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Sample records for additional mechanistic information

  1. Informing Mechanistic Toxicology with Computational Molecular Models

    EPA Science Inventory

    Computational molecular models of chemicals interacting with biomolecular targets provides toxicologists a valuable, affordable, and sustainable source of in silico molecular level information that augments, enriches, and complements in vitro and in vivo effo...

  2. Perspectives on the Application of Mechanistic Information in Chemical Hazard and Dose-Response Assessments

    EPA Science Inventory

    This overview summarizes several EPA Assessment publications reviewing approaches for applying mechanistic information in human health risk assessment and exploring opportunities for progress in this area.

  3. Predicting interactions from mechanistic information: Can omic data validate theories?

    SciTech Connect

    Borgert, Christopher J.

    2007-09-01

    To address the most pressing and relevant issues for improving mixture risk assessment, researchers must first recognize that risk assessment is driven by both regulatory requirements and scientific research, and that regulatory concerns may expand beyond the purely scientific interests of researchers. Concepts of 'mode of action' and 'mechanism of action' are used in particular ways within the regulatory arena, depending on the specific assessment goals. The data requirements for delineating a mode of action and predicting interactive toxicity in mixtures are not well defined from a scientific standpoint due largely to inherent difficulties in testing certain underlying assumptions. Understanding the regulatory perspective on mechanistic concepts will be important for designing experiments that can be interpreted clearly and applied in risk assessments without undue reliance on extrapolation and assumption. In like fashion, regulators and risk assessors can be better equipped to apply mechanistic data if the concepts underlying mechanistic research and the limitations that must be placed on interpretation of mechanistic data are understood. This will be critically important for applying new technologies to risk assessment, such as functional genomics, proteomics, and metabolomics. It will be essential not only for risk assessors to become conversant with the language and concepts of mechanistic research, including new omic technologies, but also, for researchers to become more intimately familiar with the challenges and needs of risk assessment.

  4. Helical-Peptide-Catalyzed Enantioselective Michael Addition Reactions and Their Mechanistic Insights.

    PubMed

    Ueda, Atsushi; Umeno, Tomohiro; Doi, Mitsunobu; Akagawa, Kengo; Kudo, Kazuaki; Tanaka, Masakazu

    2016-08-05

    Helical peptide foldamer catalyzed Michael addition reactions of nitroalkane or dialkyl malonate to α,β-unsaturated ketones are reported along with the mechanistic considerations of the enantio-induction. A wide variety of α,β-unsaturated ketones, including β-aryl, β-alkyl enones, and cyclic enones, were found to be catalyzed by the helical peptide to give Michael adducts with high enantioselectivities (up to 99%). On the basis of X-ray crystallographic analysis and depsipeptide study, the amide protons, N(2)-H and N(3)-H, at the N terminus in the α-helical peptide catalyst were crucial for activating Michael donors, while the N-terminal primary amine activated Michael acceptors through the formation of iminium ion intermediates.

  5. 16 CFR 1102.16 - Additional information.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... PUBLICLY AVAILABLE CONSUMER PRODUCT SAFETY INFORMATION DATABASE Content Requirements § 1102.16 Additional... in the Database any additional information it determines to be in the public interest,...

  6. 16 CFR 1102.16 - Additional information.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... PUBLICLY AVAILABLE CONSUMER PRODUCT SAFETY INFORMATION DATABASE Content Requirements § 1102.16 Additional... in the Database any additional information it determines to be in the public interest,...

  7. 16 CFR 1102.16 - Additional information.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... PUBLICLY AVAILABLE CONSUMER PRODUCT SAFETY INFORMATION DATABASE Content Requirements § 1102.16 Additional... in the Database any additional information it determines to be in the public interest,...

  8. Can ligand addition to soil enhance Cd phytoextraction? A mechanistic model study.

    PubMed

    Lin, Zhongbing; Schneider, André; Nguyen, Christophe; Sterckeman, Thibault

    2014-11-01

    Phytoextraction is a potential method for cleaning Cd-polluted soils. Ligand addition to soil is expected to enhance Cd phytoextraction. However, experimental results show that this addition has contradictory effects on plant Cd uptake. A mechanistic model simulating the reaction kinetics (adsorption on solid phase, complexation in solution), transport (convection, diffusion) and root absorption (symplastic, apoplastic) of Cd and its complexes in soil was developed. This was used to calculate plant Cd uptake with and without ligand addition in a great number of combinations of soil, ligand and plant characteristics, varying the parameters within defined domains. Ligand addition generally strongly reduced hydrated Cd (Cd(2+)) concentration in soil solution through Cd complexation. Dissociation of Cd complex ([Formula: see text]) could not compensate for this reduction, which greatly lowered Cd(2+) symplastic uptake by roots. The apoplastic uptake of [Formula: see text] was not sufficient to compensate for the decrease in symplastic uptake. This explained why in the majority of the cases, ligand addition resulted in the reduction of the simulated Cd phytoextraction. A few results showed an enhanced phytoextraction in very particular conditions (strong plant transpiration with high apoplastic Cd uptake capacity), but this enhancement was very limited, making chelant-enhanced phytoextraction poorly efficient for Cd.

  9. Informing phenomenological structural bone remodelling with a mechanistic poroelastic model.

    PubMed

    Villette, Claire C; Phillips, Andrew T M

    2016-02-01

    Studies suggest that fluid motion in the extracellular space may be involved in the cellular mechanosensitivity at play in the bone tissue adaptation process. Previously, the authors developed a mesoscale predictive structural model of the femur using truss elements to represent trabecular bone, relying on a phenomenological strain-based bone adaptation algorithm. In order to introduce a response to bending and shear, the authors considered the use of beam elements, requiring a new formulation of the bone adaptation drivers. The primary goal of the study presented here was to isolate phenomenological drivers based on the results of a mechanistic approach to be used with a beam element representation of trabecular bone in mesoscale structural modelling. A single-beam model and a microscale poroelastic model of a single trabecula were developed. A mechanistic iterative adaptation algorithm was implemented based on fluid motion velocity through the bone matrix pores to predict the remodelled geometries of the poroelastic trabecula under 42 different loading scenarios. Regression analyses were used to correlate the changes in poroelastic trabecula thickness and orientation to the initial strain outputs of the beam model. Linear (R(2) > 0.998) and third-order polynomial (R(2) > 0.98) relationships were found between change in cross section and axial strain at the central axis, and between beam reorientation and ratio of bending strain to axial strain, respectively. Implementing these relationships into the phenomenological predictive algorithm for the mesoscale structural femur has the potential to produce a model combining biofidelic structure and mechanical behaviour with computational efficiency.

  10. Toward a mechanistic understanding of the effect of biochar addition on soil water retention

    NASA Astrophysics Data System (ADS)

    Yi, S.; Chang, N.; Guo, M.; Imhoff, P. T.

    2014-12-01

    Biochar (BC) is a carbon-rich product produced by thermal degradation of biomass in an oxygen-free environment, whose application to sediment is said to improve water retention. However, BC produced from different feedstocks and pyrolyzed at different temperatures have distinct properties, which may alter water retention in ways difficult to predict a priori. Our goal is to develop a mechanistic understanding of BC addition on water retention by examining the impact of BC from two feedstocks, poultry litter (PL) and hardwood (HW), on the soil-water retention curves (SWRC) of a uniform sand and a sandy loam (SL). For experiments with sand, BC and sand were sieved to the same particle size (~ 0.547 mm) to minimize effects of BC addition on particle size distribution. Experiments with SL contained the same sieved BC. PL and HW bicohars were added at 2 and 7% (w/w), and water retention was measured from 0 to -4.38 × 106 cm-H2O. Both BCs increased porosities for sand and SL, up to 39 and 13% for sand and SL, respectively, with 7% HW BC addition. The primary cause for these increases was the internal porosity of BC particles. While the matric potential for air-entry was unchanged with BC addition, BC amendment increased water retention for sand and SL in the capillary region (0 to -15,000 cm-H2O) by an average of 26 and 33 % for 7% PL and HW BC in sand, respectively, but only 7 and 14 % for 7% PL and HW BC in SL. The most dramatic influence of BC amendment on water retention occurred in the adsorption region (< -15,000 cm-H2O), where water retention increased by a factor of 11 and 22 for 7% PL and HW BC in sand, respectively, but by 140 and 190 % for 7% PL and HW BC in SL, respectively. The impact of BC on water retention in these sediments is explained primarily by the additional surface area and internal porosity of PL and HW BC particles. van Genuchten (VG) models were fitted to the water retention data. For SL where the impact of BC addition on water retention was

  11. 16 CFR 1102.16 - Additional information.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... PUBLICLY AVAILABLE CONSUMER PRODUCT SAFETY INFORMATION DATABASE (Eff. Jan. 10, 2011) Content Requirements... notices, the CPSC shall include in the Database any additional information it determines to be in...

  12. Uniform Additivity in Classical and Quantum Information

    NASA Astrophysics Data System (ADS)

    Cross, Andrew; Li, Ke; Smith, Graeme

    2017-01-01

    Information theory quantifies the optimal rates of resource interconversions, usually in terms of entropies. However, nonadditivity often makes evaluating entropic formulas intractable. In a few auspicious cases, additivity allows a full characterization of optimal rates. We study uniform additivity of formulas, which is easily evaluated and captures all known additive quantum formulas. Our complete characterization of uniform additivity exposes an intriguing new additive quantity and identifies a remarkable coincidence—the classical and quantum uniformly additive functions with one auxiliary variable are identical.

  13. 10 CFR 810.14 - Additional information.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Additional information. 810.14 Section 810.14 Energy DEPARTMENT OF ENERGY ASSISTANCE TO FOREIGN ATOMIC ENERGY ACTIVITIES § 810.14 Additional information. The Department of Energy may at any time require a person engaging in any generally or specifically...

  14. 10 CFR 810.14 - Additional information.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Additional information. 810.14 Section 810.14 Energy DEPARTMENT OF ENERGY ASSISTANCE TO FOREIGN ATOMIC ENERGY ACTIVITIES § 810.14 Additional information. The Department of Energy may at any time require a person engaging in any generally or specifically...

  15. 12 CFR 1010.116 - Additional information.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 8 2013-01-01 2013-01-01 false Additional information. 1010.116 Section 1010.116 Banks and Banking BUREAU OF CONSUMER FINANCIAL PROTECTION LAND REGISTRATION (REGULATION J) Reporting Requirements § 1010.116 Additional information. (a) Property Owners' Association. (1) Will there be a property owners' association for...

  16. 12 CFR 1010.116 - Additional information.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 8 2014-01-01 2014-01-01 false Additional information. 1010.116 Section 1010.116 Banks and Banking BUREAU OF CONSUMER FINANCIAL PROTECTION LAND REGISTRATION (REGULATION J) Reporting Requirements § 1010.116 Additional information. (a) Property Owners' Association. (1) Will there be a property owners' association for...

  17. 24 CFR 1710.116 - Additional information.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 5 2014-04-01 2014-04-01 false Additional information. 1710.116 Section 1710.116 Housing and Urban Development Regulations Relating to Housing and Urban Development... URBAN DEVELOPMENT (INTERSTATE LAND SALES REGISTRATION PROGRAM) LAND REGISTRATION Reporting...

  18. 24 CFR 1710.216 - Additional information.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 5 2014-04-01 2014-04-01 false Additional information. 1710.216 Section 1710.216 Housing and Urban Development Regulations Relating to Housing and Urban Development... URBAN DEVELOPMENT (INTERSTATE LAND SALES REGISTRATION PROGRAM) LAND REGISTRATION Reporting...

  19. 18 CFR 5.21 - Additional information.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Additional information. 5.21 Section 5.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT INTEGRATED LICENSE APPLICATION PROCESS §...

  20. 18 CFR 5.21 - Additional information.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Additional information. 5.21 Section 5.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT INTEGRATED LICENSE APPLICATION PROCESS §...

  1. 18 CFR 5.21 - Additional information.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Additional information. 5.21 Section 5.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT INTEGRATED LICENSE APPLICATION PROCESS §...

  2. 18 CFR 5.21 - Additional information.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Additional information. 5.21 Section 5.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT INTEGRATED LICENSE APPLICATION PROCESS §...

  3. 18 CFR 5.21 - Additional information.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Additional information. 5.21 Section 5.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT INTEGRATED LICENSE APPLICATION PROCESS §...

  4. 24 CFR 1710.116 - Additional information.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 5 2013-04-01 2013-04-01 false Additional information. 1710.116 Section 1710.116 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR HOUSING-FEDERAL HOUSING COMMISSIONER, DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT (INTERSTATE LAND...

  5. 27 CFR 41.197 - Additional information.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ..., § 41.197 was revised, effective Aug. 26, 2013 through Aug. 26, 2016. ... 27 Alcohol, Tobacco Products and Firearms 2 2014-04-01 2014-04-01 false Additional information. 41.197 Section 41.197 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE...

  6. 18 CFR 33.10 - Additional information.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Additional information. 33.10 Section 33.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT APPLICATIONS UNDER FEDERAL POWER ACT SECTION...

  7. 1,4-Addition of TMSCCl₃ to nitroalkenes: efficient reaction conditions and mechanistic understanding.

    PubMed

    Wu, Na; Wahl, Benoit; Woodward, Simon; Lewis, William

    2014-06-16

    Improved synthetic conditions allow preparation of TMSCCl3 in good yield (70%) and excellent purity. Compounds of the type NBu4X [X=Ph3SiF2 (TBAT), F (tetrabutylammonium fluoride, TBAF), OAc, Cl and Br] act as catalytic promoters for 1,4-additions to a range of cyclic and acyclic nitroalkenes, in THF at 0-25 °C, typically in moderate to excellent yields (37-95%). TBAT is the most effective promoter and bromide the least effective. Multinuclear NMR studies ((1)H, (19)F, (13)C and (29)Si) under anaerobic conditions indicate that addition of TMSCCl3 to TBAT (both 0.13 M) at -20 °C, in the absence of nitroalkene, leads immediately to mixtures of Me3SiF, Ph3SiF and NBu4CCl3. The latter is stable to at least 0 °C and does not add nitroalkene from -20 to 0 °C, even after extended periods. Nitroalkene, in the presence of TMSCCl3 (both 0.13 M at -20 °C), when treated with TBAT, leads to immediate formation of the 1,4-addition product, suggesting the reaction proceeds via a transient [Me3Si(alkene)CCl3] species, in which (alkene) indicates an Si⋅⋅⋅O coordinated nitroalkene. The anaerobic catalytic chain is propagated through the kinetic nitronate anion resulting from 1,4 CCl3(-) addition to the nitroalkene. This is demonstrated by the fact that isolated NBu4[CH2=NO2] is an efficient promoter. Use of H2C=CH(CH2)2CH=CHNO2 in air affords radical-derived bicyclic products arising from aerobic oxidation.

  8. 1,4-Addition of TMSCCl3 to Nitroalkenes: Efficient Reaction Conditions and Mechanistic Understanding

    PubMed Central

    Wu, Na; Wahl, Benoit; Woodward, Simon; Lewis, William

    2014-01-01

    Improved synthetic conditions allow preparation of TMSCCl3 in good yield (70 %) and excellent purity. Compounds of the type NBu4X [X=Ph3SiF2 (TBAT), F (tetrabutylammonium fluoride, TBAF), OAc, Cl and Br] act as catalytic promoters for 1,4-additions to a range of cyclic and acyclic nitroalkenes, in THF at 0–25 °C, typically in moderate to excellent yields (37–95 %). TBAT is the most effective promoter and bromide the least effective. Multinuclear NMR studies (1H, 19F, 13C and 29Si) under anaerobic conditions indicate that addition of TMSCCl3 to TBAT (both 0.13 M) at −20 °C, in the absence of nitroalkene, leads immediately to mixtures of Me3SiF, Ph3SiF and NBu4CCl3. The latter is stable to at least 0 °C and does not add nitroalkene from −20 to 0 °C, even after extended periods. Nitroalkene, in the presence of TMSCCl3 (both 0.13 M at −20 °C), when treated with TBAT, leads to immediate formation of the 1,4-addition product, suggesting the reaction proceeds via a transient [Me3Si(alkene)CCl3] species, in which (alkene) indicates an Si⋅⋅⋅O coordinated nitroalkene. The anaerobic catalytic chain is propagated through the kinetic nitronate anion resulting from 1,4 CCl3− addition to the nitroalkene. This is demonstrated by the fact that isolated NBu4[CH2−NO2] is an efficient promoter. Use of H2C−CH(CH2)2CH−CHNO2 in air affords radical-derived bicyclic products arising from aerobic oxidation. PMID:24849249

  9. Organocatalyzed asymmetric Michael addition by an efficient bifunctional carbohydrate-thiourea hybrid with mechanistic DFT analysis.

    PubMed

    Azad, Chandra S; Khan, Imran A; Narula, Anudeep K

    2016-12-28

    A series of thiourea based bifunctional organocatalysts having d-glucose as a core scaffold were synthesized and examined as catalysts for the asymmetric Michael addition reaction of aryl/alkyl trans-β-nitrostyrenes over cyclohexanone and other Michael donors having active methylene. Excellent enantioselectivities (<95%), diastereoselectivities (<99%), and yields (<99%) were attained under solvent free conditions using 10 mol% of 1d0. The obtained results were explained through DFT calculations using the B3LYP/6-311G(d,p)//B3LYP/6-31G(d) basic set. The QM/MM calculations revealed the role of cyclohexanone as a solvent as well as reactant in the rate determining step imparting 31.91 kcal mol(-1) of energy towards the product formation.

