solely the oxidation of o-diphenolic compounds. Aurone synthase from Coreopsis grandiflora (AUS1) is a specialized plant PPO involved in the anabolic pathway of aurones. We present, to our knowledge, the first crystal structures of a latent plant PPO, its mature active and inactive form, caused by a sulfation of a copper binding histidine. Analysis of the latent proenzyme's interface between the shielding C-terminal domain and the main core provides insights into its activation mechanisms. As AUS1 did not accept common tyrosinase substrates (tyrosine and tyramine), the enzyme is classified as a catechol oxidase. However, AUS1 showed hydroxylase activity toward its natural substrate (isoliquiritigenin), revealing that the hydroxylase activity is not correlated with the acceptance of common tyrosinase substrates. Therefore, we propose that the hydroxylase reaction is a general functionality of PPOs. Molecular dynamics simulations of docked substrate-enzyme complexes were performed, and a key residue was identified that influences the plant PPO's acceptance or rejection of tyramine. Based on the evidenced hydroxylase activity and the interactions of specific residues with the substrates during the molecular dynamics simulations, a novel catalytic reaction mechanism for plant PPOs is proposed. The presented results strongly suggest that the physiological role of plant catechol oxidases were previously underestimated, as they might hydroxylate their--so far unknown--natural substrates in vivo.

  16. Aurone synthase is a catechol oxidase with hydroxylase activity and provides insights into the mechanism of plant polyphenol oxidases.

    PubMed

    Molitor, Christian; Mauracher, Stephan Gerhard; Rompel, Annette

    2016-03-29

    Tyrosinases and catechol oxidases belong to the family of polyphenol oxidases (PPOs). Tyrosinases catalyze theo-hydroxylation and oxidation of phenolic compounds, whereas catechol oxidases were so far defined to lack the hydroxylation activity and catalyze solely the oxidation of o-diphenolic compounds. Aurone synthase from Coreopsis grandiflora (AUS1) is a specialized plant PPO involved in the anabolic pathway of aurones. We present, to our knowledge, the first crystal structures of a latent plant PPO, its mature active and inactive form, caused by a sulfation of a copper binding histidine. Analysis of the latent proenzyme's interface between the shielding C-terminal domain and the main core provides insights into its activation mechanisms. As AUS1 did not accept common tyrosinase substrates (tyrosine and tyramine), the enzyme is classified as a catechol oxidase. However, AUS1 showed hydroxylase activity toward its natural substrate (isoliquiritigenin), revealing that the hydroxylase activity is not correlated with the acceptance of common tyrosinase substrates. Therefore, we propose that the hydroxylase reaction is a general functionality of PPOs. Molecular dynamics simulations of docked substrate-enzyme complexes were performed, and a key residue was identified that influences the plant PPO's acceptance or rejection of tyramine. Based on the evidenced hydroxylase activity and the interactions of specific residues with the substrates during the molecular dynamics simulations, a novel catalytic reaction mechanism for plant PPOs is proposed. The presented results strongly suggest that the physiological role of plant catechol oxidases were previously underestimated, as they might hydroxylate their--so far unknown--natural substrates in vivo. PMID:26976571

  17. Aurone synthase is a catechol oxidase with hydroxylase activity and provides insights into the mechanism of plant polyphenol oxidases

    PubMed Central

    Molitor, Christian; Mauracher, Stephan Gerhard

    2016-01-01

    Tyrosinases and catechol oxidases belong to the family of polyphenol oxidases (PPOs). Tyrosinases catalyze the o-hydroxylation and oxidation of phenolic compounds, whereas catechol oxidases were so far defined to lack the hydroxylation activity and catalyze solely the oxidation of o-diphenolic compounds. Aurone synthase from Coreopsis grandiflora (AUS1) is a specialized plant PPO involved in the anabolic pathway of aurones. We present, to our knowledge, the first crystal structures of a latent plant PPO, its mature active and inactive form, caused by a sulfation of a copper binding histidine. Analysis of the latent proenzyme’s interface between the shielding C-terminal domain and the main core provides insights into its activation mechanisms. As AUS1 did not accept common tyrosinase substrates (tyrosine and tyramine), the enzyme is classified as a catechol oxidase. However, AUS1 showed hydroxylase activity toward its natural substrate (isoliquiritigenin), revealing that the hydroxylase activity is not correlated with the acceptance of common tyrosinase substrates. Therefore, we propose that the hydroxylase reaction is a general functionality of PPOs. Molecular dynamics simulations of docked substrate–enzyme complexes were performed, and a key residue was identified that influences the plant PPO’s acceptance or rejection of tyramine. Based on the evidenced hydroxylase activity and the interactions of specific residues with the substrates during the molecular dynamics simulations, a novel catalytic reaction mechanism for plant PPOs is proposed. The presented results strongly suggest that the physiological role of plant catechol oxidases were previously underestimated, as they might hydroxylate their—so far unknown—natural substrates in vivo. PMID:26976571

  18. Transcranial electric stimulation (tES) and NeuroImaging: the state-of-the-art, new insights and prospects in basic and clinical neuroscience.

    PubMed

    Soekadar, Surjo R; Herring, Jim Don; McGonigle, David

    2016-10-15

    Transcranial electric stimulation (tES) of the brain has attracted an increased interest in recent years. Yet, despite remarkable research efforts to date, the underlying neurobiological mechanisms of tES' effects are still incompletely understood. This Special Issue aims to provide a comprehensive and up-to-date overview of the state-of-the-art in studies combining tES and neuroimaging, while introducing most recent insights and outlining future prospects related to this new and rapidly growing field. The findings reported here combine methodological advancements with insights into the underlying mechanisms of tES itself. At the same time, they also point to the many caveats and specific challenges associated with such studies, which can arise from both technical and biological sources. Besides promising to advance basic neuroscience, combined tES and neuroimaging studies may also substantially change previous conceptions about the methods of action of electric or magnetic stimulation on the brain.

  19. Transcranial electric stimulation (tES) and NeuroImaging: the state-of-the-art, new insights and prospects in basic and clinical neuroscience.

    PubMed

    Soekadar, Surjo R; Herring, Jim Don; McGonigle, David

    2016-10-15

    Transcranial electric stimulation (tES) of the brain has attracted an increased interest in recent years. Yet, despite remarkable research efforts to date, the underlying neurobiological mechanisms of tES' effects are still incompletely understood. This Special Issue aims to provide a comprehensive and up-to-date overview of the state-of-the-art in studies combining tES and neuroimaging, while introducing most recent insights and outlining future prospects related to this new and rapidly growing field. The findings reported here combine methodological advancements with insights into the underlying mechanisms of tES itself. At the same time, they also point to the many caveats and specific challenges associated with such studies, which can arise from both technical and biological sources. Besides promising to advance basic neuroscience, combined tES and neuroimaging studies may also substantially change previous conceptions about the methods of action of electric or magnetic stimulation on the brain. PMID:27633745

  20. Mutational activation of niche-specific genes provides insight into regulatory networks and bacterial function in a complex environment

    PubMed Central

    Giddens, Stephen R.; Jackson, Robert W.; Moon, Christina D.; Jacobs, Michael A.; Zhang, Xue-Xian; Gehrig, Stefanie M.; Rainey, Paul B.

    2007-01-01

    The genome of the plant-colonizing bacterium Pseudomonas fluorescens SBW25 harbors a subset of genes that are expressed specifically on plant surfaces. The function of these genes is central to the ecological success of SBW25, but their study poses significant challenges because no phenotype is discernable in vitro. Here, we describe a genetic strategy with general utility that combines suppressor analysis with IVET (SPyVET) and provides a means of identifying regulators of niche-specific genes. Central to this strategy are strains carrying operon fusions between plant environment-induced loci (EIL) and promoterless ′dapB. These strains are prototrophic in the plant environment but auxotrophic on laboratory minimal medium. Regulatory elements were identified by transposon mutagenesis and selection for prototrophs on minimal medium. Approximately 106 mutants were screened for each of 27 strains carrying ′dapB fusions to plant EIL and the insertion point for the transposon determined in approximately 2,000 putative regulator mutants. Regulators were functionally characterized and used to provide insight into EIL phenotypes. For one strain carrying a fusion to the cellulose-encoding wss operon, five different regulators were identified including a diguanylate cyclase, the flagella activator, FleQ, and alginate activator, AmrZ (AlgZ). Further rounds of suppressor analysis, possible by virtue of the SPyVET strategy, revealed an additional two regulators including the activator AlgR, and allowed the regulatory connections to be determined. PMID:17989226

  1. Insights into the different dioxygen activation pathways of methane and toluene monooxygenase hydroxylases

    PubMed Central

    Bochevarov, Arteum D.; Li, Jianing; Song, Woon Ju; Friesner, Richard A.; Lippard, Stephen J.

    2010-01-01

    The methane and toluene monooxygenase hydroxylases (MMOH and TMOH, respectively) have almost identical active sites yet the physical and chemical properties of their oxygenated intermediates, designated P*, Hperoxo, Q and Q* in MMOH and ToMOHperoxo in ToMOH, are substantially different. We review and compare the structural differences in the vicinity of the active sites of these enzymes and discuss which changes could give rise to the different behavior of Hperoxo and Q. In particular, analysis of multiple crystal structures reveals that T213 in MMOH and the analogous T201 in TMOH, located in the immediate vicinity of the active site, have different rotatory configurations. We study the rotation energy profiles of these threonine residues with the use of molecular mechanics (MM) and quantum mechanics/molecular mechanics (QM/MM) computational methods and put forward a hypothesis according to which T201 and T213 play an important role in the formation of different types of peroxodiiron(III) species in MMOH and ToMOH. The hypothesis is indirectly supported by QM/MM calculations of the peroxodiiron(III) models of ToMOH and the theoretically computed Mössbauer spectra. It also helps explain the formation of two distinct peroxodiiron(III) species in the T201S mutant of ToMOH. Additionally, a role for the ToMOD regulatory protein, which is essential for intermediate formation and the protein functioning in the ToMO system, is advanced. We find that the low quadrupole splitting parameter in the Mössbauer spectrum observed for a ToMOHperoxo intermediate can be explained by protonation of the peroxo moiety, possibly stabilized by the T201 residue. PMID:21517016

  2. New Insights on the Mechanism of the K+-Independent Activity of Crenarchaeota Pyruvate Kinases

    PubMed Central

    De la Vega-Ruíz, Gustavo; Domínguez-Ramírez, Lenin; Riveros-Rosas, Héctor; Guerrero-Mendiola, Carlos; Torres-Larios, Alfredo; Hernández-Alcántara, Gloria; García-Trejo, José J.; Ramírez-Silva, Leticia

    2015-01-01

    Eukarya pyruvate kinases have glutamate at position 117 (numbered according to the rabbit muscle enzyme), whereas in Bacteria have either glutamate or lysine and in Archaea have other residues. Glutamate at this position makes pyruvate kinases K+-dependent, whereas lysine confers K+-independence because the positively charged residue substitutes for the monovalent cation charge. Interestingly, pyruvate kinases from two characterized Crenarchaeota exhibit K+-independent activity, despite having serine at the equivalent position. To better understand pyruvate kinase catalytic activity in the absence of K+ or an internal positive charge, the Thermofilum pendens pyruvate kinase (valine at the equivalent position) was characterized. The enzyme activity was K+-independent. The kinetic mechanism was random order with a rapid equilibrium, which is equal to the mechanism of the rabbit muscle enzyme in the presence of K+ or the mutant E117K in the absence of K+. Thus, the substrate binding order of the T. pendens enzyme was independent despite lacking an internal positive charge. Thermal stability studies of this enzyme showed two calorimetric transitions, one attributable to the A and C domains (Tm of 99.2°C), and the other (Tm of 105.2°C) associated with the B domain. In contrast, the rabbit muscle enzyme exhibits a single calorimetric transition (Tm of 65.2°C). The calorimetric and kinetic data indicate that the B domain of this hyperthermophilic enzyme is more stable than the rest of the protein with a conformation that induces the catalytic readiness of the enzyme. B domain interactions of pyruvate kinases that have been determined in Pyrobaculum aerophilum and modeled in T. pendens were compared with those of the rabbit muscle enzyme. The results show that intra- and interdomain interactions of the Crenarchaeota enzymes may account for their higher B domain stability. Thus the structural arrangement of the T. pendens pyruvate kinase could allow charge

  3. Theoretical insights on the antioxidant activity of edaravone free radical scavengers derivatives

    NASA Astrophysics Data System (ADS)

    Cerón-Carrasco, José P.; Roy, Hélène M.; Cerezo, Javier; Jacquemin, Denis; Laurent, Adèle D.

    2014-04-01

    The prediction of antioxidant properties is not straightforward due to the complexity of the in vivo systems. Here, we use theoretical descriptors, including the potential of ionization, the electrodonating power and the spin density distribution, to characterize the antioxidant capacity of edaravone (EDV) derivatives. Our computations reveal the relationship between these parameters and their potential bioactivity as free radical scavengers. We conclude that more efficient antioxidants could be synthesized by tuning the R1 and R2 positions of the EDV structure, rather than modifying the R3 group. Such modifications might improve the antioxidant activity in neutral and deprotonated forms.

  4. Active Reward Processing during Human Sleep: Insights from Sleep-Related Eating Disorder.

    PubMed

    Perogamvros, Lampros; Baud, Patrick; Hasler, Roland; Cloninger, Claude Robert; Schwartz, Sophie; Perrig, Stephen

    2012-01-01

    In this paper, we present two carefully documented cases of patients with sleep-related eating disorder (SRED), a parasomnia which is characterized by involuntary compulsive eating during the night and whose pathophysiology is not known. Using video-polysomnography, a dream diary and psychometric examination, we found that both patients present elevated novelty seeking and increased reward sensitivity. In light of new evidence on the mesolimbic dopaminergic implication in compulsive eating disorders, our findings suggest a role of an active reward system during sleep in the manifestation of SRED.

  5. Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing.

    PubMed

    Placencio, Veronica R; DeClerck, Yves A

    2015-08-01

    Despite its function as an inhibitor of urokinase and tissue-type plasminogen activator (PA), PA inhibitor-1 (PAI-1) has a paradoxical protumorigenic role in cancer, promoting angiogenesis and tumor cell survival. In this review, we summarize preclinical evidence in support of the protumorigenic function of PAI-1 that has led to the testing of small-molecule PAI-1 inhibitors, initially developed as antithrombotic agents, in animal models of cancer. The review discusses the challenges and the opportunities that lay ahead to the development of efficacious and nontoxic PAI-1 inhibitors as anticancer agents.

  6. Active Reward Processing during Human Sleep: Insights from Sleep-Related Eating Disorder

    PubMed Central

    Perogamvros, Lampros; Baud, Patrick; Hasler, Roland; Cloninger, Claude Robert; Schwartz, Sophie; Perrig, Stephen

    2012-01-01

    In this paper, we present two carefully documented cases of patients with sleep-related eating disorder (SRED), a parasomnia which is characterized by involuntary compulsive eating during the night and whose pathophysiology is not known. Using video-polysomnography, a dream diary and psychometric examination, we found that both patients present elevated novelty seeking and increased reward sensitivity. In light of new evidence on the mesolimbic dopaminergic implication in compulsive eating disorders, our findings suggest a role of an active reward system during sleep in the manifestation of SRED. PMID:23205019

  7. Io’s active volcanoes during the New Horizons era: Insights from New Horizons imaging

    NASA Astrophysics Data System (ADS)

    Rathbun, J. A.; Spencer, J. R.; Lopes, R. M.; Howell, R. R.

    2014-03-01

    In February 2007, the New Horizons spacecraft flew by the Jupiter system, obtaining images of Io, the most volcanically active body in the Solar System. The Multicolor Visible Imaging Camera (MVIC), a four-color (visible to near infrared) camera, obtained 17 sets of images. The Long-Range Reconnaissance Imager (LORRI), a high-resolution panchromatic camera, obtained 190 images, including many of Io eclipsed by Jupiter. We present a complete view of the discrete point-like emission sources in all images obtained by these two instruments. We located 54 emission sources and determined their brightnesses. These observations, the first that observed individual Ionian volcanoes on short timescales of seconds to minutes, demonstrate that the volcanoes have stable brightnesses on these timescales. The active volcanoes Tvashtar (63N, 124W) and E. Girru (22N, 245W) were observed by both LORRI and MVIC, both in the near-infrared (NIR) and methane (CH4) filters. Tvashtar was additionally observed in the red filter, which allowed us to calculate a color temperature of approximately 1200 K. We found that, with some exceptions, most of the volcanoes frequently active during the Galileo era continued to be active during the New Horizons flyby. We found that none of the seven volcanoes observed by New Horizons multiple times over short timescales showed substantial changes on the order of seconds and only one, E. Girru exhibited substantial variation over minutes to days, increasing by 25% in just over an hour and decreasing by a factor of 4 over 6 days. Observations of Tvashtar are consistent with a current eruption similar to previously observed eruptions and are more consistent with the thermal emission of a lava flow than the fire fountains inferred from the November 1999 observations. These data also present new puzzles regarding Ionian volcanism. Since there is no associated surface change or low albedo feature that could be identified nearby, the source of the emission from

  8. Active states and structure transformations in accreting white dwarfs

    NASA Astrophysics Data System (ADS)

    Boneva, Daniela; Kaygorodov, Pavel

    2016-07-01

    Active states in white dwarfs are usually associated with light curve's effects that concern to the bursts, flickering or flare-up occurrences. It is common that a gas-dynamics source exists for each of these processes there. We consider the white dwarf binary stars with accretion disc around the primary. We suggest a flow transformation modeling of the mechanisms that are responsible for ability to cause some flow instability and bring the white dwarfs system to the outburst's development. The processes that cause the accretion rate to sufficiently increase are discussed. Then the transition from a quiescent to an active state is realized. We analyze a quasi-periodic variability in the luminosity of white dwarf binary stars systems. The results are supported with an observational data.

  9. Mining Claim Activity on Federal Land in the United States

    USGS Publications Warehouse

    Causey, J. Douglas

    2007-01-01

    Several statistical compilations of mining claim activity on Federal land derived from the Bureau of Land Management's LR2000 database have previously been published by the U.S Geological Survey (USGS). The work in the 1990s did not include Arkansas or Florida. None of the previous reports included Alaska because it is stored in a separate database (Alaska Land Information System) and is in a different format. This report includes data for all states for which there are Federal mining claim records, beginning in 1976 and continuing to the present. The intent is to update the spatial and statistical data associated with this report on an annual basis, beginning with 2005 data. The statistics compiled from the databases are counts of the number of active mining claims in a section of land each year from 1976 to the present for all states within the United States. Claim statistics are subset by lode and placer types, as well as a dataset summarizing all claims including mill site and tunnel site claims. One table presents data by case type, case status, and number of claims in a section. This report includes a spatial database for each state in which mining claims were recorded, except North Dakota, which only has had two claims. A field is present that allows the statistical data to be joined to the spatial databases so that spatial displays and analysis can be done by using appropriate geographic information system (GIS) software. The data show how mining claim activity has changed in intensity, space, and time. Variations can be examined on a state, as well as a national level. The data are tied to a section of land, approximately 640 acres, which allows it to be used at regional, as well as local scale. The data only pertain to Federal land and mineral estate that was open to mining claim location at the time the claims were staked.

  10. Insights on the Phytochemical Profile (Cyclopeptides) and Biological Activities of Calotropis procera Latex Organic Fractions

    PubMed Central

    Jucá, Thiago Lustosa; Ramos, Márcio Viana; Moreno, Frederico Bruno Mendes Batista; Viana de Matos, Mayara Patrícia; Marinho-Filho, José Delano Barreto; Moreira, Renato Azevedo; Monteiro-Moreira, Ana Cristina de Oliveira

    2013-01-01

    Calotropis procera is a medicinal plant whose pharmacological properties are associated with its latex. Here, the Calotropis procera latex fractions were investigated in an attempt to trace its phytochemical profile and measure its anti-inflammatory and toxicity activity. The crude latex was partitioned, yielding five fractions (49.4% hexane, 5.2% dichloromethane, 2.0% ethyl acetate, 2.1% n-butanol, and 41.1% aqueous). Phytochemical screening and spectroscopy analysis revealed that dichloromethane is the most chemically diverse fraction. Triterpenes were detected in both the hexane and dichloromethane fractions, while flavonoids were detected in the dichloromethane and ethyl acetate fractions. These fractions were cytotoxic to cancer cell lines (LD50 0.05 to 3.9 μg/mL) and lethal to brine shrimp (LD50 10.9 to 65.7 μg/mL). Reduced neutrophil migration in rats was observed in carrageenan-induced peritonitis for the dichloromethane (67%), ethyl acetate (56%), and aqueous (72%) fractions. A positive reaction with tolidine and ninhydrin suggested that cyclopeptides are in the ethyl acetate fraction. It is therefore concluded that Calotropis procera latex dichloromethane and ethyl acetate fractions exhibit both in vitro and in vivo activities as well as anti-inflammatory properties. Cyclopeptide detection is especially interesting because previous attempts to investigate these low-molecular cyclic amino acid sequences in C. procera have failed. PMID:24348174

  11. Streaming potential modeling in fractured rock: Insights into the identification of hydraulically active fractures

    NASA Astrophysics Data System (ADS)

    Roubinet, D.; Linde, N.; Jougnot, D.; Irving, J.

    2016-05-01

    Numerous field experiments suggest that the self-potential (SP) geophysical method may allow for the detection of hydraulically active fractures and provide information about fracture properties. However, a lack of suitable numerical tools for modeling streaming potentials in fractured media prevents quantitative interpretation and limits our understanding of how the SP method can be used in this regard. To address this issue, we present a highly efficient two-dimensional discrete-dual-porosity approach for solving the fluid flow and associated self-potential problems in fractured rock. Our approach is specifically designed for complex fracture networks that cannot be investigated using standard numerical methods. We then simulate SP signals associated with pumping conditions for a number of examples to show that (i) accounting for matrix fluid flow is essential for accurate SP modeling and (ii) the sensitivity of SP to hydraulically active fractures is intimately linked with fracture-matrix fluid interactions. This implies that fractures associated with strong SP amplitudes are likely to be hydraulically conductive, attracting fluid flow from the surrounding matrix.

  12. Structural insights into the polypharmacological activity of quercetin on serine/threonine kinases

    PubMed Central

    Baby, Bincy; Antony, Priya; Al Halabi, Walaa; Al Homedi, Zahrah; Vijayan, Ranjit

    2016-01-01

    Polypharmacology, the discovery or design of drug molecules that can simultaneously interact with multiple targets, is gaining interest in contemporary drug discovery. Serine/threonine kinases are attractive targets for therapeutic intervention in oncology due to their role in cellular phosphorylation and altered expression in cancer. Quercetin, a naturally occurring flavonoid, inhibits multiple cancer cell lines and is used as an anticancer drug in Phase I clinical trial. Quercetin glycosides have also received some attention due to their high bioavailability and activity against various diseases including cancer. However, these have been studied to a lesser extent. In this study, the structural basis of the multitarget inhibitory activity of quercetin and isoquercitrin, a glycoside derivative, on serine/threonine kinases using molecular modeling was explored. Structural analysis showed that both quercetin and isoquercitrin exhibited good binding energies and interacted with aspartate in the highly conserved Asp–Phe–Gly motif. The results indicate that isoquercitrin could be a more potent inhibitor of several members of the serine/threonine kinase family. In summary, the current structural evaluation highlights the multitarget inhibitory property of quercetin and its potential to be a chemical platform for oncological polypharmacology. PMID:27729770

  13. Structural and mechanistic insights into Helicobacter pylori NikR activation

    PubMed Central

    Bahlawane, C.; Dian, C.; Muller, C.; Round, A.; Fauquant, C.; Schauer, K.; de Reuse, H.; Terradot, L.; Michaud-Soret, I.

    2010-01-01

    NikR is a transcriptional metalloregulator central in the mandatory response to acidity of Helicobacter pylori that controls the expression of numerous genes by binding to specific promoter regions. NikR/DNA interactions were proposed to rely on protein activation by Ni(II) binding to high-affinity (HA) and possibly secondary external (X) sites. We describe a biochemical characterization of HpNikR mutants that shows that the HA sites are essential but not sufficient for DNA binding, while the secondary external (X) sites and residues from the HpNikR dimer–dimer interface are important for DNA binding. We show that a second metal is necessary for HpNikR/DNA binding, but only to some promoters. Small-angle X-ray scattering shows that HpNikR adopts a defined conformation in solution, resembling the cis-conformation and suggests that nickel does not trigger large conformational changes in HpNikR. The crystal structures of selected mutants identify the effects of each mutation on HpNikR structure. This study unravels key structural features from which we derive a model for HpNikR activation where: (i) HA sites and an hydrogen bond network are required for DNA binding and (ii) metallation of a unique secondary external site (X) modulates HpNikR DNA binding to low-affinity promoters by disruption of a salt bridge. PMID:20089510

  14. Insights on the phytochemical profile (cyclopeptides) and biological activities of Calotropis procera latex organic fractions.

    PubMed

    Jucá, Thiago Lustosa; Ramos, Márcio Viana; Moreno, Frederico Bruno Mendes Batista; Viana de Matos, Mayara Patrícia; Marinho-Filho, José Delano Barreto; Moreira, Renato Azevedo; de Oliveira Monteiro-Moreira, Ana Cristina

    2013-01-01

    Calotropis procera is a medicinal plant whose pharmacological properties are associated with its latex. Here, the Calotropis procera latex fractions were investigated in an attempt to trace its phytochemical profile and measure its anti-inflammatory and toxicity activity. The crude latex was partitioned, yielding five fractions (49.4% hexane, 5.2% dichloromethane, 2.0% ethyl acetate, 2.1% n-butanol, and 41.1% aqueous). Phytochemical screening and spectroscopy analysis revealed that dichloromethane is the most chemically diverse fraction. Triterpenes were detected in both the hexane and dichloromethane fractions, while flavonoids were detected in the dichloromethane and ethyl acetate fractions. These fractions were cytotoxic to cancer cell lines (LD50 0.05 to 3.9  μ g/mL) and lethal to brine shrimp (LD50 10.9 to 65.7  μ g/mL). Reduced neutrophil migration in rats was observed in carrageenan-induced peritonitis for the dichloromethane (67%), ethyl acetate (56%), and aqueous (72%) fractions. A positive reaction with tolidine and ninhydrin suggested that cyclopeptides are in the ethyl acetate fraction. It is therefore concluded that Calotropis procera latex dichloromethane and ethyl acetate fractions exhibit both in vitro and in vivo activities as well as anti-inflammatory properties. Cyclopeptide detection is especially interesting because previous attempts to investigate these low-molecular cyclic amino acid sequences in C. procera have failed. PMID:24348174

  15. Protumor Activities of the Immune Response: Insights in the Mechanisms of Immunological Shift, Oncotraining, and Oncopromotion

    PubMed Central

    Chimal-Ramírez, G. K.; Espinoza-Sánchez, N. A.; Fuentes-Pananá, E. M.

    2013-01-01

    Experimental and clinical studies indicate that cells of the innate and adaptive immune system have both anti- and pro-tumor activities. This dual role of the immune system has led to a conceptual shift in the role of the immune system's regulation of cancer, in which immune-tumor cell interactions are understood as a dynamic process that comprises at least five phases: immunosurveillance, immunoselection, immunoescape, oncotraining, and oncopromotion. The tumor microenvironment shifts immune cells to perform functions more in tune with the tumor needs (oncotraining); these functions are related to chronic inflammation and tissue remodeling activities. Among them are increased proliferation and survival, increased angiogenesis and vessel permeability, protease secretion, acquisition of migratory mesenchymal characteristics, and self-renewal properties that altogether promote tumor growth and metastasis (oncopromotion). Important populations in all these pro-tumor processes are M2 macrophages, N2 neutrophils, regulatory T cells, and myeloid derived suppressor cells; the main effectors molecules are CSF-1, IL-6, metalloproteases, VEGF, PGE-2, TGF-β, and IL-10. Cancer prognosis correlates with densities and concentrations of protumoral populations and molecules, providing ideal targets for the intelligent design of directed preventive or anticancer therapies. PMID:23577028

  16. Insights into the emission reductions of multiple unintentional persistent organic pollutants from industrial activities.

    PubMed

    Liu, Guorui; Zheng, Minghui; Jiang, Xiaoxu; Jin, Rong; Zhao, Yuyang; Zhan, Jiayu

    2016-02-01

    Industrial activities result in unintentional production of multiple types of persistent organic pollutants (POPs) at various concentrations. Because of the potential adverse effect of these POPs on the environment, biota and human health, methods for controlling emission of POPs are required. Development and application of techniques for controlling emissions of POPs can be a technical and economic burden for the industry involved. Therefore, from the point of view of cost-benefit analysis, reducing emissions of multiple pollutants at the same time is optimal for sustainable industrial development. Although techniques have been developed for reducing the emissions of individual POPs, such as dioxins, further work is required on multi-POP control emissions from industrial activities. This paper discusses three important aspects that need to be taken to achieve multi-POP control. These aspects include the establishment of a comprehensive system for evaluating the risk from emissions of multiple POPs, determination of indicators for total emissions of multiple POPs, and the preparation and application of functional materials to inhibit formation of multiple POPs. These discussion might be helpful for the future research on the multi-POP control in industry.

  17. New Insights into the Active Tectonics of Eastern Indonesia from GPS Measurements

    NASA Astrophysics Data System (ADS)

    Susilo, S.; Koulali Idrissi, A.; McClusky, S.; Meilano, I.; Cummins, P. R.; Tregoning, P.; Syafii, A.

    2014-12-01

    The Indonesian archipelago encompasses a wide range of tectonic environments, including island arc volcanism, subduction zones, and arc-continent collision. Many of the details of this tectonic activity are still poorly understood, especially where the Australian continent collides with Indonesia, separating the Sunda Arc in west from that at the Banda Arc in the east. While it seems clear that the Australian plate is subducted under both the Sunda and Banda Arcs, it is not clear what happens along the 1000 km -long stretch in between. The question of just where the plate motion is accommodated is of major importance to assessments of earthquake and tsunami hazard in the region. To help resolve these questions the Geospatial Information Agency of Indonesia has collaborated with the Australian National University and the Bandung Institute of Technology in a GPS campaign spanning much of eastern Indonesia, from Lombok in the west to Alor in the east. We have combined these data with those from previous campaigns, resulting in over 27 campaign and 18 continuous GPS sites being used in the analysis. The improvement in site density allowed us to develop of a more complete description of tectonic activity in this region than has been obtained in previous studies. Our preliminary results suggests that there is a relatively simple transition from subduction at the Java Trench off east Java, to a partitioned convergence along both the Timor Trough and the Flores Thrust in the Nusa Tenggara region.

  18. Long pulse and steady state operation activities at KSTAR

    NASA Astrophysics Data System (ADS)

    Bae, Young-Soon; KSTAR Team; KAERI Collaboration; JAEA Collaboration; PPPL Collaboration; SNU Collaboration

    2014-10-01

    The mission of Korea Superconducting Tokamak Advanced Research (KSTAR) is to develop a steady state capable advanced tokamak (AT) operation. The original AT operation mode at KSTAR is a reversed shear scenario with the plasma current of 2 MA, the toroidal magnetic field of 3.5 T, βN of 5, safety factor q95 of 3.7. Recently, the stationary long pulse H-mode discharge is sustained for maximum pulse duration of 20 s using heating of 2.5-MW NBI and 0.7-MW, X3 170 GHz ECH with low density level ~ 0.3 × 1020/m3. The main activities of long pulse and steady state operation in KSTAR are the density feedback control, optimization of plasma shape and vertical control, real-time β control, and steady state capable heating upgrade. For the longer pulse H-mode discharge at the increased plasma current upcoming KSTAR campaign, there have been improvements in plasma control system and upgraded heating systems. Meanwhile, steady state operation scenario in KSTAR next 4-year is being investigated using time-dependent integrated transport simulation code with possible heating upgrade-schemes. The promising steady state scenario near future is a reversed shear using a new 4 MW off-axis neutral beam injector for broad pressure profile peaked at off-axis, and using ECH for local current profile control aiming at βN > 3 with Ip ~ 1 MA. This paper present activities and plan for steady state operation in KSTAR as well as the long pulse H-mode discharge results in the recent KSTAR campaign.

  19. Involvement of spinal recurrent inhibition in spasticity. Further insight into the regulation of Renshaw cell activity.

    PubMed

    Mazzocchio, R; Rossi, A

    1997-06-01

    Changes in the excitability of the soleus H-reflex are were studied after oral administration of L-acetylcarnitine, a cholinomimetic substance, in eight healthy control subjects and 23 spastic patients presenting with slowly progressive paraparesis (n = 10), a cord lesion (n = 9) and a cerebral lesion (n = 4). Changes in the amount of recurrent inhibition of soleus motor neurons at rest were also estimated in order to assess the level of activity of Renshaw cells before and after L-acetylcarnitine administration. Recurrent inhibition elicited by a conditioning reflex discharge (H1) was assessed by a subsequent test reflex (H'). Four patients lacked an H' reflex. In approximately 50% of the remaining patients, recurrent inhibition was normal, while in the other half there was evidence of reduced or absent inhibitory activity at rest. Pooling the data relative to the effect of L-acetylcarnitine on the H-reflex in relation to the strength of recurrent inhibition disclosed that the ratio of peak-to-peak amplitude values of the maximum H reflex to maximum M wave responses (Hmax:Mmax) was reduced in all the cases in which the recurrent inhibition at rest was normal, while such a reduction was never observed in the patients in whom recurrent inhibition was found to be decreased at rest. In the former cases, the size of the H' reflex evoked by the same conditioning H1 discharge was further depressed after L-acetylcarnitine, pointing to a potentiating effect of the drug on Renshaw cells; in the latter cases no such effect was seen. A significant decrease in the mean Hmax:Mmax ratio after L-acetylcarnitine intake was also seen in the healthy control subjects. Possible changes in the amount of presynaptic inhibition on Ia terminals on soleus motor neurons after L-acetylcarnitine were ruled out. It is proposed that the differential effect of the drug on the H-reflex excitability is directly related to the level of Renshaw cell activity, a reduction of which probably follows a

  20. Mechanistic Insights into the Palladium-Catalyzed Aziridination of Aliphatic Amines by C-H Activation.

    PubMed

    Smalley, Adam P; Gaunt, Matthew J

    2015-08-26

    Detailed kinetic studies and computational investigations have been performed to elucidate the mechanism of a palladium-catalyzed C-H activation aziridination. A theoretical rate law has been derived that matches with experimental observations and has led to an improvement in the reaction conditions. Acetic acid was found to be beneficial in controlling the formation of an off-cycle intermediate, allowing a decrease in catalyst loading and improved yields. Density functional theory (DFT) studies were performed to examine the selectivities observed in the reaction. Evidence for electronic-controlled regioselectivity for the cyclopalladation step was obtained by a distortion-interaction analysis, whereas the aziridination product was justified through dissociation of acetic acid from the palladium(IV) intermediate preceding the product-forming reductive elimination step. The understanding of this reaction mechanism under the synthesis conditions should provide valuable assistance in the comprehension and design of palladium-catalyzed reactions on similar systems. PMID:26247373

  1. Silicate species of water glass and insights for alkali-activated green cement

    SciTech Connect

    Jansson, Helén; Bernin, Diana; Ramser, Kerstin

    2015-06-15

    Despite that sodium silicate solutions of high pH are commonly used in industrial applications, most investigations are focused on low to medium values of pH. Therefore we have investigated such solutions in a broad modulus range and up to high pH values (∼14) by use of infrared (IR) spectroscopy and silicon nuclear magnetic resonance ({sup 29}Si-NMR). The results show that the modulus dependent pH value leads to more or less charged species, which affects the configurations of the silicate units. This in turn, influences the alkali-activation process of low CO{sub 2} footprint cements, i.e. materials based on industrial waste or by-products.

  2. Recommended survey designs for occupancy modelling using motion-activated cameras: insights from empirical wildlife data

    PubMed Central

    Lewis, Jesse S.; Gerber, Brian D.

    2014-01-01

    Motion-activated cameras are a versatile tool that wildlife biologists can use for sampling wild animal populations to estimate species occurrence. Occupancy modelling provides a flexible framework for the analysis of these data; explicitly recognizing that given a species occupies an area the probability of detecting it is often less than one. Despite the number of studies using camera data in an occupancy framework, there is only limited guidance from the scientific literature about survey design trade-offs when using motion-activated cameras. A fuller understanding of these trade-offs will allow researchers to maximise available resources and determine whether the objectives of a monitoring program or research study are achievable. We use an empirical dataset collected from 40 cameras deployed across 160 km2 of the Western Slope of Colorado, USA to explore how survey effort (number of cameras deployed and the length of sampling period) affects the accuracy and precision (i.e., error) of the occupancy estimate for ten mammal and three virtual species. We do this using a simulation approach where species occupancy and detection parameters were informed by empirical data from motion-activated cameras. A total of 54 survey designs were considered by varying combinations of sites (10–120 cameras) and occasions (20–120 survey days). Our findings demonstrate that increasing total sampling effort generally decreases error associated with the occupancy estimate, but changing the number of sites or sampling duration can have very different results, depending on whether a species is spatially common or rare (occupancy = ψ) and easy or hard to detect when available (detection probability = p). For rare species with a low probability of detection (i.e., raccoon and spotted skunk) the required survey effort includes maximizing the number of sites and the number of survey days, often to a level that may be logistically unrealistic for many studies. For common species with

  3. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection

    PubMed Central

    Shankar, Esaki M; Velu, Vijayakumar; Kamarulzaman, Adeeba; Larsson, Marie

    2015-01-01

    Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB co-infection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis. PMID:25674514

  4. Mechanistic Insights into the Palladium-Catalyzed Aziridination of Aliphatic Amines by C-H Activation.

    PubMed

    Smalley, Adam P; Gaunt, Matthew J

    2015-08-26

    Detailed kinetic studies and computational investigations have been performed to elucidate the mechanism of a palladium-catalyzed C-H activation aziridination. A theoretical rate law has been derived that matches with experimental observations and has led to an improvement in the reaction conditions. Acetic acid was found to be beneficial in controlling the formation of an off-cycle intermediate, allowing a decrease in catalyst loading and improved yields. Density functional theory (DFT) studies were performed to examine the selectivities observed in the reaction. Evidence for electronic-controlled regioselectivity for the cyclopalladation step was obtained by a distortion-interaction analysis, whereas the aziridination product was justified through dissociation of acetic acid from the palladium(IV) intermediate preceding the product-forming reductive elimination step. The understanding of this reaction mechanism under the synthesis conditions should provide valuable assistance in the comprehension and design of palladium-catalyzed reactions on similar systems.

  5. Recommended survey designs for occupancy modelling using motion-activated cameras: insights from empirical wildlife data.

    PubMed

    Shannon, Graeme; Lewis, Jesse S; Gerber, Brian D

    2014-01-01

    Motion-activated cameras are a versatile tool that wildlife biologists can use for sampling wild animal populations to estimate species occurrence. Occupancy modelling provides a flexible framework for the analysis of these data; explicitly recognizing that given a species occupies an area the probability of detecting it is often less than one. Despite the number of studies using camera data in an occupancy framework, there is only limited guidance from the scientific literature about survey design trade-offs when using motion-activated cameras. A fuller understanding of these trade-offs will allow researchers to maximise available resources and determine whether the objectives of a monitoring program or research study are achievable. We use an empirical dataset collected from 40 cameras deployed across 160 km(2) of the Western Slope of Colorado, USA to explore how survey effort (number of cameras deployed and the length of sampling period) affects the accuracy and precision (i.e., error) of the occupancy estimate for ten mammal and three virtual species. We do this using a simulation approach where species occupancy and detection parameters were informed by empirical data from motion-activated cameras. A total of 54 survey designs were considered by varying combinations of sites (10-120 cameras) and occasions (20-120 survey days). Our findings demonstrate that increasing total sampling effort generally decreases error associated with the occupancy estimate, but changing the number of sites or sampling duration can have very different results, depending on whether a species is spatially common or rare (occupancy = ψ) and easy or hard to detect when available (detection probability = p). For rare species with a low probability of detection (i.e., raccoon and spotted skunk) the required survey effort includes maximizing the number of sites and the number of survey days, often to a level that may be logistically unrealistic for many studies. For common species with

  6. Silicate species of water glass and insights for alkali-activated green cement

    NASA Astrophysics Data System (ADS)

    Jansson, Helén; Bernin, Diana; Ramser, Kerstin

    2015-06-01

    Despite that sodium silicate solutions of high pH are commonly used in industrial applications, most investigations are focused on low to medium values of pH. Therefore we have investigated such solutions in a broad modulus range and up to high pH values (˜14) by use of infrared (IR) spectroscopy and silicon nuclear magnetic resonance (29Si-NMR). The results show that the modulus dependent pH value leads to more or less charged species, which affects the configurations of the silicate units. This in turn, influences the alkali-activation process of low CO2 footprint cements, i.e. materials based on industrial waste or by-products.

  7. Molecular insights into cold active polygalacturonase enzyme for its potential application in food processing.

    PubMed

    Ramya, L N; Pulicherla, K K

    2015-09-01

    Pectin is a complex structural heteropolysaccharide that require numerous pectinolytic enzymes for its complete degradation. Polygalacturonase from mesophilic or thermophilic origin are being widely used in fruit and vegetable processing in the recent decades to degrade pectic substances. Recently cold active pectinases are finding added advantages over meso and thermophilic counterparts, to use in industrial scale particularly in food processing industry. They facilitate in conservation of several properties of foods so that the end product retains its naturality and also generates economic benefits. In the present study, Pseudoalteromonas haloplanktis, a well reported marine psychrophile is taken as a model organism for cold active polygalacturonase and is evaluated in comparision to the routinely used mesophilic and thermophilic enzymes by insicio approach. Polygalacturonase sequences from industrially important microbial sources were subjected to MEME and Pfam wherein motifs and domains involved in the conservation were analyzed. Dendrogram revealed sequence level similarity and motifs showed uniform distribution of conserved regions that are involved in important functions. It was also observed through clustalW analysis that the amount of arginine content of psychrophiles is less when compared with thermophiles. Finally, all the modeled enzyme structures were subjected to docking studies using Autodock 4.2 with the substrate polygalacturonic acid and binding energies were found to be -5.73, -6.22 and -7.27 KCals/mole for meso, thermo and psychrophiles respectively which indicates the efficiency of psychrophilic enzymes when compared with its counterparts giving scope for further experimentation to find their better usage in various food industry applications. PMID:26344963

  8. New insights into relationships between active and dormant organisms, phylogenetic diversity and ecosystem productivity.

    PubMed

    Cram, Jacob A

    2015-12-01

    Marine microbes make up a key part of ocean food webs and drive ocean chemistry through a range of metabolic processes. A fundamental question in ecology is whether the diversity of organisms in a community shapes the ecological functions of that community. While there is substantial evidence to support a positive link between diversity and ecological productivity for macro-organisms in terrestrial environments, this relationship has not previously been verified for marine microbial communities. One factor complicating the understanding of this relationship is that many marine microbes are dormant and are easily dispersed by ocean currents, making it difficult to ensure that the organisms found in a given environmental sample accurately reflect processes occurring in that environment. Another complication is that, due to microbes great range of genotypic and phenotypic variability, communities with distantly related species may have greater range of metabolic functions than communities have the same richness and evenness, but in which the species present are more closely related to each other. In this issue of Molecular Ecology, Galand et al. (2015) provide compelling evidence that the most metabolically active communities are those in which the nondormant portion of the microbial community has the highest phylogenetic diversity. They also illustrate that focusing on the active portion of the community allows for detection of temporal patterns in community structure that would not be otherwise evident. The authors' point out that the presence of many dormant organisms that do not contribute to ecosystem functioning is a feature that makes microbial ecosystems fundamentally different from macro-ecosystems and that this difference needs to be accounted for in microbial ecology theory. PMID:26607213

  9. Insight into normal thymic activity by assessment of peripheral blood samples.

    PubMed

    Machnes-Maayan, Diti; Lev, Atar; Katz, Uriel; Mishali, David; Vardi, Amir; Simon, Amos J; Somech, Raz

    2015-03-01

    The thymus is a highly specialized organ for T cell receptor (TCR) rearrangement and selection mechanisms that ensure the formation of functional and self-tolerant cells. Little is known about how peripheral blood assessment of thymic function reflects thymus activity during infancy. We compared thymic function-related markers in the thymus with those in peripheral blood in order to check their correlations. We concomitantly blood samples from immunocompetent infants who underwent cardiac surgery that involved thymectomy. The studied thymic markers included TCR excision circles (TRECs), four different TCRD (TCR delta chain) gene rearrangements, the TCR repertoire, regulatory T cells (Tregs, defined as the CD4+CD25+FOXP3+ cell population) and real-time quantitative polymerase chain reaction (RQ-PCR) mRNA expression of forkhead box P3 (FOXP3). Twenty patients were enrolled in this study. Their mean age at the time of the surgery was 3 months/5 days ± 3 months/18 days. There was a significant correlation between thymic and peripheral blood levels of TREC, all four TCRD gene rearrangements and the amount of Tregs. The levels of these parameters were significantly higher in the thymus than those detected in the peripheral blood. The TCR repertoire distribution in both samples was similar. FOXP3 mRNA levels in the thymus and peripheral blood correlated well. Our findings demonstrated a strong and significant correlation between peripheral blood and intra-thymic activity parameters during infancy. Assessment of these parameters in peripheral blood can be used to accurately estimate different intra-thymic capacities for assessing T cell function in health and disease.

  10. Climate impacts on human settlement and agricultural activities in northern Norway: new insights from biogeochemistry

    NASA Astrophysics Data System (ADS)

    D'anjou, R. M.; Bradley, R. S.; Balascio, N. L.; Finkelstein, D. B.

    2012-12-01

    Disentangling the effects of climate change and anthropogenic activities on the environment is a major challenge in paleoenvironmental research. Here, we used fecal sterols and other biogeochemical compounds in lake sediments from northern Norway to identify both natural and anthropogenic signals of environmental change during the late Holocene. The area was first occupied by humans and their grazing animals at ~2,250±75 cal yr BP. The arrival of humans is indicated by an abrupt increase in coprostanol (and its epimer epicoprostanol) in the sediments, and an associated increase in 5β-stigmastanol (and 5β-epistigmastanol), which resulted from human and animal feces washing into the lake. Human settlement was accompanied by an abrupt increase in landscape fires (indicated by the rise in pyrolytic polycyclic aromatic hydrocarbons, PAHs) and a decline in woodland (registered by a change in n-alkane chain lengths from leaf waxes), accelerating a process that began earlier in the Holocene. Human activity and associated landscape changes in the region over the last two millennia were mainly driven by summer temperatures, as indicated by independent tree-ring reconstructions, though there were periods when socio-economic factors played an equally important role. This is the first time that fecal sterols in lake sediments have been used to provide a record of human occupancy through time. This approach may be useful in many archeological studies, both to confirm the presence of humans and grazing animals, and to distinguish between anthropogenic and natural factors that have influenced the environment in the past.

  11. Insights on Glucocorticoid Receptor Activity Modulation through the Binding of Rigid Steroids

    PubMed Central

    Presman, Diego M.; Alvarez, Lautaro D.; Levi, Valeria; Eduardo, Silvina; Digman, Michelle A.; Martí, Marcelo A.; Veleiro, Adriana S.; Burton, Gerardo; Pecci, Adali

    2010-01-01

    Background The glucocorticoid receptor (GR) is a transcription factor that regulates gene expression in a ligand-dependent fashion. This modular protein is one of the major pharmacological targets due to its involvement in both cause and treatment of many human diseases. Intense efforts have been made to get information about the molecular basis of GR activity. Methodology/Principal Findings Here, the behavior of four GR-ligand complexes with different glucocorticoid and antiglucocorticoid properties were evaluated. The ability of GR-ligand complexes to oligomerize in vivo was analyzed by performing the novel Number and Brightness assay. Results showed that most of GR molecules form homodimers inside the nucleus upon ligand binding. Additionally, in vitro GR-DNA binding analyses suggest that ligand structure modulates GR-DNA interaction dynamics rather than the receptor's ability to bind DNA. On the other hand, by coimmunoprecipitation studies we evaluated the in vivo interaction between the transcriptional intermediary factor 2 (TIF2) coactivator and different GR-ligand complexes. No correlation was found between GR intranuclear distribution, cofactor recruitment and the homodimerization process. Finally, Molecular determinants that support the observed experimental GR LBD-ligand/TIF2 interaction were found by Molecular Dynamics simulation. Conclusions/Significance The data presented here sustain the idea that in vivo GR homodimerization inside the nucleus can be achieved in a DNA-independent fashion, without ruling out a dependent pathway as well. Moreover, since at least one GR-ligand complex is able to induce homodimer formation while preventing TIF2 coactivator interaction, results suggest that these two events might be independent from each other. Finally, 21-hydroxy-6,19-epoxyprogesterone arises as a selective glucocorticoid with potential pharmacological interest. Taking into account that GR homodimerization and cofactor recruitment are considered essential

  12. Structural Analysis and Insights into the Oligomeric State of an Arginine-Dependent Transcriptional Regulator from Bacillus halodurans.

    PubMed

    Park, Young Woo; Kang, Jina; Yeo, Hyun Ku; Lee, Jae Young

    2016-01-01

    The arginine repressor (ArgR) is an arginine-dependent transcription factor that regulates the expression of genes encoding proteins involved in the arginine biosynthesis and catabolic pathways. ArgR is a functional homolog of the arginine-dependent repressor/activator AhrC from Bacillus subtilis, and belongs to the ArgR/AhrC family of transcriptional regulators. In this research, we determined the structure of the ArgR (Bh2777) from Bacillus halodurans at 2.41 Å resolution by X-ray crystallography. The ArgR from B. halodurans appeared to be a trimer in a size exclusion column and in the crystal structure. However, it formed a hexamer in the presence of L-arginine in multi-angle light scattering (MALS) studies, indicating the oligomerization state was dependent on the presence of L-arginine. The trimeric structure showed that the C-terminal domains form the core, which was made by inter-subunit interactions mainly through hydrophobic contacts, while the N-terminal domains containing a winged helix-turn-helix DNA binding motif were arranged around the periphery. The arrangement of trimeric structure in the B. halodurans ArgR was different from those of other ArgR homologs previously reported. We finally showed that the B. halodurans ArgR has an arginine-dependent DNA binding property by an electrophoretic mobility shift assay. PMID:27171430

  13. Structural Analysis and Insights into the Oligomeric State of an Arginine-Dependent Transcriptional Regulator from Bacillus halodurans

    PubMed Central

    Park, Young Woo; Kang, Jina; Yeo, Hyun Ku; Lee, Jae Young

    2016-01-01

    The arginine repressor (ArgR) is an arginine-dependent transcription factor that regulates the expression of genes encoding proteins involved in the arginine biosynthesis and catabolic pathways. ArgR is a functional homolog of the arginine-dependent repressor/activator AhrC from Bacillus subtilis, and belongs to the ArgR/AhrC family of transcriptional regulators. In this research, we determined the structure of the ArgR (Bh2777) from Bacillus halodurans at 2.41 Å resolution by X-ray crystallography. The ArgR from B. halodurans appeared to be a trimer in a size exclusion column and in the crystal structure. However, it formed a hexamer in the presence of L-arginine in multi-angle light scattering (MALS) studies, indicating the oligomerization state was dependent on the presence of L-arginine. The trimeric structure showed that the C-terminal domains form the core, which was made by inter-subunit interactions mainly through hydrophobic contacts, while the N-terminal domains containing a winged helix-turn-helix DNA binding motif were arranged around the periphery. The arrangement of trimeric structure in the B. halodurans ArgR was different from those of other ArgR homologs previously reported. We finally showed that the B. halodurans ArgR has an arginine-dependent DNA binding property by an electrophoretic mobility shift assay. PMID:27171430

  14. Spectroscopy of non-heme iron thiolate complexes: insight into the electronic structure of the low-spin active site of nitrile hydratase.

    PubMed

    Kennepohl, Pierre; Neese, Frank; Schweitzer, Dirk; Jackson, Henry L; Kovacs, Julie A; Solomon, Edward I

    2005-03-21

    Detailed spectroscopic and computational studies of the low-spin iron complexes [Fe(III)(S2(Me2)N3 (Pr,Pr))(N3)] (1) and [Fe(III)(S2(Me2)N3 (Pr,Pr))]1+ (2) were performed to investigate the unique electronic features of these species and their relation to the low-spin ferric active sites of nitrile hydratases. Low-temperature UV/vis/NIR and MCD spectra of 1 and 2 reflect electronic structures that are dominated by antibonding interactions of the Fe 3d manifold and the equatorial thiolate S 3p orbitals. The six-coordinate complex 1 exhibits a low-energy S(pi) --> Fe 3d(xy) (approximately 13,000 cm(-1)) charge-transfer transition that results predominantly from the low energy of the singly occupied Fe 3d(xy) orbital, due to pure pi interactions between this acceptor orbital and both thiolate donor ligands in the equatorial plane. The 3d(pi) --> 3d(sigma) ligand-field transitions in this species occur at higher energies (>15,000 cm(-1)), reflecting its near-octahedral symmetry. The Fe 3d(xz,yz) --> Fe 3d(xy) (d(pi) --> d(pi)) transition occurs in the near-IR and probes the Fe(III)-S pi-donor bond; this transition reveals vibronic structure that reflects the strength of this bond (nu(e) approximately 340 cm(-1)). In contrast, the ligand-field transitions of the five-coordinate complex 2 are generally at low energy, and the S(pi) --> Fe charge-transfer transitions occur at much higher energies relative to those in 1. This reflects changes in thiolate bonding in the equatorial plane involving the Fe 3d(xy) and Fe 3d(x2-y2) orbitals. The spectroscopic data lead to a simple bonding model that focuses on the sigma and pi interactions between the ferric ion and the equatorial thiolate ligands, which depend on the S-Fe-S bond angle in each of the complexes. These electronic descriptions provide insight into the unusual S = 1/2 ground spin state of these complexes: the orientation of the thiolate ligands in these complexes restricts their pi-donor interactions to the

  15. Insights into the inhibitory mechanisms of the regulatory protein IIA(Glc) on melibiose permease activity.

    PubMed

    Hariharan, Parameswaran; Guan, Lan

    2014-11-21

    The phosphotransfer protein IIA(Glc) of the bacterial phosphoenolpyruvate:carbohydrate phosphotransferase system plays a key role in the regulation of carbohydrate metabolism. Melibiose permease (MelB) is one among several permeases subject to IIA(Glc) regulation. The regulatory mechanisms are poorly understood; in addition, thermodynamic features of IIA(Glc) binding to other proteins are also unknown. Applying isothermal titration calorimetry and amine-specific cross-linking, we show that IIA(Glc) directly binds to MelB of Salmonella typhimurium (MelB(St)) and Escherichia coli MelB (MelB(Ec)) at a stoichiometry of unity in the absence or presence of melibiose. The dissociation constant values are 3-10 μM for MelB(St) and 25 μM for MelB(Ec). All of the binding is solely driven by favorable enthalpy forces. IIA(Glc) binding to MelB(St) in the absence or presence of melibiose yields a large negative heat capacity change; in addition, the conformational entropy is constrained upon the binding. We further found that the IIA(Glc)-bound MelB(St) exhibits a decreased binding affinity for melibiose or nitrophenyl-α-galactoside. It is believed that sugar binding to the permease is involved in an induced fit mechanism, and the transport process requires conformational cycling between different states. Thus, the thermodynamic data are consistent with the interpretation that IIA(Glc) inhibits the induced fit process and restricts the conformational dynamics of MelB(St). PMID:25296751

  16. Theta activity and meditative states: spectral changes during concentrative meditation.

    PubMed

    Baijal, Shruti; Srinivasan, Narayanan

    2010-02-01

    Brain oscillatory activity is associated with different cognitive processes and plays a critical role in meditation. In this study, we investigated the temporal dynamics of oscillatory changes during Sahaj Samadhi meditation (a concentrative form of meditation that is part of Sudarshan Kriya yoga). EEG was recorded during Sudarshan Kriya yoga meditation for meditators and relaxation for controls. Spectral and coherence analysis was performed for the whole duration as well as specific blocks extracted from the initial, middle, and end portions of Sahaj Samadhi meditation or relaxation. The generation of distinct meditative states of consciousness was marked by distinct changes in spectral powers especially enhanced theta band activity during deep meditation in the frontal areas. Meditators also exhibited increased theta coherence compared to controls. The emergence of the slow frequency waves in the attention-related frontal regions provides strong support to the existing claims of frontal theta in producing meditative states along with trait effects in attentional processing. Interestingly, increased frontal theta activity was accompanied reduced activity (deactivation) in parietal-occipital areas signifying reduction in processing associated with self, space and, time.

  17. Structural insights into ligand-induced activation of the insulin receptor

    SciTech Connect

    Ward, C.; Lawrence, M.; Streltsov, V.; Garrett, T.; McKern, N.; Lou, M.-Z.; Lovrecz, G.; Adams, T.

    2008-04-29

    The current model for insulin binding to the insulin receptor proposes that there are two binding sites, referred to as sites 1 and 2, on each monomer in the receptor homodimer and two binding surfaces on insulin, one involving residues predominantly from the dimerization face of insulin (the classical binding surface) and the other residues from the hexamerization face. High-affinity binding involves one insulin molecule using its two surfaces to make bridging contacts with site 1 from one receptor monomer and site 2 from the other. Whilst the receptor dimer has two identical site 1-site 2 pairs, insulin molecules cannot bridge both pairs simultaneously. Our structures of the insulin receptor (IR) ectodomain dimer and the L1-CR-L2 fragments of IR and insulin-like growth factor receptor (IGF-1R) explain many of the features of ligand-receptor binding and allow the two binding sites on the receptor to be described. The IR dimer has an unexpected folded-over conformation which places the C-terminal surface of the first fibronectin-III domain in close juxtaposition to the known L1 domain ligand-binding surface suggesting that the C-terminal surface of FnIII-1 is the second binding site involved in high-affinity binding. This is very different from previous models based on three-dimensional reconstruction from scanning transmission electron micrographs. Our single-molecule images indicate that IGF-1R has a morphology similar to that of IR. In addition, the structures of the first three domains (L1-CR-L2) of the IR and IGF-1R show that there are major differences in the two regions governing ligand specificity. The implications of these findings for ligand-induced receptor activation will be discussed. This review summarizes the key findings regarding the discovery and characterization of the insulin receptor, the identification and arrangement of its structural domains in the sequence and the key features associated with ligand binding. The remainder of the review

  18. Export of earthquake-triggered landslides in active mountain ranges: insights from 2D morphodynamic modelling.

    NASA Astrophysics Data System (ADS)

    Croissant, Thomas; Lague, Dimitri; Davy, Philippe; Steer, Philippe

    2016-04-01

    In active mountain ranges, large earthquakes (Mw > 5-6) trigger numerous landslides that impact river dynamics. These landslides bring local and sudden sediment piles that will be eroded and transported along the river network causing downstream changes in river geometry, transport capacity and erosion efficiency. The progressive removal of landslide materials has implications for downstream hazards management and also for understanding landscape dynamics at the timescale of the seismic cycle. The export time of landslide-derived sediments after large-magnitude earthquakes has been studied from suspended load measurements but a full understanding of the total process, including the coupling between sediment transfer and channel geometry change, still remains an issue. Note that the transport of small sediment pulses has been studied in the context of river restoration, but the magnitude of sediment pulses generated by landslides may make the problem different. Here, we study the export of large volumes (>106 m3) of sediments with the 2D hydro-morphodynamic model, Eros. This model uses a new hydrodynamic module that resolves a reduced form of the Saint-Venant equations with a particle method. It is coupled with a sediment transport and lateral and vertical erosion model. Eros accounts for the complex retroactions between sediment transport and fluvial geometry, with a stochastic description of the floods experienced by the river. Moreover, it is able to reproduce several features deemed necessary to study the evacuation of large sediment pulses, such as river regime modification (single-thread to multi-thread), river avulsion and aggradation, floods and bank erosion. Using a synthetic and simple topography we first present how granulometry, landslide volume and geometry, channel slope and flood frequency influence 1) the dominance of pulse advection vs. diffusion during its evacuation, 2) the pulse export time and 3) the remaining volume of sediment in the catchment

  19. Neural correlates of insight in dreaming and psychosis.

    PubMed

    Dresler, Martin; Wehrle, Renate; Spoormaker, Victor I; Steiger, Axel; Holsboer, Florian; Czisch, Michael; Hobson, J Allan

    2015-04-01

    The idea that dreaming can serve as a model for psychosis has a long and honourable tradition, however it is notoriously speculative. Here we demonstrate that recent research on the phenomenon of lucid dreaming sheds new light on the debate. Lucid dreaming is a rare state of sleep in which the dreamer gains insight into his state of mind during dreaming. Recent electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) data for the first time allow very specific hypotheses about the dream-psychosis relationship: if dreaming is a reasonable model for psychosis, then insight into the dreaming state and insight into the psychotic state should share similar neural correlates. This indeed seems to be the case: cortical areas activated during lucid dreaming show striking overlap with brain regions that are impaired in psychotic patients who lack insight into their pathological state. This parallel allows for new therapeutic approaches and ways to test antipsychotic medication. PMID:25092021

  20. Neural correlates of insight in dreaming and psychosis.

    PubMed

    Dresler, Martin; Wehrle, Renate; Spoormaker, Victor I; Steiger, Axel; Holsboer, Florian; Czisch, Michael; Hobson, J Allan

    2015-04-01

    The idea that dreaming can serve as a model for psychosis has a long and honourable tradition, however it is notoriously speculative. Here we demonstrate that recent research on the phenomenon of lucid dreaming sheds new light on the debate. Lucid dreaming is a rare state of sleep in which the dreamer gains insight into his state of mind during dreaming. Recent electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) data for the first time allow very specific hypotheses about the dream-psychosis relationship: if dreaming is a reasonable model for psychosis, then insight into the dreaming state and insight into the psychotic state should share similar neural correlates. This indeed seems to be the case: cortical areas activated during lucid dreaming show striking overlap with brain regions that are impaired in psychotic patients who lack insight into their pathological state. This parallel allows for new therapeutic approaches and ways to test antipsychotic medication.