  10. A Mechanistic Study of Halogen Addition and Photoelimination from π-Conjugated Tellurophenes.

    PubMed

    Carrera, Elisa I; Lanterna, Anabel E; Lough, Alan J; Scaiano, Juan C; Seferos, Dwight S

    2016-03-02

    The ability to drive reactivity using visible light is of importance for many disciplines of chemistry and has significant implications for sustainable chemistry. Identifying photochemically active compounds and understanding photochemical mechanisms is important for the development of useful materials for synthesis and catalysis. Here we report a series of photoactive diphenyltellurophene compounds bearing electron-withdrawing and electron-donating substituents synthesized by alkyne coupling/ring closing or palladium-catalyzed ipso-arylation chemistry. The redox chemistry of these compounds was studied with respect to oxidative addition and photoelimination of bromine, which is of importance for energy storage reactions involving X2. The oxidative addition reaction mechanism was studied using density functional theory, the results of which support a three-step mechanism involving the formation of an initial η(1) association complex, a monobrominated intermediate, and finally the dibrominated product. All of the tellurophene derivatives undergo photoreduction using 430, 447, or 617 nm light depending on the absorption properties of the compound. Compounds bearing electron-withdrawing substituents have the highest photochemical quantum efficiencies in the presence of an alkene trap, with efficiencies of up to 42.4% for a pentafluorophenyl-functionalized tellurophene. The photoelimination reaction was studied in detail through bromine trapping experiments and laser flash photolysis, and a mechanism is proposed. The photoreaction, which occurs by release of bromine radicals, is competitive with intersystem crossing to the triplet state of the brominated species, as evidenced by the formation of singlet oxygen. These findings should be useful for the design of new photochemically active compounds supported by main-group elements.

  11. [Information about phosphorus additives and nutritional counseling].

    PubMed

    Kido, Shinsuke; Nomura, Kengo; Sasaki, Shohei; Shiozaki, Yuji; Segawa, Hiroko; Tatsumi, Sawako

    2012-10-01

    Hyperphosphatemia is a common disorder in patients with chronic kidney disease (CKD) , and may result in hyperparathyroidism and renal osteodystrophy. Hyperphosphatemia also may contribute to deterioration vascular calcification and increase mortality. Hence, correction and prevention of hyperphosphatemia is a main component of the management of CKD. This goal is usually approached both by administering phosphorus binders and by restricting dietary phosphorus (P) intake. Dietary intake of phosphorus (P) is derived largely from foods with high protein content or food additives and is an important determinant of P balance in patient with CKD. Food additives (PO4) can dramatically increase the amount of P consumed in the daily diet, especially because P is more readily absorbed in its inorganic form. In addition, information about the P content and type in prepared foods is often unavailable or misleading. Therefore, during dietary counseling of patients with CKD, we recommended that they consider both the absolute dietary P content and the P-to-protein ratio of foods and meals including food additives.

  12. A mechanistic investigation of oxidative addition of methyl iodide to [Tp*Rh(CO)(L)].

    PubMed

    Chauby, Valérie; Daran, Jean-Claude; Serra-Le Berre, Carole; Malbosc, François; Kalck, Philippe; Delgado Gonzalez, Oscar; Haslam, Claire E; Haynes, Anthony

    2002-06-17

    Reaction of methyl iodide with square planar [kappa(2)-Tp*Rh(CO)(PMe(3))] 1a (Tp* = HB(3,5-Me(2)pz)(3)) at room temperature affords [kappa(3)-Tp*Rh(CO)(PMe(3))(Me)]I 2a, which was fully characterized by spectroscopy and X-ray crystallography. The pseudooctahedral geometry of cationic 2a, which contains a kappa(3)-coordinated Tp* ligand, indicates a reaction mechanism in which nucleophilic attack by Rh on MeI is accompanied by coordination of the pendant pyrazolyl group. In solution 2a transforms slowly into a neutral (acetyl)(iodo) rhodium complex [kappa(3)-Tp*Rh(PMe(3))(COMe)I] 3a, for which an X-ray crystal structure is also reported. Kinetic studies on the reactions of [kappa(2)-Tp*Rh(CO)(L)] (L = PMe(3), PMe(2)Ph, PMePh(2), PPh(3), CO)] with MeI show second-order behavior with large negative activation entropies, consistent with an S(N)2 mechanism. The second-order rate constants correlate well with phosphine basicity. For L = CO, reaction with MeI gives an acetyl complex, [kappa(3)-Tp*Rh(CO)(COMe)I]. The bis(pyrazolyl)borate complexes [kappa(2)-Bp*Rh(CO)(L)] (L = PPh(3), CO) are much less reactive toward MeI than the Tp* analogues, indicating the importance of the third pyrazolyl group and the accessibility of a kappa(3) coordination mode. The results strengthen the evidence in favor of an S(N)2 mechanism for oxidative addition of MeI to square planar d(8) transition metal complexes.

  13. Mechanistic Details of Pd(II)-Catalyzed C-H Iodination with Molecular I2: Oxidative Addition vs Electrophilic Cleavage.

    PubMed

    Haines, Brandon E; Xu, Huiying; Verma, Pritha; Wang, Xiao-Chen; Yu, Jin-Quan; Musaev, Djamaladdin G

    2015-07-22

    Transition metal-catalyzed C-H bond halogenation is an important alternative to the highly utilized directed-lithiation methods and increases the accessibility of the synthetically valuable aryl halide compounds. However, this approach often requires impractical reagents, such as IOAc, or strong co-oxidants. Therefore, the development of methodology utilizing inexpensive oxidants and catalyst containing earth-abundant transition metals under mild experimental conditions would represent a significant advance in the field. Success in this endeavor requires a full understanding of the mechanisms and reactivity governing principles of this process. Here, we report intimate mechanistic details of the Pd(II)-catalyzed C-H iodination with molecular I2 as the sole oxidant. Namely, we elucidate the impact of the: (a) Pd-directing group (DG) interaction, (b) nature of oxidant, and (c) nature of the functionalized C-H bond [C(sp(2))-H vs C(sp(3))-H] on the Pd(II)/Pd(IV) redox and Pd(II)/Pd(II) redox-neutral mechanisms of this reaction. We find that both monomeric and dimeric Pd(II) species may act as an active catalyst during the reaction, which preferentially proceeds via the Pd(II)/Pd(II) redox-neutral electrophilic cleavage (EC) pathway for all studied substrates with a functionalized C(sp(2))-H bond. In general, a strong Pd-DG interaction increases the EC iodination barrier and reduces the I-I oxidative addition (OA) barrier. However, the increase in Pd-DG interaction alone is not enough to make the mechanistic switch from EC to OA: This occurs only upon changing to substrates with a functionalized C(sp(3))-H bond. We also investigated the impact of the nature of the electrophile on the C(sp(2))-H bond halogenation. We predicted molecular bromine (Br2) to be more effective electrophile for the C(sp(2))-H halogenation than I2. Subsequent experiments on the stoichiometric C(sp(2))-H bromination by Pd(OAc)2 and Br2 confirmed this prediction.The findings of this study advance

  14. 47 CFR 25.111 - Additional information.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Service (BSS) in Appendix 30 of the ITU Radio Regulations (RR) and associated feeder-link plans in Appendix 30A of the ITU RR, if the system has technical characteristics differing from those specified in... provide the Commission with the information required by Appendix 4 of the ITU RR for advance...

  15. 47 CFR 25.111 - Additional information.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES SATELLITE COMMUNICATIONS... Administrations. (c) In the Direct Broadcast Satellite service, applicants and licensees shall also provide the Commission with all information it requires in order to modify the Appendix 30 Broadcasting-Satellite...

  16. 47 CFR 25.111 - Additional information.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES SATELLITE COMMUNICATIONS... Administrations. (c) In the Direct Broadcast Satellite service, applicants and licensees shall also provide the Commission with all information it requires in order to modify the Appendix 30 Broadcasting-Satellite...

  17. 47 CFR 25.111 - Additional information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES SATELLITE COMMUNICATIONS... Administrations. (c) In the Direct Broadcast Satellite service, applicants and licensees shall also provide the Commission with all information it requires in order to modify the Appendix 30 Broadcasting-Satellite...

  18. INCORPORATION OF MECHANISTIC INFORMATION IN THE ARSENIC PBPK MODEL DEVELOPMENT PROCESS

    EPA Science Inventory

    INCORPORATING MECHANISTIC INSIGHTS IN A PBPK MODEL FOR ARSENIC

    Elaina M. Kenyon, Michael F. Hughes, Marina V. Evans, David J. Thomas, U.S. EPA; Miroslav Styblo, University of North Carolina; Michael Easterling, Analytical Sciences, Inc.

    A physiologically based phar...

  19. Mechanistic insights into hydroacylation with non-chelating aldehydes†Electronic supplementary information (ESI) available: Materials and methods, reaction procedures, characterization data. CCDC 1012849. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4sc02026jClick here for additional data file.

    PubMed

    Murphy, Stephen K; Bruch, Achim; Dong, Vy M

    2015-01-01

    The combination of a small-bite-angle diphosphine bis(dicyclohexylphosphino)methane (dcpm) and [Rh(cod)OMe]2 catalyses the hydroacylation of 2-vinylphenols with a wide range of non-chelating aldehydes. Here we present a detailed experimental study that elucidates the factors contributing to the broad aldehyde scope and high reactivity. A variety of catalytically relevant intermediates were isolated and a [Rh(dcpm)(vinylphenolate)] complex was identified as the major catalytically relevant species. A variety of off-cycle intermediates were also identified that can re-enter the catalytic cycle by substrate- or 1,5-cyclooctadiene-mediated pathways. Saturation kinetics with respect to the 2-vinylphenol were observed, and this may contribute to the high selectivity for hydroacylation over aldehyde decarbonylation. A series of deuterium labelling experiments and Hammett studies support the oxidative addition of Rh to the aldehyde C-H bond as an irreversible and turnover-limiting step. The small bite angle of dcpm is crucial for lowering the barrier of this step and providing excellent reactivity with a variety of aldehydes.

  20. The Value of Mechanistic Biophysical Information for Systems-Level Understanding of Complex Biological Processes Such as Cytokinesis

    PubMed Central

    Pollard, Thomas D.

    2014-01-01

    This review illustrates the value of quantitative information including concentrations, kinetic constants and equilibrium constants in modeling and simulating complex biological processes. Although much has been learned about some biological systems without these parameter values, they greatly strengthen mechanistic accounts of dynamical systems. The analysis of muscle contraction is a classic example of the value of combining an inventory of the molecules, atomic structures of the molecules, kinetic constants for the reactions, reconstitutions with purified proteins and theoretical modeling to account for the contraction of whole muscles. A similar strategy is now being used to understand the mechanism of cytokinesis using fission yeast as a favorable model system. PMID:25468329

  1. 10 CFR 71.39 - Requirement for additional information.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Requirement for additional information. 71.39 Section 71.39 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) PACKAGING AND TRANSPORTATION OF RADIOACTIVE MATERIAL Application for Package Approval § 71.39 Requirement for additional information. The...

  2. 78 FR 75568 - Notice of Request for Additional Information

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-12

    ... From the Federal Register Online via the Government Publishing Office FEDERAL MARITIME COMMISSION Notice of Request for Additional Information The Commission gives notice that it has formally requested that the parties to the below listed agreement provide additional information pursuant to 46 U.S.C. 40304(d). This action prevents the...

  3. Combining Empirical Relationships with Data Based Mechanistic Modeling to Inform Solute Tracer Investigations across Stream Orders

    NASA Astrophysics Data System (ADS)

    Herrington, C.; Gonzalez-Pinzon, R.; Covino, T. P.; Mortensen, J.

    2015-12-01

    Solute transport studies in streams and rivers often begin with the introduction of conservative and reactive tracers into the water column. Information on the transport of these substances is then captured within tracer breakthrough curves (BTCs) and used to estimate, for instance, travel times and dissolved nutrient and carbon dynamics. Traditionally, these investigations have been limited to systems with small discharges (< 200 L/s) and with small reach lengths (< 500 m), partly due to the need for a priori information of the reach's hydraulic characteristics (e.g., channel geometry, resistance and dispersion coefficients) to predict arrival times, times to peak concentrations of the solute and mean travel times. Current techniques to acquire these channel characteristics through preliminary tracer injections become cost prohibitive at higher stream orders and the use of semi-continuous water quality sensors for collecting real-time information may be affected from erroneous readings that are masked by high turbidity (e.g., nitrate signals with SUNA instruments or fluorescence measures) and/or high total dissolved solids (e.g., making prohibitively expensive the use of salt tracers such as NaCl) in larger systems. Additionally, a successful time-of-travel study is valuable for only a single discharge and river stage. We have developed a method to predict tracer BTCs to inform sampling frequencies at small and large stream orders using empirical relationships developed from multiple tracer injections spanning several orders of magnitude in discharge and reach length. This method was successfully tested in 1st to 8th order systems along the Middle Rio Grande River Basin in New Mexico, USA.

  4. 29 CFR 502.44 - Additional information, if required.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... ENFORCEMENT OF CONTRACTUAL OBLIGATIONS FOR TEMPORARY ALIEN AGRICULTURAL WORKERS ADMITTED UNDER SECTION 218 OF... Administrative Law Judge's Decision § 502.44 Additional information, if required. Where the ARB has determined...

  5. 29 CFR 502.44 - Additional information, if required.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... ENFORCEMENT OF CONTRACTUAL OBLIGATIONS FOR TEMPORARY ALIEN AGRICULTURAL WORKERS ADMITTED UNDER SECTION 218 OF... Administrative Law Judge's Decision § 502.44 Additional information, if required. Where the ARB has determined...

  6. 29 CFR 502.44 - Additional information, if required.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ENFORCEMENT OF CONTRACTUAL OBLIGATIONS FOR TEMPORARY ALIEN AGRICULTURAL WORKERS ADMITTED UNDER SECTION 218 OF... Administrative Law Judge's Decision § 502.44 Additional information, if required. Where the ARB has determined...

  7. 29 CFR 502.44 - Additional information, if required.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... ENFORCEMENT OF CONTRACTUAL OBLIGATIONS FOR TEMPORARY ALIEN AGRICULTURAL WORKERS ADMITTED UNDER SECTION 218 OF... Administrative Law Judge's Decision § 502.44 Additional information, if required. Where the ARB has determined...

  8. 29 CFR 502.44 - Additional information, if required.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... ENFORCEMENT OF CONTRACTUAL OBLIGATIONS FOR TEMPORARY ALIEN AGRICULTURAL WORKERS ADMITTED UNDER SECTION 218 OF... Administrative Law Judge's Decision § 502.44 Additional information, if required. Where the ARB has determined...

  9. A Mechanistic Understanding of a Binary Additive System to Synergistically Boost Efficiency in All-Polymer Solar Cells

    PubMed Central

    Kim, Yu Jin; Ahn, Sunyong; Wang, Dong Hwan; Park, Chan Eon

    2015-01-01

    All-polymer solar cells are herein presented utilizing the PBDTTT-CT donor and the P(NDI2OD-T2) acceptor with 1,8-diiodooctane (DIO) and 1-chloronaphthalene (CN) binary solvent additives. A systematic study of the polymer/polymer bulk heterojunction photovoltaic cells processed from the binary additives revealed that the microstructures and photophysics were quite different from those of a pristine system. The combination of DIO and CN with a DIO/CN ratio of 3:1 (3 vol% DIO, 1 vol% CN and 96 vol% o-DCB) led to suitable penetrating polymer networks, efficient charge generation and balanced charge transport, which were all beneficial to improving the efficiency. This improvement is attributed to increase in power conversion efficiency from 2.81% for a device without additives to 4.39% for a device with the binary processing additives. A detailed investigation indicates that the changes in the polymer:polymer interactions resulted in the formation of a percolating nasnoscale morphology upon processing with the binary additives. Depth profile measurements with a two-dimensional grazing incidence wide-angle X-ray scattering confirm this optimum phase feature. Furthermore impedance spectroscopy also finds evidence for synergistically boosting the device performance. PMID:26658472

  10. A Mechanistic Understanding of a Binary Additive System to Synergistically Boost Efficiency in All-Polymer Solar Cells

    NASA Astrophysics Data System (ADS)

    Kim, Yu Jin; Ahn, Sunyong; Wang, Dong Hwan; Park, Chan Eon

    2015-12-01

    All-polymer solar cells are herein presented utilizing the PBDTTT-CT donor and the P(NDI2OD-T2) acceptor with 1,8-diiodooctane (DIO) and 1-chloronaphthalene (CN) binary solvent additives. A systematic study of the polymer/polymer bulk heterojunction photovoltaic cells processed from the binary additives revealed that the microstructures and photophysics were quite different from those of a pristine system. The combination of DIO and CN with a DIO/CN ratio of 3:1 (3 vol% DIO, 1 vol% CN and 96 vol% o-DCB) led to suitable penetrating polymer networks, efficient charge generation and balanced charge transport, which were all beneficial to improving the efficiency. This improvement is attributed to increase in power conversion efficiency from 2.81% for a device without additives to 4.39% for a device with the binary processing additives. A detailed investigation indicates that the changes in the polymer:polymer interactions resulted in the formation of a percolating nasnoscale morphology upon processing with the binary additives. Depth profile measurements with a two-dimensional grazing incidence wide-angle X-ray scattering confirm this optimum phase feature. Furthermore impedance spectroscopy also finds evidence for synergistically boosting the device performance.

  11. A Mechanistic Understanding of a Binary Additive System to Synergistically Boost Efficiency in All-Polymer Solar Cells.

    PubMed

    Kim, Yu Jin; Ahn, Sunyong; Wang, Dong Hwan; Park, Chan Eon

    2015-12-11

    All-polymer solar cells are herein presented utilizing the PBDTTT-CT donor and the P(NDI2OD-T2) acceptor with 1,8-diiodooctane (DIO) and 1-chloronaphthalene (CN) binary solvent additives. A systematic study of the polymer/polymer bulk heterojunction photovoltaic cells processed from the binary additives revealed that the microstructures and photophysics were quite different from those of a pristine system. The combination of DIO and CN with a DIO/CN ratio of 3:1 (3 vol% DIO, 1 vol% CN and 96 vol% o-DCB) led to suitable penetrating polymer networks, efficient charge generation and balanced charge transport, which were all beneficial to improving the efficiency. This improvement is attributed to increase in power conversion efficiency from 2.81% for a device without additives to 4.39% for a device with the binary processing additives. A detailed investigation indicates that the changes in the polymer:polymer interactions resulted in the formation of a percolating nasnoscale morphology upon processing with the binary additives. Depth profile measurements with a two-dimensional grazing incidence wide-angle X-ray scattering confirm this optimum phase feature. Furthermore impedance spectroscopy also finds evidence for synergistically boosting the device performance.

  12. Mechanistically-informed damage detection using dynamic measurements: Extended constitutive relation error

    NASA Astrophysics Data System (ADS)

    Hu, X.; Prabhu, S.; Atamturktur, S.; Cogan, S.

    2017-02-01

    Model-based damage detection entails the calibration of damage-indicative parameters in a physics-based computer model of an undamaged structural system against measurements collected from its damaged counterpart. The approach relies on the premise that changes identified in the damage-indicative parameters during calibration reveal the structural damage in the system. In model-based damage detection, model calibration has traditionally been treated as a process, solely operating on the model output without incorporating available knowledge regarding the underlying mechanistic behavior of the structural system. In this paper, the authors propose a novel approach for model-based damage detection by implementing the Extended Constitutive Relation Error (ECRE), a method developed for error localization in finite element models. The ECRE method was originally conceived to identify discrepancies between experimental measurements and model predictions for a structure in a given healthy state. Implementing ECRE for damage detection leads to the evaluation of a structure in varying healthy states and determination of discrepancy between model predictions and experiments due to damage. The authors developed an ECRE-based damage detection procedure in which the model error and structural damage are identified in two distinct steps and demonstrate feasibility of the procedure in identifying the presence, location and relative severity of damage on a scaled two-story steel frame for damage scenarios of varying type and severity.

  13. 21 CFR 71.4 - Samples; additional information.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Samples; additional information. 71.4 Section 71.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL COLOR... samples of the color additive, articles used as components thereof, or of the food, drug, or cosmetic...

  14. 21 CFR 71.4 - Samples; additional information.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Samples; additional information. 71.4 Section 71.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL COLOR... samples of the color additive, articles used as components thereof, or of the food, drug, or cosmetic...

  15. Fundamental Mechanistic Investigations of Silane and Chlorocarbon Addition to Low Valent Palladium Species and their Application to Catalysis

    SciTech Connect

    Fink, Mark J.

    2009-01-27

    The collaboration between Mark Fink (Tulane University) and R. Morris Bullock (Brookhaven National Laboratory, currently at PNL) is an effort to understand some of the fundamental processes involved in catalytic bond activations with low coordinate palladium species. The project involves the photochemical generation of reactive low-valent palladium species as transients using nanosecond laser flash photolysis and the subsequent investigation of their reactions with chloroarenes and hydrosilanes. In the case of Si-H activation of hydrosilanes, relatively long-lived sigma complexes are implicated. These complexes may be important models for C-H activation in hydrocarbons. The information obtained from these studies will help in the understanding of fundamental processes involved in a number of important catalytic reactions in the petrochemical and environmental areas.

  16. Traveling-wave Ion Mobility-Mass Spectrometry Reveals Additional Mechanistic Details in the Stabilization of Protein Complex Ions through Tuned Salt Additives

    PubMed Central

    Han, Linjie; Ruotolo, Brandon T.

    2013-01-01

    Ion mobility–mass spectrometry is often applied to the structural elucidation of multiprotein assemblies in cases where X-ray crystallography or NMR experiments have proved challenging. Such applications are growing steadily as we continue to probe regions of the proteome that are less-accessible to such high-resolution structural biology tools. Since ion mobility measures protein structure in the absence of bulk solvent, strategies designed to more-broadly stabilize native-like protein structures in the gas-phase would greatly enable the application of such measurements to challenging structural targets. Recently, we have begun investigating the ability of salt-based solution additives that remain bound to protein ions in the gas-phase to stabilize native-like protein structures. These experiments, which utilize collision induced unfolding and collision induced dissociation in a tandem mass spectrometry mode to measure protein stability, seek to develop a rank-order similar to the Hofmeister series that categorizes the general ability of different anions and cations to stabilize gas-phase protein structure. Here, we study magnesium chloride as a potential stabilizing additive for protein structures in vacuo, and find that the addition of this salt to solutions prior to nano-electrospray ionization dramatically enhances multiprotein complex structural stability in the gas-phase. Based on these experiments, we also refine the physical mechanism of cation-based protein complex ion stabilization by tracking the unfolding transitions experienced by cation-bound complexes. Upon comparison with unbound proteins, we find strong evidence that stabilizing cations act to tether protein complex structure. We conclude by putting the results reported here in context, and by projecting the future applications of this method. PMID:23539363

  17. Indium-mediated asymmetric Barbier-type propargylations: additions to aldehydes and ketones and mechanistic investigation of the organoindium reagents.

    PubMed

    Haddad, Terra D; Hirayama, Lacie C; Buckley, Jannise J; Singaram, Bakthan

    2012-01-20

    We report a simple, efficient, and general method for the indium-mediated enantioselective propargylation of aromatic and aliphatic aldehydes under Barbier-type conditions in a one-pot synthesis affording the corresponding chiral alcohol products in very good yield (up to 90%) and enantiomeric excess (up to 95%). The extension of this methodology to ketones demonstrated the need for electrophilic ketones more reactive than acetophenone as the reaction would not proceed with just acetophenone. Using the Lewis acid indium triflate [In(OTf)(3)] induced regioselective formation of the corresponding homoallenic alcohol product from acetophenone. However, this methodology demonstrated excellent chemoselectivity in formation of only the corresponding secondary homopropargylic alcohol product in the presence of a ketone functionality. Investigation of the organoindium intermediates under our reaction conditions shows the formation of allenylindium species, and we suggest that these species contain an indium(III) center. In addition, we have observed the presence of a shiny, indium(0) nugget throughout the reaction, irrespective of the stoichiometry, indicating disproportionation of indium halide byproduct formed during the reaction.

  18. Phorbol ester and A23187 have additive but mechanistically separate effects on vasopressin action in rabbit collecting tubule.

    PubMed Central

    Ando, Y; Jacobson, H R; Breyer, M D

    1988-01-01

    AVP on CCT at 37 degrees C. (b) When stimulated simultaneously these two intracellular mediators are additive in their antagonism of AVP action. These results suggest that stimulated PIP2 breakdown may be an important modulator of water transport in CCT. (c) Different mechanisms underlie PKC and Ca-mediated suppression of the AVP-induced water transport. The inhibition of AVP action by increased [Ca++]i is primarily pre-cAMP, and involves a cyclooxygenase metabolite(s) of arachidonic acid, while the inhibition by PKC is post-cAMP, and independent of cyclooxygenase products of arachidonic acid. Images PMID:3130397

  19. 25 CFR 227.7 - Additional information from applicant.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Additional information from applicant. 227.7 Section 227.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR ENERGY AND MINERALS LEASING OF CERTAIN LANDS IN WIND RIVER INDIAN RESERVATION, WYOMING, FOR OIL AND GAS MINING How to Acquire...

  20. 25 CFR 227.7 - Additional information from applicant.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Additional information from applicant. 227.7 Section 227.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR ENERGY AND MINERALS LEASING OF CERTAIN LANDS IN WIND RIVER INDIAN RESERVATION, WYOMING, FOR OIL AND GAS MINING How to Acquire Leases §...

  1. 25 CFR 227.7 - Additional information from applicant.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Additional information from applicant. 227.7 Section 227.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR ENERGY AND MINERALS LEASING OF CERTAIN LANDS IN WIND RIVER INDIAN RESERVATION, WYOMING, FOR OIL AND GAS MINING How to Acquire...

  2. 25 CFR 215.17 - Additional information required.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Additional information required. 215.17 Section 215.17 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR ENERGY AND MINERALS LEAD AND ZINC MINING... interested in lead and zinc mining leases, or land under the jurisdiction of the Quapaw Indian Agency,...

  3. 38 CFR 39.3 - Decisionmakers, notifications, and additional information.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Decisionmakers, notifications, and additional information. 39.3 Section 39.3 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) AID TO STATES FOR ESTABLISHMENT, EXPANSION, AND IMPROVEMENT...

  4. 25 CFR 227.7 - Additional information from applicant.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Additional information from applicant. 227.7 Section 227.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR ENERGY AND MINERALS LEASING OF CERTAIN LANDS IN WIND RIVER INDIAN RESERVATION, WYOMING, FOR OIL AND GAS MINING How to Acquire...

  5. 25 CFR 227.7 - Additional information from applicant.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Additional information from applicant. 227.7 Section 227.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR ENERGY AND MINERALS LEASING OF CERTAIN LANDS IN WIND RIVER INDIAN RESERVATION, WYOMING, FOR OIL AND GAS MINING How to Acquire...

  6. 21 CFR 207.31 - Additional drug listing information.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Additional drug listing information. 207.31 Section 207.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL...

  7. 21 CFR 207.31 - Additional drug listing information.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Additional drug listing information. 207.31 Section 207.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL...

  8. 21 CFR 207.31 - Additional drug listing information.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Additional drug listing information. 207.31 Section 207.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL...

  9. 29 CFR 2570.39 - Opportunities to submit additional information.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Opportunities to submit additional information. 2570.39 Section 2570.39 Labor Regulations Relating to Labor (Continued) EMPLOYEE BENEFITS SECURITY ADMINISTRATION, DEPARTMENT OF LABOR ADMINISTRATION AND ENFORCEMENT UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF...

  10. 29 CFR 2570.39 - Opportunities to submit additional information.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 9 2013-07-01 2013-07-01 false Opportunities to submit additional information. 2570.39 Section 2570.39 Labor Regulations Relating to Labor (Continued) EMPLOYEE BENEFITS SECURITY ADMINISTRATION, DEPARTMENT OF LABOR ADMINISTRATION AND ENFORCEMENT UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF...

  11. 29 CFR 2570.39 - Opportunities to submit additional information.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 9 2012-07-01 2012-07-01 false Opportunities to submit additional information. 2570.39 Section 2570.39 Labor Regulations Relating to Labor (Continued) EMPLOYEE BENEFITS SECURITY ADMINISTRATION, DEPARTMENT OF LABOR ADMINISTRATION AND ENFORCEMENT UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF...

  12. 43 CFR 3922.30 - Application-Additional information.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 2 2014-10-01 2014-10-01 false Application-Additional information. 3922.30 Section 3922.30 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) OIL SHALE LEASING...

  13. 43 CFR 3922.30 - Application-Additional information.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 2 2011-10-01 2011-10-01 false Application-Additional information. 3922.30 Section 3922.30 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR RANGE MANAGEMENT (4000) OIL SHALE LEASING...

  14. 43 CFR 3922.30 - Application-Additional information.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 2 2012-10-01 2012-10-01 false Application-Additional information. 3922.30 Section 3922.30 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) OIL SHALE LEASING...

  15. 43 CFR 3922.30 - Application-Additional information.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 2 2013-10-01 2013-10-01 false Application-Additional information. 3922.30 Section 3922.30 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) OIL SHALE LEASING...

  16. 46 CFR 535.606 - Requests for additional information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 9 2010-10-01 2010-10-01 false Requests for additional information. 535.606 Section 535.606 Shipping FEDERAL MARITIME COMMISSION REGULATIONS AFFECTING OCEAN SHIPPING IN FOREIGN COMMERCE OCEAN COMMON CARRIER AND MARINE TERMINAL OPERATOR AGREEMENTS SUBJECT TO THE SHIPPING ACT OF 1984...

  17. Censored data treatment using additional information in intelligent medical systems

    NASA Astrophysics Data System (ADS)

    Zenkova, Z. N.

    2015-11-01

    Statistical procedures are a very important and significant part of modern intelligent medical systems. They are used for proceeding, mining and analysis of different types of the data about patients and their diseases; help to make various decisions, regarding the diagnosis, treatment, medication or surgery, etc. In many cases the data can be censored or incomplete. It is a well-known fact that censorship considerably reduces the efficiency of statistical procedures. In this paper the author makes a brief review of the approaches which allow improvement of the procedures using additional information, and describes a modified estimation of an unknown cumulative distribution function involving additional information about a quantile which is known exactly. The additional information is used by applying a projection of a classical estimator to a set of estimators with certain properties. The Kaplan-Meier estimator is considered as an estimator of the unknown cumulative distribution function, the properties of the modified estimator are investigated for a case of a single right censorship by means of simulations.

  18. To be or not to be butterfly: New mechanistic insights in the Aza-Michael asymmetric addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide.

    PubMed

    Nieto, Carlos T; Díez, David; Garrido, Narciso M

    2014-09-30

    The asymmetric Aza-Michael addition of homochiral lithium benzylamides to α,β-unsaturated esters represents an extended protocol to obtain enantioenriched β-amino esters. An exhaustive mechanistic revision of the originally proposed mechanism is reported, developing a quantum mechanics/molecular mechanics protocol for the asymmetric Aza-Michael reaction of homochiral lithium benzylamides. Explicit and implicit solvent schemes were considered, together with a proper account of long-range dispersion forces, evaluated through a density functional theory benchmark of different functionals. Theoretical results showed that the diastereoselectivity is mainly controlled by the N-α-methylbenzyl moiety placing, deriving a Si/Re 99:1 diastereoselective ratio, in good agreement with reported experimental results. The main transition state geometries are two transition state conformers in a "V-stacked" orientation of the amide's phenyl rings, differing in the tetrahydrofuran molecule arrangement coordinated to the metal center. Extensive conformational sampling and quantum-level refinement give reasonable good speed/accuracy results, allowing this protocol to be extended to other similar Aza-Michael reaction systems.

  19. Progress in the experimental observation of thiamin diphosphate-bound intermediates on enzymes and mechanistic information derived from these observations.

    PubMed

    Jordan, Frank; Nemeria, Natalia S

    2014-12-01

    Thiamin diphosphate (ThDP), the vitamin B1 coenzyme is an excellent representative of coenzymes, which carry out electrophilic catalysis by forming a covalent complex with their substrates. The function of ThDP is to greatly increase the acidity of two carbon acids by stabilizing their conjugate bases, the ylide/carbene/C2-carbanion of the thiazolium ring and the C2α-carbanion/enamine, once the substrate binds to ThDP. In recent years, several ThDP-bound intermediates on such pathways have been characterized by both solution and solid-state methods. Prominent among these advances are X-ray crystallographic results identifying both oxidative and non-oxidative intermediates, rapid chemical quench followed by NMR detection of several intermediates which are stable under acidic conditions, solid-state NMR and circular dichroism detection of the states of ionization and tautomerization of the 4'-aminopyrimidine moiety of ThDP in some of the intermediates. These methods also enabled in some cases determination of the rate-limiting step in the complex series of steps. This review is an update of a review with the same title published by the authors in 2005 in this Journal. Much progress has been made in the intervening decade in the identification of the intermediates and their application to gain additional mechanistic insight.

  20. How to retrieve additional information from the multiplicity distributions

    NASA Astrophysics Data System (ADS)

    Wilk, Grzegorz; Włodarczyk, Zbigniew

    2017-01-01

    Multiplicity distributions (MDs) P(N) measured in multiparticle production processes are most frequently described by the negative binomial distribution (NBD). However, with increasing collision energy some systematic discrepancies have become more and more apparent. They are usually attributed to the possible multi-source structure of the production process and described using a multi-NBD form of the MD. We investigate the possibility of keeping a single NBD but with its parameters depending on the multiplicity N. This is done by modifying the widely known clan model of particle production leading to the NBD form of P(N). This is then confronted with the approach based on the so-called cascade-stochastic formalism which is based on different types of recurrence relations defining P(N). We demonstrate that a combination of both approaches allows the retrieval of additional valuable information from the MDs, namely the oscillatory behavior of the counting statistics apparently visible in the high energy data.

  1. 31 CFR 26.5 - Upgrades and additional environmental information.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., such environmental information from the MDB (e.g., environmental chapters from project feasibility studies or environmental data sheets) which contains this environmental analysis. The MDB Office...

  2. 76 FR 34639 - Notice of Proposed Additional Information Collection: Advisory Committee and Research and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-14

    ... Notice of Proposed Additional Information Collection: Advisory Committee and Research and Promotion... approved information collection of the Advisory Committee and Research and Promotion Background Information... . SUPPLEMENTARY INFORMATION: Title: Advisory Committee and Research and Promotion Background Information....