  1. Ordering Dynamics in Neuron Activity Pattern Model: An Insight to Brain Functionality

    PubMed Central

    Gundh, Jasleen; Singh, Awaneesh; Singh, R. K. Brojen

    2015-01-01

    We study the domain ordering kinetics in d = 2 ferromagnets which corresponds to populated neuron activities with both long-ranged interactions, V(r) ∼ r−n and short-ranged interactions. We present the results from comprehensive Monte Carlo (MC) simulations for the nonconserved Ising model with n ≥ 2, interaction range considering near and far neighbors. Our model results could represent the long-ranged neuron kinetics (n ≤ 4) in consistent with the same dynamical behaviour of short-ranged case (n ≥ 4) at far below and near criticality. We found that emergence of fast and slow kinetics of long and short ranged case could imitate the formation of connections among near and distant neurons. The calculated characteristic length scale in long-ranged interaction is found to be n independent (L(t) ∼ t1/(n−2)), whereas short-ranged interaction follows L(t) ∼ t1/2 law and approximately preserve universality in domain kinetics. Further, we did the comparative study of phase ordering near the critical temperature which follows different behaviours of domain ordering near and far critical temperature but follows universal scaling law. PMID:26506525

  2. New insights into dietary supplements used in sport: active substances, pharmacological and side effects.

    PubMed

    Koncic, Marijana Zovko; Tomczyk, Michal

    2013-08-01

    As a society we are increasingly concerned about our physical appearance. For example, as much as 24% of people in developed countries admittedly exercise to improve their performance. Professional sportsmen and amateurs alike are in a constant search for new means that will enable them better sport results in shorter time. Among those means, a prominent place belongs to dietary supplements. However, the producers often advertise products whose use in sports is neither scientifically founded nor safe. This brings on an irrational use of herbal supplements which sometimes leads to unwanted side effects, but is more often of little use. Thus, the aim of this review will be to systematically evaluate some of the herbal supplements that are used as adaptogenic and ergogenic aids in sport. The review will include available data on Rhodiola rosea, Withania somnifera, Schisandra chinensis, Tribulus terrestris, Vitis vinifera, Citrus aurantium, and others. Their effects, active ingredients as well as possible adverse effects will be discussed with special focus on clinical studies. PMID:23574283

  3. Insights into the effect of mixed engineered nanoparticles on activated sludge performance

    PubMed Central

    Eduok, Samuel; Hendry, Callum; Ferguson, Robert; Martin, Ben; Villa, Raffaella; Jefferson, Bruce; Coulon, Frédéric

    2015-01-01

    In this study, the effects, fate and transport of ENPs in wastewater treatment plants (WWTP) were investigated using three parallel pilot WWTPs operated under identical conditions. The WWTPs were spiked with (i) an ENP mixture consisting of silver oxide, titanium dioxide and zinc oxide, and (ii) bulk metal salts. The third plant served as control (unspiked). ENP effects were evaluated for (i) bulk contaminant removal, (ii) activated sludge (AS) process performance, (iii) microbial community structure and dynamics and (iv) microbial inhibition. ENPs showed a strong affinity for biosolids and induced a specific oxygen uptake rate two times higher than the control. The heterotrophic biomass retained its ability to nitrify and degrade organic matter. However, non-recovery of ammonia- and nitrite-oxidizing bacteria such as Nitrosomonas, Nitrobacter or Nitrospira in the ENP spiked reactors suggests selective inhibitory effects. The results further suggest that ENPs and metal salts have antimicrobial properties which can reduce synthesis of extracellular polymeric substances and therefore floc formation. Scanning electron microscopy evidenced selective damage to some microbes, whereas lipid fingerprinting and 454 pyrosequencing indicated a temporal shift in the microbial community structure and diversity. Acidovorax, Rhodoferax, Comamonas and Methanosarcina were identified as nano-tolerant species. Competitive growth advantage of the nano-tolerant species influenced the removal processes and unlike other xenobiotic compounds, ENPs can hasten the natural selection of microbial species in AS. PMID:26187478

  4. Insights into the effect of mixed engineered nanoparticles on activated sludge performance.

    PubMed

    Eduok, Samuel; Hendry, Callum; Ferguson, Robert; Martin, Ben; Villa, Raffaella; Jefferson, Bruce; Coulon, Frédéric

    2015-07-01

    In this study, the effects, fate and transport of ENPs in wastewater treatment plants (WWTP) were investigated using three parallel pilot WWTPs operated under identical conditions. The WWTPs were spiked with (i) an ENP mixture consisting of silver oxide, titanium dioxide and zinc oxide, and (ii) bulk metal salts. The third plant served as control (unspiked). ENP effects were evaluated for (i) bulk contaminant removal, (ii) activated sludge (AS) process performance, (iii) microbial community structure and dynamics and (iv) microbial inhibition. ENPs showed a strong affinity for biosolids and induced a specific oxygen uptake rate two times higher than the control. The heterotrophic biomass retained its ability to nitrify and degrade organic matter. However, non-recovery of ammonia- and nitrite-oxidizing bacteria such as Nitrosomonas, Nitrobacter or Nitrospira in the ENP spiked reactors suggests selective inhibitory effects. The results further suggest that ENPs and metal salts have antimicrobial properties which can reduce synthesis of extracellular polymeric substances and therefore floc formation. Scanning electron microscopy evidenced selective damage to some microbes, whereas lipid fingerprinting and 454 pyrosequencing indicated a temporal shift in the microbial community structure and diversity. Acidovorax, Rhodoferax, Comamonas and Methanosarcina were identified as nano-tolerant species. Competitive growth advantage of the nano-tolerant species influenced the removal processes and unlike other xenobiotic compounds, ENPs can hasten the natural selection of microbial species in AS. PMID:26187478

  5. New insights into the anti-obesity activity of xanthones from Garcinia mangostana.

    PubMed

    Liu, Qian-Yu; Wang, Yi-Tao; Lin, Li-Gen

    2015-02-01

    Obesity has reached epidemic proportions worldwide. This condition, and its related diseases such as diabetes and cardiovascular diseases, have become major public health challenges. Fruits are important dietary components, and bioactive constituents from fruits are considered to be a promising source for developing effective and safe anti-obesity drugs. Garcinia mangostana Linn. (Clusiaceae) is a tropical evergreen tree, and its fruit, mangosteen, is called 'Queen of Fruit'. The pericarp of G. mangostana has been used for centuries in Southeast Asia as a medicinal agent for treatment of various diseases. Products derived from mangosteen are widely consumed to ameliorate metabolic dysfunction and resultant metabolic syndrome. However, the chemical principles and mechanisms underlying these effects are unclear. This review summarizes the recent chemical and pharmacological studies related to G. mangostana, including weight reduction, anti-adipogenesis, anti-inflammation and anti-oxidation activity. The aim of this review is to shed light on the role of G. mangostana and its constituents in preventing and treating obesity, which should encourage more interest in the development of relevant therapeutic methods. PMID:25520256

  6. New insights into dietary supplements used in sport: active substances, pharmacological and side effects.

    PubMed

    Koncic, Marijana Zovko; Tomczyk, Michal

    2013-08-01

    As a society we are increasingly concerned about our physical appearance. For example, as much as 24% of people in developed countries admittedly exercise to improve their performance. Professional sportsmen and amateurs alike are in a constant search for new means that will enable them better sport results in shorter time. Among those means, a prominent place belongs to dietary supplements. However, the producers often advertise products whose use in sports is neither scientifically founded nor safe. This brings on an irrational use of herbal supplements which sometimes leads to unwanted side effects, but is more often of little use. Thus, the aim of this review will be to systematically evaluate some of the herbal supplements that are used as adaptogenic and ergogenic aids in sport. The review will include available data on Rhodiola rosea, Withania somnifera, Schisandra chinensis, Tribulus terrestris, Vitis vinifera, Citrus aurantium, and others. Their effects, active ingredients as well as possible adverse effects will be discussed with special focus on clinical studies.

  7. New insights into the anti-obesity activity of xanthones from Garcinia mangostana.

    PubMed

    Liu, Qian-Yu; Wang, Yi-Tao; Lin, Li-Gen

    2015-02-01

    Obesity has reached epidemic proportions worldwide. This condition, and its related diseases such as diabetes and cardiovascular diseases, have become major public health challenges. Fruits are important dietary components, and bioactive constituents from fruits are considered to be a promising source for developing effective and safe anti-obesity drugs. Garcinia mangostana Linn. (Clusiaceae) is a tropical evergreen tree, and its fruit, mangosteen, is called 'Queen of Fruit'. The pericarp of G. mangostana has been used for centuries in Southeast Asia as a medicinal agent for treatment of various diseases. Products derived from mangosteen are widely consumed to ameliorate metabolic dysfunction and resultant metabolic syndrome. However, the chemical principles and mechanisms underlying these effects are unclear. This review summarizes the recent chemical and pharmacological studies related to G. mangostana, including weight reduction, anti-adipogenesis, anti-inflammation and anti-oxidation activity. The aim of this review is to shed light on the role of G. mangostana and its constituents in preventing and treating obesity, which should encourage more interest in the development of relevant therapeutic methods.

  8. New Insights on Late-A and Early-F Star Activity

    NASA Astrophysics Data System (ADS)

    Freire Ferrero, R.; Catalano, S.; Marilli, E.; Gouttebroze, P.; Talavera, A.; Bruhweiler, F.

    The onset of chromospheric activity in late-A and early-F stars is here discussed. The detection of Ly- emission core in several A and F atars with the IUE satellite, gives evidence for the presence of chromospheric layers in these stars up to B - V = 0m.19 (Marilli et al., 1996). Semiempirical chromospheric models for Altair allowed us (Freire Ferrero et al., 1995) to explain the observed emission profiles taking into account normal H I interstellar (IS) absorption. However, due to the very high rotational velocity, we analysed alternative hypotheses to explain the observed emissions: (1) circumstellar or shell matter; (2) co-rotating expanding optically thin wind. We ruled out these hypotheses because their effects are negligible and as a consequence, this result reinforces the chromospheric origin of the observed Ly- core in Altair. The stars of our sample, having observed Ly- profilies similar to Altair's and similar stellar and IS properties, should reproduce similar chromospheric behaviour. Here we discuss several important questions that are raised by these results.

  9. Structures of CRISPR Cas3 offer mechanistic insights into Cascade-activated DNA unwinding and degradation.

    PubMed

    Huo, Yanwu; Nam, Ki Hyun; Ding, Fang; Lee, Heejin; Wu, Lijie; Xiao, Yibei; Farchione, M Daniel; Zhou, Sharleen; Rajashankar, Kanagalaghatta; Kurinov, Igor; Zhang, Rongguang; Ke, Ailong

    2014-09-01

    CRISPR drives prokaryotic adaptation to invasive nucleic acids such as phages and plasmids, using an RNA-mediated interference mechanism. Interference in type I CRISPR-Cas systems requires a targeting Cascade complex and a degradation machine, Cas3, which contains both nuclease and helicase activities. Here we report the crystal structures of Thermobifida fusca Cas3 bound to single-stranded (ss) DNA substrate and show that it is an obligate 3'-to-5' ssDNase that preferentially accepts substrate directly from the helicase moiety. Conserved residues in the HD-type nuclease coordinate two irons for ssDNA cleavage. We demonstrate ATP coordination and conformational flexibility of the SF2-type helicase domain. Cas3 is specifically guided toward Cascade-bound target DNA by a PAM sequence, through physical interactions with both the nontarget substrate strand and the CasA protein. The sequence of recognition events ensures well-controlled DNA targeting and degradation of foreign DNA by Cascade and Cas3.

  10. [Activities of Center for Nondestructive Evaluation, Iowa State University

    NASA Technical Reports Server (NTRS)

    Gray, Joe

    2002-01-01

    The final report of NASA funded activities at Iowa State University (ISU) for the period between 1/96 and 1/99 includes two main areas of activity. The first is the development and delivery of an x-ray simulation package suitable for evaluating the impact of parameters affects the inspectability of an assembly of parts. The second area was the development of images processing tools to remove reconstruction artifacts in x-ray laminagraphy images. The x-ray simulation portion of this work was done by J. Gray and the x-ray laminagraphy work was done by J. Basart. The report is divided into two sections covering the two activities respectively. In addition to this work reported the funding also covered NASA's membership in the NSF University/Industrial Cooperative Research Center.

  11. Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling

    PubMed Central

    Lin, Chuwen; Yao, Erica; Wang, Kevin; Nozawa, Yoko; Shimizu, Hirohito; Johnson, Jeffrey R.; Chen, Jau-Nian; Krogan, Nevan J.

    2014-01-01

    Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step in mammalian Hedgehog (Hh) signaling, but how this is achieved in the nucleus is unknown. We found that Hh signaling results in reduced Sufu protein levels and Sufu dissociation from Gli proteins in the nucleus, highlighting critical functions of Sufu in the nucleus. Through a proteomic approach, we identified several Sufu-interacting proteins, including p66β (a member of the NuRD [nucleosome remodeling and histone deacetylase] repressor complex) and Mycbp (a Myc-binding protein). p66β negatively and Mycbp positively regulate Hh signaling in cell-based assays and zebrafish. They function downstream from the membrane receptors, Patched and Smoothened, and the primary cilium. Sufu, p66β, Mycbp, and Gli are also detected on the promoters of Hh targets in a dynamic manner. Our results support a new model of Hh signaling in the nucleus. Sufu recruits p66β to block Gli-mediated Hh target gene expression. Meanwhile, Mycbp forms a complex with Gli and Sufu without Hh stimulation but remains inactive. Hh pathway activation leads to dissociation of Sufu/p66β from Gli, enabling Mycbp to promote Gli protein activity and Hh target gene expression. These studies provide novel insight into how Sufu controls Hh signaling in the nucleus. PMID:25403183

  12. Biogeochemical Activity of Siderophilic Cyanobacteria and Insights from their Genomes Implications for the Development of New Biosignatures

    NASA Technical Reports Server (NTRS)

    Brown, I. I.; Bryant, D. A.; Thomas,-Keprta, K. L.; Tringe, S. G.; Sarkisova, S. A.; Galindo, C., Jr.; Malley, K.; Sosa, O.; Garrison, D. H.; McKay, David S.

    2010-01-01

    Verifying the links between genomie features in living organisms and their mineralization/demineralization activity will help to reveal traces of life on Earth and beyond. Among contemporary environments, iron-depositing hot springs (IDHS) may represent one of the most appropriate natural models for insights into ancient life since organisms may have originated on Earth and possibly Mars in association with hydrothennal activity and high [Fe(2+)]. Siderophilic or "iron-loving" cyanobacteria (CB) inhabiting IDHS may have genomic features and properties similar to those of ancient organisms because abundant Fe(2+) in IDHS has a strong potential to increase the magnitude of oxidative stress. That is why specific and/or additional proteins involved in Fe mineralization by siderophilic CB are expected. Inorganic polyphosphates (PPi) are known to increase the viability of prokaryotes Linder heavy metal concentrations and UV stress conditions. PPi have also been proposed as biosignatures. Ancient CB could have also been stressed by occasional migrations from the Fe(2+) rich Ocean to the basaltic land which was almost devoid of dissolved Fe(2+). Thus, the study of the adaptation reactions of siderophilic CB to fluctuation of dissolved Fe level may shed light on the paleophysiology of ancient oxygenic prokaryotes. Moreover, bioweathered Fe, Al, P, Cu, Ti and rare earth elements can be thought of as candidate organomarkers that document the effects of or ganic molecules in weathered rocks. However, the molecular mechanisms of the maintenance of Fe homeostasis in siderophilic CB, the role of PPi for this process and bioweathering activities are poorly understood. Here we present preliminary results describing a new mechanism of Fe mineralization in siderophilic CB, the effect of Fe on the generation of PPi bodies in siderophilic CB, their bioweathering activity and preliminary analysis of the diversity of proteins involved in the prevention of oxidative stress in phototrophs

  13. Structural Insights into the Activation and Inhibition of Histo-Aspartic Protease from Plasmodium falciparum

    SciTech Connect

    Bhaumik, Prasenjit; Xiao, Huogen; Hidaka, Koushi; Gustchina, Alla; Kiso, Yoshiaki; Yada, Rickey Y.; Wlodawer, Alexander

    2012-09-17

    Histo-aspartic protease (HAP) from Plasmodium falciparum is a promising target for the development of novel antimalarial drugs. The sequence of HAP is highly similar to those of pepsin-like aspartic proteases, but one of the two catalytic aspartates, Asp32, is replaced with histidine. Crystal structures of the truncated zymogen of HAP and of the complex of the mature enzyme with inhibitor KNI-10395 have been determined at 2.1 and 2.5 {angstrom} resolution, respectively. As in other proplasmepsins, the propeptide of the zymogen interacts with the C-terminal domain of the enzyme, forcing the N- and C-terminal domains apart, thereby separating His32 and Asp215 and preventing formation of the mature active site. In the inhibitor complex, the enzyme forms a tight domain-swapped dimer, not previously seen in any aspartic proteases. The inhibitor is found in an unprecedented conformation resembling the letter U, stabilized by two intramolecular hydrogen bonds. Surprisingly, the location and conformation of the inhibitor are similar to those of the fragment of helix 2 comprising residues 34p-38p in the prosegments of the zymogens of gastric aspartic proteases; a corresponding helix assumes a vastly different orientation in proplasmepsins. Each inhibitor molecule is in contact with two molecules of HAP, interacting with the carboxylate group of the catalytic Asp215 of one HAP protomer through a water molecule, while also making a direct hydrogen bond to Glu278A' of the other protomer. A comparison of the shifts in the positions of the catalytic residues in the inhibitor complex presented here with those published previously gives further hints regarding the enzymatic mechanism of HAP.

  14. Incipient mantle delamination, active tectonics and crustal thickening in Northern Morocco: Insights from gravity data and numerical modeling

    NASA Astrophysics Data System (ADS)

    Baratin, Laura-May; Mazzotti, Stéphane; Chéry, Jean; Vernant, Philippe; Tahayt, Abdelilah; Mourabit, Taoufik

    2016-11-01

    The Betic-Rif orocline surrounding the Alboran Sea, the westernmost tip of the Mediterranean Sea, accommodates the NW-SE convergence between the Nubia and Eurasia plates. Recent GPS observations indicate a ∼4 mm/yr SW motion of the Rif Mountains, relative to stable Nubia, incompatible with a simple two-plate model. New gravity data acquired in this study define a pronounced negative Bouguer anomaly south of the Rif, interpreted as a ∼40 km-thick crust in a state of non-isostatic equilibrium. We study the correlation between these present-day kinematic and geodynamic processes using a finite-element code to model in 2-D the first-order behavior of a lithosphere affected by a downward normal traction (representing the pull of a high-density body in the upper mantle). We show that intermediate viscosities for the lower crust and uppermost mantle (1021-1022Pas) allow an efficient coupling between the mantle and the base of the brittle crust, thus enabling (1) the conversion of vertical movement, resulting from the downward traction, to horizontal movement and (2) shortening in the brittle upper crust. Our results show that incipient delamination of the Nubian continental lithosphere, linked to slab pull, can explain the present-day abnormal tectonics, contribute to the gravity anomaly observed in northern Morocco, and give insight into recent tectonics in the Western Mediterranean region.

  15. Learning shapes spontaneous activity itinerating over memorized states.

    PubMed

    Kurikawa, Tomoki; Kaneko, Kunihiko

    2011-01-01

    Learning is a process that helps create neural dynamical systems so that an appropriate output pattern is generated for a given input. Often, such a memory is considered to be included in one of the attractors in neural dynamical systems, depending on the initial neural state specified by an input. Neither neural activities observed in the absence of inputs nor changes caused in the neural activity when an input is provided were studied extensively in the past. However, recent experimental studies have reported existence of structured spontaneous neural activity and its changes when an input is provided. With this background, we propose that memory recall occurs when the spontaneous neural activity changes to an appropriate output activity upon the application of an input, and this phenomenon is known as bifurcation in the dynamical systems theory. We introduce a reinforcement-learning-based layered neural network model with two synaptic time scales; in this network, I/O relations are successively memorized when the difference between the time scales is appropriate. After the learning process is complete, the neural dynamics are shaped so that it changes appropriately with each input. As the number of memorized patterns is increased, the generated spontaneous neural activity after learning shows itineration over the previously learned output patterns. This theoretical finding also shows remarkable agreement with recent experimental reports, where spontaneous neural activity in the visual cortex without stimuli itinerate over evoked patterns by previously applied signals. Our results suggest that itinerant spontaneous activity can be a natural outcome of successive learning of several patterns, and it facilitates bifurcation of the network when an input is provided.

  16. Learning Shapes Spontaneous Activity Itinerating over Memorized States

    PubMed Central

    Kurikawa, Tomoki; Kaneko, Kunihiko

    2011-01-01

    Learning is a process that helps create neural dynamical systems so that an appropriate output pattern is generated for a given input. Often, such a memory is considered to be included in one of the attractors in neural dynamical systems, depending on the initial neural state specified by an input. Neither neural activities observed in the absence of inputs nor changes caused in the neural activity when an input is provided were studied extensively in the past. However, recent experimental studies have reported existence of structured spontaneous neural activity and its changes when an input is provided. With this background, we propose that memory recall occurs when the spontaneous neural activity changes to an appropriate output activity upon the application of an input, and this phenomenon is known as bifurcation in the dynamical systems theory. We introduce a reinforcement-learning-based layered neural network model with two synaptic time scales; in this network, I/O relations are successively memorized when the difference between the time scales is appropriate. After the learning process is complete, the neural dynamics are shaped so that it changes appropriately with each input. As the number of memorized patterns is increased, the generated spontaneous neural activity after learning shows itineration over the previously learned output patterns. This theoretical finding also shows remarkable agreement with recent experimental reports, where spontaneous neural activity in the visual cortex without stimuli itinerate over evoked patterns by previously applied signals. Our results suggest that itinerant spontaneous activity can be a natural outcome of successive learning of several patterns, and it facilitates bifurcation of the network when an input is provided. PMID:21408170

  17. Altered resting-state activity in seasonal affective disorder.

    PubMed

    Abou Elseoud, Ahmed; Nissilä, Juuso; Liettu, Anu; Remes, Jukka; Jokelainen, Jari; Takala, Timo; Aunio, Antti; Starck, Tuomo; Nikkinen, Juha; Koponen, Hannu; Zang, Yu-Feng; Tervonen, Osmo; Timonen, Markku; Kiviniemi, Vesa

    2014-01-01

    At present, our knowledge about seasonal affective disorder (SAD) is based mainly up on clinical symptoms, epidemiology, behavioral characteristics and light therapy. Recently developed measures of resting-state functional brain activity might provide neurobiological markers of brain disorders. Studying functional brain activity in SAD could enhance our understanding of its nature and possible treatment strategies. Functional network connectivity (measured using ICA-dual regression), and amplitude of low-frequency fluctuations (ALFF) were measured in 45 antidepressant-free patients (39.78 ± 10.64, 30 ♀, 15 ♂) diagnosed with SAD and compared with age-, gender- and ethnicity-matched healthy controls (HCs) using resting-state functional magnetic resonance imaging. After correcting for Type 1 error at high model orders (inter-RSN correction), SAD patients showed significantly increased functional connectivity in 11 of the 47 identified RSNs. Increased functional connectivity involved RSNs such as visual, sensorimotor, and attentional networks. Moreover, our results revealed that SAD patients compared with HCs showed significant higher ALFF in the visual and right sensorimotor cortex. Abnormally altered functional activity detected in SAD supports previously reported attentional and psychomotor symptoms in patients suffering from SAD. Further studies, particularly under task conditions, are needed in order to specifically investigate cognitive deficits in SAD.

  18. Fe, O, and C Charge States Associated with Quiescent Versus Active Current Sheets in the Solar Wind

    NASA Technical Reports Server (NTRS)

    Suess, S. T.; Ko, Y.-K.; vonSteiger, R.

    2008-01-01

    Ulysses MAG data were used to locate the heliospheric current sheet in data from 1991 through 2006. The purpose was to characterize typical charge states for Fe, O, and C in the vicinity of the current sheet and provide insight into the physical sources for these charge states in the corona. A study of He/H around the current sheets has led to a clear distinction between quiescent current sheets at times of low solar activity and active current sheets associated with magnetic clouds (and, presumably, ICMES). It has been shown that high ionization state Fe is produced in the corona in current sheets associated with CMEs through spectroscopic observations of the corona and through in situ detection at Ulysses. Here we show that the ionization state of Fe is typically only enhanced around active current sheets while the ionization states of O and C are commonly enhanced around both quiescent and active current sheets. This is consistent with UV coronal spectroscopy, which has shown that reconnection in current sheets behind CMEs leads to high temperatures not typically seen above quiet streamers.

  19. A state-of-the-art assessment of active structures

    NASA Technical Reports Server (NTRS)

    1992-01-01

    A state-of-the-art assessment of active structures with emphasis towards the applications in aeronautics and space is presented. It is felt that since this technology area is growing at such a rapid pace in many different disciplines, it is not feasible to cover all of the current research but only the relevant work as relates to aeronautics and space. Research in smart actuation materials, smart sensors, and control of smart/intelligent structures is covered. In smart actuation materials, piezoelectric, magnetostrictive, shape memory, electrorheological, and electrostrictive materials are covered. For sensory materials, fiber optics, dielectric loss, and piezoelectric sensors are examined. Applications of embedded sensors and smart sensors are discussed.

  20. Decoding mental states from brain activity in humans.

    PubMed

    Haynes, John-Dylan; Rees, Geraint

    2006-07-01

    Recent advances in human neuroimaging have shown that it is possible to accurately decode a person's conscious experience based only on non-invasive measurements of their brain activity. Such 'brain reading' has mostly been studied in the domain of visual perception, where it helps reveal the way in which individual experiences are encoded in the human brain. The same approach can also be extended to other types of mental state, such as covert attitudes and lie detection. Such applications raise important ethical issues concerning the privacy of personal thought.

  1. Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight.

    PubMed

    Purohit, Rituraj

    2014-01-01

    KIT receptor is the prime target in gastrointestinal stromal tumor (GISTs) therapy. Second generation inhibitor, Sunitinib, binds to an inactivated conformation of KIT receptor and stabilizes it in order to prevent tumor formation. Here, we investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop (EAL) region (805-850) by conducting molecular dynamics simulation (∼100 ns). We analyzed different properties such as root mean square cutoff or deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, hydrogen bonding network analysis, and essential dynamics. Apart from this, clustering and cross-correlation matrix approach was used to explore the conformational space of the wild type and mutant EAL region of KIT receptor. Molecular dynamics analysis indicated that mutation (D816H) was able to alter intramolecular hydrogen bonding pattern and affected the structural flexibility of EAL region. Moreover, flexible secondary elements, specially, coil and turns were dominated in EAL region of mutant KIT receptor during simulation. This phenomenon increased the movement of EAL region which in turn helped in shifting the equilibrium towards the active kinase conformation. Our atomic investigation of mutant KIT receptor which emphasized on EAL region provided a better insight into the understanding of Sunitinib resistance mechanism of KIT receptor and would help to discover new therapeutics for KIT-based resistant tumor cells in GIST therapy.

  2. [Investigation of Aerosol Mixed State and CCN Activity in Nanjing].

    PubMed

    Zhu, Lin; Ma, Yan; Zheng, Jun; Li, Shi-zheng; Wang, Li-peng

    2016-04-15

    During 11-18 September 2014, the size-resolved aerosol Cloud Condensation Nuclei (CCN) activity and mixing state were measured using Cloud Condensation Nuclei Counter (CCNC), Aerosol Particle Mass (APM) and Scanning Mobility Particle Sizer (SMPS). The results showed that aerosols mainly existed as an internal mixture. For 76, 111, 138 and 181 nm particles, black carbon (BC) accounted for 5.4%, 10%, l0.7% and 6.7% of the particle mass, but as high as 51%, 57%, 70% and 59% of the particle number concentrations, respectively, suggesting that BC was a type of important condensation nuclei in the atmosphere and made significant contributions to particle numbers. The occasionally observed external mixtures were mainly present in 111 and 138 nm particles. The critical supersaturation was 0.25%, 0.13%, 0.06% and 0.015% for 76, 111, 138 and 181 nm particles, respectively. Precipitation and haze had significant effects on the particle CCN activity. The hygroscopicity parameter K was 0.37, 0.29 and 0.39 in rainy, clear and hazy days, respectively. Particle density and CCN activity were impacted by chemical compositions. Compared with clear days, higher contents of inorganic salts and lower contents of organics were found on hazy days, accompanied by lower particle density and higher CCN activity. PMID:27548938

  3. Update on nutrition monitoring activities in the United States.

    PubMed

    Kuczmarski, M F; Moshfegh, A; Briefel, R

    1994-07-01

    This article provides an overview of planned and proposed nutrition monitoring activities of the National Nutrition Monitoring and Related Research (NNMRR) Program. Key provisions of the NNMRR Act of 1990 are described, including the roles and responsibilities of the Interagency Board of Nutrition Monitoring and Related Research (IBNMRR) and the National Nutrition Monitoring Advisory Council and the development of the Ten-Year Comprehensive Plan. The Plan, which was developed under the guidance of the IBNMRR and reviewed by the National Nutrition Monitoring Advisory Council, is the basis for planning and coordinating the monitoring activities of 22 federal agencies. Also discussed are the resources generated from nutrition monitoring activities, from publications to conferences, that are available to dietitians and nutritionists. Professionals view the scientific reports that describe the nutritional status of the US population and the directories of federal and state monitoring activities as valuable resources. Suggestions from users of nutrition monitoring data related to their information and research needs have been extremely helpful to federal agencies in the development of future monitoring publications and the Ten-Year Comprehensive Plan. Continued communication between dietitians and the federal agencies responsible for the NNMRR Program is important. PMID:8021417

  4. Ambulatory physical activity during United States Army basic combat training.

    PubMed

    Knapik, J J; Darakjy, S; Hauret, K G; Canada, S; Marin, R; Jones, B H

    2007-02-01

    Electronic pedometers were used to quantify locomotor physical activity during an entire 9-week United States Army Basic Combat Training (BCT) cycle. Pedometers were worn on the hips of 4 trainees in each of 10 BCT companies during all BCT activities. Investigators obtained pedometer readings (steps) on a daily basis, and estimated travel distances were obtained by multiplying steps by the average individual step length. A short questionnaire was administered daily to assure trainees wore the pedometers and trained with their companies all day. Trainees performed an average +/- SD of 16 311 +/- 5826 steps/day and traveled an estimated 11.7 +/- 4.4 kilometers/day. The highest daily locomotor activity was during the field training exercise in which trainees took an average +/- SD of 22 372 +/- 12 517 steps/day traveling an estimated 16.2 +/- 9.7 kilometers/day. Differences among the 10 companies ranged from 14 720 +/- 6649 steps/day to 18 729 +/- 6328 steps/day. This survey provided the first examination of locomotor physical activity during an entire BCT cycle.

  5. Polarization states of diffracted light. Changes accompanying fiber activation.

    PubMed Central

    Chen, J S; Baskin, R J; Baskin, R J; Burton, K; Shen, S; Yeh, Y

    1989-01-01

    Measurement of the state of optical polarization of light diffracted from single, skinned and intact fibers of anterior tibialis muscle from Rana pipiens revealed a dependence upon rigor, activation, and sarcomere length (SL) change. Changes in total birefringence, delta nT, and differential field ratio value, rT, were determined. In a relaxed, skinned fiber the total birefringence value, delta nT, decreases as sarcomere length is increased from 2.1 microns to approximately 2.8-3.0 microns. From there it increases significantly to a value of approximately 1.8 x 10(-3) at a sarcomere length of 3.6 microns. The differential field ratio, rT, also shows a biphasic response to increasing sarcomere length, first exhibiting a rapid decrease over shorter SL and leveling out after the SL is beyond 3.0 microns. In comparison, relaxed intact fibers change substantially less upon sarcomere length change, showing little change in birefringence and a small bi-phasic change in rT. Skinned fibers were activated using a solution that has the same ionic strength as the relaxing solution and allows repeatable, and sustained activation. A decrease in both delta nT and rT was observed upon fiber activation. The decrease in delta nT and rT was slightly larger at shorter sarcomere lengths than at longer lengths. Relaxed fibers placed in rigor showed changes in delta nT and rT similar to those observed in activated fibers. These results are consistent with the hypothesis that, after activation, a significant portion of the thick filament cross-bridges rotate towards the actin filament resulting in redistribution of the interfilament mass content. They are also consistent with an average orientation of crossbridges in the overlap region different from that in the nonoverlap region. PMID:2790140

  6. Polarization states of diffracted light. Changes accompanying fiber activation.

    PubMed

    Chen, J S; Baskin, R J; Baskin, R J; Burton, K; Shen, S; Yeh, Y

    1989-09-01

    Measurement of the state of optical polarization of light diffracted from single, skinned and intact fibers of anterior tibialis muscle from Rana pipiens revealed a dependence upon rigor, activation, and sarcomere length (SL) change. Changes in total birefringence, delta nT, and differential field ratio value, rT, were determined. In a relaxed, skinned fiber the total birefringence value, delta nT, decreases as sarcomere length is increased from 2.1 microns to approximately 2.8-3.0 microns. From there it increases significantly to a value of approximately 1.8 x 10(-3) at a sarcomere length of 3.6 microns. The differential field ratio, rT, also shows a biphasic response to increasing sarcomere length, first exhibiting a rapid decrease over shorter SL and leveling out after the SL is beyond 3.0 microns. In comparison, relaxed intact fibers change substantially less upon sarcomere length change, showing little change in birefringence and a small bi-phasic change in rT. Skinned fibers were activated using a solution that has the same ionic strength as the relaxing solution and allows repeatable, and sustained activation. A decrease in both delta nT and rT was observed upon fiber activation. The decrease in delta nT and rT was slightly larger at shorter sarcomere lengths than at longer lengths. Relaxed fibers placed in rigor showed changes in delta nT and rT similar to those observed in activated fibers. These results are consistent with the hypothesis that, after activation, a significant portion of the thick filament cross-bridges rotate towards the actin filament resulting in redistribution of the interfilament mass content. They are also consistent with an average orientation of crossbridges in the overlap region different from that in the nonoverlap region.

  7. Insights into activation and RNA binding of trp RNA-binding attenuation protein (TRAP) through all-atom simulations.

    PubMed

    Murtola, Teemu; Vattulainen, Ilpo; Falck, Emma

    2008-06-01

    Tryptophan biosynthesis in Bacillus stearothermophilus is regulated by a trp RNA binding attenuation protein (TRAP). It is a ring-shaped 11-mer of identical 74 residue subunits. Tryptophan binding pockets are located between adjacent subunits, and tryptophan binding activates TRAP to bind RNA. Here, we report results from all-atom molecular dynamics simulations of the system, complementing existing extensive experimental studies. We focus on two questions. First, we look at the activation mechanism, of which relatively little is known experimentally. We find that the absence of tryptophan allows larger motions close to the tryptophan binding site, and we see indication of a conformational change in the BC loop. However, complete deactivation seems to occur on much longer time scales than the 40 ns studied here. Second, we study the TRAP-RNA interactions. We look at the relative flexibilities of the different bases in the complex and analyze the hydrogen bonds between the protein and RNA. We also study the role of Lys37, Lys56, and Arg58, which have been experimentally identified as essential for RNA binding. Hydrophobic stacking of Lys37 with the nearby RNA base is confirmed, but we do not see direct hydrogen bonding between RNA and the other two residues, in contrast to the crystal structure. Rather, these residues seem to stabilize the RNA-binding surface, and their positive charge may also play a role in RNA binding. Simulations also indicate that TRAP is able to attract RNA nonspecifically, and the interactions are quantified in more detail using binding energy calculations. The formation of the final binding complex is a very slow process: within the simulation time scale of 40 ns, only two guanine bases become bound (and no others), indicating that the binding initiates at these positions. In general, our results are in good agreement with experimental studies, and provide atomic-scale insights into the processes. PMID:18186477

  8. Histopathological and molecular insights into the ovicidal activities of two entomopathogenic fungi against two-spotted spider mite.

    PubMed

    Zhang, Lei; Shi, Wei-Bing; Feng, Ming-Guang

    2014-03-01

    Entomopathogenic fungi can infect and kill spider mite eggs but their ovicidal activities are poorly understood. Here we gain histopathogenical and molecular insights into the ovicidal activities of Beauveria bassiana and Isaria fumosorosea against the two-spotted spider mite, Tetranychus urticae. Scanning electronic microscopy indicated successful adhesion and germination of fungal conidia on egg shell at 24h post-spray (HPS). Germ tubes of both fungi could penetrate into egg shell with penetration pegs at 48 HPS. Interestingly, the germ tubes of B. bassiana may elongate on egg surface to locate appropriate sites for penetration, acting as 'searching' hyphae. Aside from the normal penetration, the germ tubes of I. fumosorosea can be completely or partially embedded into egg shell for a distance of extension, forming shell humps. Light microscopy of ultrathin sections of infected eggs showed shrunken (affected) or disrupted embryos at 48-96 HPS despite little effect on egg cleavage at 24 HPS. However, distinguishable hyphal cells were hardly found inside the embryos lacking oxygen although fungal outgrowths were abundant on unhatched (killed) eggs. In PCR with specific probes, the 18S rDNA signals of B. bassiana (412 bp) and I. fumosorosea (454 bp) in the DNA extracts from surface-cleaned mite eggs increased at 0-96 HPS, confirming fungal colonization in the infected eggs. We consider that the colonization on shell surface and underside could rely upon extending hyphae for uptake of egg nutrition, resulting in embryo disruption. Our observations add knowledge to microbial control of spider mites.

  9. Capacity-building activities in the Arab States.

    PubMed

    El Sioufi, M

    1996-03-01

    The UN Centre for Human Settlements (UNCHS) (Habitat) Training and Capacity-Building Section has been active in several of the Arab States. Beginning in 1995, Belgium funded a 3-year project, "Localising Agenda 21: Action Planning for Sustainable Urban Development," in Essaouira, Morocco. A local team was established, and an Action Planning Consultation Workshop was held in January 1996. Local participants, Belgian experts, and the UNCHS Training and Capacity-Building Section attended the workshop, the goal of which was to guide the town in achieving sustainable development. The experiences from this project will be disseminated throughout the region. In Egypt, the Training and Capacity Building Section has initiated the "Sustainable Ismailia Project," a training program, which may be expanded nationally, for locally elected leadership. The Egyptian government will be responsible for the majority of the implementation funding; training materials are being prepared, and training should begin in 1996. The Palestinian Authority (Gaza Strip), Jordan, Mauritania, and Yemen have requested capacity-building programs. The "Urban Settlements and Management Programme" has requested a training program for Somalia after the country stabilizes. "A Regional Capacity-Building Programme" is being designed for national training institutions in the Arab States; the program will focus on the training of trainers, urban managers, and elected leadership. UNCHS training materials and handbooks are being translated into Arabic. This training was requested by Member States during the 15th session of the Commission on Human Settlements.

  10. GPi Oscillatory Activity Differentiates Tics from the Resting State, Voluntary Movements, and the Unmedicated Parkinsonian State

    PubMed Central

    Jimenez-Shahed, Joohi; Telkes, Ilknur; Viswanathan, Ashwin; Ince, Nuri F.

    2016-01-01

    Background: Deep brain stimulation (DBS) is an emerging treatment strategy for severe, medication-refractory Tourette syndrome (TS). Thalamic (Cm-Pf) and pallidal (including globus pallidus interna, GPi) targets have been the most investigated. While the neurophysiological correlates of Parkinson's disease (PD) in the GPi and subthalamic nucleus (STN) are increasingly recognized, these patterns are not well characterized in other disease states. Recent findings indicate that the cross-frequency coupling (CFC) between beta band and high frequency oscillations (HFOs) within the STN in PD patients is pathologic. Methods: We recorded intraoperative local field potentials (LFPs) from the postero-ventrolateral GPi in three adult patients with TS at rest, during voluntary movements, and during tic activity and compared them to the intraoperative GPi-LFP activity recorded from four unmedicated PD patients at rest. Results: In all PD patients, we noted excessive beta band activity (13–30 Hz) at rest which consistently modulated the amplitude of the co-existent HFOs observed between 200 and 400 Hz, indicating the presence of beta-HFO CFC. In all 3TS patients at rest, we observed theta band activity (4–7 Hz) and HFOs. Two patients had beta band activity, though at lower power than theta oscillations. Tic activity was associated with increased high frequency (200–400 Hz) and gamma band (35–200 Hz) activity. There was no beta-HFO CFC in TS patients at rest. However, CFC between the phase of 5–10 Hz band activity and the amplitude of HFOs was found in two TS patients. During tics, this shifted to CFC between the phase of beta band activity and the amplitude of HFOs in all subjects. Conclusions: To our knowledge this is the first study that shows that beta-HFO CFC exists in the GPi of TS patients during tics and at rest in PD patients, and suggests that this pattern might be specific to pathologic/involuntary movements. Furthermore, our findings suggest that during tics

  11. Global metabolite analysis of the land snail Theba pisana hemolymph during active and aestivated states.

    PubMed

    Bose, U; Centurion, E; Hodson, M P; Shaw, P N; Storey, K B; Cummins, S F

    2016-09-01

    The state of metabolic dormancy has fascinated people for hundreds of years, leading to research exploring the identity of natural molecular components that may induce and maintain this state. Many animals lower their metabolism in response to high temperatures and/or arid conditions, a phenomenon called aestivation. The biological significance for this is clear; by strongly suppressing metabolic rate to low levels, animals minimize their exposure to stressful conditions. Understanding blood or hemolymph metabolite changes that occur between active and aestivated animals can provide valuable insights relating to those molecular components that regulate hypometabolism in animals, and how they afford adaptation to their different environmental conditions. In this study, we have investigated the hemolymph metabolite composition from the land snail Theba pisana, a remarkably resilient mollusc that displays an annual aestivation period. Using LC-MS-based metabolomics analysis, we have identified those hemolymph metabolites that show significant changes in relative abundance between active and aestivated states. We show that certain metabolites, including some phospholipids [e.g. LysoPC(14:0)], and amino acids such as l-arginine and l-tyrosine, are present at high levels within aestivated snails. Further investigation of our T. pisana RNA-sequencing data elucidated the entire repertoire of phospholipid-synthesis genes in the snail digestive gland, as a precursor towards future comparative investigation between the genetic components of aestivating and non-aestivating species. In summary, we have identified a large number of metabolites that are elevated in the hemolymph of aestivating snails, supporting their role in protecting against heat or desiccation. PMID:27318654

  12. Global metabolite analysis of the land snail Theba pisana hemolymph during active and aestivated states.

    PubMed

    Bose, U; Centurion, E; Hodson, M P; Shaw, P N; Storey, K B; Cummins, S F

    2016-09-01

    The state of metabolic dormancy has fascinated people for hundreds of years, leading to research exploring the identity of natural molecular components that may induce and maintain this state. Many animals lower their metabolism in response to high temperatures and/or arid conditions, a phenomenon called aestivation. The biological significance for this is clear; by strongly suppressing metabolic rate to low levels, animals minimize their exposure to stressful conditions. Understanding blood or hemolymph metabolite changes that occur between active and aestivated animals can provide valuable insights relating to those molecular components that regulate hypometabolism in animals, and how they afford adaptation to their different environmental conditions. In this study, we have investigated the hemolymph metabolite composition from the land snail Theba pisana, a remarkably resilient mollusc that displays an annual aestivation period. Using LC-MS-based metabolomics analysis, we have identified those hemolymph metabolites that show significant changes in relative abundance between active and aestivated states. We show that certain metabolites, including some phospholipids [e.g. LysoPC(14:0)], and amino acids such as l-arginine and l-tyrosine, are present at high levels within aestivated snails. Further investigation of our T. pisana RNA-sequencing data elucidated the entire repertoire of phospholipid-synthesis genes in the snail digestive gland, as a precursor towards future comparative investigation between the genetic components of aestivating and non-aestivating species. In summary, we have identified a large number of metabolites that are elevated in the hemolymph of aestivating snails, supporting their role in protecting against heat or desiccation.

  13. Hypoxia Induces a Prothrombotic State Independently of the Physical Activity

    PubMed Central

    Ninivaggi, Marisa; de Laat, Marieke; Lancé, Marcus M. D.; Kicken, Cécile H.; Pelkmans, Leonie; Bloemen, Saartje; Dirks, Marlou L.; van Loon, Luc J. C.; Govers-Riemslag, José W. P.; Lindhout, Theo; Konings, Joke; de Laat, Bas

    2015-01-01

    Hypoxia (oxygen deprivation) is known to be associated with deep vein thrombosis and venous thromboembolism. We attempted to get a better comprehension of its mechanism by going to high altitude, thereby including the potential contributing role of physical activity. Two groups of 15 healthy individuals were exposed to hypoxia by going to an altitude of 3900 meters, either by climbing actively (active group) or transported passively by cable car (passive group). Both groups were tested for plasma fibrinogen, von Willebrand factor and factor VIII levels, fibrinolysis, thrombin generating capacity, heart rate, oxygen saturation levels and blood pressure. As a control for the passive group, 7 healthy volunteers stayed immobile in bed for 7 days at normoxic conditions. The heart rate increased and oxygen saturation levels decreased with increasing altitude. Fibrinolysis and fibrinogen levels were not affected. Factor VIII and von Willebrand factor levels levels increased significantly in the active group, but not in the passive group. Plasma thrombin generation remained unchanged in both the active and passive group with increasing altitude and during 7 days of immobility in healthy subjects. However, by applying whole blood thrombin generation, we found an increased peak height and endogenous thrombin potential, and a decreased lagtime and time-to-peak with increasing levels of hypoxia in both groups. In conclusion, by applying whole blood thrombin generation we demonstrated that hypoxia causes a prothrombotic state. As thrombin generation in plasma did not increase, our results suggest that the cellular part of the blood is involved in the prothrombotic phenotype induced by hypoxia. PMID:26516774

  14. Resting-state EEG theta activity and risk learning: sensitivity to reward or punishment?

    PubMed

    Massar, Stijn A A; Kenemans, J Leon; Schutter, Dennis J L G

    2014-03-01

    Increased theta (4-7 Hz)-beta (13-30 Hz) power ratio in resting state electroencephalography (EEG) has been associated with risky disadvantageous decision making and with impaired reinforcement learning. However, the specific contributions of theta and beta power in risky decision making remain unclear. The first aim of the present study was to replicate the earlier found relationship and examine the specific contributions of theta and beta power in risky decision making using the Iowa Gambling Task. The second aim of the study was to examine whether the relation were associated with differences in reward or punishment sensitivity. We replicated the earlier found relationship by showing a positive association between theta/beta ratio and risky decision making. This correlation was mainly driven by theta oscillations. Furthermore, theta power correlated with reward motivated learning, but not with punishment learning. The present results replicate and extend earlier findings by providing novel insights into the relation between thetabeta ratios and risky decision making. Specifically, findings show that resting-state theta activity is correlated with reinforcement learning, and that this association may be explained by differences in reward sensitivity.

  15. Communicating Climate Change in the Agricultural Sector: Insights from Surveys and Interviews with Agricultural Advisors in the Midwestern United States

    NASA Astrophysics Data System (ADS)

    Prokopy, L. S.; Carlton, S.; Dunn, M.

    2014-12-01

    Understanding U.S. agricultural stakeholder views about the existence of climate change and what influences these views is central to developing communication in support of adaptation and mitigation. It has been postulated in the literature that extreme weather events can shape people's climate change beliefs and adaptation attitudes. In this presentation, we use data from pre- and post-extreme event surveys and interviews to examine the effects of the 2012 Midwestern US drought on agricultural advisors' climate change beliefs, adaptation attitudes, and risk perceptions. We found that neither climate change beliefs nor attitudes toward adaptation changed significantly as a result of the drought. Risk perceptions did change, however, with advisors becoming more concerned about risks from drought and pests and less concerned about risks related to flooding and ponding. Qualitative interviews revealed that while advisors readily accept the occurrence of extreme weather as a risk, the irregularity and unpredictability of extreme events for specific localities limits day-to-day consideration in respect to prescribed management advice. Instead, advisors' attention is directed towards planning for short-term changes encompassing weather, pests, and the market, as well as planning for long-term trends related to water availability. These findings provide important insights for communicating climate change in this critical sector while illustrating the importance of social science research in planning and executing communication campaigns.

  16. Glycosylation at Asn211 Regulates the Activation State of the Discoidin Domain Receptor 1 (DDR1)*

    PubMed Central

    Fu, Hsueh-Liang; Valiathan, Rajeshwari R.; Payne, Leo; Kumarasiri, Malika; Mahasenan, Kiran V.; Mobashery, Shahriar; Huang, Paul; Fridman, Rafael

    2014-01-01

    Discoidin domain receptor 1 (DDR1) belongs to a unique family of receptor tyrosine kinases that signal in response to collagens. DDR1 undergoes autophosphorylation in response to collagen binding with a slow and sustained kinetics that is unique among members of the receptor tyrosine kinase family. DDR1 dimerization precedes receptor activation suggesting a structural inhibitory mechanism to prevent unwarranted phosphorylation. However, the mechanism(s) that maintains the autoinhibitory state of the DDR1 dimers is unknown. Here, we report that N-glycosylation at the Asn211 residue plays a unique role in the control of DDR1 dimerization and autophosphorylation. Using site-directed mutagenesis, we found that mutations that disrupt the conserved 211NDS N-glycosylation motif, but not other N-glycosylation sites (Asn260, Asn371, and Asn394), result in collagen I-independent constitutive phosphorylation. Mass spectrometry revealed that the N211Q mutant undergoes phosphorylation at Tyr484, Tyr520, Tyr792, and Tyr797. The N211Q traffics to the cell surface, and its ectodomain displays collagen I binding with an affinity similar to that of the wild-type DDR1 ectodomain. However, unlike the wild-type receptor, the N211Q mutant exhibits enhanced receptor dimerization and sustained activation upon ligand withdrawal. Taken together, these data suggest that N-glycosylation at the highly conserved 211NDS motif evolved to act as a negative repressor of DDR1 phosphorylation in the absence of ligand. The presence of glycan moieties at that site may help to lock the collagen-binding domain in the inactive state and prevent unwarranted signaling by receptor dimers. These studies provide a novel insight into the structural mechanisms that regulate DDR activation. PMID:24509848

  17. Substrate-bound outward-open state of the betaine transporter BetP provides insights into Na+ coupling

    NASA Astrophysics Data System (ADS)

    Perez, Camilo; Faust, Belinda; Mehdipour, Ahmad Reza; Francesconi, Kevin A.; Forrest, Lucy R.; Ziegler, Christine

    2014-07-01

    The Na+-coupled betaine symporter BetP shares a highly conserved fold with other sequence unrelated secondary transporters, for example, with neurotransmitter symporters. Recently, we obtained atomic structures of BetP in distinct conformational states, which elucidated parts of its alternating-access mechanism. Here, we report a structure of BetP in a new outward-open state in complex with an anomalous scattering substrate, adding a fundamental piece to an unprecedented set of structural snapshots for a secondary transporter. In combination with molecular dynamics simulations these structural data highlight important features of the sequential formation of the substrate and sodium-binding sites, in which coordinating water molecules play a crucial role. We observe a strictly interdependent binding of betaine and sodium ions during the coupling process. All three sites undergo progressive reshaping and dehydration during the alternating-access cycle, with the most optimal coordination of all substrates found in the closed state.

  18. Insights into the Nature of the Exotic Fractional Quantum Hall States from Ultra-low Temperature Transport

    NASA Astrophysics Data System (ADS)

    Csathy, Gabor

    2012-02-01

    It is believed that the ν=5/2 and 12/5 fractional quantum Hall states (FQHS) in the second Landau level of a two-dimensional electron gas support excitations with non-Abelian braiding statistics. Two outstanding questions concerning the nature of the both the odd and even denominator FQHS of the second Landau level as probed by transport measurements at temperatures as low as 5mK will be addressed. We report the discovery of a new odd denominator FQHS state at ν=2+6/13. The energy gaps of this and other states at ν=2+1/3, 2+2/3, and 2+2/5 reveal a markedly different dependence on the effective magnetic field as compared to that of the corresponding lowest Landau level states at 6/13, 1/3, 2/3, and 2/5. If, in addition, we assume a Landau level-independent effective mass, we find that the 7/3 and 8/3 states are consistent, whereas the 2+2/5 and the 2+6/13 states show a strong deviation from the predictions of the model of free composite fermions. For the even denominator states at ν=5/2 and 7/2 we extended measurements to the new regime of very low densities and to samples grown in two MBE chambers: one at Princeton and one at Purdue. Comparisons found in the literature of the experimentally measured intrinsic gaps at ν=5/2 with numerical results are confusing: three methods find a large difference whereas a fourth method finds a good agreement. Our data suggests that the former three methods have deficiencies and therefore cannot be used. Using the fourth and a new method we introduce we find an excellent agreement of the experimental and numerical intrinsic gaps at ν=5/2. These findings lend a strong support to the Pfaffian description of the ν=5/2 fractional state. Work done in collaboration with A. Kumar, N. Samkharadze, N. Deng, J. Watson, G. Gardner, M. Manfra, L. Pfeiffer, and K. West. G.A.C. has been supported by the NSF DMR-0907172 and DOE DE-SC0006671 grants.

  19. Metabolomic profiling in Selaginella lepidophylla at various hydration states provides new insights into the mechanistic basis of desiccation tolerance.

    PubMed

    Yobi, Abou; Wone, Bernard W M; Xu, Wenxin; Alexander, Danny C; Guo, Lining; Ryals, John A; Oliver, Melvin J; Cushman, John C

    2013-03-01

    Selaginella lepidophylla is one of only a few species of spike mosses (Selaginellaceae) that have evolved desiccation tolerance (DT) or the ability to 'resurrect' from an air-dried state. In order to understand the metabolic basis of DT, S. lepidophylla was subjected to a five-stage, rehydration/dehydration cycle, then analyzed using non-biased, global metabolomics profiling technology based on GC/MS and UHLC/MS/MS(2) platforms. A total of 251 metabolites including 167 named (66.5%) and 84 (33.4%) unnamed compounds were characterized. Only 42 (16.7%) and 74 (29.5%) of compounds showed significantly increased or decreased abundance, respectively, indicating that most compounds were produced constitutively, including highly abundant trehalose, sucrose, and glucose. Several glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle intermediates showed increased abundance at 100% relative water content (RWC) and 50% RWC. Vanillate, a potent antioxidant, was also more abundant in the hydrated state. Many different sugar alcohols and sugar acids were more abundant in the hydrated state. These polyols likely decelerate the rate of water loss during the drying process as well as slow water absorption during rehydration, stabilize proteins, and scavenge reactive oxygen species (ROS). In contrast, nitrogen-rich and γ-glutamyl amino acids, citrulline, and nucleotide catabolism products (e.g. allantoin) were more abundant in the dry states, suggesting that these compounds might play important roles in nitrogen remobilization during rehydration or in ROS scavenging. UV-protective compounds such as 3-(3-hydroxyphenyl)propionate, apigenin, and naringenin, were more abundant in the dry states. Most lipids were produced constitutively, with the exception of choline phosphate, which was more abundant in dry states and likely plays a role in membrane hydration and stabilization. In contrast, several polyunsaturated fatty acids were more abundant in the hydrated states

  20. Designing Anti-Influenza Aptamers: Novel Quantitative Structure Activity Relationship Approach Gives Insights into Aptamer – Virus Interaction

    PubMed Central

    Musafia, Boaz; Oren-Banaroya, Rony; Noiman, Silvia

    2014-01-01

    This study describes the development of aptamers as a therapy against influenza virus infection. Aptamers are oligonucleotides (like ssDNA or RNA) that are capable of binding to a variety of molecular targets with high affinity and specificity. We have studied the ssDNA aptamer BV02, which was designed to inhibit influenza infection by targeting the hemagglutinin viral protein, a protein that facilitates the first stage of the virus’ infection. While testing other aptamers and during lead optimization, we realized that the dominant characteristics that determine the aptamer’s binding to the influenza virus may not necessarily be sequence-specific, as with other known aptamers, but rather depend on general 2D structural motifs. We adopted QSAR (quantitative structure activity relationship) tool and developed computational algorithm that correlate six calculated structural and physicochemical properties to the aptamers’ binding affinity to the virus. The QSAR study provided us with a predictive tool of the binding potential of an aptamer to the influenza virus. The correlation between the calculated and actual binding was R2 = 0.702 for the training set, and R2 = 0.66 for the independent test set. Moreover, in the test set the model’s sensitivity was 89%, and the specificity was 87%, in selecting aptamers with enhanced viral binding. The most important properties that positively correlated with the aptamer’s binding were the aptamer length, 2D-loops and repeating sequences of C nucleotides. Based on the structure-activity study, we have managed to produce aptamers having viral affinity that was more than 20 times higher than that of the original BV02 aptamer. Further testing of influenza infection in cell culture and animal models yielded aptamers with 10 to 15 times greater anti-viral activity than the BV02 aptamer. Our insights concerning the mechanism of action and the structural and physicochemical properties that govern the interaction with the

  1. The Effect of Cellulose Crystal Structure and Solid-State Morphology on the Activity of Cellulases

    SciTech Connect

    Stipanovic, Arthur J

    2014-11-17

    Consistent with the US-DOE and USDA “Roadmap” objective of producing ethanol and chemicals from cellulosic feedstocks more efficiently, a three year research project entitled “The Effect of Cellulose Crystal Structure and Solid-State Morphology on the Activity of Cellulases” was initiated in early 2003 under DOE sponsorship (Project Number DE-FG02-02ER15356). A three year continuation was awarded in June 2005 for the period September 15, 2005 through September 14, 2008. The original goal of this project was to determine the effect of cellulose crystal structure, including allomorphic crystalline form (Cellulose I, II, III, IV and sub-allomorphs), relative degree of crystallinity and crystallite size, on the activity of different types of genetically engineered cellulase enzymes to provide insight into the mechanism and kinetics of cellulose digestion by “pure” enzymes rather than complex mixtures. We expected that such information would ultimately help enhance the accessibility of cellulose to enzymatic conversion processes thereby creating a more cost-effective commercial process yielding sugars for fermentation into ethanol and other chemical products. Perhaps the most significant finding of the initial project phase was that conversion of native bacterial cellulose (Cellulose I; BC-I) to the Cellulose II (BC-II) crystal form by aqueous NaOH “pretreatment” provided an increase in cellulase conversion rate approaching 2-4 fold depending on enzyme concentration and temperature, even when initial % crystallinity values were similar for both allomorphs.