  3. 10 CFR 1.3 - Sources of additional information.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... fall within an exemption to the Act's openness requirement and the Commission also has determined that... availability of NRC records under the Freedom of Information Act and Privacy Act of 1974 may be obtained...

  4. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  5. 77 FR 39573 - Additional Identifying Information Associated With Persons Whose Property and Interests in...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-03

    ... Office of Foreign Assets Control Additional Identifying Information Associated With Persons Whose... Treasury's Office of Foreign Assets Control (``OFAC'') is publishing additional indentifying information... on June 1, 2012. FOR FURTHER INFORMATION CONTACT: Assistant Director, Sanctions...

  6. A Mechanistically Informed User-Friendly Model to Predict Greenhouse Gas (GHG) Fluxes and Carbon Storage from Coastal Wetlands

    NASA Astrophysics Data System (ADS)

    Abdul-Aziz, O. I.; Ishtiaq, K. S.

    2015-12-01

    We present a user-friendly modeling tool on MS Excel to predict the greenhouse gas (GHG) fluxes and estimate potential carbon sequestration from the coastal wetlands. The dominant controls of wetland GHG fluxes and their relative mechanistic linkages with various hydro-climatic, sea level, biogeochemical and ecological drivers were first determined by employing a systematic data-analytics method, including Pearson correlation matrix, principal component and factor analyses, and exploratory partial least squares regressions. The mechanistic knowledge and understanding was then utilized to develop parsimonious non-linear (power-law) models to predict wetland carbon dioxide (CO2) and methane (CH4) fluxes based on a sub-set of climatic, hydrologic and environmental drivers such as the photosynthetically active radiation, soil temperature, water depth, and soil salinity. The models were tested with field data for multiple sites and seasons (2012-13) collected from the Waquoit Bay, MA. The model estimated the annual wetland carbon storage by up-scaling the instantaneous predicted fluxes to an extended growing season (e.g., May-October) and by accounting for the net annual lateral carbon fluxes between the wetlands and estuary. The Excel Spreadsheet model is a simple ecological engineering tool for coastal carbon management and their incorporation into a potential carbon market under a changing climate, sea level and environment. Specifically, the model can help to determine appropriate GHG offset protocols and monitoring plans for projects that focus on tidal wetland restoration and maintenance.

  7. 40 CFR 141.154 - Required additional health information.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Hotline (800-426-4791). (b) Ending in the report due by July 1, 2001, a system which detects arsenic at... system that detects arsenic above 0.005 mg/L and up to and including 0.010 mg/L: (1) Must include in its report a short informational statement about arsenic, using language such as: While your drinking...

  8. 40 CFR 141.154 - Required additional health information.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Hotline (800-426-4791). (b) Ending in the report due by July 1, 2001, a system which detects arsenic at... system that detects arsenic above 0.005 mg/L and up to and including 0.010 mg/L: (1) Must include in its report a short informational statement about arsenic, using language such as: While your drinking...

  9. 40 CFR 141.154 - Required additional health information.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... consultation with the Primacy Agency. (c) A system which detects nitrate at levels above 5 mg/l, but below the MCL: (1) Must include a short informational statement about the impacts of nitrate on children using language such as: Nitrate in drinking water at levels above 10 ppm is a health risk for infants of...

  10. 40 CFR 141.154 - Required additional health information.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... consultation with the Primacy Agency. (c) A system which detects nitrate at levels above 5 mg/l, but below the MCL: (1) Must include a short informational statement about the impacts of nitrate on children using language such as: Nitrate in drinking water at levels above 10 ppm is a health risk for infants of...

  11. 40 CFR 141.154 - Required additional health information.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... consultation with the Primacy Agency. (c) A system which detects nitrate at levels above 5 mg/l, but below the MCL: (1) Must include a short informational statement about the impacts of nitrate on children using language such as: Nitrate in drinking water at levels above 10 ppm is a health risk for infants of...

  12. SNP Markers as Additional Information to Resolve Complex Kinship Cases

    PubMed Central

    Pontes, M. Lurdes; Fondevila, Manuel; Laréu, Maria Victoria; Medeiros, Rui

    2015-01-01

    Summary Background DNA profiling with sets of highly polymorphic autosomal short tandem repeat (STR) markers has been applied in various aspects of human identification in forensic casework for nearly 20 years. However, in some cases of complex kinship investigation, the information provided by the conventionally used STR markers is not enough, often resulting in low likelihood ratio (LR) calculations. In these cases, it becomes necessary to increment the number of loci under analysis to reach adequate LRs. Recently, it has been proposed that single nucleotide polymorphisms (SNPs) could be used as a supportive tool to STR typing, eventually even replacing the methods/markers now employed. Methods In this work, we describe the results obtained in 7 revised complex paternity cases when applying a battery of STRs, as well as 52 human identification SNPs (SNPforID 52plex identification panel) using a SNaPshot methodology followed by capillary electrophoresis. Results Our results show that the analysis of SNPs, as complement to STR typing in forensic casework applications, would at least increase by a factor of 4 total PI values and correspondent Essen-Möller's W value. Conclusions We demonstrated that SNP genotyping could be a key complement to STR information in challenging casework of disputed paternity, such as close relative individualization or complex pedigrees subject to endogamous relations. PMID:26733770

  13. 78 FR 77119 - Proposed Information Collection Request; Comment Request; Regulation of Fuels and Fuel Additives...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-20

    ... AGENCY Proposed Information Collection Request; Comment Request; Regulation of Fuels and Fuel Additives: 2011 Renewable Fuel Standards-- Petition for International Aggregate Compliance Approach AGENCY... to submit an information collection request (ICR), ``Regulation of Fuels and Fuel Additives:...

  14. 30 CFR 75.1200-1 - Additional information on mine map.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Additional information on mine map. 75.1200-1... SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Maps § 75.1200-1 Additional information on mine map. Additional information required to be shown on mine maps under § 75.1200...

  15. 30 CFR 75.1200-1 - Additional information on mine map.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Additional information on mine map. 75.1200-1... SAFETY AND HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Maps § 75.1200-1 Additional information on mine map. Additional information required to be shown on mine maps under § 75.1200...

  16. Oxidative N-Heterocyclic Carbene-Catalyzed γ-Carbon Addition of Enals to Imines: Mechanistic Studies and Access to Antimicrobial Compounds.

    PubMed

    Zheng, Peng-Cheng; Cheng, Jiajia; Su, Shihu; Jin, Zhichao; Wang, Yu-Huang; Yang, Song; Jin, Lin-Hong; Song, Bao-An; Chi, Yonggui Robin

    2015-07-06

    The reaction mechanism of the γ-carbon addition of enal to imine under oxidative N-heterocyclic carbene catalysis is studied experimentally. The oxidation, γ-carbon deprotonation, and nucleophilic addition of γ-carbon to imine were found to be facile steps. The results of our study also provide highly enantioselective access to tricyclic sulfonyl amides that exhibit interesting antimicrobial activities against X. oryzae, a bacterium that causes bacterial disease in rice growing.

  17. Mechanistic implications of the enantioselective addition of alkylzinc reagents to aldehydes catalyzed by nickel complexes with α-amino amide ligands.

    PubMed

    Escorihuela, Jorge; Burguete, M Isabel; Ujaque, Gregori; Lledós, Agustí; Luis, Santiago V

    2016-11-29

    The enantioselective alkylation of aldehydes catalysed by nickel(ii)-complexes derived from α-amino amides was studied by means of density functional theory (DFT) and ONIOM (B3LYP:UFF) calculations. A mechanism was proposed in order to investigate the origin of enantioselectivity. The chirality-determining step for the alkylation was the formation of the intermediate complexes with the involvement of a 5/4/4-fused tricyclic transition state. The predominant products predicted theoretically were of (S)-configuration, in good agreement with experimental observations. The scope of the reaction was examined and high yields and enantioselectivities were observed for the enantioselective addition of Et2Zn and Me2Zn to aromatic and aliphatic aldehydes.

  18. Synthesis of Bridged Heterocycles via Sequential 1,4- and 1,2-Addition Reactions to α,β-Unsaturated N-Acyliminium Ions: Mechanistic and Computational Studies.

    PubMed

    Yazici, Arife; Wille, Uta; Pyne, Stephen G

    2016-02-19

    Novel tricyclic bridged heterocyclic systems can be readily prepared from sequential 1,4- and 1,2-addition reactions of allyl and 3-substituted allylsilanes to indolizidine and quinolizidine α,β-unsaturated N-acyliminium ions. These reactions involve a novel N-assisted, transannular 1,5-hydride shift. Such a mechanism was supported by examining the reaction of a dideuterated indolizidine, α,β-unsaturated N-acyliminium ion precursor, which provided specifically dideuterated tricyclic bridged heterocyclic products, and from computational studies. In contrast, the corresponding pyrrolo[1,2-a]azepine system did not provide the corresponding tricyclic bridged heterocyclic product and gave only a bis-allyl adduct, while more substituted versions gave novel furo[3,2-d]pyrrolo[1,2-a]azepine products. Such heterocyclic systems would be expected to be useful scaffolds for the preparation of libraries of novel compounds for new drug discovery programs.

  19. 49 CFR 260.25 - Additional information for Applicants not having a credit rating.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... prospective traffic base; (3) System-wide plans to maintain equipment and rights-of-way at current or improved... 49 Transportation 4 2014-10-01 2014-10-01 false Additional information for Applicants not having a... Financial Assistance § 260.25 Additional information for Applicants not having a credit rating....

  20. 49 CFR 260.25 - Additional information for Applicants not having a credit rating.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... prospective traffic base; (3) System-wide plans to maintain equipment and rights-of-way at current or improved... 49 Transportation 4 2013-10-01 2013-10-01 false Additional information for Applicants not having a... Financial Assistance § 260.25 Additional information for Applicants not having a credit rating....

  1. 16 CFR 2.20 - Petitions for review of requests for additional information or documentary material.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... additional information or documentary material. 2.20 Section 2.20 Commercial Practices FEDERAL TRADE... material, or recommend such modification to the responsible Assistant Director of the Bureau of Competition... investigation. A request for additional information or documentary material may be modified only in...

  2. 47 CFR 25.111 - Additional information and ITU cost recovery.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 2 2014-10-01 2014-10-01 false Additional information and ITU cost recovery....111 Additional information and ITU cost recovery. (a) The Commission may request from any party at any... interference caused by radio stations authorized by other Administrations is guaranteed unless ITU...

  3. 49 CFR 260.25 - Additional information for Applicants not having a credit rating.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Additional information for Applicants not having a... Financial Assistance § 260.25 Additional information for Applicants not having a credit rating. Each application submitted by Applicants not having a recent credit rating from one or more nationally...

  4. 33 CFR 148.107 - What additional information may be required?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... What additional information may be required? (a) The Commandant (CG-5), in coordination with MARAD, may... analysis, explanation, or other information he or she deems necessary. (b) The Commandant (CG-5) may... (CG-5) may set a deadline for receiving the information. (1) If the applicant states that the...

  5. 33 CFR 148.107 - What additional information may be required?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... What additional information may be required? (a) The Commandant (CG-5), in coordination with MARAD, may... analysis, explanation, or other information he or she deems necessary. (b) The Commandant (CG-5) may... (CG-5) may set a deadline for receiving the information. (1) If the applicant states that the...

  6. 75 FR 77645 - Agency Information Collection Activities; Proposed Collection; Comment Request; Color Additive...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-13

    ... Collection; Comment Request; Color Additive Certification Requests and Recordkeeping AGENCY: Food and Drug... certification of color additives manufactured for use in foods, drugs, cosmetics or medical devices in the... of information technology. Color Additive Certification Requests and Recordkeeping--21 CFR Part...

  7. Defense Health Care: Additional Information Needed about Mental Health Provider Staffing Needs

    DTIC Science & Technology

    2015-01-01

    DEFENSE HEALTH CARE Additional Information Needed about Mental Health Provider Staffing Needs Report to the...REPORT TYPE 3. DATES COVERED 00-00-2015 to 00-00-2015 4. TITLE AND SUBTITLE Defense Health Care: Additional Information Needed about Mental ...Z39-18 Page i GAO-15-184 DOD Mental Health Staffing Letter 1 Background 4 DOD and the Military Services Have Increased the

  8. 78 FR 52803 - Agency Information Collection Activities; Submission for OMB Review; Comment Request; Additional...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-26

    ... OMB under the PRA and displays a currently valid OMB Control Number. In addition, notwithstanding any... collection of information that does not display a valid Control Number. See 5 CFR 1320.5(a) and 1320.6. The DOL obtains OMB approval for this information collection under Control Number 1218-0237....

  9. "The Dose Makes the Poison": Informing Consumers About the Scientific Risk Assessment of Food Additives.

    PubMed

    Bearth, Angela; Cousin, Marie-Eve; Siegrist, Michael

    2016-01-01

    Intensive risk assessment is required before the approval of food additives. During this process, based on the toxicological principle of "the dose makes the poison,ˮ maximum usage doses are assessed. However, most consumers are not aware of these efforts to ensure the safety of food additives and are therefore sceptical, even though food additives bring certain benefits to consumers. This study investigated the effect of a short video, which explains the scientific risk assessment and regulation of food additives, on consumers' perceptions and acceptance of food additives. The primary goal of this study was to inform consumers and enable them to construct their own risk-benefit assessment and make informed decisions about food additives. The secondary goal was to investigate whether people have different perceptions of food additives of artificial (i.e., aspartame) or natural origin (i.e., steviolglycoside). To attain these research goals, an online experiment was conducted on 185 Swiss consumers. Participants were randomly assigned to either the experimental group, which was shown a video about the scientific risk assessment of food additives, or the control group, which was shown a video about a topic irrelevant to the study. After watching the video, the respondents knew significantly more, expressed more positive thoughts and feelings, had less risk perception, and more acceptance than prior to watching the video. Thus, it appears that informing consumers about complex food safety topics, such as the scientific risk assessment of food additives, is possible, and using a carefully developed information video is a successful strategy for informing consumers.

  10. Mechanistic investigations of CO-photoextrusion and oxidative addition reactions of early transition-metal carbonyls: (η(5)-C5H5)M(CO)4 (M = V, Nb, Ta).

    PubMed

    Su, Shih-Hao; Su, Ming-Der

    2016-06-28

    The mechanisms for the photochemical Si-H bond activation reaction are studied theoretically using a model system of the group 5 organometallic compounds, η(5)-CpM(CO)4 (M = V, Nb, and Ta), with the M06-2X method and the Def2-SVPD basis set. Three types of reaction pathways that lead to final insertion products are identified. The structures of the intersystem crossings, which play a central role in these photo-activation reactions, are determined. The intermediates and transitional structures in either the singlet or triplet states are also calculated to provide a mechanistic explanation of the reaction pathways. All of the potential energy surfaces for the group 5 η(5)-CpM(CO)4 complexes are quite similar. In particular, the theoretical evidence suggests that after irradiation using light, η(5)-CpM(CO)4 quickly loses one CO ligand to yield two tricarbonyls, in either the singlet or the triplet states. The triplet tricarbonyl 16-electron intermediates, ([η(5)-CpM(CO)3](3)), play a key role in the formation of the final oxidative addition product, η(5)-CpM(CO)3(H)(SiMe3). However, the singlet counterparts, ([η(5)-CpM(CO)3](1)), play no role in the formation of the final product molecule, but their singlet metal centers interact weakly with solvent molecules ((Me3)SiH) to produce alkyl-solvated organometallic complexes, which are observable experimentally. This theoretical evidence is in accordance with the available experimental observations.

  11. 24 CFR 1710.200 - Instructions for Statement of Record, Additional Information and Documentation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 5 2014-04-01 2014-04-01 false Instructions for Statement of Record, Additional Information and Documentation. 1710.200 Section 1710.200 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued) OFFICE OF ASSISTANT SECRETARY FOR...

  12. 10 CFR 52.158 - Contents of application; additional technical information.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 2 2014-01-01 2014-01-01 false Contents of application; additional technical information. 52.158 Section 52.158 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Manufacturing Licenses § 52.158 Contents of application;...

  13. 10 CFR 52.158 - Contents of application; additional technical information.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 2 2013-01-01 2013-01-01 false Contents of application; additional technical information. 52.158 Section 52.158 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Manufacturing Licenses § 52.158 Contents of application;...

  14. 10 CFR 52.158 - Contents of application; additional technical information.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 2 2012-01-01 2012-01-01 false Contents of application; additional technical information. 52.158 Section 52.158 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Manufacturing Licenses § 52.158 Contents of application;...

  15. 10 CFR 52.158 - Contents of application; additional technical information.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Contents of application; additional technical information. 52.158 Section 52.158 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Manufacturing Licenses § 52.158 Contents of application;...

  16. 10 CFR 52.158 - Contents of application; additional technical information.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 2 2011-01-01 2011-01-01 false Contents of application; additional technical information. 52.158 Section 52.158 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Manufacturing Licenses § 52.158 Contents of application;...

  17. 16 CFR 803.20 - Requests for additional information or documentary material.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Requests for additional information or documentary material. 803.20 Section 803.20 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976...

  18. 16 CFR 803.20 - Requests for additional information or documentary material.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Requests for additional information or documentary material. 803.20 Section 803.20 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976...

  19. 16 CFR 803.20 - Requests for additional information or documentary material.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Requests for additional information or documentary material. 803.20 Section 803.20 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976...