  2. Insights from a Survey of Astronomy Instructors in Community and Other Teaching-Oriented Colleges in the United States

    ERIC Educational Resources Information Center

    Fraknoi, Andrew

    2004-01-01

    Estimates are that approximately 100,000 to 125,000 students take introductory astronomy classes each year at colleges and universities that do not grant bachelor's or higher degrees in physics or astronomy. This represents roughly 40% to 50% of the total number of students taking intro astronomy in the United States. Such nonresearch institutions…

  3. New Insights into Mutable Collagenous Tissue: Correlations between the Microstructure and Mechanical State of a Sea-Urchin Ligament

    PubMed Central

    Ribeiro, Ana R.; Barbaglio, Alice; Benedetto, Cristiano D.; Ribeiro, Cristina C.; Wilkie, Iain C.; Carnevali, Maria D. C.; Barbosa, Mário A.

    2011-01-01

    The mutable collagenous tissue (MCT) of echinoderms has the ability to undergo rapid and reversible changes in passive mechanical properties that are initiated and modulated by the nervous system. Since the mechanism of MCT mutability is poorly understood, the aim of this work was to provide a detailed morphological analysis of a typical mutable collagenous structure in its different mechanical states. The model studied was the compass depressor ligament (CDL) of a sea urchin (Paracentrotus lividus), which was characterized in different functional states mimicking MCT mutability. Transmission electron microscopy, histochemistry, cryo-scanning electron microscopy, focused ion beam/scanning electron microscopy, and field emission gun-environmental scanning electron microscopy were used to visualize CDLs at the micro- and nano-scales. This investigation has revealed previously unreported differences in both extracellular and cellular constituents, expanding the current knowledge of the relationship between the organization of the CDL and its mechanical state. Scanning electron microscopies in particular provided a three-dimensional overview of CDL architecture at the micro- and nano-scales, and clarified the micro-organization of the ECM components that are involved in mutability. Further evidence that the juxtaligamental cells are the effectors of these changes in mechanical properties was provided by a correlation between their cytology and the tensile state of the CDLs. PMID:21935473

  4. Metabolomic profiling in Selaginella lepidophylla at various hydration states provides new insights into the mechanistic basis of desiccation tolerance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Selaginella lepidophylla is one of only a few species of spike mosses (Selaginellaceae) that have evolved desiccation tolerance (DT) or the ability to ‘resurrect’ from an air-dried state. In order to understand the metabolic basis of DT, S. lepidophylla was subjected to a five-stage, rehydration/de...

  5. Resting-State Oscillatory Activity in Autism Spectrum Disorders

    PubMed Central

    Cornew, Lauren; Blaskey, Lisa; Edgar, J. Christopher

    2013-01-01

    Neural oscillatory anomalies in autism spectrum disorders (ASD) suggest an excitatory/inhibitory imbalance; however, the nature and clinical relevance of these anomalies are unclear. Whole-cortex magnetoencephalography data were collected while 50 children (27 with ASD, 23 controls) underwent an eyes-closed resting-state exam. A Fast Fourier Transform was applied and oscillatory activity examined from 1 to 120 Hz at 15 regional sources. Associations between oscillatory anomalies and symptom severity were probed. Children with ASD exhibited regionally specific elevations in delta (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), and high frequency (20–120 Hz) power, supporting an imbalance of neural excitation/inhibition as a neurobiological feature of ASD. Increased temporal and parietal alpha power was associated with greater symptom severity and thus is of particular interest. PMID:22207057

  6. Passive resting state and history of antagonist muscle activity shape active extensions in an insect limb

    PubMed Central

    Ache, Jan M.

    2012-01-01

    Limb movements can be driven by muscle contractions, external forces, or intrinsic passive forces. For lightweight limbs like those of insects or small vertebrates, passive forces can be large enough to overcome the effects of gravity and may even generate limb movements in the absence of active muscle contractions. Understanding the sources and actions of such forces is therefore important in understanding motor control. We describe passive properties of the femur-tibia joint of the locust hind leg. The resting angle is determined primarily by passive properties of the relatively large extensor tibiae muscle and is influenced by the history of activation of the fast extensor tibiae motor neuron. The resting angle is therefore better described as a history-dependent resting state. We selectively stimulated different flexor tibiae motor neurons to generate a range of isometric contractions of the flexor tibiae muscle and then stimulated the fast extensor tibiae motor neuron to elicit active tibial extensions. Residual forces in the flexor muscle have only a small effect on subsequent active extensions, but the effect is larger for distal than for proximal flexor motor neurons and varies with the strength of flexor activation. We conclude that passive properties of a lightweight limb make substantial and complex contributions to the resting state of the limb that must be taken into account in the patterning of neuronal control signals driving its active movements. Low variability in the effects of the passive forces may permit the nervous system to accurately predict their contributions to behavior. PMID:22357791

  7. Preliminary insights into an integrated geophysical approach for a better understanding of Strombolian activity at Yasur volcano, Vanuatu

    NASA Astrophysics Data System (ADS)

    Meier, K.; Garaebiti, E.; Gerst, A.; Harrison, M.; Hort, M. K.; Kremers, S.; Wassermann, J. M.; Weiss, B.

    2009-12-01

    In August/September 2008 we carried out a two-week multi-parameter measurement on Yasur volcano, Vanuatu to gain new insights into the mechanism of Strombolian eruptions by simultaneously recording data from a wide range of different experiments. The measurement was mainly designed to map conduit and explosion processes, i.e. the rise of gas slugs and their discharge into the atmosphere. We deployed four seismic arrays around the volcano each consisting of one broadband and three short-period sensors in order to monitor the occurrence of LP signals occurring before an explosion, as well as to record high frequency transients related to the explosion sequence itself. In order to quantify the general surface activity, and to analyse the explosion sequence in greater detail we installed two Doppler radars and one infrared camera at the crater rim. In order to investigate the exit conditions, we recorded acoustic pressure signals associated with the explosions by deploying four infrasonic arrays and one broadband infrasound sensor on and around the volcano. Additionally, for monitoring the gas composition of the erupted volcanic plume, a mini-DOAS was installed during our measurements. At the time of our experiment the activity of the volcano was at a relatively high level with sometimes several events per minute. The infrared video data show that a major part of the events consisted in Strombolian explosions, showing either a clear bursting of lava bubbles, a jet-like explosion pattern or very ash rich explosions. The recorded radar data reveal that one of both craters was clearly more active at the time with approximately 900 to 1500 events per day in comparison to some 500 events per day, respectively. However, the seismic recordings show an even greater overall event rate (2500 to 3000 transients per day) outlining the presence of processes which are not accompanied by any surface activity. A first correlation of the signals’ onset time of some selected data

  8. Water-temperature data acquisition activities in the United States

    USGS Publications Warehouse

    Pauszek, F.H.

    1972-01-01

    Water Data Coordination, U.S. Geological Survey, and published in the "Catalog of Information on Water Data, Index to Water Quality Section, Edition 1970." This is one of four indexes, each of which is a separate section of the Catalog. Three of the indexes, "Index to Water-Quality Section," "Index to Surface-Water Section," and "Index to Ground-.Water Stations," contain information on data acquired on a recurrent basis at specific locations for a period of 3 years or more. The fourth section, "Index to Areal Investigations and Miscellaneous Activities," is concerned with specific projects or shorter-term data activities that involve field or laboratory measurements or observations not included in any other section of the Catalog. The Catalog is a record of activities throughout the country (and in some places along the international border between the United States and Canada) conducted by Federal and non-Federal agencies engaged in the acquisition of water data and who furnish such information for presentation in the Catalog. The Catalog itself is an outgrowth of an assignment to the Department of the Interior and in turn to the Geological Survey, by the Office of Management and Budget, through the medium of OMB Circular A-67. This Circular states in part that one of the assigned responsibilities will be maintenance of a "central catalog of information on...water data and on Federal activities being planned or conducted to acquire such data." As an extension of this activity, non-Federal agencies are solicited to participate in the program. In this report, information is presented by means of tables and illustrations preceded by brief explanations. It includes the agencies collecting the data, the number of stations located on surface and ground waters where temperature measurements are made, the distribution of stations by States and by the 21 regions of the Water Resources Council (WRC) (a Federal agency created in accordance with the Water Resources Planning Act of

  9. How Does Interfacial Hydration Alter during Rod to Sphere Transition in DDAB/Water/Cyclohexane Reverse Micelles? Insights from Excited State Proton Transfer and Fluorescence Anisotropy.

    PubMed

    Phukon, Aparajita; Ray, Sudipta; Sahu, Kalyanasis

    2016-07-01

    How does microscopic organization of an organized assembly alter during macroscopic structural transition? The question may be important to ascertain driving forces responsible for such transitions. Didodecyldimethylammonium bromide (DDAB)/water/cyclohexane reverse micelle is an attractive assembly that undergoes structural transition from rod to spherical shape when the amount of water loading, w0 ([water]/[surfactant]), exceeds a particular value (w0 ∼ 8). Here, we intend to investigate the effect of the morphological change upon interfacial hydration using steady-state and time-resolved fluorescence measurements. The anionic fluorophore 8-hydroxypyrene-1,3,6-trisulfonate (HPTS or pyranine) is expected to be trapped within the positively charged RM interface. The fluorophore can undergo excited-state proton transfer (ESPT) in the presence of water and, thus, is able to provide insight on the level of hydration within the interface. The ESPT process is markedly inhibited within the interface at low w0 and gradually favored with increase of w0. The time-resolved fluorescence decays could be best analyzed by assuming distribution of HPTS over two distinct interfacial regions- partly hydrated and mostly dehydrated. The relative population of the two regions varies distinctly at low w0 (<6) and high w0 (>6) regimes. Moreover, fluorescence anisotropy (steady-state and time-resolved) varies differently with respect to w0, before and after the transition point (w0 ∼ 8). PMID:27292367

  10. Thiamin Diphosphate Activation in 1-Deoxy-d-xylulose 5-Phosphate Synthase: Insights into the Mechanism and Underlying Intermolecular Interactions.

    PubMed

    White, Justin K; Handa, Sumit; Vankayala, Sai Lakshmana; Merkler, David J; Woodcock, H Lee

    2016-09-22

    1-Deoxy-d-xylulose 5-phosphate synthase (DXS) is a thiamin diphosphate (TDP) dependent enzyme that marks the beginning of the methylerythritol 4-phosphate isoprenoid biosynthesis pathway. The mechanism of action for DXS is still poorly understood and begins with the formation of a thiazolium ylide. This TDP activation step is thought to proceed through an intramolecular deprotonation by the 4'-aminopyrimidine ring of TDP; however, this step would occur only after an initial deprotonation of its own 4'-amino group. The mechanism of the initial deprotonation has been hypothesized, by analogy to transketolases, to occur via a histidine or an active site water molecule. Results from hybrid quantum mechanical/molecular mechanical (QM/MM) reaction path calculations reveal an ∼10 kcal/mol difference in transition state energies, favoring a water mediated mechanism over direct deprotonation by histidine. This difference was determined to be largely governed by electrostatic changes induced by conformational variations in the active site. Additionally, mutagenesis studies reveal DXS to be an evolutionarily resilient enzyme. Particularly, we hypothesize that residues H82 and H304 may act in a compensatory fashion if the other is lost due to mutation. Further, nucleus-independent chemical shifts (NICSs) and aromatic stabilization energy (ASE) calculations suggest that reduction in TDP aromaticity also serves as a factor for regulating ylide formation and controlling reactivity.

  11. 12 CFR 362.11 - Activities of insured State savings associations.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... associations. 362.11 Section 362.11 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY ACTIVITIES OF INSURED STATE BANKS AND INSURED SAVINGS ASSOCIATIONS Activities of Insured State Savings Associations § 362.11 Activities of insured State savings associations. (a)...

  12. Self-assembly of PEGylated tetra-phenylalanine derivatives: structural insights from solution and solid state studies

    PubMed Central

    Diaferia, Carlo; Mercurio, Flavia Anna; Giannini, Cinzia; Sibillano, Teresa; Morelli, Giancarlo; Leone, Marilisa; Accardo, Antonella

    2016-01-01

    Water soluble fibers of PEGylated tetra-phenylalanine (F4), chemically modified at the N-terminus with the DOTA chelating agent, have been proposed as innovative contrast agent (CA) in Magnetic Resonance Imaging (MRI) upon complexation of the gadolinium ion. An in-depth structural characterization of PEGylated F4-fibers, in presence (DOTA-L6-F4) and in absence of DOTA (L6-F4), is reported in solution and at the solid state, by a multiplicity of techniques including CD, FTIR, NMR, DLS, WAXS and SAXS. This study aims to better understand how the aggregation process influences the performance of nanostructures as MRI CAs. Critical aggregation concentrations for L6-F4 (43 μM) and DOTA-L6-F4 (75 μM) indicate that self-aggregation process occurs in the same concentration range, independently of the presence of the CA. The driving force for the aggregation is the π-stacking between the side chains of the aromatic framework. CD, FTIR and WAXS measurements indicate an antiparallel β-sheet organization of the monomers in the resulting fibers. Moreover, WAXS and FTIR experiments point out that in solution the nanomaterials retain the same morphology and monomer organizations of the solid state, although the addition of the DOTA chelating agent affects the size and the degree of order of the fibers. PMID:27220817

  13. Self-assembly of PEGylated tetra-phenylalanine derivatives: structural insights from solution and solid state studies.

    PubMed

    Diaferia, Carlo; Mercurio, Flavia Anna; Giannini, Cinzia; Sibillano, Teresa; Morelli, Giancarlo; Leone, Marilisa; Accardo, Antonella

    2016-01-01

    Water soluble fibers of PEGylated tetra-phenylalanine (F4), chemically modified at the N-terminus with the DOTA chelating agent, have been proposed as innovative contrast agent (CA) in Magnetic Resonance Imaging (MRI) upon complexation of the gadolinium ion. An in-depth structural characterization of PEGylated F4-fibers, in presence (DOTA-L6-F4) and in absence of DOTA (L6-F4), is reported in solution and at the solid state, by a multiplicity of techniques including CD, FTIR, NMR, DLS, WAXS and SAXS. This study aims to better understand how the aggregation process influences the performance of nanostructures as MRI CAs. Critical aggregation concentrations for L6-F4 (43 μM) and DOTA-L6-F4 (75 μM) indicate that self-aggregation process occurs in the same concentration range, independently of the presence of the CA. The driving force for the aggregation is the π-stacking between the side chains of the aromatic framework. CD, FTIR and WAXS measurements indicate an antiparallel β-sheet organization of the monomers in the resulting fibers. Moreover, WAXS and FTIR experiments point out that in solution the nanomaterials retain the same morphology and monomer organizations of the solid state, although the addition of the DOTA chelating agent affects the size and the degree of order of the fibers. PMID:27220817

  14. Science insights.

    PubMed

    Tanabe, Kazuyuki

    2015-06-01

    "Below is an essay by Prof. Tanabe originally written in Japanese. It gives an insight to Prof. Tanabe's inquiring mind and his approach to science. He also seek, as always, to inspire and nudge the young to scientific discovery".

  15. The Effect of Detergent, Temperature, and Lipid on the Oligomeric State of MscL Constructs: Insights from Mass Spectrometry.

    PubMed

    Reading, Eamonn; Walton, Troy A; Liko, Idlir; Marty, Michael T; Laganowsky, Arthur; Rees, Douglas C; Robinson, Carol V

    2015-05-21

    The mechanosensitive channel of large conductance (MscL) acts as an emergency release valve for osmotic shock of bacteria preventing cell lysis. The large pore size, essential for function, requires the formation of oligomers with tetramers, pentamers, or hexamers observed depending on the species and experimental approach. We applied non-denaturing (native) mass spectrometry to five different homologs of MscL to determine the oligomeric state under more than 50 different experimental conditions elucidating lipid binding and subunit stoichiometry. We found equilibrium between pentameric and tetrameric species, which can be altered by detergent, disrupted by binding specific lipids, and perturbed by increasing temperature (37°C). We also established the presence of lipopolysaccharide bound to MscL and other membrane proteins expressed in Escherichia coli, revealing a potential source of heterogeneity. More generally, we highlight the use of mass spectrometry in probing membrane proteins under a variety of detergent-lipid environments relevant to structural biology.

  16. Membrane Mediated Antimicrobial and Antitumor Activity of Cathelicidin 6: Structural Insights from Molecular Dynamics Simulation on Multi-Microsecond Scale

    PubMed Central

    Sahoo, Bikash Ranjan; Fujiwara, Toshimichi

    2016-01-01

    The cathelicidin derived bovine antimicrobial peptide BMAP27 exhibits an effective microbicidal activity and moderate cytotoxicity towards erythrocytes. Irrespective of its therapeutic and multidimensional potentiality, the structural studies are still elusive. Moreover, the mechanism of BMAP27 mediated pore formation in heterogeneous lipid membrane systems is poorly explored. Here, we studied the effect of BMAP27 in model cell-membrane systems such as zwitterionic, anionic, thymocytes-like (TLM) and leukemia-like membranes (LLM) by performing molecular dynamics (MD) simulation longer than 100 μs. All-atom MD studies revealed a stable helical conformation in the presence of anionic lipids, however, significant loss of helicity was identified in TLM and zwitterionic systems. A peptide tilt (~45˚) and central kink (at residue F10) was found in anionic and LLM models, respectively, with an average membrane penetration of < 0.5 nm. Coarse-grained (CG) MD analysis on a multi-μs scale shed light on the membrane-dependent peptide and lipid organization. Stable micelle and end-to-end like oligomers were formed in zwitterionic and TLM models, respectively. In contrast, unstable oligomer formation and monomeric BMAP27 penetration were observed in anionic and LLM systems with selective anionic lipid aggregation (in LLM). Peptide penetration up to ~1.5 nm was observed in CG-MD systems with the BMAP27 C-terminal oriented towards the bilayer core. Structural inspection suggested membrane penetration by micelle/end-to-end like peptide oligomers (carpet-model like) in the zwitterionic/TLM systems, and transmembrane-mode (toroidal-pore like) in the anionic/LLM systems, respectively. Structural insights and energetic interpretation in BMAP27 mutant highlighted the role of F10 and hydrophobic residues in mediating a membrane-specific peptide interaction. Free energy profiling showed a favorable (-4.58 kcal mol-1 for LLM) and unfavorable (+0.17 kcal mol-1 for TLM) peptide insertion

  17. Modulation of red cell metabolism by states of decreased activation: comparison between states.

    PubMed

    Jevning, R; Wilson, A F; Pirkle, H; Guich, S; Walsh, R N

    1985-11-01

    Marked decline of red cell metabolism has been described during the acute state of decreased activation associated with the stylized mental technique of transcendental meditation (TM) in long-term meditators (5-10 years regular elicitation, TM instructors). It is not known whether unstylized rest is accompanied by a similar effect and it is not known what effector(s) may contribute to red cell metabolic changes in these states. In the present study ordinary, unstylized rest was found to be accompanied by small increase of red cell glycolytic rate. Apparently, either repeated elicitation of TM behavior or some special feature of this practice become associated with new mechanisms of metabolic control than those previously in operation. Although the data of this study do not permit isolation of the precise psychological determinants of this effect, the range of possible physiological effectors can be delimited. Blood pH, PCO2, PO2, and phosphate can be eliminated as significant for red cell metabolic control during both TM and rest, and based upon related studies, several known hormones such as insulin, T3, T4, arginine vasopressin, oxytocin, prolactin and growth hormone can also be eliminated as responsible effector(s).

  18. What Should Be the Roles of Conscious States and Brain States in Theories of Mental Activity?**

    PubMed Central

    Dulany, Donelson E.

    2011-01-01

    Answers to the title’s question have been influenced by a history in which an early science of consciousness was rejected by behaviourists on the argument that this entails commitment to ontological dualism and “free will” in the sense of indeterminism. This is, however, a confusion of theoretical assertions with metaphysical assertions. Nevertheless, a legacy within computational and information-processing views of mind rejects or de-emphasises a role for consciousness. This paper sketches a mentalistic metatheory in which conscious states are the sole carriers of symbolic representations, and thus have a central role in the explanation of mental activity and action-while specifying determinism and materialism as useful working assumptions. A mentalistic theory of causal learning, experimentally examined with phenomenal reports, is followed by examination of these questions: Are there common roles for phenomenal reports and brain imaging? Is there defensible evidence for unconscious brain states carrying symbolic representations? Are there interesting dissociations within consciousness? PMID:21694964

  19. Spectroscopic and computational insight into the activation of O2 by the mononuclear Cu center in polysaccharide monooxygenases.

    PubMed

    Kjaergaard, Christian H; Qayyum, Munzarin F; Wong, Shaun D; Xu, Feng; Hemsworth, Glyn R; Walton, Daniel J; Young, Nigel A; Davies, Gideon J; Walton, Paul H; Johansen, Katja Salomon; Hodgson, Keith O; Hedman, Britt; Solomon, Edward I

    2014-06-17

    Strategies for O2 activation by copper enzymes were recently expanded to include mononuclear Cu sites, with the discovery of the copper-dependent polysaccharide monooxygenases, also classified as auxiliary-activity enzymes 9-11 (AA9-11). These enzymes are finding considerable use in industrial biofuel production. Crystal structures of polysaccharide monooxygenases have emerged, but experimental studies are yet to determine the solution structure of the Cu site and how this relates to reactivity. From X-ray absorption near edge structure and extended X-ray absorption fine structure spectroscopies, we observed a change from four-coordinate Cu(II) to three-coordinate Cu(I) of the active site in solution, where three protein-derived nitrogen ligands coordinate the Cu in both redox states, and a labile hydroxide ligand is lost upon reduction. The spectroscopic data allowed for density functional theory calculations of an enzyme active site model, where the optimized Cu(I) and (II) structures were consistent with the experimental data. The O2 reactivity of the Cu(I) site was probed by EPR and stopped-flow absorption spectroscopies, and a rapid one-electron reduction of O2 and regeneration of the resting Cu(II) enzyme were observed. This reactivity was evaluated computationally, and by calibration to Cu-superoxide model complexes, formation of an end-on Cu-AA9-superoxide species was found to be thermodynamically favored. We discuss how this thermodynamically difficult one-electron reduction of O2 is enabled by the unique protein structure where two nitrogen ligands from His1 dictate formation of a T-shaped Cu(I) site, which provides an open coordination position for strong O2 binding with very little reorganization energy. PMID:24889637

  20. Estimability of recharge through groundwater model calibration: Insights from a field-scale steady-state example

    NASA Astrophysics Data System (ADS)

    Knowling, Matthew J.; Werner, Adrian D.

    2016-09-01

    The ability of groundwater models to inform recharge through calibration is hampered by the correlation between recharge and aquifer parameters such as hydraulic conductivity (K), and the insufficient information content of observation datasets. These factors collectively result in non-uniqueness of parameter estimates. Previous studies that jointly estimate spatially distributed recharge and hydraulic parameters are limited to synthetic test cases and/or do not evaluate the effect of non-uniqueness. The extent to which recharge can be informed by calibration is largely unknown for practical situations, in which complexities such as parameter heterogeneities are inherent. In this study, a systematic investigation of recharge, inferred through model calibration, is undertaken using a series of numerical experiments that include varying degrees of hydraulic parameter information. The analysis involves the use of a synthetic reality, based on a regional-scale, highly parameterised, steady-state groundwater model of Uley South Basin, South Australia. Parameter identifiability is assessed to evaluate the ability of parameters to be estimated uniquely. Results show that a reasonable inference of recharge (average recharge error <10%) requires a surprisingly large number of preferred value regularisation constraints (>100 K values across the 129 km2 study area). The introduction of pumping data into the calibration reduces error in both the average recharge and its spatial variability, whereas submarine groundwater discharge (as a calibration target) reduces average recharge error only. Nonetheless, the estimation of steady-state recharge through inverse modelling may be impractical for real-world settings, limited by the need for unrealistic amounts of hydraulic parameter and groundwater level data. This study provides a useful benchmark for evaluating the extent to which field-scale groundwater models can be used to inform recharge subject to practical data

  1. Universal spatial correlations in the anisotropic Kondo screening cloud: Analytical insights and numerically exact results from a coherent state expansion

    NASA Astrophysics Data System (ADS)

    Florens, Serge; Snyman, Izak

    2015-11-01

    We analyze the spatial correlation structure of the spin density of an electron gas in the vicinity of an antiferromagnetically coupled Kondo impurity. Our analysis extends to the regime of spin-anisotropic couplings, where there are no quantitative results for spatial correlations in the literature. We use an original and numerically exact method, based on a systematic coherent-state expansion of the ground state of the underlying spin-boson Hamiltonian. It has not yet been applied to the computation of observables that are specific to the fermionic Kondo model. We also present an important technical improvement to the method that obviates the need to discretize modes of the Fermi sea, and allows one to tackle the problem in the thermodynamic limit. As a result, one can obtain excellent spatial resolution over arbitrary length scales, for a relatively low computational cost, a feature that gives the method an advantage over popular techniques such as the numerical and density-matrix renormalization groups. We find that the anisotropic Kondo model shows rich universal scaling behavior in the spatial structure of the entanglement cloud. First, SU(2) spin-symmetry is dynamically restored in a finite domain in the parameter space in the vicinity of the isotropic line, as expected from poor man's scaling. More surprisingly, we are able to obtain in closed analytical form a set of different, yet universal, scaling curves for strong exchange asymmetry, which are parametrized by the longitudinal exchange coupling. Deep inside the cloud, i.e., for distances smaller than the Kondo length, the correlation between the electron spin density and the impurity spin oscillates between ferromagnetic and antiferromagnetic values at the scale of the Fermi wavelength, an effect that is drastically enhanced at strongly anisotropic couplings. Our results also provide further numerical checks and alternative analytical approximations for the Kondo overlaps that were recently computed by

  2. Destination state screening of active spaces in spin dynamics simulations

    NASA Astrophysics Data System (ADS)

    Krzystyniak, M.; Edwards, Luke J.; Kuprov, Ilya

    2011-06-01

    We propose a novel avenue for state space reduction in time domain Liouville space spin dynamics simulations, using detectability as a selection criterion - only those states that evolve into or affect other detectable states are kept in the simulation. This basis reduction procedure (referred to as destination state screening) is formally exact and can be applied on top of the existing state space restriction techniques. As demonstrated below, in many cases this results in further reduction of matrix dimension, leading to considerable acceleration of many spin dynamics simulation types. Destination state screening is implemented in the latest version of the Spinach library (http://spindynamics.org).

  3. The activated state of a sodium channel voltage sensor in a membrane environment

    PubMed Central

    Chakrapani, Sudha; Sompornpisut, Pornthep; Intharathep, Pathumwadee; Roux, Benoît; Perozo, Eduardo

    2010-01-01

    Direct structural insights on the fundamental mechanisms of permeation, selectivity, and gating remain unavailable for the Na+ and Ca2+ channel families. Here, we report the spectroscopic structural characterization of the isolated Voltage-Sensor Domain (VSD) of the prokaryotic Na+ channel NaChBac in a lipid bilayer. Site-directed spin-labeling and EPR spectroscopy were carried out for 118 mutants covering all of the VSD. EPR environmental data were used to unambiguously assign the secondary structure elements, define membrane insertion limits, and evaluate the activated conformation of the isolated-VSD in the membrane using restrain-driven molecular dynamics simulations. The overall three-dimensional fold of the NaChBac-VSD closely mirrors those seen in KvAP, Kv1.2, Kv1.2-2.1 chimera, and MlotiK1. However, in comparison to the membrane-embedded KvAP-VSD, the structural dynamics of the NaChBac-VSD reveals a much tighter helix packing, with subtle differences in the local environment of the gating charges and their interaction with the rest of the protein. Using cell complementation assays we show that the NaChBac-VSD can provide a conduit to the transport of ions in the resting or “down” conformation, a feature consistent with our EPR water accessibility measurements in the activated or “up” conformation. These results suggest that the overall architecture of VSD’s is remarkably conserved among K+ and Na+ channels and that pathways for gating-pore currents may be intrinsic to most voltage-sensors. Cell complementation assays also provide information about the putative location of the gating charges in the “down/resting” state and hence a glimpse of the extent of conformational changes during activation. PMID:20207950

  4. 20 CFR 631.41 - Allowable State activities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) States may use funds reserved under § 631.32(c) of this part, subject to the provisions of the State... than basic and remedial education, literacy and English for non-English speakers training,...

  5. A Simulated Intermediate State for Folding and Aggregation Provides Insights into ΔN6 β2-Microglobulin Amyloidogenic Behavior

    PubMed Central

    Estácio, Sílvia G.; Krobath, Heinrich; Vila-Viçosa, Diogo; Machuqueiro, Miguel; Shakhnovich, Eugene I.; Faísca, Patrícia F. N.

    2014-01-01

    A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of β2-microglobulin (ΔN6) lacking the first six N-terminal residues. Here we perform a computational study on ΔN6, which provides clues to understand the amyloidogenicity of the full-length β2-microglobulin. Contrary to the wild-type form, ΔN6 is able to efficiently nucleate fibrillogenesis in vitro at physiological pH. This behavior is enhanced by a mild acidification of the medium such as that occurring in the synovial fluid of DRA patients. Results reported in this work, based on molecular simulations, indicate that deletion of the N-terminal hexapeptide triggers the formation of an intermediate state for folding and aggregation with an unstructured strand A and a native-like core. Strand A plays a pivotal role in aggregation by acting as a sticky hook in dimer assembly. This study further predicts that the detachment of strand A from the core is maximized at pH 6.2 resulting into higher aggregation efficiency. The structural mapping of the dimerization interface suggests that Tyr10, His13, Phe30 and His84 are hot-spot residues in ΔN6 amyloidogenesis. PMID:24809460

  6. Subsidence along the Atlantic Coast of the United States: Insights from GPS and late Holocene relative sea level data

    NASA Astrophysics Data System (ADS)

    A Karegar, M.; Engelhart, S. E.; Dixon, T. H.

    2015-12-01

    Subsidence along the Atlantic coast of the United States is the largest amplitude collapse of a pro-glacial forebulge on Earth. High-quality geological records of late Holocene Relative Sea Level (RSL) are now available for this region. These data provide an independent constraint on Glacial Isostatic Adjustments (GIA), for comparison to continuous GPS measurements that directly measure net vertical crustal motion from GIA and other processes. Installation of more than 130 permanent GPS stations since 2006 represents an improvement towards precise determination of present-day subsidence rates along the coastal plain. We present an improved vertical velocity field for the eastern seaboard of the U.S. and parts of Atlantic Canada with uncertainty estimates that incorporate time-correlated noise. We use the geologic rates of RSL as an independent constraint to separate the long-term GIA-induced displacement (average motion over past 4 ka) from the GPS vertical displacement (average of one or two decades). Differences between the two are important for mitigating coastal land loss and predicting future storm surge inundation. Our results indicate that for most areas of the U.S. eastern seaboard there is no difference between GPS rates and late Holocene RSL rates. Exceptions are related to areas of recent excessive groundwater extraction in Virginia and South Carolina. The present-day subsidence rates in these areas are approximately double the long-term geologic rates.

  7. The local physical structure of amorphous hydrogenated boron carbide: insights from magic angle spinning solid-state NMR spectroscopy.

    PubMed

    Paquette, Michelle M; Li, Wenjing; Sky Driver, M; Karki, Sudarshan; Caruso, A N; Oyler, Nathan A

    2011-11-01

    Magic angle spinning solid-state nuclear magnetic resonance spectroscopy techniques are applied to the elucidation of the local physical structure of an intermediate product in the plasma-enhanced chemical vapour deposition of thin-film amorphous hydrogenated boron carbide (B(x)C:H(y)) from an orthocarborane precursor. Experimental chemical shifts are compared with theoretical shift predictions from ab initio calculations of model molecular compounds to assign atomic chemical environments, while Lee-Goldburg cross-polarization and heteronuclear recoupling experiments are used to confirm atomic connectivities. A model for the B(x)C:H(y) intermediate is proposed wherein the solid is dominated by predominantly hydrogenated carborane icosahedra that are lightly cross-linked via nonhydrogenated intraicosahedral B atoms, either directly through B-B bonds or through extraicosahedral hydrocarbon chains. While there is no clear evidence for extraicosahedral B aside from boron oxides, ∼40% of the C is found to exist as extraicosahedral hydrocarbon species that are intimately bound within the icosahedral network rather than in segregated phases.

  8. Insights into reactivity properties of the ground state structures of (CuS)x (x=1-7) using DFT

    NASA Astrophysics Data System (ADS)

    Luque Ceballos, Jonathan; Posada Amarillas, Alvaro

    The extraordinary properties of nanoscale materials have generated an enormous interest in the study of nanomaterials, because of the difference of their properties as compared to the corresponding bulk materials. Polyatomic nanomaterials have become important in recent years, due to the possibility of synthesize new materials with similar or better physical and chemical properties, than those of the monoatomic materials, or with a lower cost, to be used in technological applications in medicine, biology, electronics, or catalysis. Among these materials, copper sulfide is one of the transition metal chalcogenides that exhibits different stoichiometric forms with crystal structure varying from orthogonal to hexagonal. In this work we obtained the ground state structures of cooper sulfide nanoparticles (CuS)x, x=1-7. The corresponding frontier orbitals (HOMO and LUMO) are analyzed, and different reactivity parameters are obtained. We also present the molecular electrostatic potential, which is used to determine the higher and lower electron density regions on the clusters' structure. All calculations were performed using the TZVP basis set for S and the Christianssen-Ermler pseudopotential for Cu, employing two different exchange-correlation functionals, PBE and PBE0.

  9. Student Activity Packet for the California State Capitol Museum.

    ERIC Educational Resources Information Center

    2001

    This packet contains materials to help fourth and fifth grade teachers provide their students with background information for field trips to the California State Capitol Museum (Sacramento). The working museum focuses on the theme areas of California history, the state government/legislative process, and state symbols. The packet presents teacher…

  10. Local and Global Resting State Activity in the Noradrenergic and Dopaminergic Pathway Modulated by Reboxetine and Amisulpride in Healthy Subjects

    PubMed Central

    Wiegers, Maike; Walter, Martin; Abler, Birgit; Graf, Heiko

    2016-01-01

    Background: Various psychiatric populations are currently investigated with resting state fMRI, with the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-related neural alterations, but with the common psychopharmacological medication limiting interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers to further the understanding of the respective effects independent from disease-related alterations. Methods: Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19 healthy male subjects by resting state fMRI after the intake of reboxetine (4mg/d), amisulpride (200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state functional connectivity (rs-FC). Results: fALFF revealed alterations of local rs-activity within regions of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e. the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of regions within the dopaminergic pathway, with the altered signal in the putamen correlating with amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the dopaminergic pathway comprising the substantia nigra and putamen. Conclusion: Our data provide evidence of how psychopharmacological agents alter local and global rs-activity within the respective neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric

  11. Defect states at organic-inorganic interfaces: Insight from first principles calculations for pentaerythritol tetranitrate on MgO surface

    NASA Astrophysics Data System (ADS)

    Tsyshevsky, Roman V.; Rashkeev, Sergey N.; Kuklja, Maija M.

    2015-07-01

    Light-responsive organic-inorganic interfaces offer experimental opportunities that are otherwise difficult to achieve. Since laser light can be manipulated very precisely, it becomes possible to engineer selective, predictive, and highly controlled interface properties. Photochemistry of organic-inorganic energetic interfaces is a rapidly emerging research field in which energy absorption and interface stability mechanisms have yet to be established. To explore the interaction of the laser irradiation with molecular materials, we performed first principle calculations of a prototype organic-inorganic interface between a nitroester (pentaerythritol tetranitrate, PETN, C5H8N4O12) and a magnesium oxide (MgO) surface. We found that the light absorption is defined by the band alignment between interface components and interfacial charge transfer coupled with electronic states in the band gap, generated by oxide surface defects. Hence the choice of an oxide substrate and its morphology makes the optical absorption tunable and governs both the energy accumulation and energy release at the interface. The obtained results offer a possible consistent interpretation of experiments on selective laser initiation of energetic materials, which reported that the presence of metal oxide additives triggered the photoinitiation by excitation energy much lower than the band gap. We suggest that PETN photodecomposition is catalyzed by oxygen vacancies (F0 centers) at the MgO surface. Our conclusions predict ways for a complete separation of thermo- and photo-stimulated interface chemistry of molecular materials, which is imperative for highly controllable fast decomposition and was not attainable before. The methodology described here can be applied to any type of molecular material/wide band gap dielectric interfaces. It provides a solid basis for novel design and targeted improvements of organic-inorganic interfaces with desired properties that promise to enable vastly new concepts

  12. P-wave tomography of the western United States: Insight into the Yellowstone hotspot and the Juan de Fuca slab

    NASA Astrophysics Data System (ADS)

    Tian, You; Zhao, Dapeng

    2012-06-01

    We used 190,947 high-quality P-wave arrival times from 8421 local earthquakes and 1,098,022 precise travel-time residuals from 6470 teleseismic events recorded by the EarthScope/USArray transportable array to determine a detailed three-dimensional P-wave velocity model of the crust and mantle down to 1000 km depth under the western United States (US). Our tomography revealed strong heterogeneities in the crust and upper mantle under the western US. Prominent high-velocity anomalies are imaged beneath Idaho Batholith, central Colorado Plateau, Cascadian subduction zone, stable North American Craton, Transverse Ranges, and Southern Sierra Nevada. Prominent low-velocity anomalies are imaged at depths of 0-200 km beneath Snake River Plain, which may represent a small-scale convection beneath the western US. The low-velocity structure deviates variably from a narrow vertical plume conduit extending down to ˜1000 km depth, suggesting that the Yellowstone hotspot may have a lower-mantle origin. The Juan de Fuca slab is imaged as a dipping high-velocity anomaly under the western US. The slab geometry and its subducted depth vary in the north-south direction. In the southern parts the slab may have subducted down to >600 km depth. A "slab hole" is revealed beneath Oregon, which shows up as a low-velocity anomaly at depths of ˜100 to 300 km. The formation of the slab hole may be related to the Newberry magmatism. The removal of flat subducted Farallon slab may have triggered the vigorous magmatism in the Basin and Range and southern part of Rocky Mountains and also resulted in the uplift of the Colorado Plateau and Rocky Mountains.

  13. Correlated transition between two activity states of neurons

    NASA Astrophysics Data System (ADS)

    Uchida, Go; Fukuda, Mitsuhiro; Tanifuji, Manabu

    2006-03-01

    In order to understand the dynamical properties of a neural network, it is important to characterize the relation between spike trains of two neurons in the network. In this study, we show that in some neuron pairs in inferior temporal cortices of macaque monkeys, spike trains of a pair are described by a two-dimensional Poisson process whose means are modulated by a common two-state Markov process. The common two-state Markov process describes a correlated state transition between firing and nonfiring states of the constituent neurons of the pair.

  14. Changing Schools: Insights.

    ERIC Educational Resources Information Center

    Office of Policy and Planning (ED), Washington, DC.

    Over 1,000 communities in 45 states, territories, and the District of Columbia, are mobilized under the AMERICA 2000 banner to reach the 6 National Education Goals. This collection of papers, written by those who have wrestled with the process of school reform, offers useful insights to communities as they begin their process of transforming…

  15. How active site protonation state influences the reactivity and ligation of the heme in chlorite dismutase

    PubMed Central

    Streit, Bennett R.; Blanc, Béatrice; Lukat-Rodgers, Gudrun S.; Rodgers, Kenton R.; DuBois, Jennifer L.

    2010-01-01

    Chlorite dismutase catalyzes O2 release from chlorite with exquisite efficiency and specificity. The spectroscopic properties, ligand binding affinities, and steady state kinetics of chlorite dismutase from Dechloromonas aromatica were examined over pH 3–11.5 to gain insight into how the protonation state of the heme environment influences dioxygen formation. An acid/base transition was observed by UV/visible and resonance Raman spectroscopy with a pKa of 8.7, 2–3 pH units below analogous transitions observed in typical His-ligated peroxidases. This transition marks the conversion of a five coordinate high spin Fe(III) to a mixed high/low spin ferric-hydroxide, as confirmed by resonance Raman (rR) spectroscopy. The two Fe–OH stretching frequencies are quite low, consistent with a weak Fe–OH bond, despite the nearly neutral imidazole side chain of the proximal histidine ligand. The hydroxide is proposed to interact strongly with a distal H-bond donor, thereby weakening the Fe–OH bond. The rR spectra of Cld-CO as a function of pH reveal two forms of the complex, one in which there is minimal interaction of distal residues with the carbonyl oxygen and another, acidic form in which the oxygen is under the influence of positive charge. Recent crystallographic data reveal arginine 183 as the lone H-bond donating residue in the distal pocket. It is likely that this Arg is the strong, positively charged H-bond donor implicated by vibrational data to interact with exogenous axial heme ligands. The same Arg in its neutral (pKa ~ 6.5) form also appears to act as the active site base in binding reactions of protonated ligands, such as HCN, to ferric Cld. The steady state profile for the rate of chlorite decomposition is characterized by these same pKas. The 5 coordinate high spin acidic Cld is more active than the alkaline hydroxide-bound form. The acid form decomposes chlorite most efficiently when the distal Arg is protonated/cationic (maximum kcat = 2.0 (±0.6)

  16. 40 CFR 745.325 - Lead-based paint activities: State and Tribal program requirements.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL STRUCTURES State and Indian Tribal Programs § 745.325 Lead-based paint activities: State and... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Lead-based paint activities: State...

  17. 40 CFR 745.325 - Lead-based paint activities: State and Tribal program requirements.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL STRUCTURES State and Indian Tribal Programs § 745.325 Lead-based paint activities: State and... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Lead-based paint activities: State...

  18. 40 CFR 745.325 - Lead-based paint activities: State and Tribal program requirements.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL STRUCTURES State and Indian Tribal Programs § 745.325 Lead-based paint activities: State and... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Lead-based paint activities: State...

  19. 40 CFR 745.325 - Lead-based paint activities: State and Tribal program requirements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL STRUCTURES State and Indian Tribal Programs § 745.325 Lead-based paint activities: State and... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Lead-based paint activities: State...

  20. 40 CFR 745.325 - Lead-based paint activities: State and Tribal program requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Lead-based paint activities: State and... AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT LEAD-BASED PAINT POISONING PREVENTION IN CERTAIN RESIDENTIAL STRUCTURES State and Indian Tribal Programs § 745.325 Lead-based paint activities: State...

  1. Issues for Active State Management of the JTPA Title III Grant: A Guide for State Planners and Managers.

    ERIC Educational Resources Information Center

    Reesman, Cilla J.

    This technical assistance guide presents the various options available to state planners and managers in considering five elements of active grant management. Each element is treated in a separate chapter. Chapter 1 addresses issues surrounding the setting of policies that ensure that Title III grants complement state agendas. Chapter 2 concerns…

  2. SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

    PubMed Central

    Tovmasyan, Artak; Roberts, Emily R. H.; Vujaskovic, Zeljko; Leong, Kam W.; Spasojevic, Ivan

    2014-01-01

    Abstract Significance: Superoxide dismutase (SOD) enzymes are indispensable and ubiquitous antioxidant defenses maintaining the steady-state levels of O2·−; no wonder, thus, that their mimics are remarkably efficacious in essentially any animal model of oxidative stress injuries thus far explored. Recent Advances: Structure-activity relationship (half-wave reduction potential [E1/2] versus log kcat), originally reported for Mn porphyrins (MnPs), is valid for any other class of SOD mimics, as it is dominated by the superoxide reduction and oxidation potential. The biocompatible E1/2 of ∼+300 mV versus normal hydrogen electrode (NHE) allows powerful SOD mimics as mild oxidants and antioxidants (alike O2·−) to readily traffic electrons among reactive species and signaling proteins, serving as fine mediators of redox-based signaling pathways. Based on similar thermodynamics, both SOD enzymes and their mimics undergo similar reactions, however, due to vastly different sterics, with different rate constants. Critical Issues: Although log kcat(O2·−) is a good measure of therapeutic potential of SOD mimics, discussions of their in vivo mechanisms of actions remain mostly of speculative character. Most recently, the therapeutic and mechanistic relevance of oxidation of ascorbate and glutathionylation and oxidation of protein thiols by MnP-based SOD mimics and subsequent inactivation of nuclear factor κB has been substantiated in rescuing normal and killing cancer cells. Interaction of MnPs with thiols seems to be, at least in part, involved in up-regulation of endogenous antioxidative defenses, leading to the healing of diseased cells. Future Directions: Mechanistic explorations of single and combined therapeutic strategies, along with studies of bioavailability and translational aspects, will comprise future work in optimizing redox-active drugs. Antioxid. Redox Signal. 20, 2372–2415. PMID:23875805

  3. 12 CFR 362.3 - Activities of insured State banks.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... circumstances warrant such action. (c) Core standards. For any insured State bank to be eligible to conduct... application. An insured State bank that meets and continues to meet the applicable capital standards set by... that the department meets the core standards of paragraph (c) of this section or submits an...

  4. Mechanistic insights into ferredoxin-NADP(H) reductase catalysis involving the conserved glutamate in the active site.

    PubMed

    Dumit, Verónica I; Essigke, Timm; Cortez, Néstor; Ullmann, G Matthias

    2010-04-01

    Plant-type ferredoxin-NADP(H) reductases (FNRs) are flavoenzymes harboring one molecule of noncovalently bound flavin adenine dinucleotide that catalyze reversible reactions between obligatory one-electron carriers and obligatory two-electron carriers. A glutamate next to the C-terminus is strictly conserved in FNR and has been proposed to function as proton donor/acceptor during catalysis. However, experimental studies of this proposed function led to contradicting conclusions about the role of this glutamate in the catalytic mechanism. In the present work, we study the titration behavior of the glutamate in the active site of FNR using theoretical methods. Protonation probabilities for maize FNR were computed for the reaction intermediates of the catalytic cycle by Poisson-Boltzmann electrostatic calculations and Metropolis Monte Carlo titration. The titration behavior of the highly conserved glutamate was found to vary depending on the bound substrates NADP(H) and ferredoxin and also on the redox states of these substrates and the flavin adenine dinucleotide. Our results support the involvement of the glutamate in the FNR catalytic mechanism not only as a proton donor but also as a key residue for stabilizing and destabilizing reaction intermediates. On the basis of our findings, we propose a model rationalizing the function of the glutamate in the reaction cycle, which allows reinterpretation of previous experimental results.

  5. Crystal Structure of the Human Ubiquitin-activating Enzyme 5 (UBA5) Bound to ATP Mechanistic Insights into a Minimalistic E1 Enzyme

    SciTech Connect

    Bacik, John-Paul; Walker, John R.; Ali, Mohsin; Schimmer, Aaron D.; Dhe-Paganon, Sirano

    2010-08-30

    E1 ubiquitin-activating enzymes (UBAs) are large multidomain proteins that catalyze formation of a thioester bond between the terminal carboxylate of a ubiquitin or ubiquitin-like modifier (UBL) and a conserved cysteine in an E2 protein, producing reactive ubiquityl units for subsequent ligation to substrate lysines. Two important E1 reaction intermediates have been identified: a ubiquityl-adenylate phosphoester and a ubiquityl-enzyme thioester. However, the mechanism of thioester bond formation and its subsequent transfer to an E2 enzyme remains poorly understood. We have determined the crystal structure of the human UFM1 (ubiquitin-fold modifier 1) E1-activating enzyme UBA5, bound to ATP, revealing a structure that shares similarities with both large canonical E1 enzymes and smaller ancestral E1-like enzymes. In contrast to other E1 active site cysteines, which are in a variably sized domain that is separate and flexible relative to the adenylation domain, the catalytic cysteine of UBA5 (Cys{sup 250}) is part of the adenylation domain in an {alpha}-helical motif. The novel position of the UBA5 catalytic cysteine and conformational changes associated with ATP binding provides insight into the possible mechanisms through which the ubiquityl-enzyme thioester is formed. These studies reveal structural features that further our understanding of the UBA5 enzyme reaction mechanism and provide insight into the evolution of ubiquitin activation.

  6. Program activities: DOE State and Local Assistance Programs, 1983 report

    SciTech Connect

    Not Available

    1983-10-01

    Progress achieved by the Department of Energy State and Local Assistance programs during FY 1983 and prior years is summarized. These programs provide financial and technical assistance to and through state and local governments, enabling them to plan and implement measures to improve the energy efficiency of industry, transportation, commercial establishments, public buildings and residences. The programs covered here are: State Energy Conservation, Energy Extension Service, Weatherization Assistance, Institutional Conservation, Energy-Related Inventions, Appropriate Technology Small Grants, and Grants Management and Technical Assistance. (MHR)

  7. Report to the Congress from The President of the United States. United States Aeronautics and Space Activities 1967.

    ERIC Educational Resources Information Center

    Johnson, Lyndon B.

    This report extensively reviews the progress of the United States in space during 1967, the tenth year of the space age. The first chapter of the report summarizes the 1967 space activities; and each of the remaining 13 chapters is devoted to reviewing the space-related activities of a particular federal agency (13 agencies included). Appendices…

  8. 78 FR 54637 - Agency Information Collection Activities; Comment Request; State Educational Agency, Local...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-05

    ... Agency Information Collection Activities; Comment Request; State Educational Agency, Local Educational... information technology. Please note that written comments received in response to this notice will be considered public records. Title of Collection: State Educational Agency, Local Educational Agency,...

  9. New Insights of the Fenton Reaction Using Glycerol as the Experimental Model. Effect of O2, Inhibition by Mg(2+), and Oxidation State of Fe.

    PubMed

    Vitale, Arturo Alberto; Bernatene, Eduardo A; Vitale, Martín Gustavo; Pomilio, Alicia Beatriz

    2016-07-21

    The use of iron ions as catalyst of oxidation with hydrogen peroxide, known as the Fenton reaction, is important for industry and biological systems. It has been widely studied since its discovery in the 19th century, but important aspects of the reaction as which is the oxidant, the role of oxygen, and the oxidation state of Fe still remain unclear. In this work new mechanistic insights of the oxidation of carbohydrates by the Fenton reaction using glycerol as experimental model are described. The reaction was studied by means of oxidation reduction potential (ORP) measures. The stoichiometry was measured, showing the important role of oxygen for lowering H2O2 consumption under aerobic conditions. Evidence is provided to demonstrate that in this system Fe(2+) generates a catalyst by reacting with a substrate to produce a complex, which gives rise to singlet oxygen after reacting with H2O2. This is the first time that the inhibitor effect of Mg(2+) is reported in this reaction, and its participation in the mechanism is described. A rational mechanism for the oxidation of glycerol using the Fenton reaction under these specific conditions is proposed. The role of oxygen, the participation of Fe(2+), and the inhibition by Mg(2+) are fully demonstrated experimentally.

  10. New insights into the structure and chemistry of Titan's tholins via 13C and 15N solid state nuclear magnetic resonance spectroscopy

    NASA Astrophysics Data System (ADS)

    Derenne, S.; Coelho, C.; Anquetil, C.; Szopa, C.; Quirico, E.; Bonhomme, C.

    2012-09-01

    Titan, the largest moon of Saturn, is characterized by a dense atmosphere, mainly composed of N2 (ca. 97 %) and CH4 (ca. 2 %). In the upper atmosphere, methane and nitrogen molecules undergo dissociation under the influence of solar UV radiation and electron impacts, followed by recombination reactions leading to a large variety of organic molecules. Some of these compounds form a thick, orange-coloured haze composed of solid organic aerosols that subsequently fall to the surface or remain in suspension in the atmosphere. To gain insight into the chemical composition and structural nature of these complex organic compounds, analogous materials, termed Titan's tholins, are produced in the laboratory, in particular using plasma discharge in gaseous N2 - CH4 mixtures with similar proportions as in Titan's atmosphere. Titan's tholins have been analysed using a wide variety of techniques which provided a wealth of information about potential functional groups and structural building blocks present within the tholin samples. Taken together, the results converge on a structure based on a CxHyNz chemistry that can contain a variety of C-C, C-N, N-H etc single or multiple bonds. It is now necessary to build on that information to refine the chemical and structural models for the Titan's tholins. Here we used solid state NMR techniques to investigate the carbon and nitrogen bonding environments in a 13C- and 15Nenriched sample.

  11. Laser cleaning in conservation of stone, metal, and painted artifacts: state of the art and new insights on the use of the Nd:YAG lasers

    NASA Astrophysics Data System (ADS)

    Siano, S.; Agresti, J.; Cacciari, I.; Ciofini, D.; Mascalchi, M.; Osticioli, I.; Mencaglia, A. A.

    2012-02-01

    In the present work the application of laser cleaning in the conservation of cultural assets is reviewed and some further developments on the interpretation of the associated laser-material interaction regimes are reported. Both the state of the art and new insights mainly focus on systematic approaches addressed to the solution of representative cleaning problems, including stone and metal artifacts along with wall and easel paintings. The innovative part is entirely dedicated to the extension of the application perspective of the Nd:YAG lasers by exploiting the significant versatility provided by their different pulse durations. Besides extensively discussing the specific conservation and physical problems involved in stone and metal cleaning, a significant effort was also made to explore the application potential for wall and easel paintings. The study of the latter was confined to preliminary irradiation tests carried out on prepared samples. We characterized the ablation phenomenology, optical properties, and photomechanical generation associated with the irradiation of optically absorbing varnishes using pulse durations of 10 and 120 ns. Further results concern the nature of the well-known problem of the yellowish appearance in stone cleaning, removal of biological growths and graffiti from stones, cleaning of bronze and iron artifacts and related aspects of laser conversion of unstable minerals, removal of calcareous stratification from wall paintings, and other features.

  12. Activism in Concrete: Student Union, San Francisco State University

    ERIC Educational Resources Information Center

    Progressive Architecture, 1978

    1978-01-01

    The San Francisco State University Student Union is a futurist design of two steel space-frame pyramids. Each contains a stairway leading to four partial floors that diminish in size as the pyramid tapers. (Author/MLF)

  13. Insights into induced earthquakes and aftershock activity with in-situ measurements of seismic velocity variations in an active underground mine

    NASA Astrophysics Data System (ADS)

    Brenguier, F.; Olivier, G.; Campillo, M.; Roux, P.; Shapiro, N.; Lynch, R.

    2015-12-01

    The behaviour of the crust shortly after large earthquakes has been the subject of numerous studies, but many co- and post-seismic processes remain poorly understood. Damage and healing of the bulk rock mass, post-seismic deformation and the mechanisms of earthquake triggering are still not well understood. These processes are important to properly model and understand the behaviour of faults and earthquake cycles.In this presentation, we will show how in-situ measurements of seismic velocity variations have given new insights into these co- and post-seismic processes. An experiment was performed where a blast was detonated in a tunnel in an underground mine, while seismic velocity variations were accurately (0.005 %) measured with ambient seismic noise correlations. Additionally, aftershock activity was examined and the influence of the removal of a piece of solid rock was estimated with elastic static stress modelling. The majority of the aftershocks were delayed with respect to the passing of the dynamic waves from the blast, while the locations of the aftershocks appeared clustered and not homogeneously spread around the blast location. A significant velocity drop is visible during the time of the blast, which is interpreted as co-seismic damage and plastic deformation. These non-elastic effects are healed by the confining stresses over a period of 5 days until the seismic velocity converges to a new baseline level. The instantaneous weakening and gradual healing observed from the velocity variations are qualitatively similar to results reported in laboratory studies. The change in the baseline level of the seismic velocity before and after the blast indicate a change in the static stress that is comparable to the results of elastic static stress modelling. The differences between the elastic model predictions and the seismic velocity variations could be due to zones of fractured rock, indicated by the spatial clustering of the aftershocks, that are not

  14. Excited states in the active media of oxygen - iodine lasers

    SciTech Connect

    Azyazov, V N

    2009-11-30

    A review of investigations of kinetic processes in active media oxygen - iodine lasers (OILs) performed in the last decade is presented. The mechanisms of pumping and quenching of electronically and vibrationally excited O{sub 2} and I{sub 2} molecules are considered, and dissociation mechanisms of I{sub 2} in the active medium of the OIL are analysed. The values of kinetic constants of processes proceeding in the active media of OILs are recommended. (review)

  15. On the Heat Stability of Amyloid-Based Biological Activity: Insights from Thermal Degradation of Insulin Fibrils

    PubMed Central

    Surmacz-Chwedoruk, Weronika; Malka, Iwona; Bożycki, Łukasz; Nieznańska, Hanna; Dzwolak, Wojciech

    2014-01-01

    Formation of amyloid fibrils in vivo has been linked to disorders such as Alzheimer’s disease and prion-associated transmissible spongiform encephalopathies. One of the characteristic features of amyloid fibrils is the high thermodynamic stability relative both to native and disordered states which is also thought to underlie the perplexingly remarkable heat resistance of prion infectivity. Here, we are comparing high-temperature degradation of native and fibrillar forms of human insulin. Decomposition of insulin amyloid has been studied under helium atmosphere and in the temperature range from ambient conditions to 750°C using thermogravimetry and differential scanning calorimetry coupled to mass spectrometry. While converting native insulin into amyloid does upshift onset of thermal decomposition by ca. 75°C, fibrils remain vulnerable to covalent degradation at temperatures below 300°C, as reflected by mass spectra of gases released upon heating of amyloid samples, as well as morphology and infrared spectra of fibrils subjected to incubation at 250°C. Mass spectra profiles of released gases indicate that degradation of fibrils is much more cooperative than degradation of native insulin. The data show no evidence of water of crystallization trapped within insulin fibrils. We have also compared untreated and heated amyloid samples in terms of capacity to seed daughter fibrils. Kinetic traces of seed-induced insulin fibrillation have shown that the seeding potency of amyloid samples decreases significantly already after exposure to 200°C, even though corresponding electron micrographs indicated persisting fibrillar morphology. Our results suggest that amyloid-based biological activity may not survive extremely high temperature treatments, at least in the absence of other stabilizing factors. PMID:24466022

  16. Altered baseline brain activity with 72 h of simulated microgravity--initial evidence from resting-state fMRI.

    PubMed

    Liao, Yang; Zhang, Jinsong; Huang, Zhiping; Xi, Yibin; Zhang, Qianru; Zhu, Tianli; Liu, Xufeng

    2012-01-01

    To provide the basis and reference to further insights into the neural activity of the human brain in a microgravity environment, we discuss the amplitude changes of low-frequency brain activity fluctuations using a simulated microgravity model. Twelve male participants between 24 and 31 years old received resting-state fMRI scans in both a normal condition and after 72 hours in a -6° head down tilt (HDT). A paired sample t-test was used to test the amplitude differences of low-frequency brain activity fluctuations between these two conditions. With 72 hours in a -6° HDT, the participants showed a decreased amplitude of low-frequency fluctuations in the left thalamus compared with the normal condition (a combined threshold of P<0.005 and a minimum cluster size of 351 mm(3) (13 voxels), which corresponded with the corrected threshold of P<0.05 determined by AlphaSim). Our findings indicate that a gravity change-induced redistribution of body fluid may disrupt the function of the left thalamus in the resting state, which may contribute to reduced motor control abilities and multiple executive functions in astronauts in a microgravity environment. PMID:23285086

  17. Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity

    PubMed Central

    Sharpe, Robert J.; Malinowski, Justin T.; Sorana, Federico; Luft, J. Christopher; Bowerman, Charles J.; DeSimone, Joseph M.; Johnson, Jeffrey S.