  20. 16 CFR 803.21 - Additional information shall be supplied within reasonable time.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Additional information shall be supplied within reasonable time. 803.21 Section 803.21 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF...

  1. 16 CFR 803.21 - Additional information shall be supplied within reasonable time.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Additional information shall be supplied within reasonable time. 803.21 Section 803.21 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF...

  2. 16 CFR 803.21 - Additional information shall be supplied within reasonable time.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Additional information shall be supplied within reasonable time. 803.21 Section 803.21 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF...

  3. 16 CFR 803.21 - Additional information shall be supplied within reasonable time.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Additional information shall be supplied within reasonable time. 803.21 Section 803.21 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF...

  4. 16 CFR 803.21 - Additional information shall be supplied within reasonable time.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Additional information shall be supplied within reasonable time. 803.21 Section 803.21 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF...

  5. 16 CFR 803.20 - Requests for additional information or documentary material.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Requests for additional information or documentary material. 803.20 Section 803.20 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND INTERPRETATIONS UNDER THE HART-SCOTT-RODINO ANTITRUST IMPROVEMENTS ACT OF 1976...

  6. 18 CFR 33.3 - Additional information requirements for applications involving horizontal competitive impacts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Additional information... and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE... reserve existing transmission capacity needed for native load growth and network transmission...

  7. 18 CFR 33.3 - Additional information requirements for applications involving horizontal competitive impacts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Additional information... and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE... reserve existing transmission capacity needed for native load growth and network transmission...

  8. 18 CFR 33.3 - Additional information requirements for applications involving horizontal competitive impacts.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Additional information... and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE... reserve existing transmission capacity needed for native load growth and network transmission...

  9. 40 CFR Table 42 to Subpart Uuu of... - Additional Information for Initial Notification of Compliance Status

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 13 2012-07-01 2012-07-01 false Additional Information for Initial Notification of Compliance Status 42 Table 42 to Subpart UUU of Part 63 Protection of Environment ENVIRONMENTAL... applicable emission limit and the continuous opacity or that the emission monitoring system meets...

  10. 17 CFR 229.1118 - (Item 1118) Reports and additional information.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false (Item 1118) Reports and additional information. 229.1118 Section 229.1118 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION STANDARD INSTRUCTIONS FOR FILING FORMS UNDER SECURITIES ACT OF 1933, SECURITIES EXCHANGE ACT...

  11. 17 CFR 229.1118 - (Item 1118) Reports and additional information.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 2 2013-04-01 2013-04-01 false (Item 1118) Reports and additional information. 229.1118 Section 229.1118 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION STANDARD INSTRUCTIONS FOR FILING FORMS UNDER SECURITIES ACT OF 1933, SECURITIES EXCHANGE ACT...

  12. 38 CFR 39.4 - Decision makers, notifications, and additional information.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false Decision makers, notifications, and additional information. 39.4 Section 39.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) AID TO STATES FOR ESTABLISHMENT, EXPANSION, AND IMPROVEMENT,...

  13. 38 CFR 39.4 - Decision makers, notifications, and additional information.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2012-07-01 2012-07-01 false Decision makers, notifications, and additional information. 39.4 Section 39.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) AID FOR THE ESTABLISHMENT, EXPANSION, AND IMPROVEMENT, OR...

  14. 38 CFR 39.4 - Decision makers, notifications, and additional information.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2013-07-01 2013-07-01 false Decision makers, notifications, and additional information. 39.4 Section 39.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) AID FOR THE ESTABLISHMENT, EXPANSION, AND IMPROVEMENT, OR...

  15. 38 CFR 39.4 - Decision makers, notifications, and additional information.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2014-07-01 2014-07-01 false Decision makers, notifications, and additional information. 39.4 Section 39.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) AID FOR THE ESTABLISHMENT, EXPANSION, AND IMPROVEMENT, OR...

  16. 30 CFR 250.418 - What additional information must I submit with my APD?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Applying for A Permit to Drill § 250.418 What additional information must I submit with my APD? You must include the following with the APD: (a) Rated capacities of the drilling...

  17. 30 CFR 250.418 - What additional information must I submit with my APD?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Applying for A Permit to Drill § 250.418 What additional information must I submit with my APD? You must include the following with the APD: (a) Rated capacities of the drilling...

  18. 30 CFR 250.418 - What additional information must I submit with my APD?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Applying for A Permit to Drill § 250.418 What additional information must I submit with my APD? You must include the following with the APD: (a) Rated capacities of the drilling...

  19. 30 CFR 250.418 - What additional information must I submit with my APD?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Applying for A Permit to Drill § 250.418 What additional information must I submit with my APD? You must include the following with the APD: (a) Rated capacities of the drilling rig and...

  20. 38 CFR 61.15 - Capital grants-obtaining additional information and awarding capital grants.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2013-07-01 2013-07-01 false Capital grants-obtaining additional information and awarding capital grants. 61.15 Section 61.15 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) VA HOMELESS PROVIDERS GRANT AND PER DIEM...

  1. 38 CFR 61.15 - Obtaining additional information and awarding capital grants.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2012-07-01 2012-07-01 false Obtaining additional information and awarding capital grants. 61.15 Section 61.15 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) VA HOMELESS PROVIDERS GRANT AND PER DIEM PROGRAM § 61.15...

  2. 38 CFR 61.15 - Obtaining additional information and awarding capital grants.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false Obtaining additional information and awarding capital grants. 61.15 Section 61.15 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) VA HOMELESS PROVIDERS GRANT AND PER DIEM PROGRAM § 61.15...

  3. 38 CFR 61.15 - Capital grants-obtaining additional information and awarding capital grants.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2014-07-01 2014-07-01 false Capital grants-obtaining additional information and awarding capital grants. 61.15 Section 61.15 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) VA HOMELESS PROVIDERS GRANT AND PER DIEM...

  4. 18 CFR 33.4 - Additional information requirements for applications involving vertical competitive impacts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Additional information... and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE... entities that provides inputs to electricity products and one or more merging entities that...

  5. 18 CFR 33.4 - Additional information requirements for applications involving vertical competitive impacts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Additional information... and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE... entities that provides inputs to electricity products and one or more merging entities that...

  6. 18 CFR 33.4 - Additional information requirements for applications involving vertical competitive impacts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Additional information... and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE... entities that provides inputs to electricity products and one or more merging entities that...

  7. PAT-1 safety analysis report addendum author responses to request for additional information.

    SciTech Connect

    Weiner, Ruth F.; Schmale, David T.; Kalan, Robert J.; Akin, Lili A.; Miller, David Russell; Knorovsky, Gerald Albert; Yoshimura, Richard Hiroyuki; Lopez, Carlos; Harding, David Cameron; Jones, Perry L.; Morrow, Charles W.

    2010-09-01

    The Plutonium Air Transportable Package, Model PAT-1, is certified under Title 10, Code of Federal Regulations Part 71 by the U.S. Nuclear Regulatory Commission (NRC) per Certificate of Compliance (CoC) USA/0361B(U)F-96 (currently Revision 9). The National Nuclear Security Administration (NNSA) submitted SAND Report SAND2009-5822 to NRC that documented the incorporation of plutonium (Pu) metal as a new payload for the PAT-1 package. NRC responded with a Request for Additional Information (RAI), identifying information needed in connection with its review of the application. The purpose of this SAND report is to provide the authors responses to each RAI. SAND Report SAND2010-6106 containing the proposed changes to the Addendum is provided separately.

  8. 41 CFR 102-79.111 - Where may Executive agencies find additional information on Integrated Workplace concepts?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... agencies find additional information on Integrated Workplace concepts? 102-79.111 Section 102-79.111 Public... Space Integrated Workplace § 102-79.111 Where may Executive agencies find additional information on Integrated Workplace concepts? The GSA Office of Governmentwide Policy provides additional guidance in...

  9. 41 CFR 102-79.111 - Where may Executive agencies find additional information on Integrated Workplace concepts?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... agencies find additional information on Integrated Workplace concepts? 102-79.111 Section 102-79.111 Public... Space Integrated Workplace § 102-79.111 Where may Executive agencies find additional information on Integrated Workplace concepts? The GSA Office of Governmentwide Policy provides additional guidance in...

  10. 41 CFR 102-79.111 - Where may Executive agencies find additional information on Integrated Workplace concepts?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... agencies find additional information on Integrated Workplace concepts? 102-79.111 Section 102-79.111 Public... Space Integrated Workplace § 102-79.111 Where may Executive agencies find additional information on Integrated Workplace concepts? The GSA Office of Governmentwide Policy provides additional guidance in...

  11. 41 CFR 102-79.111 - Where may Executive agencies find additional information on Integrated Workplace concepts?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... agencies find additional information on Integrated Workplace concepts? 102-79.111 Section 102-79.111 Public... Space Integrated Workplace § 102-79.111 Where may Executive agencies find additional information on Integrated Workplace concepts? The GSA Office of Governmentwide Policy provides additional guidance in...

  12. Dehydrofluorination of Hydrofluorocarbons by Titanium Alkylidynes via Sequential C-H/C-F Bond Activation Reactions. A Synthetic, Structural, and Mechanistic Study of 1,2-CH Bond Addition and [beta]-Fluoride Elimination

    SciTech Connect

    Fout, A.R.; Scott, J.; Miller, D.L.; Bailey, B.C.; Pink, M.; Mindiola, D.J.

    2009-01-07

    The neopentylidene-neopentyl complex (PNP)Ti=CH{sup t}Bu(CH{sub 2}{sup t}Bu) (1); (PNP{sup -} = N[2-P(CHMe{sub 2}){sub 2}-4-methylphenyl]{sub 2}) extrudes neopentane in neat fluorobenzene under mild conditions (25 C) to generate the transient titanium alkylidyne (PNP)Ti-C{sup t}Bu (A), which subsequently undergoes regioselective 1,2-CH bond addition of a fluorobenzene across the Ti-C linkage to generate (PNP)Ti=CH{sup t}Bu(o-FC{sub 6}H{sub 4}) (2). Kinetic and mechanistic studies suggest that the C-H activation process is pseudo-first-order in titanium, with the {alpha}-hydrogen abstraction being the rate-determining step and the post-rate-determining step being the C-H bond activation of fluorobenzene. At 100 C complex 2 does not equilibrate back to A and the preference for C-H activation in benzene versus fluorobenzene is 2:3, respectively. Compound 1 also reacts readily, and in most cases cleanly, with a series of hydrofluoroarenes (HAr{sub F}), to form a family of alkylidene-arylfluoride derivatives of the type (PNP)Ti=CH{sup t}Bu(Ar{sub F}). Thermolysis of the latter compounds generates the titanium alkylidene-fluoride (PNP)Ti=CH{sup t}Bu(F) (14) by a {beta}-fluoride elimination, concurrent with formation of o-benzyne. {beta}-Fluoride elimination to yield 14 occurs from 2 under elevated temperatures with k{sub average} = 4.96(16) x 10{sup -5} s{sup -1} and with activation parameters {Delta}H{sub {-+}} = 29(1) kcal/mol and {Delta}S{sub {-+}} = -3(4) cal/mol {center_dot}K. It was found that {beta}-fluoride elimination is accelerated when electron-rich groups are adjacent to the fluoride group, thus implying that a positive charge buildup at the arylfluoride ring occurs in the activated complex of 2. The alkylidene derivative (PNP)Ti=CHSiMe{sub 3}(CH{sub 2}SiMe{sub 3}) (15) also undergoes {alpha}-hydrogen abstraction to form the putative (PNP)Ti'-CSiMe{sub 3} (B) at higher temperatures (>70 C) and dehydrofluorinates the same series of HArF when the reaction

  13. Emerging Technologies in the Built Environment: Geographic Information Science (GIS), 3D Printing, and Additive Manufacturing

    SciTech Connect

    New, Joshua Ryan

    2014-01-01

    Abstract 1: Geographic information systems emerged as a computer application in the late 1960s, led in part by projects at ORNL. The concept of a GIS has shifted through time in response to new applications and new technologies, and is now part of a much larger world of geospatial technology. This presentation discusses the relationship of GIS and estimating hourly and seasonal energy consumption profiles in the building sector at spatial scales down to the individual parcel. The method combines annual building energy simulations for city-specific prototypical buildings and commonly available geospatial data in a GIS framework. Abstract 2: This presentation focuses on 3D printing technologies and how they have rapidly evolved over the past couple of years. At a basic level, 3D printing produces physical models quickly and easily from 3D CAD, BIM (Building Information Models), and other digital data. Many AEC firms have adopted 3D printing as part of commercial building design development and project delivery. This presentation includes an overview of 3D printing, discusses its current use in building design, and talks about its future in relation to the HVAC industry. Abstract 3: This presentation discusses additive manufacturing and how it is revolutionizing the design of commercial and residential facilities. Additive manufacturing utilizes a broad range of direct manufacturing technologies, including electron beam melting, ultrasonic, extrusion, and laser metal deposition for rapid prototyping. While there is some overlap with the 3D printing talk, this presentation focuses on the materials aspect of additive manufacturing and also some of the more advanced technologies involved with rapid prototyping. These technologies include design of carbon fiber composites, lightweight metals processing, transient field processing, and more.

  14. Prepositioned Stocks: Additional Information and a Consistent Definition Would Make DOD’s Annual Report More Useful

    DTIC Science & Technology

    2015-06-01

    PREPOSITIONED STOCKS Additional Information and a Consistent Definition Would Make DOD’s Annual Report More Useful...COVERED 00-00-2015 to 00-00-2015 4. TITLE AND SUBTITLE Prepositioned Stocks: Additional Information and a Consistent Definition Would Make DOD’s...STOCKS Additional Information and a Consistent Definition Would Make DOD’s Annual Report More Useful Why GAO Did This Study DOD prepositions stocks

  15. Mechanistic models in computational social science

    NASA Astrophysics Data System (ADS)

    Holme, Petter; Liljeros, Fredrik

    2015-09-01

    Quantitative social science is not only about regression analysis or, in general, data inference. Computer simulations of social mechanisms have an over 60 years long history. They have been used for many different purposes—to test scenarios, to test the consistency of descriptive theories (proof-of-concept models), to explore emergent phenomena, for forecasting, etc. In this essay, we sketch these historical developments, the role of mechanistic models in the social sciences and the influences from the natural and formal sciences. We argue that mechanistic computational models form a natural common ground for social and natural sciences, and look forward to possible future information flow across the social-natural divide.

  16. Food for Thought ... Mechanistic Validation

    PubMed Central

    Hartung, Thomas; Hoffmann, Sebastian; Stephens, Martin

    2013-01-01

    Summary Validation of new approaches in regulatory toxicology is commonly defined as the independent assessment of the reproducibility and relevance (the scientific basis and predictive capacity) of a test for a particular purpose. In large ring trials, the emphasis to date has been mainly on reproducibility and predictive capacity (comparison to the traditional test) with less attention given to the scientific or mechanistic basis. Assessing predictive capacity is difficult for novel approaches (which are based on mechanism), such as pathways of toxicity or the complex networks within the organism (systems toxicology). This is highly relevant for implementing Toxicology for the 21st Century, either by high-throughput testing in the ToxCast/ Tox21 project or omics-based testing in the Human Toxome Project. This article explores the mostly neglected assessment of a test's scientific basis, which moves mechanism and causality to the foreground when validating/qualifying tests. Such mechanistic validation faces the problem of establishing causality in complex systems. However, pragmatic adaptations of the Bradford Hill criteria, as well as bioinformatic tools, are emerging. As critical infrastructures of the organism are perturbed by a toxic mechanism we argue that by focusing on the target of toxicity and its vulnerability, in addition to the way it is perturbed, we can anchor the identification of the mechanism and its verification. PMID:23665802

  17. 77 FR 31068 - Additional Identifying Information Associated With Persons Whose Property and Interests in...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-24

    ... Information Technology AGENCY: Office of Foreign Assets Control, Treasury. ACTION: Notice. SUMMARY: The... Technology,'' whose property and interests in property are blocked. FOR FURTHER INFORMATION CONTACT... Information Technology,'' (the ``Order'') pursuant to, inter alia, the International Emergency Economic...

  18. 77 FR 67655 - Agency Information Collection Activities; Proposed Collection; Comment Request; Food Additive...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-13

    ...) Moderate Category: For a food additive petition without complex chemistry, manufacturing, efficacy, or...) Complex Category: For a food additive petition with complex chemistry, manufacturing, efficacy, and/or... investigational food additive file without complex chemistry, manufacturing, efficacy, or safety issues,...