    2015-01-01

    The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin’s biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation. PMID:25792144

  18. Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: insight into functional group effects and biological activity.

    PubMed

    Sharpe, Robert J; Malinowski, Justin T; Sorana, Federico; Luft, J Christopher; Bowerman, Charles J; DeSimone, Joseph M; Johnson, Jeffrey S

    2015-04-15

    The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin's biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation. PMID:25792144

  19. State monitoring activities related to Pfiesteria-like organisms.

    PubMed Central

    Magnien, R E

    2001-01-01

    In response to potential threats to human health and fish populations, six states along the east coast of the United States initiated monitoring programs related to Pfiesteria-like organisms in 1998. These actions were taken in the wake of toxic outbreaks of Pfiesteria piscicida Steidinger & Burkholder in Maryland during 1997 and previous outbreaks in North Carolina. The monitoring programs have two major purposes. The first, rapid response, is to ensure public safety by responding immediately to conditions that may indicate the presence of Pfiesteria or related organisms in a toxic state. The second, comprehensive assessment, is to provide a more complete understanding of where Pfiesteria-like organisms may become a threat, to understand what factors may stimulate their growth and toxicity, and to evaluate the impacts of these organisms upon fish and other aquatic life. In states where human health studies are being conducted, the data from both types of monitoring are used to provide information on environmental exposure. The three elements included in each monitoring program are identification of Pfiesteria-like organisms, water quality measurements, and assessments of fish health. Identification of Pfiesteria-like organisms is a particularly difficult element of the monitoring programs, as these small species cannot be definitively identified using light microscopy; newly applied molecular techniques, however, are starting to provide alternatives to traditional methods. State monitoring programs also offer many opportunities for collaborations with research initiatives targeting both environmental and human health issues related to Pfiesteria-like organisms. PMID:11677180

  20. Illinois State Bar Association Law Day Activities Guide. 2001 Edition.

    ERIC Educational Resources Information Center

    Illinois State Bar Association, Springfield.

    These law-related lessons and activities can facilitate participation in a Law Day program. Following an introduction, this activities guide is divided into these sections: "Tips for Teachers" ("What Can a Lawyer Add to the Classroom?"; "So You Have Been Asked to Speak to Kids about the Law"; "A Checklist for Lawyers and Judges in the Classroom");…

  1. Physical Activity Opportunity in United States Public Elementary Schools

    ERIC Educational Resources Information Center

    Beaulieu, Lisa; Butterfield, Stephen A.; Pratt, Phillip

    2009-01-01

    Recent evidence indicates that many elementary schools have curtailed recess and Physical Education (Morrow, Jackson & Payne 1999). These finding are at a variance with the goal of Healthy People 2010 to increase physical activity. The purpose of this study was to examine physical activity opportunities (PAO) in U. S. public elementary schools.…

  2. Large-Scale Brain Networks in Board Game Experts: Insights from a Domain-Related Task and Task-Free Resting State

    PubMed Central

    Duan, Xujun; Liao, Wei; Liang, Dongmei; Qiu, Lihua; Gao, Qing; Liu, Chengyi; Gong, Qiyong; Chen, Huafu

    2012-01-01

    Cognitive performance relies on the coordination of large-scale networks of brain regions that are not only temporally correlated during different tasks, but also networks that show highly correlated spontaneous activity during a task-free state. Both task-related and task-free network activity has been associated with individual differences in cognitive performance. Therefore, we aimed to examine the influence of cognitive expertise on four networks associated with cognitive task performance: the default mode network (DMN) and three other cognitive networks (central-executive network, dorsal attention network, and salience network). During fMRI scanning, fifteen grandmaster and master level Chinese chess players (GM/M) and fifteen novice players carried out a Chinese chess task and a task-free resting state. Modulations of network activity during task were assessed, as well as resting-state functional connectivity of those networks. Relative to novices, GM/Ms showed a broader task-induced deactivation of DMN in the chess problem-solving task, and intrinsic functional connectivity of DMN was increased with a connectivity pattern associated with the caudate nucleus in GM/Ms. The three other cognitive networks did not exhibit any difference in task-evoked activation or intrinsic functional connectivity between the two groups. These findings demonstrate the effect of long-term learning and practice in cognitive expertise on large-scale brain networks, suggesting the important role of DMN deactivation in expert performance and enhanced functional integration of spontaneous activity within widely distributed DMN-caudate circuitry, which might better support high-level cognitive control of behavior. PMID:22427852

  3. Unusual non-fluorescent broad spectrum siderophore activity (SID EGYII) by Pseudomonas aeruginosa strain EGYII DSM 101801 and a new insight towards simple siderophore bioassay.

    PubMed

    Embaby, Amira M; Heshmat, Yasmin; Hussein, Ahmed

    2016-03-01

    Present study highlights an unusual non-fluorescent hydroxamate broad spectrum siderophore (SID EGYII) activity from Pseudomonas aeruginosa strain EGYII DSM 101801, a soil bacterial isolate, along with simple low cost effective siderophore bioassay. Detection of SID EGYII activity qualitatively was proved by masking this activity against Erwinia amylovora strain EGY1 DSM 101800, an indicator strain, in well-cut diffusion assay containing 100 µM FeCl3. SID EGYII activity was expressed quantitatively as arbitrary units [Siderophore arbitrary units (SAU)] 380 SAU/mL against E. amylovora strain EGY1 DSM 101800. Maximal SID EGYII activity was achieved upon growing P. aeruginosa strain EGYII DSM 101801 in PYB broth at 180 rpm for 24 h. SID EGYII displayed a broad spectrum antimicrobial activity against some human pathogens (i.e., Gram-positive bacteria, Gram-negative bacteria and yeasts) and a fireblight plant pathogen. Interestingly, transformants of Escherichia coli JM109 (DE3)pSID/EGYII harboring P. aeruginosa strain EGYII DSM 101801 plasmid demonstrated a perceivable antimicrobial activity against E. amylovora strain EGY1 DSM 101800. The broad spectrum antimicrobial activity of the unusual non-fluorescent SID EGYII would underpin its high potential in targeting bacterial pathogens posing probable threats to human health and agricultural economy. The present simple low cost effective bioassay is a new insight towards an alternative to the expensive cumbersome siderophore Chrome Azurol S assay. PMID:27015845

  4. Program activities, DOE state and local assistance programs, 1980 report

    SciTech Connect

    Chiogioji, Melvin H.

    1981-01-01

    Progress achieved by DOE State and Local Assistance Programs during FY 1980 and since they were established is summarized. These programs enable improved energy efficiency of industry, transportation, commercial establishments, public buildings, and residences. Eight programs (State Energy Conservation, Energy Extension Service, Weatherization Assistance, Institutional Buildings Grants, Energy-Related Inventions, Appropriate Technology Small Grants, Emergency Energy Conservation, Emergency Building Temperature Restrictions) are described. They provide the impetus for thousands of individual and organizational actions that have significantly affected national energy use patterns. (MCW)

  5. Resting-State Oscillatory Activity in Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Cornew, Lauren; Roberts, Timothy P. L.; Blaskey, Lisa; Edgar, J. Christopher

    2012-01-01

    Neural oscillatory anomalies in autism spectrum disorders (ASD) suggest an excitatory/inhibitory imbalance; however, the nature and clinical relevance of these anomalies are unclear. Whole-cortex magnetoencephalography data were collected while 50 children (27 with ASD, 23 controls) underwent an eyes-closed resting-state exam. A Fast Fourier…

  6. 34 CFR 300.814 - Other State-level activities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... CHILDREN WITH DISABILITIES Preschool Grants for Children with Disabilities § 300.814 Other State-level... process required by section 615(e) of the Act), which may benefit children with disabilities younger than three or older than five as long as those services also benefit children with disabilities aged...

  7. 34 CFR 300.814 - Other State-level activities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CHILDREN WITH DISABILITIES Preschool Grants for Children with Disabilities § 300.814 Other State-level... process required by section 615(e) of the Act), which may benefit children with disabilities younger than three or older than five as long as those services also benefit children with disabilities aged...

  8. An active state of the BL Lacertae object Markarian 421 detected by INTEGRAL in April 2013

    NASA Astrophysics Data System (ADS)

    Pian, E.; Türler, M.; Fiocchi, M.; Boissay, R.; Bazzano, A.; Foschini, L.; Tavecchio, F.; Bianchin, V.; Castignani, G.; Ferrigno, C.; Raiteri, C. M.; Villata, M.; Beckmann, V.; D'Ammando, F.; Hudec, R.; Malaguti, G.; Maraschi, L.; Pursimo, T.; Romano, P.; Soldi, S.; Stamerra, A.; Treves, A.; Ubertini, P.; Vercellone, S.; Walter, R.

    2014-10-01

    Aims: Multiwavelength variability of blazars offers indirect, but very effective, insight into their powerful engines and on the mechanisms through which energy is propagated from the centre down the jet. The BL Lac object Mkn 421 is a TeV emitter, a bright blazar at all wavelengths, and therefore an excellent target for variability studies. Methods: We activated INTEGRAL observations of Mkn 421 in an active state on 16-21 April 2013, and complemented them with Fermi-LAT data. Results: We obtained well sampled optical, soft, and hard X-ray light curves that show the presence of two flares and time-resolved spectra in the 3.5-60 keV (JEM-X and IBIS/ISGRI) and 0.1-100 GeV (Fermi-LAT) ranges. The average flux in the 20-100 keV range is 9.1 × 10-11 erg s-1 cm-2 (~4.5 mCrab) and the nuclear average apparent magnitude, corrected for Galactic extinction, is V ≃ 12.2. In the time-resolved X-ray spectra, which are described by broken power laws and, marginally better, by log-parabolic laws, we see a hardening that correlates with flux increase, as expected in refreshed energy injections in a population of electrons that later cool via synchrotron radiation. The hardness ratios between the JEM-X fluxes in two different bands and between the JEM-X and IBIS/ISGRI fluxes confirm this trend. During the observation, the variability level increases monotonically from the optical to the hard X-rays, while the large LAT errors do not allow a significant assessment of the MeV-GeV variability. The cross-correlation analysis during the onset of the most prominent flare suggests a monotonically increasing delay of the lower frequency emission with respect to that at higher frequency, with a maximum time-lag of about 70 min, that is however not well constrained. The spectral energy distributions from the optical to the TeV domain were compared to homogeneous models of blazar emission based on synchrotron radiation and synchrotron self-Compton scattering. They represent a satisfactory

  9. Novel Insights Into The Mode of Inhibition of Class A SHV-1 Beta-Lactamases Revealed by Boronic Acid Transition State Inhibitors

    SciTech Connect

    W Ke; J Sampson; C Ori; F Prati; S Drawz; C Bethel; R Bonomo; F van den Akker

    2011-12-31

    Boronic acid transition state inhibitors (BATSIs) are potent class A and C {beta}-lactamase inactivators and are of particular interest due to their reversible nature mimicking the transition state. Here, we present structural and kinetic data describing the inhibition of the SHV-1 {beta}-lactamase, a clinically important enzyme found in Klebsiella pneumoniae, by BATSI compounds possessing the R1 side chains of ceftazidime and cefoperazone and designed variants of the latter, compounds 1 and 2. The ceftazidime and cefoperazone BATSI compounds inhibit the SHV-1 {beta}-lactamase with micromolar affinity that is considerably weaker than their inhibition of other {beta}-lactamases. The solved crystal structures of these two BATSIs in complex with SHV-1 reveal a possible reason for SHV-1's relative resistance to inhibition, as the BATSIs adopt a deacylation transition state conformation compared to the usual acylation transition state conformation when complexed to other {beta}-lactamases. Active-site comparison suggests that these conformational differences might be attributed to a subtle shift of residue A237 in SHV-1. The ceftazidime BATSI structure revealed that the carboxyl-dimethyl moiety is positioned in SHV-1's carboxyl binding pocket. In contrast, the cefoperazone BATSI has its R1 group pointing away from the active site such that its phenol moiety moves residue Y105 from the active site via end-on stacking interactions. To work toward improving the affinity of the cefoperazone BATSI, we synthesized two variants in which either one or two extra carbons were added to the phenol linker. Both variants yielded improved affinity against SHV-1, possibly as a consequence of releasing the strain of its interaction with the unusual Y105 conformation.

  10. Antitrust enforcement in the healthcare industry: the expanding scope of state activity.

    PubMed Central

    Hellinger, F J

    1998-01-01

    OBJECTIVE: To describe the landscape of state antitrust activity and review related research and policy issues. In particular, to examine state laws that attempt to immunize mergers among healthcare providers from state and federal antitrust prosecution and consent decrees issued by state attorneys general permitting healthcare providers to merge. DATA SOURCES: State laws attempting to immunize collaborative activities from state and federal antitrust prosecution and consent decrees between state attorneys general and collaborating healthcare providers. PRINCIPAL FINDINGS: State antitrust agencies have been more willing than federal antitrust agencies to approve mergers that are contingent on the fulfillment of specific conditions that require continued oversight. CONCLUSIONS: Research is needed to inform policymakers about the consequences of state-approved mergers on market performance. PMID:9865230

  11. [Functional cerebral activity in a state of rest: connectivity networks].

    PubMed

    Proal, Erika; Alvarez-Segura, Mar; de la Iglesia-Vayá, María; Martí-Bonmatí, Luis; Castellanos, F Xavier

    2011-03-01

    Functional connectivity can be measured during task-based functional magnetic resonance imaging (fMRI), or in the absence of specific stimuli or tasks. In either case, the study of low frequency fluctuations in the BOLD signal reveals patterns of synchronization which delineate the intrinsic functional architecture of the brain. The scientific community now has available shared resources to accelerate the exploitation of resting state fMRI with the objectives of improving diagnostic methods and leading to better treatments grounded in neuroscience. Fomenting a collaborative scientific culture will accelerate our understanding of the underlying phenonmemna. Recently, the Spanish Resting State Network (SRSN) has joined this collaborative effort by creating a setting to facilitate collaboration among the various neuroscience research groups working in Spanish (http://www.nitrc.org/projects/srsn). PMID:21365601

  12. Decoding of the sound frequency from the steady-state neural activities in rat auditory cortex.

    PubMed

    Shiramatsu, Tomoyo I; Noda, Takahiro; Kanzaki, Ryohei; Takahashi, Hirokazu

    2013-01-01

    In the auditory cortex, onset activities have been extensively investigated as a cortical representation of sound information such as sound frequency. Yet, less attention has been paid to date to steady-state activities following the onset activities. In this study, we used machine learning to investigate whether steady-state activities in the presence of continuous sounds represent the sound frequency. Sparse Logistic Regression (SLR) decoded the sound frequency from band specific power or phase locking value (PLV) of local field potentials (LFP) from the fourth layer of the auditory cortex of anesthetized rats. Consequently, we found that SLR was able to decode the sound frequency from steady-state neural activities as well as onset activities. This result demonstrates that the steady-state activities contain information about the sound such as sound frequency.

  13. Tracking Sodium-Antimonide Phase Transformations in Sodium-Ion Anodes: Insights from Operando Pair Distribution Function Analysis and Solid-State NMR Spectroscopy.

    PubMed

    Allan, Phoebe K; Griffin, John M; Darwiche, Ali; Borkiewicz, Olaf J; Wiaderek, Kamila M; Chapman, Karena W; Morris, Andrew J; Chupas, Peter J; Monconduit, Laure; Grey, Clare P

    2016-02-24

    Operando pair distribution function (PDF) analysis and ex situ (23)Na magic-angle spinning solid-state nuclear magnetic resonance (MAS ssNMR) spectroscopy are used to gain insight into the alloying mechanism of high-capacity antimony anodes for sodium-ion batteries. Subtraction of the PDF of crystalline NaxSb phases from the total PDF, an approach constrained by chemical phase information gained from (23)Na ssNMR in reference to relevant model compounds, identifies two previously uncharacterized intermediate species formed electrochemically; a-Na(3-x)Sb (x ≈ 0.4-0.5), a structure locally similar to crystalline Na3Sb (c-Na3Sb) but with significant numbers of sodium vacancies and a limited correlation length, and a-Na(1.7)Sb, a highly amorphous structure featuring some Sb-Sb bonding. The first sodiation breaks down the crystalline antimony to form first a-Na(3-x)Sb and, finally, crystalline Na3Sb. Desodiation results in the formation of an electrode formed of a composite of crystalline and amorphous antimony networks. We link the different reactivity of these networks to a series of sequential sodiation reactions manifesting as a cascade of processes observed in the electrochemical profile of subsequent cycles. The amorphous network reacts at higher voltages reforming a-Na(1.7)Sb, then a-Na(3-x)Sb, whereas lower potentials are required for the sodiation of crystalline antimony, which reacts to form a-Na(3-x)Sb without the formation of a-Na(1.7)Sb. a-Na(3-x)Sb is converted to crystalline Na3Sb at the end of the second discharge. We find no evidence of formation of NaSb. Variable temperature (23)Na NMR experiments reveal significant sodium mobility within c-Na3Sb; this is a possible contributing factor to the excellent rate performance of Sb anodes.

  14. Crystal Structure of PrgI-SipD: Insight into a Secretion Competent State of the Type Three Secretion System Needle Tip and its Interaction with Host Ligands

    PubMed Central

    Lunelli, Michele; Hurwitz, Robert; Lambers, Jutta; Kolbe, Michael

    2011-01-01

    Many infectious Gram-negative bacteria, including Salmonella typhimurium, require a Type Three Secretion System (T3SS) to translocate virulence factors into host cells. The T3SS consists of a membrane protein complex and an extracellular needle together that form a continuous channel. Regulated secretion of virulence factors requires the presence of SipD at the T3SS needle tip in S. typhimurium. Here we report three-dimensional structures of individual SipD, SipD in fusion with the needle subunit PrgI, and of SipD:PrgI in complex with the bile salt, deoxycholate. Assembly of the complex involves major conformational changes in both SipD and PrgI. This rearrangement is mediated via a π bulge in the central SipD helix and is stabilized by conserved amino acids that may allow for specificity in the assembly and composition of the tip proteins. Five copies each of the needle subunit PrgI and SipD form the T3SS needle tip complex. Using surface plasmon resonance spectroscopy and crystal structure analysis we found that the T3SS needle tip complex binds deoxycholate with micromolar affinity via a cleft formed at the SipD:PrgI interface. In the structure-based three-dimensional model of the T3SS needle tip, the bound deoxycholate faces the host membrane. Recently, binding of SipD with bile salts present in the gut was shown to impede bacterial infection. Binding of bile salts to the SipD:PrgI interface in this particular arrangement may thus inhibit the T3SS function. The structures presented in this study provide insight into the open state of the T3SS needle tip. Our findings present the atomic details of the T3SS arrangement occurring at the pathogen-host interface. PMID:21829362

  15. Structural changes of humic acids from sinking organic matter and surface sediments investigated by advanced solid-state NMR: Insights into sources, preservation and molecularly uncharacterized components

    NASA Astrophysics Data System (ADS)

    Mao, Jingdong; Tremblay, Luc; Gagné, Jean-Pierre

    2011-12-01

    Knowledge of the structural changes that particulate organic matter (POM) undergoes in natural systems is essential for determining its reactivity and fate. In the present study, we used advanced solid-state NMR techniques to investigate the chemical structures of sinking particulate matter collected at different depths as well as humic acids (HAs) extracted from these samples and underlying sediments from the Saguenay Fjord and the St. Lawrence Lower Estuary (Canada). Compared to bulk POM, HAs contain more non-polar alkyls, aromatics, and aromatic C-O, but less carbohydrates (or carbohydrate-like structures). In the two locations studied, the C and N contents of the samples (POM and HAs) decreased with depth and after deposition onto sediments, leaving N-poor but O-enriched HAs and suggesting the involvement of partial oxidation reactions during POM microbial degradation. Advanced NMR techniques revealed that, compared to the water-column HAs, sedimentary HAs contained more protonated aromatics, non-protonated aromatics, aromatic C-O, carbohydrates (excluding anomerics), anomerics, OC q, O-C q-O, OCH, and OCH 3 groups, but less non-polar alkyls, NCH, and mobile CH 2 groups. These results are consistent with the relatively high reactivity of lipids and proteins or peptides. In contrast, carbohydrate-like structures were selectively preserved and appeared to be involved in substitution and copolymerization reactions. Some of these trends support the selective degradation (or selective preservation) theory. The results provide insights into mechanisms that likely contribute to the preservation of POM and the formation of molecules that escape characterization by traditional methods. Despite the depletion of non-polar alkyls with depth in HAs, a significant portion of their general structure survived and can be assigned to a model phospholipid. In addition, little changes in the connectivities of different functional groups were observed. Substituted and copolymerized

  16. United States Department of Energy Thermally Activated Heat Pump Program

    SciTech Connect

    Fiskum, R.J.; Adcock, P.W.; DeVault, R.C.

    1996-06-01

    The US Department of Energy (DOE) is working with partners from the gas heating and cooling industry to improve energy efficiency using advance absorption technologies, to eliminate chlorofluorocarbons (CFCs) and hydrochlorofluorocarbons (HCFCs), to reduce global warming through more efficient combustion of natural gas, and to impact electric peak demand of air conditioning. To assist industry in developing these gas heating and cooling absorption technologies, the US DOE sponsors the Thermally Activated Heat Pump Program. It is divided into five key activities, addressing residential gas absorption heat pumps, large commercial chillers, advanced absorption fluids, computer-aided design, and advanced ``Hi-Cool`` heat pumps.

  17. 75 FR 27575 - Agency Information Collection Activities: State Water Resources Research Institute Program Annual...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-17

    ... Geological Survey Agency Information Collection Activities: State Water Resources Research Institute Program... Water Resources Research Act of 1984, as amended (42 U.S.C. 10301 et seq.), authorizes a water resources... report on its activities under the grant. The State Water Resources Research Institute Program issues...

  18. 30 CFR 1229.110 - Examination of the State activities under delegation.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., DEPARTMENT OF THE INTERIOR Natural Resources Revenue DELEGATION TO STATES Oil and Gas, Onshore Administration of Delegations § 1229.110 Examination of the State activities under delegation. (a) The Department... provisions of 30 U.S.C. 1735; and (2) That costs incurred by the State under the delegation of authority...

  19. Discussion on sea level fluctuations along the Adriatic coasts coupling to climate indices forced by solar activity: Insights into the future of Venice

    NASA Astrophysics Data System (ADS)

    Zanchettin, Davide; Traverso, Pietro; Tomasino, Mario

    2006-04-01

    The North Atlantic Oscillation (NAO), which is a dominant circulation pattern in Northern Hemisphere winter, is known to affect sea-level variability in the Mediterranean Sea mainly through the hydrostatic response of water masses to pressure anomalies and changes in evaporation/precipitation budgets. In this study the influence of the NAO on sea levels along the Adriatic coasts is re-assessed in the attempt to uncover the potential causes of the observed high sensitivity of the northern basin to NAO fluctuations. The investigation is focused on the role of the NAO as forcing factor of the winds blowing in the area and of the freshwaters input from the Po River, both of which influence the hydrodynamics of the Northern Adriatic. In addition, some insights into the future of Venice are discussed on the basis of the hypothesis that NAO phases are modulated by the varying solar activity through the intensity of the Earth's geomagnetic activity.

  20. Biological evaluation and structural insights for design of subtype-selective peroxisome proliferator activated receptor-α (PPAR-α) agonists.

    PubMed

    Gangwal, Rahul P; Damre, Mangesh V; Das, Nihar R; Sharma, Shyam S; Sangamwar, Abhay T

    2015-01-15

    Peroxisome proliferator activated receptors-α (PPAR-α) control the expression of several genes involved in diseases like diabetes, hyperlipidaemia, and inflammatory disorders. Herein, we report the biological evaluation of recently identified hits from pharmacophore based virtual screening. The most potent hits, ZINC17167211, ZINC06472206 and ZINC08438472 showed EC50 values of 0.16, 1.1 and 12.1nM in PPAR-α agonist assay, respectively. Further, comparative docking and molecular dynamics analysis of selective PPAR-α agonists revealed that Thr279, Ala333, Lys358 and Met325 residues play an important role in the selective PPAR-α agonistic activity. The insights from docking and molecular dynamic studies will serve as a guideline for the development of potent and selective PPAR-α agonists.

  1. Grass Roots Activism in the United States: Global Implications?

    ERIC Educational Resources Information Center

    Alger, Chadwick F.; Mendlovitz, Saul

    Interviews were conducted with 35 grass roots activists from middle-sized U.S. cities and small towns to learn about their perspectives and activities. No effort was made to obtain a representative sample of activists. The five main approaches to social change encountered were represented by members of the ideological and political left, by…

  2. Recognition of human activity characteristics based on state transitions modeling technique

    NASA Astrophysics Data System (ADS)

    Elangovan, Vinayak; Shirkhodaie, Amir

    2012-06-01

    Human Activity Discovery & Recognition (HADR) is a complex, diverse and challenging task but yet an active area of ongoing research in the Department of Defense. By detecting, tracking, and characterizing cohesive Human interactional activity patterns, potential threats can be identified which can significantly improve situation awareness, particularly, in Persistent Surveillance Systems (PSS). Understanding the nature of such dynamic activities, inevitably involves interpretation of a collection of spatiotemporally correlated activities with respect to a known context. In this paper, we present a State Transition model for recognizing the characteristics of human activities with a link to a prior contextbased ontology. Modeling the state transitions between successive evidential events determines the activities' temperament. The proposed state transition model poses six categories of state transitions including: Human state transitions of Object handling, Visibility, Entity-entity relation, Human Postures, Human Kinematics and Distance to Target. The proposed state transition model generates semantic annotations describing the human interactional activities via a technique called Casual Event State Inference (CESI). The proposed approach uses a low cost kinect depth camera for indoor and normal optical camera for outdoor monitoring activities. Experimental results are presented here to demonstrate the effectiveness and efficiency of the proposed technique.

  3. Allowance trading activity and state regulatory rulings: Evidence from the US Acid Rain Program

    SciTech Connect

    Bailey, E.M.

    1997-12-31

    The US Acid Rain Program is one of the first, and by far the most extensive, applications of a market based approach to pollution control. From the beginning, there has been concern whether utilities would participate in allowance trading, and whether regulatory activity at the state level would further complicate utilities` decision to trade allowances. This paper finds that public utility commission regulation has encouraged allowance trading activity in states with regulatory rulings, but that allowance trading activity has not been limited to states issuing regulations. Until there is evidence suggesting that significant additional cost savings could have been obtained if additional allowance trading activity had occurred in states without regulations or that utilities in states with regulations are still not taking advantage of all cost saving trading opportunities, this analysis suggests that there is little reason to believe that allowance trading activity is impeded by public utility commission regulations.

  4. Recent activities of the Priroda State Remote Sensing Center

    USGS Publications Warehouse

    Morrison, J.L.; Bond, A.R.

    1989-01-01

    At present the Priroda State Remote Sensing Center is the largest entity in the USSR responsible for the receipt and processing of space imagery. Besides the aforementioned consulting and training functions, Priroda, upon user request: a) processes multispectral, band-specific, and other remote sensing imagery and supplies a broad range of primary and derivative information in the form of image copies [prints and transparencies] and digital products; and b) cooperates with other GUGK bodies in the compilation of thematic map series on diverse topics. -from Authors

  5. Expression and characterization of the calcium-activated photoprotein from the ctenophore Bathocyroe fosteri: insights into light-sensitive photoproteins.

    PubMed

    Powers, Meghan L; McDermott, Amy G; Shaner, Nathan C; Haddock, Steven H D

    2013-02-01

    Calcium-binding photoproteins have been discovered in a variety of luminous marine organisms [1]. Recent interest in photoproteins from the phylum Ctenophora has stemmed from cloning and expression of several photoproteins from this group [2-5]. Additional characterization has revealed unique biochemical properties found only in ctenophore photoproteins, such as inactivation by light. Here we report the cloning, expression, and characterization of the photoprotein responsible for luminescence in the deep-sea ctenophore Bathocyroe fosteri. This animal was of particular interest due to the unique broad color spectrum observed in live specimens [6]. Full-length sequences were identified by BLAST searches of known photoprotein sequences against Bathocyroe transcripts obtained from 454 sequencing. Recombinantly expressed Bathocyroe photoprotein (BfosPP) displayed an optimal coelenterazine-loading pH of 8.5, and produced calcium-triggered luminescence with peak wavelengths closely matching the 493 nm peak observed in the spectrum of live B. fosteri specimens. Luminescence from recombinant BfosPP was inactivated most efficiently by UV and blue light. Primary structure alignment of BfosPP with other characterized photoproteins showed very strong sequence similarity to other ctenophore photoproteins and conservation of EF-hand motifs. Both alignment and structural prediction data provide more insight into the formation of the coelenterazine-binding domain and the probable mechanism of photoinactivation. PMID:23262181

  6. Monitoring and validating active site redox states in protein crystals.

    PubMed

    Antonyuk, Svetlana V; Hough, Michael A

    2011-06-01

    High resolution protein crystallography using synchrotron radiation is one of the most powerful tools in modern biology. Improvements in resolution have arisen from the use of X-ray beamlines with higher brightness and flux and the development of advanced detectors. However, it is increasingly recognised that the benefits brought by these advances have an associated cost, namely deleterious effects of X-ray radiation on the sample (radiation damage). In particular, X-ray induced reduction and damage to redox centres has been shown to occur much more rapidly than other radiation damage effects, such as loss of resolution or damage to disulphide bridges. Selection of an appropriate combination of in-situ single crystal spectroscopies during crystallographic experiments, such as UV-visible absorption and X-ray absorption spectroscopy (XAFS), allows for effective monitoring of redox states in protein crystals in parallel with structure determination. Such approaches are also essential in cases where catalytic intermediate species are generated by exposure to the X-ray beam. In this article, we provide a number of examples in which multiple single crystal spectroscopies have been key to understanding the redox status of Fe and Cu centres in crystal structures. This article is part of a Special Issue entitled: Protein Structure and Function in the Crystalline State.

  7. Structure-Function Analysis of the Drosophila melanogaster Caudal Transcription Factor Provides Insights into Core Promoter-preferential Activation.

    PubMed

    Shir-Shapira, Hila; Sharabany, Julia; Filderman, Matan; Ideses, Diana; Ovadia-Shochat, Avital; Mannervik, Mattias; Juven-Gershon, Tamar

    2015-07-10

    Regulation of RNA polymerase II transcription is critical for the proper development, differentiation, and growth of an organism. The RNA polymerase II core promoter is the ultimate target of a multitude of transcription factors that control transcription initiation. Core promoters encompass the RNA start site and consist of functional elements such as the TATA box, initiator, and downstream core promoter element (DPE), which confer specific properties to the core promoter. We have previously discovered that Drosophila Caudal, which is a master regulator of genes involved in development and differentiation, is a DPE-specific transcriptional activator. Here, we show that the mouse Caudal-related homeobox (Cdx) proteins (mCdx1, mCdx2, and mCdx4) are also preferential core promoter transcriptional activators. To elucidate the mechanism that enables Caudal to preferentially activate DPE transcription, we performed structure-function analysis. Using a systematic series of deletion mutants (all containing the intact DNA-binding homeodomain) we discovered that the C-terminal region of Caudal contributes to the preferential activation of the fushi tarazu (ftz) Caudal target gene. Furthermore, the region containing both the homeodomain and the C terminus of Caudal was sufficient to confer core promoter-preferential activation to the heterologous GAL4 DNA-binding domain. Importantly, we discovered that Drosophila CREB-binding protein (dCBP) is a co-activator for Caudal-regulated activation of ftz. Strikingly, dCBP conferred the ability to preferentially activate the DPE-dependent ftz reporter to mini-Caudal proteins that were unable to preferentially activate ftz transcription themselves. Taken together, it is the unique combination of dCBP and Caudal that enables the co-activation of ftz in a core promoter-preferential manner.

  8. The symbiotic star TX CVn has entered an active state

    NASA Astrophysics Data System (ADS)

    Munari, U.; Castellani, F.; Valisa, P.; Dallaporta, S.; Cherini, G.; Vagnozzi, A.; Righetti, G. L.; Belligoli, R.

    2014-01-01

    After the last active phase that begun in 2003, the symbiotic star TX CVn has now entered a new active phase. In 2003, TX CVn rose to B=10.5 and there it remained until the end of 2007 (Skopal 2007, AN 328, 909), when we started monitoring the variable with various ANS Collaboration telescopes in BVRI bands. Our observations show that the star has spent the following 6 years on a steady decline at a rate of 0.084 mag per year in the B band, that took it from B=10.55 on December 2007 to B=11.02 on September 2013, when the star begun a rapid brightening, reaching B=10.65 by early December 2013.

  9. State Public Health Laboratory System Quality Improvement Activities

    PubMed Central

    Vagnone, Paula Snippes

    2013-01-01

    The Association of Public Health Laboratories (APHL) and the APHL Laboratory Systems and Standards Committee manage the Laboratory System Improvement Program (L-SIP). One component of L-SIP is an assessment that allows the members and stakeholders of a laboratory system to have an open and honest discussion about the laboratory system's strengths and weaknesses. From these facilitated discussions, gaps and opportunities for improvement are identified. In some cases, ideas for how to best address these gaps emerge, and workgroups are formed. Depending on resources, both monetary and personnel, laboratory staff will then prioritize the next component of L-SIP: which quality improvement activities to undertake. This article describes a sample of quality improvement activities initiated by several public health laboratories after they conducted L-SIP assessments. These projects can result in more robust linkages between system entities, which can translate into improvements in the way the system addresses the needs of stakeholders. PMID:23997301

  10. 34 CFR 403.71 - In what additional ways may funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... agencies; (b) The support for tech-prep education as described in 34 CFR part 406; (c)(1) The support of... State Programs and State Leadership Activities? 403.71 Section 403.71 Education Regulations of the... Secretary Assist Under the Basic Programs? State Programs and State Leadership Activities § 403.71 In...

  11. 34 CFR 403.71 - In what additional ways may funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... agencies; (b) The support for tech-prep education as described in 34 CFR part 406; (c)(1) The support of... State Programs and State Leadership Activities? 403.71 Section 403.71 Education Regulations of the... Secretary Assist Under the Basic Programs? State Programs and State Leadership Activities § 403.71 In...

  12. 34 CFR 403.71 - In what additional ways may funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... agencies; (b) The support for tech-prep education as described in 34 CFR part 406; (c)(1) The support of... State Programs and State Leadership Activities? 403.71 Section 403.71 Education Regulations of the... Secretary Assist Under the Basic Programs? State Programs and State Leadership Activities § 403.71 In...

  13. 34 CFR 403.71 - In what additional ways may funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... agencies; (b) The support for tech-prep education as described in 34 CFR part 406; (c)(1) The support of... State Programs and State Leadership Activities? 403.71 Section 403.71 Education Regulations of the... Secretary Assist Under the Basic Programs? State Programs and State Leadership Activities § 403.71 In...

  14. 34 CFR 403.71 - In what additional ways may funds be used under the State Programs and State Leadership Activities?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... agencies; (b) The support for tech-prep education as described in 34 CFR part 406; (c)(1) The support of... State Programs and State Leadership Activities? 403.71 Section 403.71 Education Regulations of the... Secretary Assist Under the Basic Programs? State Programs and State Leadership Activities § 403.71 In...

  15. Active tectonic studies in the United States, 1987-1990

    SciTech Connect

    Weldon, R.J., II )

    1991-01-01

    The techniques and instrumentation used in active tectonic studies are discussed, and recent results are reviewed. It is suggested that a critical mass of data on several particular regions has been accumulated, making possible critical debates and attempts to assess earthquake hazards. Particular attention is given to studies of the Pacific Northwest region, basin and range deformation studies, and distributed deformation and hidden earthquake sources. Also included is a comprehensive bibliography for the period.

  16. United States-Russia: Environmental management activities, Summer 1998

    SciTech Connect

    1998-09-01

    A Joint Coordinating Committee for Environmental Restoration and Waste Management (JCCEM) was formed between the US and Russia. This report describes the areas of research being studied under JCCEM, namely: Efficient separations; Contaminant transport and site characterization; Mixed wastes; High level waste tank remediation; Transuranic stabilization; Decontamination and decommissioning; and Emergency response. Other sections describe: Administrative framework for cooperation; Scientist exchange; Future actions; Non-JCCEM DOE-Russian activities; and JCCEM publications.

  17. Structural elucidation of the DFG-Asp in and DFG-Asp out states of TAM kinases and insight into the selectivity of their inhibitors.

    PubMed

    Messoussi, Abdellah; Peyronnet, Lucile; Feneyrolles, Clémence; Chevé, Gwénaël; Bougrin, Khalid; Yasri, Aziz

    2014-10-10

    Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed.

  18. A New Activity of Anti-HIV and Anti-tumor Protein GAP31: DNA Adenosine Glycosidase – Structural and Modeling Insight into its Functions

    SciTech Connect

    Li, H.; Huang, P; Zhang, D; Sun, Y; Chen, H; Zhang, J; Huang, P; Kong, X; Lee-Huang, S

    2010-01-01

    We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

  19. A new activity of anti-HIV and anti-tumor protein GAP31: DNA adenosine glycosidase - Structural and modeling insight into its functions

    SciTech Connect

    Li, Hui-Guang; Huang, Philip L.; Zhang, Dawei; Sun, Yongtao; Chen, Hao-Chia; Zhang, John; Huang, Paul L.; Kong, Xiang-Peng; Lee-Huang, Sylvia

    2010-01-01

    We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

  20. What graph theory actually tells us about resting state interictal MEG epileptic activity.

    PubMed

    Niso, Guiomar; Carrasco, Sira; Gudín, María; Maestú, Fernando; Del-Pozo, Francisco; Pereda, Ernesto

    2015-01-01

    Graph theory provides a useful framework to study functional brain networks from neuroimaging data. In epilepsy research, recent findings suggest that it offers unique insight into the fingerprints of this pathology on brain dynamics. Most studies hitherto have focused on seizure activity during focal epilepsy, but less is known about functional epileptic brain networks during interictal activity in frontal focal and generalized epilepsy. Besides, it is not clear yet which measures are most suitable to characterize these networks. To address these issues, we recorded magnetoencephalographic (MEG) data using two orthogonal planar gradiometers from 45 subjects from three groups (15 healthy controls (7 males, 24 ± 6 years), 15 frontal focal (8 male, 32 ± 16 years) and 15 generalized epileptic (6 male, 27 ± 7 years) patients) during interictal resting state with closed eyes. Then, we estimated the total and relative spectral power of the largest principal component of the gradiometers, and the degree of phase synchronization between each sensor site in the frequency range [0.5-40 Hz]. We further calculated a comprehensive battery of 15 graph-theoretic measures and used the affinity propagation clustering algorithm to elucidate the minimum set of them that fully describe these functional brain networks. The results show that differences in spectral power between the control and the other two groups have a distinctive pattern: generalized epilepsy presents higher total power for all frequencies except the alpha band over a widespread set of sensors; frontal focal epilepsy shows higher relative power in the beta band bilaterally in the fronto-central sensors. Moreover, all network indices can be clustered into three groups, whose exemplars are the global network efficiency, the eccentricity and the synchronizability. Again, the patterns of differences were clear: the brain network of the generalized epilepsy patients presented greater efficiency and lower

  1. A review of recent activity in the United States.

    USGS Publications Warehouse

    Cannon, H.L.; Petrie, W.L.

    1979-01-01

    Either an overabundance or a deficiency of trace metals in the food chain can ultimately affect adversely the health of livestock and man. Increasing interest in the United States in the distribution of metals in the environment and in metal pollutants has led to widespread interdisciplinary research sponsored by governmental, private and academic groups concerning the availability of trace elements for absorption by plants and animals, and the effects of trace elements throughout the food chain. Effects on the environment of coal-fired power plants, the mining and processing of metals, asbestos, and phosphate, and the disposal of industrial and nuclear wastes have also received much attention in the past few years.-Authors

  2. Molecular insight into the differential anti-androgenic activity of resveratrol and its natural analogs: in silico approach to understand biological actions.

    PubMed

    Chakraborty, Sandipan; Kumar, Avinash; Butt, Nasir A; Zhang, Liangfen; Williams, Raquema; Rimando, Agnes M; Biswas, Pradip K; Levenson, Anait S

    2016-05-01

    The androgen receptor (AR) is a therapeutic target for the treatment of prostate cancer. Androgen receptor reactivation during the androgen-independent stage of prostate cancer is mediated by numerous mechanisms including expression of AR mutants and splice variants that become non-responsive to conventional anti-androgenic agents. Resveratrol and its natural analogs exhibit varying degrees of anti-androgenic effects on tumor growth suppression in prostate cancer. However, the structural basis for the observed differential activity remains unknown. Here, anti-androgenic activities of resveratrol and its natural analogs, namely, pterostilbene, piceatannol and trimethoxy-resveratrol were studied in LNCaP cells expressing T877A mutant AR and atomistic simulations were employed to establish the structure activity relationship. Interestingly, essential hydrogen bonding contacts and the binding energies of resveratrol analogs with AR ligand binding domain (LBD), emerge as key differentiating factors for varying anti-androgenic action. Among all the analogs, pterostilbene exhibited strongest anti-androgenic activity and its binding energy and hydrogen bonding interactions pattern closely resembled pure anti-androgen, flutamide. Principal component analysis of our simulation studies revealed that androgenic compounds bind more strongly to AR LBD compared to anti-androgenic compounds and provide conformational stabilization of the receptor in essential subspace. The present study provides critical insight into the structure-activity relationship of the anti-androgenic action of resveratrol analogs, which can be translated further to design novel highly potent anti-androgenic stilbenes. PMID:27063447

  3. New Approaches to the New Normal: Recapping 2012 Higher Education Legislative Activity in the West. Policy Insights

    ERIC Educational Resources Information Center

    Krueger, Carl

    2012-01-01

    While tax revenues in many Western states have improved since FY 2011, the 2012 legislative sessions still experienced what has become the familiar round of funding cuts to higher education, coupled with tuition increases for students. The good news is that the cuts and increases weren't as severe as in previous years, despite continued aversion…

  4. The effect of leg muscle activation state and localized muscle fatigue on tibial response during impact.

    PubMed

    Holmes, Adriana M; Andrews, David M

    2006-11-01

    The purpose of this research was to examine the effects of voluntarily manipulating muscle activation and localized muscle fatigue on tibial response parameters, including peak tibial acceleration, time to peak tibial acceleration, and the acceleration slope, measured at the knee during unshod heel impacts. A human pendulum delivered consistent impacts to 15 female and 15 male subjects. The tibialis anterior and lateral gastrocnemius were examined using electromyography, thus allowing voluntary contraction to various activation states (baseline, 15%, 30%, 45%, and 60% of the maximum activation state) and assessing localized muscle fatigue. A skin-mounted uniaxial accelerometer, preloaded medial to the tibial tuberosity, allowed tibial response parameter determination. There were significant decreases in peak acceleration during tibialis anterior fatigue, compared to baseline and all other activation states. In females, increased time to peak acceleration and decreased acceleration slope occurred during fatigue compared to 30% and 45%, and compared to 15% through 60% of the maximum activation state, respectively. Slight peak acceleration and acceleration slope increases, and decreased time to peak acceleration as activation state increased during tibialis anterior testing, were noted. When examining the lateral gastrocnemius, the time to peak acceleration was significantly higher across gender in the middle activation states than at the baseline and fatigue states. The acceleration slope decreased at all activation states above baseline in females, and decreased at 60% of the maximum activation state in males compared to the baseline and fatigue states. Findings agree with localized muscle fatigue literature, suggesting that with fatigue there is decreased impact transmission, which may protect the leg. The relative effects of leg stiffness and ankle angle on tibial response need to be verified.

  5. Crystal structure of a KSHV-SOX-DNA complex: insights into the molecular mechanisms underlying DNase activity and host shutoff.

    PubMed

    Bagnéris, Claire; Briggs, Louise C; Savva, Renos; Ebrahimi, Bahram; Barrett, Tracey E

    2011-07-01

    The early lytic phase of Kaposi's sarcoma herpesvirus infection is characterized by viral replication and the global degradation (shutoff) of host mRNA. Key to both activities is the virally encoded alkaline exonuclease KSHV SOX. While the DNase activity of KSHV SOX is required for the resolution of viral genomic DNA as a precursor to encapsidation, its exact involvement in host shutoff remains to be determined. We present the first crystal structure of a KSHV SOX-DNA complex that has illuminated the catalytic mechanism underpinning both its endo and exonuclease activities. We further illustrate that KSHV SOX, similar to its Epstein-Barr virus homologue, has an intrinsic RNase activity in vitro that although an element of host shutoff, cannot solely account for the phenomenon.

  6. Insights into the phosphatase and the synthase activities of human bisphosphoglycerate mutase: a quantum mechanics/molecular mechanics simulation.

    PubMed

    Chu, Wen-Ting; Zheng, Qing-Chuan; Zhang, Hong-Xing

    2014-03-01

    Bisphosphoglycerate mutase (BPGM) is a multi-activity enzyme. Its main function is to synthesize the 2,3-bisphosphoglycerate, the allosteric effector of hemoglobin. This enzyme can also catalyze the 2,3-bisphosphoglycerate to the 3-phosphoglycerate. In this study, the reaction mechanisms of both the phosphatase and the synthase activities of human bisphosphoglycerate mutase were theoretically calculated by using the quantum mechanics/molecular mechanics method based on the metadynamics and umbrella sampling simulations. The simulation results not only show the free energy curve of the phosphatase and the synthase reactions, but also reveal the important role of some residues in the active site. Additionally, the energy barriers of the two reactions indicate that the activity of the synthase in human bisphosphoglycerate mutase is much higher than that of the phosphatase. The estimated reaction barriers are consistent with the experimental data. Therefore, our work can give important information to understand the catalytic mechanism of the bisphosphoglycerate mutase family.

  7. United States data collection activities and requirements, volume 1

    NASA Technical Reports Server (NTRS)

    Hrin, S.; Mcgregor, D.

    1977-01-01

    The potential market for a data collection system was investigated to determine whether the user needs would be sufficient to support a satellite relay data collection system design. The activities of 107,407 data collections stations were studied to determine user needs in agriculture, climatology, environmental monitoring, forestry, geology, hydrology, meteorology, and oceanography. Descriptions of 50 distinct data collections networks are described and used to form the user data base. The computer program used to analyze the station data base is discussed, and results of the analysis are presented in maps and graphs. Information format and coding is described in the appendix.

  8. Predicting the activation states of the muscles governing upper esophageal sphincter relaxation and opening.

    PubMed

    Omari, Taher I; Jones, Corinne A; Hammer, Michael J; Cock, Charles; Dinning, Philip; Wiklendt, Lukasz; Costa, Marcello; McCulloch, Timothy M

    2016-03-15

    The swallowing muscles that influence upper esophageal sphincter (UES) opening are centrally controlled and modulated by sensory information. Activation and deactivation of neural inputs to these muscles, including the intrinsic cricopharyngeus (CP) and extrinsic submental (SM) muscles, results in their mechanical activation or deactivation, which changes the diameter of the lumen, alters the intraluminal pressure, and ultimately reduces or promotes flow of content. By measuring the changes in diameter, using intraluminal impedance, and the concurrent changes in intraluminal pressure, it is possible to determine when the muscles are passively or actively relaxing or contracting. From these "mechanical states" of the muscle, the neural inputs driving the specific motor behaviors of the UES can be inferred. In this study we compared predictions of UES mechanical states directly with the activity measured by electromyography (EMG). In eight subjects, pharyngeal pressure and impedance were recorded in parallel with CP- and SM-EMG activity. UES pressure and impedance swallow profiles correlated with the CP-EMG and SM-EMG recordings, respectively. Eight UES muscle states were determined by using the gradient of pressure and impedance with respect to time. Guided by the level and gradient change of EMG activity, mechanical states successfully predicted the activity of the CP muscle and SM muscle independently. Mechanical state predictions revealed patterns consistent with the known neural inputs activating the different muscles during swallowing. Derivation of "activation state" maps may allow better physiological and pathophysiological interpretations of UES function.

  9. A Comparative Analysis of Synthetic Quorum Sensing Modulators in Pseudomonas aeruginosa: New Insights into Mechanism, Active Efflux Susceptibility, Phenotypic Response, and Next-Generation Ligand Design

    PubMed Central

    2015-01-01

    Quorum sensing (QS) is a chemical signaling mechanism that allows bacterial populations to coordinate gene expression in response to social and environmental cues. Many bacterial pathogens use QS to initiate infection at high cell densities. Over the past two decades, chemical antagonists of QS in pathogenic bacteria have attracted substantial interest for use both as tools to further elucidate QS mechanisms and, with further development, potential anti-infective agents. Considerable recent research has been devoted to the design of small molecules capable of modulating the LasR QS receptor in the opportunistic pathogen Pseudomonas aeruginosa. These molecules hold significant promise in a range of contexts; however, as most compounds have been developed independently, comparative activity data for these compounds are scarce. Moreover, the mechanisms by which the bulk of these compounds act are largely unknown. This paucity of data has stalled the choice of an optimal chemical scaffold for further advancement. Herein, we submit the best-characterized LasR modulators to standardized cell-based reporter and QS phenotypic assays in P. aeruginosa, and we report the first comprehensive set of comparative LasR activity data for these compounds. Our experiments uncovered multiple interesting mechanistic phenomena (including a potential alternative QS-modulatory ligand binding site/partner) that provide new, and unexpected, insights into the modes by which many of these LasR ligands act. The lead compounds, data trends, and mechanistic insights reported here will significantly aid the design of new small molecule QS inhibitors and activators in P. aeruginosa, and in other bacteria, with enhanced potencies and defined modes of action. PMID:26491787

  10. Fates worse than death: the role of valued life activities in health-state evaluations.

    PubMed

    Ditto, P H; Druley, J A; Moore, K A; Danks, J H; Smucker, W D

    1996-09-01

    One hundred eight college students (Study 1) and 109 elderly adults (Study 2) rated 28 health impairments for the quality of life perceived to be possible in that state, the extent to which the state was perceived as a fate better or worse than death, and the extent to which the state was perceived to interfere with the ability to engage in the activities each individual valued most in life. States perceived most negatively were those perceived to interfere most with valued life activities. For any given health state, evaluations were more negative the more the state was perceived by individuals as likely to interfere with engagement in their valued life activities. Implications of these results for end-of-life medical decision making in general and the use of advance medical directives in particular are discussed. PMID:8891712

  11. Abnormal Baseline Brain Activity in Patients with Pulsatile Tinnitus: A Resting-State fMRI Study

    PubMed Central

    Han, Lv; Zhaohui, Liu; Fei, Yan; Ting, Li; Pengfei, Zhao; Wang, Du; Cheng, Dong; Pengde, Guo; Xiaoyi, Han; Xiao, Wang; Rui, Li; Zhenchang, Wang

    2014-01-01

    Numerous investigations studying the brain functional activity of the tinnitus patients have indicated that neurological changes are important findings of this kind of disease. However, the pulsatile tinnitus (PT) patients were excluded in previous studies because of the totally different mechanisms of the two subtype tinnitus. The aim of this study is to investigate whether altered baseline brain activity presents in patients with PT using resting-state functional magnetic resonance imaging (rs-fMRI) technique. The present study used unilateral PT patients (n = 42) and age-, sex-, and education-matched normal control subjects (n = 42) to investigate the changes in structural and amplitude of low-frequency (ALFF) of the brain. Also, we analyzed the relationships between these changes with clinical data of the PT patients. Compared with normal controls, PT patients did not show any structural changes. PT patients showed significant increased ALFF in the bilateral precuneus, and bilateral inferior frontal gyrus (IFG) and decreased ALFF in multiple occipital areas. Moreover, the increased THI score and PT duration was correlated with increased ALFF in precuneus and bilateral IFG. The abnormalities of spontaneous brain activity reflected by ALFF measurements in the absence of structural changes may provide insights into the neural reorganization in PT patients. PMID:24872895

  12. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation

    PubMed Central

    Martínez-Barricarte, Rubén; Heurich, Meike; Valdes-Cañedo, Francisco; Vazquez-Martul, Eduardo; Torreira, Eva; Montes, Tamara; Tortajada, Agustín; Pinto, Sheila; Lopez-Trascasa, Margarita; Morgan, B. Paul; Llorca, Oscar; Harris, Claire L.; Rodríguez de Córdoba, Santiago

    2010-01-01

    Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C3923ΔDG, which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H2O) by spontaneous thioester hydrolysis, C3923ΔDG generated an active AP C3-convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C3b923ΔDG and C3(H2O)923ΔDG were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase–restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3-convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments. PMID:20852386

  13. Insights into the molecular activation mechanism of the RhoA-specific guanine nucleotide exchange factor, PDZRhoGEF.

    PubMed

    Bielnicki, Jakub A; Shkumatov, Alexander V; Derewenda, Urszula; Somlyo, Avril V; Svergun, Dmitri I; Derewenda, Zygmunt S

    2011-10-01

    PDZRhoGEF (PRG) belongs to a small family of RhoA-specific nucleotide exchange factors that mediates signaling through select G-protein-coupled receptors via Gα(12/13) and activates RhoA by catalyzing the exchange of GDP to GTP. PRG is a multidomain protein composed of PDZ, regulators of G-protein signaling-like (RGSL), Dbl-homology (DH), and pleckstrin-homology (PH) domains. It is autoinhibited in cytosol and is believed to undergo a conformational rearrangement and translocation to the membrane for full activation, although the molecular details of the regulation mechanism are not clear. It has been shown recently that the main autoregulatory elements of PDZRhoGEF, the autoinhibitory "activation box" and the "GEF switch," which is required for full activation, are located directly upstream of the catalytic DH domain and its RhoA binding surface, emphasizing the functional role of the RGSL-DH linker. Here, using a combination of biophysical and biochemical methods, we show that the mechanism of PRG regulation is yet more complex and may involve an additional autoinhibitory element in the form of a molten globule region within the linker between RGSL and DH domains. We propose a novel, two-tier model of autoinhibition where the activation box and the molten globule region act synergistically to impair the ability of RhoA to bind to the catalytic DH-PH tandem. The molten globule region and the activation box become less ordered in the PRG-RhoA complex and dissociate from the RhoA-binding site, which may constitute a critical step leading to PRG activation.

  14. Uncovering the triggers for GPCR activation using solid-state NMR spectroscopy

    NASA Astrophysics Data System (ADS)

    Kimata, Naoki; Reeves, Philip J.; Smith, Steven O.

    2015-04-01

    G protein-coupled receptors (GPCRs) span cell membranes with seven transmembrane helices and respond to a diverse array of extracellular signals. Crystal structures of GPCRs have provided key insights into the architecture of these receptors and the role of conserved residues. However, the question of how ligand binding induces the conformational changes that are essential for activation remains largely unanswered. Since the extracellular sequences and structures of GPCRs are not conserved between receptor subfamilies, it is likely that the initial molecular triggers for activation vary depending on the specific type of ligand and receptor. In this article, we describe NMR studies on the rhodopsin subfamily of GPCRs and propose a mechanism for how retinal isomerization switches the receptor to the active conformation. These results suggest a general approach for determining the triggers for activation in other GPCR subfamilies using NMR spectroscopy.

  15. Activities on Facebook Reveal the Depressive State of Users

    PubMed Central

    Kwak, Jinah

    2013-01-01

    Background As online social media have become prominent, much effort has been spent on identifying users with depressive symptoms in order to aim at early diagnosis, treatment, and even prevention by using various online social media. In this paper, we focused on Facebook to discern any correlations between the platform’s features and users’ depressive symptoms. This work may be helpful in trying to reach and detect large numbers of depressed individuals more easily. Objective Our goal was to develop a Web application and identify depressive symptom–related features from users of Facebook, a popular social networking platform. Methods 55 Facebook users (male=40, female=15, mean age 24.43, SD 3.90) were recruited through advertisement fliers distributed to students in a large university in Korea. Using EmotionDiary, the Facebook application we developed, we evaluated depressive symptoms using the Center for Epidemiological Studies-Depression (CES-D) scale. We also provided tips and facts about depression to participants and measured their responses using EmotionDiary. To identify the Facebook features related to depression, correlation analyses were performed between CES-D and participants’ responses to tips and facts or Facebook social features. Last, we interviewed depressed participants (CES-D≥25) to assess their depressive symptoms by a psychiatrist. Results Facebook activities had predictive power in distinguishing depressed and nondepressed individuals. Participants’ response to tips and facts, which can be explained by the number of app tips viewed and app points, had a positive correlation (P=.04 for both cases), whereas the number of friends and location tags had a negative correlation with the CES-D scale (P=.08 and P=.045 respectively). Furthermore, in finding group differences in Facebook social activities, app tips viewed and app points resulted in significant differences (P=.01 and P=.03 respectively) between probably depressed and

  16. United States radiological health activities: inspection results of mammography facilities

    PubMed Central

    Spelic, DC; Kaczmarek, RV; Hilohi, M; Belella, S

    2007-01-01

    Purpose: The Mammography Quality Standards Act (MQSA) was enacted in 1992 to set national standards for high-quality mammography, including standards for mammographic X-ray equipment, patient dose, clinical image quality, and related technical parameters. The MQSA also requires minimum qualifications for radiologic technologists, interpreting physicians and medical physicists, mandates acceptable practices for quality-control, quality-assurance, and requires processes to audit medical outcomes. This paper presents the findings of MQSA inspections of facilities, which characterize significant factors affecting mammography quality in the United States. Materials and Methods: Trained inspectors collected data regarding X-ray technical factors, made exposure measurements for the determination of mean glandular dose (MGD), evaluated image quality, and inspected the quality of the film-processing environment. The average annual facility and total U.S. screening exam workloads were computed using workload data reported by facilities. Results: Mammography facilities have made technical improvements as evidenced by a narrower distribution of doses, higher phantom-film background optical densities associated with higher phantom image-quality scores, and better film processing. It is estimated that approximately 36 million screening mammography exams were conducted in 2006, a rate that is almost triple the exam volume estimated for 1997. Digital mammography (DM) is now in use at approximately 14% (1,191 of 8,834) of MQSA-certified mammography facilities. The results indicate that DM can offer lower dose to the patient while providing comparable or better image quality. PMID:21614276

  17. The Role of an Active Site Mg2+ in HDV Ribozyme Self-Cleavage: Insights from QM/MM Calculations

    PubMed Central

    Mlýnský, Vojtěch; Šponer, Jiří

    2014-01-01

    The hepatitis delta virus (HDV) ribozyme is a catalytic RNA motif embedded in the human pathogenic HDV RNA. It catalyzes self-cleavage of its sugar-phosphate backbone with direct participation of the active site cytosine C75. Biochemical and structural data support a general acid role of C75. Here, we used hybrid quantum mechanical/molecular mechanical (QM/MM) calculations to probe the reaction mechanism and changes in Gibbs energy along the ribozyme's reaction pathway with an N3-protonated C75H+ in the active site, which acts as the general acid, and a partially hydrated Mg2+ ion with one deprotonated, inner-shell coordinated water molecule that acts as the general base. We followed eight reaction paths with distinct position and coordination of the catalytically important active site Mg2+ ion. For six of them, we observed feasible activation barriers ranging from 14.2 to 21.9 kcal/mol, indicating that the specific position of the Mg2+ ion in the active site is predicted to strongly affect the kinetics of self-cleavage. The deprotonation of the U-1(2′-OH) nucleophile and the nucleophilic attack of the resulting U-1(2′-O−) on the scissile phosphodiester are found to be separate steps, as deprotonation precedes the nucleophilic attack. This sequential mechanism of the HDV ribozyme differs from the concerted nucleophilic activation and attack suggested for the hairpin ribozyme. We estimated the pKa of the U-1(2′-OH) group to range from 8.8 to 11.2, suggesting that the pKa is lowered by several units from that of a free ribose, comparable to and most likely smaller than the pKa of the solvated active site Mg2+ ion. Our results thus support the notion that the structure of the HDV ribozyme, and particularly the positioning of the active site Mg2+ ion, facilitates deprotonation and activation of the 2′-OH nucleophile. PMID:25412464