  19. Systematics of the family Plectopylidae in Vietnam with additional information on Chinese taxa (Gastropoda, Pulmonata, Stylommatophora)

    PubMed Central

    Páll-Gergely, Barna; Hunyadi, András; Ablett, Jonathan; Lương, Hào Văn; Fred Naggs; Asami, Takahiro

    2015-01-01

    Abstract Vietnamese species from the family Plectopylidae are revised based on the type specimens of all known taxa, more than 600 historical non-type museum lots, and almost 200 newly-collected samples. Altogether more than 7000 specimens were investigated. The revision has revealed that species diversity of the Vietnamese Plectopylidae was previously overestimated. Overall, thirteen species names (anterides Gude, 1909, bavayi Gude, 1901, congesta Gude, 1898, fallax Gude, 1909, gouldingi Gude, 1909, hirsuta Möllendorff, 1901, jovia Mabille, 1887, moellendorffi Gude, 1901, persimilis Gude, 1901, pilsbryana Gude, 1901, soror Gude, 1908, tenuis Gude, 1901, verecunda Gude, 1909) were synonymised with other species. In addition to these, Gudeodiscus hemmeni sp. n. and Gudeodiscus messageri raheemi ssp. n. are described from north-western Vietnam. Sixteen species and two subspecies are recognized from Vietnam. The reproductive anatomy of eight taxa is described. Based on anatomical information, Halongella gen. n. is erected to include Plectopylis schlumbergeri and Plectopylis fruhstorferi. Additionally, the genus Gudeodiscus is subdivided into two subgenera (Gudeodiscus and Veludiscus subgen. n.) on the basis of the morphology of the reproductive anatomy and the radula. The Chinese Gudeodiscus phlyarius werneri Páll-Gergely, 2013 is moved to synonymy of Gudeodiscus phlyarius. A spermatophore was found in the organ situated next to the gametolytic sac in one specimen. This suggests that this organ in the Plectopylidae is a diverticulum. Statistically significant evidence is presented for the presence of calcareous hook-like granules inside the penis being associated with the absence of embryos in the uterus in four genera. This suggests that these probably play a role in mating periods before disappearing when embryos develop. Sicradiscus mansuyi is reported from China for the first time. PMID:25632253

  20. 75 FR 78950 - Availability of Additional Information for the Proposed Rulemaking for Colorado's Attainment...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-17

    ... provided, unless the comment includes information claimed to be Confidential Business Information (CBI) or... contact information unless you provide it in the body of your comment. If you send an e-mail comment... information in the body of your comment and with any disk or CD-ROM you submit. If EPA cannot read...

  1. Additional information is not ignored: New evidence for information integration and inhibition in take-the-best decisions.

    PubMed

    Dummel, Sebastian; Rummel, Jan; Voss, Andreas

    2016-01-01

    Ignoring information when making a decision is at the heart of the take-the-best (TTB) strategy, according to which decision makers only consider information about the most valid cue (TTB-relevant) and ignore less valid cues (TTB-irrelevant). Results of four experiments, however, show that participants do not ignore information when cues are easily available (Experiments 1a, 1b, and 3) or when task instructions emphasize decision accuracy (Experiment 2). In all four experiments we found that the consistency between the TTB-relevant cue and a supposedly TTB-irrelevant cue systematically affected decision times and confidence ratings of even those participants whose choices were consistently driven by only the TTB-relevant cue. In Experiments 1a and 1b, we also found that these participants were more likely to ignore information when cues had to be acquired sequentially, suggesting that whether or not participants ignore information depends on information availability. Experiment 2 further showed that different task instructions (emphasizing decision accuracy vs. speed) affect whether or not participants ignore information. Finally, Experiment 3 addressed the question of how participants process information that, according to TTB, is considered irrelevant for their choices. We find first evidence that participants who consistently make choices in line with TTB inhibit information about a TTB-irrelevant cue when this information conflicts with their decisions. Findings are considered and discussed in relation to current models of decision making.

  2. Mechanistic information from volume profiles for water exchange and complex-formation reactions of aquated Ni(II). pH, buffer and medium effects.

    PubMed

    Gazzaz, Hanaa Asaad; Ember, Erika; Zahl, Achim; van Eldik, Rudi

    2009-11-21

    Rate and activation parameters for the complex-formation reaction of Ni(2+) with 4-(2-pyridylazo)-N,N-dimethyl aniline (PADA) were studied as a function of pH in different buffers in both aqueous and sodium dodecyl sulfate (SDS) micelle solutions. In aqueous Tris buffer solution, the forward and backward rate constants increased with increasing pH, while the complex-formation constant decreased due to a larger increase in the backward rate constant. The activation entropy, DeltaS(#), and activation volume, DeltaV(#), changed with increasing pH from positive to negative values, suggesting an apparent changeover from a dissociative to a more associative mechanism. Complex-formation reactions with 2,2'-bipyridine in Tris buffer showed almost no increase in the forward and backward rate constants on increasing the pH, but the DeltaS(#) and DeltaV(#) values became more negative. N-ethylmorpholine buffer showed no pH effect on the rate constants and activation parameters. Water exchange reactions of aquated Ni(2+) were also studied as a function of pH under the same conditions. The reported rate and activation parameters for water exchange in Tris and N-ethylmorpholine buffers are consistent with those found for the complex-formation reactions of Ni(2+) with PADA. The observed pH and buffer effects for both the complex-formation and water exchange reactions of aquated Ni(2+) can be accounted for in terms of the formation of a Ni(2+)-Tris complex in Tris buffer and general base catalysis by the buffer components. In SDS micelle solution, the complex-formation reaction with PADA was much faster than in aqueous solution, but the increase in rate constant with increasing pH was less significant, while DeltaS(#) and DeltaV(#) became more positive, pointing to a more dissociative mechanism. For SDS micelle solutions there was no effect on the water exchange rate constant or activation volume. Mechanistic interpretations are offered for all observed pH, buffer and medium

  3. 40 CFR 79.21 - Information and assurances to be provided by the additive manufacturer.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGISTRATION OF FUELS AND FUEL ADDITIVES Additive... application for registration submitted by the manufacturer of a designated fuel additive shall include the..., percentage by weight, and method of analysis of each element in the additive are required provided,...

  4. Toward mechanistic classification of enzyme functions.

    PubMed

    Almonacid, Daniel E; Babbitt, Patricia C

    2011-06-01

    Classification of enzyme function should be quantitative, computationally accessible, and informed by sequences and structures to enable use of genomic information for functional inference and other applications. Large-scale studies have established that divergently evolved enzymes share conserved elements of structure and common mechanistic steps and that convergently evolved enzymes often converge to similar mechanisms too, suggesting that reaction mechanisms could be used to develop finer-grained functional descriptions than provided by the Enzyme Commission (EC) system currently in use. Here we describe how evolution informs these structure-function mappings and review the databases that store mechanisms of enzyme reactions along with recent developments to measure ligand and mechanistic similarities. Together, these provide a foundation for new classifications of enzyme function.

  5. 40 CFR 79.21 - Information and assurances to be provided by the additive manufacturer.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... fuel additive will be sold, offered for sale, or introduced into commerce, and the fuel additive manufacturer's recommended range of concentration and purpose-in-use for each such type of fuel. (e) Such other... (e) of this section as provided in § 79.5(b). (g) Assurances that the additive manufacturer will...

  6. 36 CFR 1290.2 - Scope of additional records and information.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... describe the agency's: (1) Records policies and schedules; (2) Filing systems and organization; (3) Storage... Act; and (6) Reclassification to a higher level, transfer, destruction, or other information...

  7. Applying mechanistic models in bioprocess development.

    PubMed

    Lencastre Fernandes, Rita; Bodla, Vijaya Krishna; Carlquist, Magnus; Heins, Anna-Lena; Eliasson Lantz, Anna; Sin, Gürkan; Gernaey, Krist V

    2013-01-01

    The available knowledge on the mechanisms of a bioprocess system is central to process analytical technology. In this respect, mechanistic modeling has gained renewed attention, since a mechanistic model can provide an excellent summary of available process knowledge. Such a model therefore incorporates process-relevant input (critical process variables)-output (product concentration and product quality attributes) relations. The model therefore has great value in planning experiments, or in determining which critical process variables need to be monitored and controlled tightly. Mechanistic models should be combined with proper model analysis tools, such as uncertainty and sensitivity analysis. When assuming distributed inputs, the resulting uncertainty in the model outputs can be decomposed using sensitivity analysis to determine which input parameters are responsible for the major part of the output uncertainty. Such information can be used as guidance for experimental work; i.e., only parameters with a significant influence on model outputs need to be determined experimentally. The use of mechanistic models and model analysis tools is demonstrated in this chapter. As a practical case study, experimental data from Saccharomyces cerevisiae fermentations are used. The data are described with the well-known model of Sonnleitner and Käppeli (Biotechnol Bioeng 28:927-937, 1986) and the model is analyzed further. The methods used are generic, and can be transferred easily to other, more complex case studies as well.

  8. 41 CFR 102-75.140 - In addition to the title report, and all necessary environmental information and certifications...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 102-75.140 Public Contracts and Property Management Federal Property Management Regulations System... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false In addition to the title report, and all necessary environmental information and certifications, what information must...

  9. 14 CFR 121.317 - Passenger information requirements, smoking prohibitions, and additional seat belt requirements.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Passenger information requirements, smoking... OPERATIONS Instrument and Equipment Requirements § 121.317 Passenger information requirements, smoking... command. (c) No person may operate an airplane on a flight on which smoking is prohibited by part 252...

  10. 14 CFR 121.317 - Passenger information requirements, smoking prohibitions, and additional seat belt requirements.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Passenger information requirements, smoking... OPERATIONS Instrument and Equipment Requirements § 121.317 Passenger information requirements, smoking... command. (c) No person may operate an airplane on a flight on which smoking is prohibited by part 252...

  11. 14 CFR 121.317 - Passenger information requirements, smoking prohibitions, and additional seat belt requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... prohibitions, and additional seat belt requirements. 121.317 Section 121.317 Aeronautics and Space FEDERAL... prohibitions, and additional seat belt requirements. (a) Except as provided in paragraph (l) of this section... paragraph (l) of this section, the “Fasten Seat Belt” sign shall be turned on during any movement on...

  12. 14 CFR 121.317 - Passenger information requirements, smoking prohibitions, and additional seat belt requirements.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... prohibitions, and additional seat belt requirements. 121.317 Section 121.317 Aeronautics and Space FEDERAL... prohibitions, and additional seat belt requirements. (a) Except as provided in paragraph (l) of this section... paragraph (l) of this section, the “Fasten Seat Belt” sign shall be turned on during any movement on...

  13. 36 CFR 1290.2 - Scope of additional records and information.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... PRESIDENT JOHN F. KENNEDY ASSASSINATION RECORDS COLLECTION ACT OF 1992 (JFK ACT) § 1290.2 Scope of... Act; and (6) Reclassification to a higher level, transfer, destruction, or other information...

  14. 21 CFR 803.12 - Where and how do I submit reports and additional information?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... SERVICES (CONTINUED) MEDICAL DEVICES MEDICAL DEVICE REPORTING General Provisions § 803.12 Where and how do... information required under this part to FDA, CDRH, Medical Device Reporting, P.O. Box 3002, Rockville,...

  15. 21 CFR 803.12 - Where and how do I submit reports and additional information?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... SERVICES (CONTINUED) MEDICAL DEVICES MEDICAL DEVICE REPORTING General Provisions § 803.12 Where and how do... information required under this part to FDA, CDRH, Medical Device Reporting, P.O. Box 3002, Rockville,...

  16. 21 CFR 71.15 - Confidentiality of data and information in color additive petitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... has been abandoned and they no longer represent a trade secret or confidential commercial or financial... studies and tests of a color additive on animals and humans and all studies and tests on a color...

  17. 21 CFR 71.15 - Confidentiality of data and information in color additive petitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... has been abandoned and they no longer represent a trade secret or confidential commercial or financial... studies and tests of a color additive on animals and humans and all studies and tests on a color...

  18. 21 CFR 71.15 - Confidentiality of data and information in color additive petitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... established in § 20.61 of this chapter. (6) All records showing the Food and Drug Administration's testing of... studies and tests of a color additive on animals and humans and all studies and tests on a color...

  19. Twenty-five additional cases of trisomy 9 mosaic: Birth information, medical conditions, and developmental status.

    PubMed

    Bruns, Deborah A; Campbell, Emily

    2015-05-01

    Limited literature exists on children and adults diagnosed with the mosaic form of trisomy 9. Data from the Tracking Rare Incidence Syndromes (TRIS) project has provided physical characteristics and medical conditions for 14 individuals. This article provides TRIS Survey results of 25 additional cases at two data points (birth and survey completion) as well as developmental status. Results confirmed a number of phenotypic features and medical conditions. In addition, a number of cardiac anomalies were reported along with feeding and respiratory difficulties in the immediate postnatal period. In addition, developmental status data indicated a range in functioning level up to skills in the 36 and 48-month range. Strengths were also noted across the sample in language and communication, fine motor and social-emotional development. Implications for professionals caring for children with this genetic condition are offered.

  20. 21 CFR 803.12 - Where and how do I submit reports and additional information?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... information? 803.12 Section 803.12 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... health emergency, this can be brought to FDA's attention by contacting the FDA Office of Emergency Operations (HFA-615), Office of Crisis Management, Office of the Commissioner, at 301-443-1240, followed...

  1. 14 CFR 121.317 - Passenger information requirements, smoking prohibitions, and additional seat belt requirements.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... lavatory a sign or placard that reads: “Federal law provides for a penalty of up to $2,000 for tampering..., no person may operate an airplane unless it is equipped with passenger information signs that meet... signs must be constructed so that the crewmembers can turn them on and off. (b) Except as provided...

  2. 49 CFR 40.331 - To what additional parties must employers and service agents release information?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Transportation PROCEDURES FOR TRANSPORTATION WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Confidentiality and... information about that employee's drug or alcohol tests to an identified person, you must provide the... for this part and DOT agency drug and alcohol program functions. (2) All written, printed,...

  3. Software for Information Storage and Retrieval Tested, Evaluated and Compared: Part VI--Various Additional Programs.

    ERIC Educational Resources Information Center

    Sieverts, Eric G.; And Others

    1993-01-01

    Reports on tests evaluating nine microcomputer software packages designed for information storage and retrieval: BRS-Search, dtSearch, InfoBank, Micro-OPC, Q&A, STN-PFS, Strix, TINman, and ZYindex. Tables and narrative evaluations detail results related to security, hardware, user features, search capability, indexing, input, maintenance of files,…

  4. 13 CFR 126.403 - May SBA require additional information from a HUBZone SBC?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... information from a HUBZone SBC? 126.403 Section 126.403 Business Credit and Assistance SMALL BUSINESS... HUBZone SBC? (a) At the discretion of the D/HUB, SBA has the right to require that a HUBZone SBC submit... adverse inference from the failure of a HUBZone SBC to cooperate with a program examination or...

  5. 29 CFR 2590.702-1 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... diabetes. A begins to experience excessive sweating, thirst, and fatigue. A's physician examines A and... adult onset diabetes mellitus (Type 2 diabetes). (ii) Conclusion. In this Example 1, A has been... involved. The diagnosis is not based principally on genetic information. Thus, Type 2 diabetes...

  6. 45 CFR 146.122 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... diabetes. A begins to experience excessive sweating, thirst, and fatigue. A's physician examines A and... adult onset diabetes mellitus (Type 2 diabetes). (ii) Conclusion. In this Example 1, A has been... involved. The diagnosis is not based principally on genetic information. Thus, Type 2 diabetes...

  7. Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity

    PubMed Central

    Davis, Myrtle; Li, Jianying; Knight, Elaine; Eldridge, Sandy R.; Daniels, Kellye K.; Bushel, Pierre R.

    2015-01-01

    Combinations of anticancer agents may have synergistic anti-tumor effects, but enhanced hematological toxicity often limit their clinical use. We examined whether “microarray profiles” could be used to compare early molecular responses following a single dose of agents administered individually with that of the agents administered in a combination. We compared the mRNA responses within bone marrow of Sprague-Dawley rats after a single 30 min treatment with topotecan at 4.7 mg/kg or oxaliplatin at 15 mg/kg alone to that of sequentially administered combination therapy or vehicle control for 1, 6, and 24 h. We also examined the histopathology of the bone marrow following all treatments. Drug-related histopathological lesions were limited to bone marrow hypocellularity for animals dosed with either agent alone or in combination. Lesions had an earlier onset and higher incidence for animals given topotecan alone or in combination with oxaliplatin. Severity increased from mild to moderate when topotecan was administered prior to oxaliplatin compared with administering oxaliplatin first. Notably, six patterns of co-expressed genes were detected at the 1 h time point that indicate regulatory expression of genes that are dependent on the order of the administration. These results suggest alterations in histone biology, chromatin remodeling, DNA repair, bone regeneration, and respiratory and oxidative phosphorylation are among the prominent pathways modulated in bone marrow from animals treated with an oxaliplatin/topotecan combination. These data also demonstrate the potential for early mRNA patterns derived from target organs of toxicity to inform toxicological risk and molecular mechanisms for agents given in combination. PMID:25729387

  8. 10 CFR 52.80 - Contents of applications; additional technical information.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    .... 52.80 Section 52.80 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Combined Licenses § 52.80 Contents of applications; additional technical... the circumstances associated with the loss of large areas of the plant due to explosions or fire...

  9. 10 CFR 52.80 - Contents of applications; additional technical information.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    .... 52.80 Section 52.80 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Combined Licenses § 52.80 Contents of applications; additional technical... the circumstances associated with the loss of large areas of the plant due to explosions or fire...

  10. 10 CFR 52.80 - Contents of applications; additional technical information.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    .... 52.80 Section 52.80 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Combined Licenses § 52.80 Contents of applications; additional technical... the circumstances associated with the loss of large areas of the plant due to explosions or fire...

  11. 10 CFR 52.80 - Contents of applications; additional technical information.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    .... 52.80 Section 52.80 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Combined Licenses § 52.80 Contents of applications; additional technical... the circumstances associated with the loss of large areas of the plant due to explosions or fire...

  12. 10 CFR 52.80 - Contents of applications; additional technical information.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    .... 52.80 Section 52.80 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSES, CERTIFICATIONS, AND APPROVALS FOR NUCLEAR POWER PLANTS Combined Licenses § 52.80 Contents of applications; additional technical... the circumstances associated with the loss of large areas of the plant due to explosions or fire...

  13. Facing Facts: Can the Face-Name Mnemonic Strategy Accommodate Additional Factual Information?

    ERIC Educational Resources Information Center

    Carney, Russell N.; Levin, Joel R.

    2012-01-01

    In 3 experiments, undergraduates used their own best method (control) or an "imposed" face-name mnemonic strategy to associate 18 caricatured faces, names, and additional facts. On all immediate tests (prompted by the faces), and on the delayed tests of Experiments 2a and 2b combined, mnemonic students statistically outperformed control students…

  14. 40 CFR 79.21 - Information and assurances to be provided by the additive manufacturer.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... will be accepted in lieu thereof; (2) In the case of an additive for engine oil, only the name..., that a percentage figure combining the percentages of carbon, hydrogen, and/or oxygen may be provided... any 1975 or subsequent model year vehicle or engine, or that the manufacturer has obtained a...

  15. 40 CFR 79.21 - Information and assurances to be provided by the additive manufacturer.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... will be accepted in lieu thereof; (2) In the case of an additive for engine oil, only the name..., that a percentage figure combining the percentages of carbon, hydrogen, and/or oxygen may be provided... any 1975 or subsequent model year vehicle or engine, or that the manufacturer has obtained a...

  16. 40 CFR 79.21 - Information and assurances to be provided by the additive manufacturer.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... will be accepted in lieu thereof; (2) In the case of an additive for engine oil, only the name..., that a percentage figure combining the percentages of carbon, hydrogen, and/or oxygen may be provided... any 1975 or subsequent model year vehicle or engine, or that the manufacturer has obtained a...

  17. 77 FR 58911 - Additional Identifying Information for One (1) Individual Designated Pursuant to Executive Order...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-24

    ... Threaten to Disrupt the Middle East Peace Process'' (the ``Order''). DATES: The addition by the Director of... sanctions on persons who threaten to disrupt the Middle East peace process. The President identified in the... Middle East peace ] process; or (2) assist in, sponsor, or provide financial, material, or...

  18. Mechanistic Insight in the Function of Phosphite Additives for Protection of LiNi0.5Co0.2Mn0.3O2 Cathode in High Voltage Li-Ion Cells.

    PubMed

    He, Meinan; Su, Chi-Cheung; Peebles, Cameron; Feng, Zhenxing; Connell, Justin G; Liao, Chen; Wang, Yan; Shkrob, Ilya A; Zhang, Zhengcheng

    2016-05-11

    Triethlylphosphite (TEP) and tris(2,2,2-trifluoroethyl) phosphite (TTFP) have been evaluated as electrolyte additives for high-voltage Li-ion battery cells using a Ni-rich layered cathode material LiNi0.5Co0.2Mn0.3O2 (NCM523) and the conventional carbonate electrolyte. The repeated charge/discharge cycling for cells containing 1 wt % of these additives was performed using an NCM523/graphite full cell operated at the voltage window from 3.0-4.6 V. During the initial charge process, these additives decompose on the cathode surface at a lower oxidation potential than the baseline electrolyte. Impedance spectroscopy and post-test analyses indicate the formation of protective coatings by both additives on the cathode surface that prevent oxidative breakdown of the electrolyte. However, only TTFP containing cells demonstrate the improved capacity retention and Coulombic efficiency. For TEP, the protective coating is also formed, but low Li(+) ion mobility through the interphase layer results in inferior performance. These observations are rationalized through the inhibition of electrocatalytic centers present on the cathode surface and the formation of organophosphate deposits isolating the cathode surface from the electrolyte. The difference between the two phosphites clearly originates in the different properties of the resulting phosphate coatings, which may be in Li(+) ion conductivity through such materials.

  19. From mechanistic to functional behaviorism.

    PubMed

    Moxley, R A

    1992-11-01

    A shift from mechanistic behaviorism to functional behaviorism is presented against the background of two historical traditions, one with an emphasis on form, the other with an emphasis on function. Skinner's work, which made more contributions to a functional behaviorism than to a mechanistic behaviorism, exemplifies this shift. The two traditions and an account of Skinner's development of functional relations are presented in order to show Skinner's contributions to aligning modern behavior analysis with the functional tradition.

  20. 24 CFR 903.9 - May HUD request additional information in the Annual Plan of a troubled PHA?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 4 2013-04-01 2013-04-01 false May HUD request additional information in the Annual Plan of a troubled PHA? 903.9 Section 903.9 Housing and Urban Development REGULATIONS RELATING TO HOUSING AND URBAN DEVELOPMENT (CONTINUED) OFFICE OF ASSISTANT SECRETARY FOR PUBLIC...

  1. 12 CFR 516.220 - If OTS requests additional information to complete my application, how will it process my...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... complete my application, how will it process my application? 516.220 Section 516.220 Banks and Banking... Standard Treatment § 516.220 If OTS requests additional information to complete my application, how will it... your response. OTS will notify you that it has extended the period before the end of the initial...

  2. 12 CFR 390.128 - If the FDIC requests additional information to complete my application, how will it process my...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... complete my application, how will it process my application? 390.128 Section 390.128 Banks and Banking... additional information to complete my application, how will it process my application? (a) You may use the... will notify you that it has extended the period before the end of the initial 15-day period and...

  3. 12 CFR 116.220 - If the OCC requests additional information to complete my application, how will it process my...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... complete my application, how will it process my application? 116.220 Section 116.220 Banks and Banking... Treatment § 116.220 If the OCC requests additional information to complete my application, how will it... that it has extended the period before the end of the initial 15-day period and will briefly...

  4. 12 CFR 516.220 - If OTS requests additional information to complete my application, how will it process my...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... complete my application, how will it process my application? 516.220 Section 516.220 Banks and Banking... Standard Treatment § 516.220 If OTS requests additional information to complete my application, how will it... your response. OTS will notify you that it has extended the period before the end of the initial...

  5. 41 CFR 102-79.111 - Where may Executive agencies find additional information on Integrated Workplace concepts?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Where may Executive agencies find additional information on Integrated Workplace concepts? 102-79.111 Section 102-79.111 Public Contracts and Property Management Federal Property Management Regulations System (Continued)...

  6. A new species of Neparholaspis (Acari: Parholaspididae) from Russia, with additional information on Neparholaspis evansi Krantz, 1960.

    PubMed

    Marchenko, Irina I

    2016-08-23

    Neparholaspis dubatolovi sp. nov. is described and illustrated from adult females and males collected from litter and moss in montane forest in north-eastern Sikhote-Alin Ridge in the Far East of Russia. Additional morphological information and illustrations of Neparholaspis evansi Krantz, 1960 are provided, based on examination of a paratype. A key to the world species of Neparholaspis is provided.

  7. 76 FR 80377 - Notice of Submission of Proposed Information Collection to OMB Additional On-Site Data Collection...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-23

    ... of Submission of Proposed Information Collection to OMB Additional On-Site Data Collection for the... HCV programs. The proposed data collection will take place through site visits to up to 30 PHAs and... the PHA. The results of the site visits will be used to identify PHAs to participate in a...

  8. Tautomers of a Fluorescent G Surrogate and Their Distinct Photophysics Provide Additional Information Channels.

    PubMed

    Sholokh, Marianna; Improta, Roberto; Mori, Mattia; Sharma, Rajhans; Kenfack, Cyril; Shin, Dongwon; Voltz, Karine; Stote, Roland H; Zaporozhets, Olga A; Botta, Maurizio; Tor, Yitzhak; Mély, Yves

    2016-07-04

    Thienoguanosine ((th) G) is an isomorphic nucleoside analogue acting as a faithful fluorescent substitute of G, with respectable quantum yield in oligonucleotides. Photophysical analysis of (th) G reveals the existence of two ground-state tautomers with significantly shifted absorption and emission wavelengths, and high quantum yield in buffer. Using (TD)-DFT calculations, the tautomers were identified as the H1 and H3 keto-amino tautomers. When incorporated into the loop of (-)PBS, the (-)DNA copy of the HIV-1 primer binding site, both tautomers are observed and show differential sensitivity to protein binding. The red-shifted H1 tautomer is strongly favored in matched (-)/(+)PBS duplexes, while the relative emission of the H3 tautomer can be used to detect single nucleotide polymorphisms. These tautomers and their distinct environmental sensitivity provide unprecedented information channels for analyzing G residues in oligonucleotides and their complexes.

  9. Tautomers of a Fluorescent G Surrogate and Their Distinct Photophysics Provide Additional Information Channels

    PubMed Central

    Sharma, Rajhans; Kenfack, Cyril; Shin, Dongwon; Voltz, Karine; Stote, Roland H.; Zaporozhets, Olga A.; Botta, Maurizio; Tor, Yitzhak; Mély, Yves

    2016-01-01

    Thienoguanosine (thG) is an isomorphic nucleoside analogue acting as a faithful fluorescent substitute of G, with respectable quantum yield in oligonucleotides. Photophysical analysis of thG reveals the existence of two ground-state tautomers with significantly shifted absorption and emission wavelengths, and high quantum yield in buffer. Using (TD)-DFT calculations, the tautomers were identified as the H1 and H3 keto-amino tautomers. When incorporated into the loop of (−)PBS, the (−)DNA copy of the HIV-1 primer binding site, both tautomers are observed and show differential sensitivity to protein binding. The red-shifted H1 tautomer is strongly favored in matched (−)/(+)PBS duplexes, while the relative emission of the H3 tautomer can be used to detect single nucleotide polymorphisms. These tautomers and their distinct environmental sensitivity provide unprecedented information channels for analyzing G residues in oligonucleotides and their complexes. PMID:27273741

  10. Inclusion of Additional Plant Species and Trait Information in Dynamic Vegetation Modeling of Arctic Tundra and Boreal Forest Ecosystem

    NASA Astrophysics Data System (ADS)

    Euskirchen, E. S.; Patil, V.; Roach, J.; Griffith, B.; McGuire, A. D.

    2015-12-01

    Dynamic vegetation models (DVMs) have been developed to model the ecophysiological characteristics of plant functional types in terrestrial ecosystems. They have frequently been used to answer questions pertaining to processes such as disturbance, plant succession, and community composition under historical and future climate scenarios. While DVMs have proved useful in these types of applications, it has often been questioned if additional detail, such as including plant dynamics at the species-level and/or including species-specific traits would make these models more accurate and/or broadly applicable. A sub-question associated with this issue is, 'How many species, or what degree of functional diversity, should we incorporate to sustain ecosystem function in modeled ecosystems?' Here, we focus on how the inclusion of additional plant species and trait information may strengthen dynamic vegetation modeling in applications pertaining to: (1) forage for caribou in northern Alaska, (2) above- and belowground carbon storage in the boreal forest and lake margin wetlands of interior Alaska, and (3) arctic tundra and boreal forest leaf phenology. While the inclusion of additional information generally proved valuable in these three applications, this additional detail depends on field data that may not always be available and may also result in increased computational complexity. Therefore, it is important to assess these possible limitations against the perceived need for additional plant species and trait information in the development and application of dynamic vegetation models.

  11. An Internet compendium of analytical methods and spectroscopic information for monomers and additives used in food packaging plastics.

    PubMed

    Gilbert, J; Simoneau, C; Cote, D; Boenke, A

    2000-10-01

    An internet website (http:¿cpf.jrc.it/smt/) has been produced as a means of dissemination of methods of analysis and supporting spectroscopic information on monomers and additives used for food contact materials (principally packaging). The site which is aimed primarily at assisting food control laboratories in the European Union contains analytical information on monomers, starting substances and additives used in the manufacture of plastics materials. A searchable index is provided giving PM and CAS numbers for each of 255 substances. For each substance a data sheet gives regulatory information, chemical structures, physico-chemical information and background information on the use of the substance in particular plastics, and the food packaging applications. For monomers and starting substances (155 compounds) the infra-red and mass spectra are provided, and for additives (100 compounds); additionally proton NMR are available for about 50% of the entries. Where analytical methods have been developed for determining these substances as residual amounts in plastics or as trace amounts in food simulants these methods are also on the website. All information is provided in portable document file (PDF) format which means that high quality copies can be readily printed, using freely available Adobe Acrobat Reader software. The website will in future be maintained and up-dated by the European Commission's Joint Research Centre (JRC) as new substances are authorized for use by the European Commission (DG-ENTR formerly DGIII). Where analytical laboratories (food control or other) require reference substances these can be obtained free-of-charge from a reference collection housed at the JRC and maintained in conjunction with this website compendium.

  12. Supra-additive contribution of shape and surface information to individual face discrimination as revealed by fast periodic visual stimulation.

    PubMed

    Dzhelyova, Milena; Rossion, Bruno

    2014-12-24

    Face perception depends on two main sources of information--shape and surface cues. Behavioral studies suggest that both of them contribute roughly equally to discrimination of individual faces, with only a small advantage provided by their combination. However, it is difficult to quantify the respective contribution of each source of information to the visual representation of individual faces with explicit behavioral measures. To address this issue, facial morphs were created that varied in shape only, surface only, or both. Electrocephalogram (EEG) were recorded from 10 participants during visual stimulation at a fast periodic rate, in which the same face was presented four times consecutively and the fifth face (the oddball) varied along one of the morphed dimensions. Individual face discrimination was indexed by the periodic EEG response at the oddball rate (e.g., 5.88 Hz/5 = 1.18 Hz). While shape information was discriminated mainly at right occipitotemporal electrode sites, surface information was coded more bilaterally and provided a larger response overall. Most importantly, shape and surface changes alone were associated with much weaker responses than when both sources of information were combined in the stimulus, revealing a supra-additive effect. These observations suggest that the two kinds of information combine nonlinearly to provide a full individual face representation, face identity being more than the sum of the contribution of shape and surface cues.

  13. Website Use and Effects of Online Information About Tobacco Additives Among the Dutch General Population: A Randomized Controlled Trial

    PubMed Central

    Crutzen, Rik; Kienhuis, Anne S; Talhout, Reinskje; de Vries, Hein

    2017-01-01

    Background As a legal obligation, the Dutch government publishes online information about tobacco additives to make sure that it is publicly available. Little is known about the influence this website (”tabakinfo”) has on visitors and how the website is evaluated by them. Objective This study assesses how visitors use the website and its effect on their knowledge, risk perception, attitude, and smoking behavior. The study will also assess how the website is evaluated by visitors using a sample of the Dutch general population, including smokers and nonsmokers. Methods A randomized controlled trial was conducted, recruiting participants from an online panel. At baseline, participants (N=672) were asked to fill out an online questionnaire about tobacco additives. Next, participants were randomly allocated to either one of two experimental groups and invited to visit the website providing information about tobacco additives (either with or without a database containing product-specific information) or to a control group that had no access to the website. After 3 months, follow-up measurements took place. Results At follow-up (n=492), no statistically significant differences were found for knowledge, risk perception, attitude, or smoking behavior between the intervention and control groups. Website visits were positively related to younger participants (B=–0.07, 95% CI –0.12 to –0.01; t11=–2.43, P=.02) and having a low risk perception toward tobacco additives (B=–0.32, 95% CI –0.63 to –0.02; t11=–2.07, P=.04). In comparison, having a lower education (B=–0.67, 95% CI –1.14 to –0.17; t11=–2.65, P=.01) was a significant predictor for making less use of the website. Furthermore, the website was evaluated less positively by smokers compared to nonsmokers (t324=–3.55, P<.001), and males compared to females (t324=–2.21, P=.02). Conclusions The website did not change perceptions of tobacco additives or smoking behavior. Further research is

  14. [Rad-Esito: new informational additions in the integration of content of hospital discharge cards for acute patients].

    PubMed

    Rini, F; Piscioneri, C; Consolante, C; Fara, G M

    2009-01-01

    Since the January 2008 the tracking of additional information about hospital discharge card's content has been activated in Latium. The new data, noticed by RAD-Esito card, regard the hospitalizations for acute myocardial infarction, femoral neck fracture and coronary artery bypass surgery. This study's objective has been to evaluate the quality of the data collected with the new card, at the end of the 1st semester of experimentation, concerning two institutes of care of Latium, the Casilino Polyclinic (ASL Rome B) and the Anzio-Nettuno hospital (Assembled Hospitals, ASL Rome H). Furthermore, any significant correlation's existence between a few variables for acute myocardial infarction and femoral fracture with the mortality rate and the average hospitalization period has been statistically verified. This study's preliminary results show how the integration of the hospital informative flow with the new clinical variables will be able to allow the promotion of the quality in the coding of the diagnosis and procedures, according to the current international innovations. This additional information will also be able to support the regional appropriateness and outcome of the treatments evaluation programs.

  15. Individuals with post-stroke hemiparesis are able to use additional sensory information to reduce postural sway.

    PubMed

    Cunha, B P; Alouche, S R; Araujo, I M G; Freitas, S M S F

    2012-03-28

    The present study aimed to investigate whether stroke survivals are able to use the additional somatosensory information provided by the light touch to reduce their postural sway during the upright stance. Eight individuals, naturally right-handed pre-stroke, and eight healthy age-matched adults stood as quiet as possible on a force plate during 35s. Participants performed two trials for each visual condition (eyes open and closed) and somatosensory condition (with and without the right or left index fingertip touching an instrumented rigid and fixed bar). When participants touched the bar, they were asked to apply less than 1N of vertical force. The postural sway was assessed by the center of pressure (COP) displacement area, mean amplitude and velocity. In addition, the mean and standard deviation of the force vertically applied on the bar during the trials with touch were assessed. The averaged values of COP area, amplitude and velocity were greater for stroke individuals compared to healthy adults during all visual and somatosensory conditions. For both groups, the values of all variables increased when participants stood with eyes closed and reduced when they touched the bar regardless of the side of the touch. Overall, the results suggested that, as healthy individuals, persons with post-stroke hemiparesis are able to use the additional somatosensory information provided by the light touch to reduce the postural sway.

  16. Radical behaviorism and scientific frameworks. From mechanistic to relational accounts.

    PubMed

    Chiesa, M

    1992-11-01

    A substantial portion of B. F. Skinner's scholarship was devoted to developing methods and terms for a scientific study of behavior. Three concepts central to scientific accounts--cause, explanation, and theory--are examined to illustrate the distinction between mechanistic and relational frameworks and radical behaviorism's relationship to those frameworks. Informed by a scientific tradition that explicitly rejects mechanistic interpretations, radical behaviorism provides a distinctive stance in contemporary psychology. The present analysis suggests that radical behaviorism makes closer contact with the "new world view" advocated by physicists and philosophers of science than does much of contemporary psychology.

  17. Explanation and inference: mechanistic and functional explanations guide property generalization.

    PubMed

    Lombrozo, Tania; Gwynne, Nicholas Z

    2014-01-01

    The ability to generalize from the known to the unknown is central to learning and inference. Two experiments explore the relationship between how a property is explained and how that property is generalized to novel species and artifacts. The experiments contrast the consequences of explaining a property mechanistically, by appeal to parts and processes, with the consequences of explaining the property functionally, by appeal to functions and goals. The findings suggest that properties that are explained functionally are more likely to be generalized on the basis of shared functions, with a weaker relationship between mechanistic explanations and generalization on the basis of shared parts and processes. The influence of explanation type on generalization holds even though all participants are provided with the same mechanistic and functional information, and whether an explanation type is freely generated (Experiment 1), experimentally provided (Experiment 2), or experimentally induced (Experiment 2). The experiments also demonstrate that explanations and generalizations of a particular type (mechanistic or functional) can be experimentally induced by providing sample explanations of that type, with a comparable effect when the sample explanations come from the same domain or from a different domains. These results suggest that explanations serve as a guide to generalization, and contribute to a growing body of work supporting the value of distinguishing mechanistic and functional explanations.

  18. Explanation and inference: mechanistic and functional explanations guide property generalization

    PubMed Central

    Lombrozo, Tania; Gwynne, Nicholas Z.

    2014-01-01

    The ability to generalize from the known to the unknown is central to learning and inference. Two experiments explore the relationship between how a property is explained and how that property is generalized to novel species and artifacts. The experiments contrast the consequences of explaining a property mechanistically, by appeal to parts and processes, with the consequences of explaining the property functionally, by appeal to functions and goals. The findings suggest that properties that are explained functionally are more likely to be generalized on the basis of shared functions, with a weaker relationship between mechanistic explanations and generalization on the basis of shared parts and processes. The influence of explanation type on generalization holds even though all participants are provided with the same mechanistic and functional information, and whether an explanation type is freely generated (Experiment 1), experimentally provided (Experiment 2), or experimentally induced (Experiment 2). The experiments also demonstrate that explanations and generalizations of a particular type (mechanistic or functional) can be experimentally induced by providing sample explanations of that type, with a comparable effect when the sample explanations come from the same domain or from a different domains. These results suggest that explanations serve as a guide to generalization, and contribute to a growing body of work supporting the value of distinguishing mechanistic and functional explanations. PMID:25309384

  19. 43 CFR 3276.13 - What additional information must I give BLM in the monthly report for flash and dry steam...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... BLM in the monthly report for flash and dry steam facilities? 3276.13 Section 3276.13 Public Lands... What additional information must I give BLM in the monthly report for flash and dry steam facilities? In addition to the regular monthly report information required by § 3276.12, send to BLM: (a)...

  20. 43 CFR 3276.13 - What additional information must I give BLM in the monthly report for flash and dry steam...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... BLM in the monthly report for flash and dry steam facilities? 3276.13 Section 3276.13 Public Lands... What additional information must I give BLM in the monthly report for flash and dry steam facilities? In addition to the regular monthly report information required by § 3276.12, send to BLM: (a)...

  1. 43 CFR 3276.13 - What additional information must I give BLM in the monthly report for flash and dry steam...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... BLM in the monthly report for flash and dry steam facilities? 3276.13 Section 3276.13 Public Lands... What additional information must I give BLM in the monthly report for flash and dry steam facilities? In addition to the regular monthly report information required by § 3276.12, send to BLM: (a)...

  2. 43 CFR 3276.13 - What additional information must I give BLM in the monthly report for flash and dry steam...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... BLM in the monthly report for flash and dry steam facilities? 3276.13 Section 3276.13 Public Lands... What additional information must I give BLM in the monthly report for flash and dry steam facilities? In addition to the regular monthly report information required by § 3276.12, send to BLM: (a)...

  3. Mechanistic investigations of the ethylene tetramerisation reaction.

    PubMed

    Overett, Matthew J; Blann, Kevin; Bollmann, Annette; Dixon, John T; Haasbroek, Daleen; Killian, Esna; Maumela, Hulisani; McGuinness, David S; Morgan, David H

    2005-08-03

    The unprecedented selective tetramerisation of ethylene to 1-octene was recently reported. In the present study various mechanistic aspects of this novel transformation were investigated. The unusually high 1-octene selectivity in chromium-catalyzed ethylene tetramerisation reactions is caused by the unique extended metallacyclic mechanism in operation. Both 1-octene and higher 1-alkenes are formed by further ethylene insertion into a metallacycloheptane intermediate, whereas 1-hexene is formed by elimination from this species as in other reported trimerisation reactions. This is supported by deuterium labeling studies, analysis of the molar distribution of 1-alkene products, and identification of secondary co-oligomerization reaction products. In addition, the formation of two C6 cyclic products, methylenecyclopentane and methylcyclopentane, is discussed, and a bimetallic disproportionation mechanism to account for the available data is proposed.

  4. On the additional information content of hyperspectral remote sensing data for estimating ecosystem carbon dioxde and energy exchange

    NASA Astrophysics Data System (ADS)

    Wohlfahrt, Georg; Hammerle, Albin; Tomelleri, Enrico

    2015-04-01

    Radiation reflected back from an ecosystem carries a spectral signature resulting from the interaction of radiation with the vegetation canopy and the underlying soil and thus allows drawing conclusions about the structure and functioning of an ecosystem. When this information is linked to a model of the leaf CO2 exchange, the ecosystem-scale CO2 exchange can be simulated. A well-known and very simplistic example for this approach is the light-use efficiency (LUE) model proposed by Monteith which links the flux of absorbed photosynthetically active radiation times a LUE parameter, both of which may be estimated based on remote sensing data, to predict the ecosystem gross photosynthesis. Here we explore the ability of a more elaborate approach by using near-surface remote sensing of hyperspectral reflected radiation, eddy covariance CO2 and energy flux measurements and a coupled radiative transfer and soil-vegetation-atmosphere-transfer (SVAT) model. Our main objective is to understand to what degree the joint assimilation of hyperspectral reflected radiation and eddy covariance flux measurements into the model helps to better constrain model parameters. To this end we use the SCOPE model, a combination of the well-known PROSAIL model and a SVAT model, and the Bayesian inversion algorithm DREAM. In order to explicitly link reflectance in the visible light and the leaf CO2 exchange, a novel parameterisation of the maximum carboxylation capacity parameter (Vcmax) on the leaf a+b chlorophyll content parameter of PROSAIL is introduced. Results are discussed with respect to the additional information content the hyperspectral data yield for simulating canopy photosynthesis.

  5. Adiponectin Provides Additional Information to Conventional Cardiovascular Risk Factors for Assessing the Risk of Atherosclerosis in Both Genders

    PubMed Central

    Yoon, Jin-Ha; Kim, Sung-Kyung; Choi, Ho-June; Choi, Soo-In; Cha, So-Youn; Koh, Sang-Baek

    2013-01-01

    Background This study evaluated the relation between adiponectin and atherosclerosis in both genders, and investigated whether adiponectin provides useful additional information for assessing the risk of atherosclerosis. Methods We measured serum adiponectin levels and other cardiovascular risk factors in 1033 subjects (454 men, 579 women) from the Korean Genomic Rural Cohort study. Carotid intima–media-thickness (CIMT) was used as measure of atherosclerosis. Odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated using multiple logistic regression, and receiver operating characteristic curves (ROC), the category-free net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated. Results After adjustment for conventional cardiovascular risk factors, such as age, waist circumference, smoking history, low-density and high-density lipoprotein cholesterol, triglycerides, systolic blood pressure and insulin resistance, the ORs (95%CI) of the third tertile adiponectin group were 0.42 (0.25–0.72) in men and 0.47 (0.29–0.75) in women. The area under the curve (AUC) on the ROC analysis increased significantly by 0.025 in men and 0.022 in women when adiponectin was added to the logistic model of conventional cardiovascular risk factors (AUC in men: 0.655 to 0.680, p = 0.038; AUC in women: 0.654 to 0.676, p = 0.041). The NRI was 0.32 (95%CI: 0.13–0.50, p<0.001), and the IDI was 0.03 (95%CI: 0.01–0.04, p<0.001) for men. For women, the category-free NRI was 0.18 (95%CI: 0.02–0.34, p = 0.031) and the IDI was 0.003 (95%CI: −0.002–0.008, p = 0.189). Conclusion Adiponectin and atherosclerosis were significantly related in both genders, and these relationships were independent of conventional cardiovascular risk factors. Furthermore, adiponectin provided additional information to conventional cardiovascular risk factors regarding the risk of atherosclerosis. PMID:24116054

  6. HTGR Mechanistic Source Terms White Paper

    SciTech Connect

    Wayne Moe

    2010-07-01

    The primary purposes of this white paper are: (1) to describe the proposed approach for developing event specific mechanistic source terms for HTGR design and licensing, (2) to describe the technology development programs required to validate the design methods used to predict these mechanistic source terms and (3) to obtain agreement from the NRC that, subject to appropriate validation through the technology development program, the approach for developing event specific mechanistic source terms is acceptable

  7. Rational and Mechanistic Perspectives on Reinforcement Learning

    ERIC Educational Resources Information Center

    Chater, Nick

    2009-01-01

    This special issue describes important recent developments in applying reinforcement learning models to capture neural and cognitive function. But reinforcement learning, as a theoretical framework, can apply at two very different levels of description: "mechanistic" and "rational." Reinforcement learning is often viewed in mechanistic terms--as…

  8. Bridging Mechanistic and Phenomenological Models of Complex Biological Systems

    PubMed Central

    Transtrum, Mark K.; Qiu, Peng

    2016-01-01

    The inherent complexity of biological systems gives rise to complicated mechanistic models with a large number of parameters. On the other hand, the collective behavior of these systems can often be characterized by a relatively small number of phenomenological parameters. We use the Manifold Boundary Approximation Method (MBAM) as a tool for deriving simple phenomenological models from complicated mechanistic models. The resulting models are not black boxes, but remain expressed in terms of the microscopic parameters. In this way, we explicitly connect the macroscopic and microscopic descriptions, characterize the equivalence class of distinct systems exhibiting the same range of collective behavior, and identify the combinations of components that function as tunable control knobs for the behavior. We demonstrate the procedure for adaptation behavior exhibited by the EGFR pathway. From a 48 parameter mechanistic model, the system can be effectively described by a single adaptation parameter τ characterizing the ratio of time scales for the initial response and recovery time of the system which can in turn be expressed as a combination of microscopic reaction rates, Michaelis-Menten constants, and biochemical concentrations. The situation is not unlike modeling in physics in which microscopically complex processes can often be renormalized into simple phenomenological models with only a few effective parameters. The proposed method additionally provides a mechanistic explanation for non-universal features of the behavior. PMID:27187545

  9. 36 CFR 1281.12 - What information must be provided to NARA for its report to Congress on a change or addition to a...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... provided to NARA for its report to Congress on a change or addition to a Presidential library facility... ADMINISTRATION NARA FACILITIES PRESIDENTIAL LIBRARY FACILITIES § 1281.12 What information must be provided to NARA for its report to Congress on a change or addition to a Presidential library facility? (a)...

  10. 36 CFR 1281.12 - What information must be provided to NARA for its report to Congress on a change or addition to a...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... provided to NARA for its report to Congress on a change or addition to a Presidential library facility... ADMINISTRATION NARA FACILITIES PRESIDENTIAL LIBRARY FACILITIES § 1281.12 What information must be provided to NARA for its report to Congress on a change or addition to a Presidential library facility? (a)...

  11. 36 CFR 1281.12 - What information must be provided to NARA for its report to Congress on a change or addition to a...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... provided to NARA for its report to Congress on a change or addition to a Presidential library facility... ADMINISTRATION NARA FACILITIES PRESIDENTIAL LIBRARY FACILITIES § 1281.12 What information must be provided to NARA for its report to Congress on a change or addition to a Presidential library facility? (a)...

  12. 36 CFR 1281.12 - What information must be provided to NARA for its report to Congress on a change or addition to a...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... provided to NARA for its report to Congress on a change or addition to a Presidential library facility... ADMINISTRATION NARA FACILITIES PRESIDENTIAL LIBRARY FACILITIES § 1281.12 What information must be provided to NARA for its report to Congress on a change or addition to a Presidential library facility? (a)...

  13. 36 CFR 1281.12 - What information must be provided to NARA for its report to Congress on a change or addition to a...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... provided to NARA for its report to Congress on a change or addition to a Presidential library facility... ADMINISTRATION NARA FACILITIES PRESIDENTIAL LIBRARY FACILITIES § 1281.12 What information must be provided to NARA for its report to Congress on a change or addition to a Presidential library facility? (a)...

  14. Fact Sheets and Additional information Regarding the 2012 Particulate Matter (PM) National Ambient Air Quality Standards (NAAQS)

    EPA Pesticide Factsheets

    Find tools for particulate matter, maps of nonattainment areas, an overview of the proposal, and information on designations, monitoring and permitting requirements and a presentation on the 2012 PM NAAQS revision.

  15. Modeling Bird Migration under Climate Change: A Mechanistic Approach

    NASA Technical Reports Server (NTRS)

    Smith, James A.

    2009-01-01

    behavior can be maintained over increasing and sustained environmental change. Also, the problem is much more complex than described by the current processes captured in our model. We have taken some important and interesting steps, and our model does demonstrate how local scale information about individual stop-over sites can be linked into the migratory flyway as a whole. We are incorporating additional, species specific, mechanistic processes to better reflect different climate change scenarios

  16. Negative mechanistic reasoning in medical intervention assessment.

    PubMed

    Jerkert, Jesper

    2015-12-01

    Traditionally, mechanistic reasoning has been assigned a negligible role in standard EBM (evidence-based medicine) literature, although some recent authors have argued for an upgrade. Even so, the mechanistic reasoning that has received attention has almost exclusively been positive--both in an epistemic sense of claiming that there is a mechanistic chain and in a health-related sense of there being claimed benefits for the patient. Negative mechanistic reasoning has been neglected, both in the epistemic and in the health-related sense. I distinguish three main types of negative mechanistic reasoning and subsume them under a new definition of mechanistic reasoning in the context of assessing medical interventions. This definition is wider than a previous suggestion in the literature. Each negative type corresponds to a range of evidential strengths, and it is argued that there are differences with respect to typical evidential strengths. The variety of negative mechanistic reasoning should be acknowledged in EBM, and it presents a serious challenge to proponents of so-called medical hierarchies of evidence.

  17. Processing time of addition or withdrawal of single or combined balance-stabilizing haptic and visual information

    PubMed Central

    Honeine, Jean-Louis; Crisafulli, Oscar; Sozzi, Stefania

    2015-01-01

    We investigated the integration time of haptic and visual input and their interaction during stance stabilization. Eleven subjects performed four tandem-stance conditions (60 trials each). Vision, touch, and both vision and touch were added and withdrawn. Furthermore, vision was replaced with touch and vice versa. Body sway, tibialis anterior, and peroneus longus activity were measured. Following addition or withdrawal of vision or touch, an integration time period elapsed before the earliest changes in sway were observed. Thereafter, sway varied exponentially to a new steady-state while reweighting occurred. Latencies of sway changes on sensory addition ranged from 0.6 to 1.5 s across subjects, consistently longer for touch than vision, and were regularly preceded by changes in muscle activity. Addition of vision and touch simultaneously shortened the latencies with respect to vision or touch separately, suggesting cooperation between sensory modalities. Latencies following withdrawal of vision or touch or both simultaneously were shorter than following addition. When vision was replaced with touch or vice versa, adding one modality did not interfere with the effect of withdrawal of the other, suggesting that integration of withdrawal and addition were performed in parallel. The time course of the reweighting process to reach the new steady-state was also shorter on withdrawal than addition. The effects of different sensory inputs on posture stabilization illustrate the operation of a time-consuming, possibly supraspinal process that integrates and fuses modalities for accurate balance control. This study also shows the facilitatory interaction of visual and haptic inputs in integration and reweighting of stance-stabilizing inputs. PMID:26334013

  18. 33 CFR 148.108 - What if a Federal or State agency or other interested party requests additional information?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... must state briefly why the information is needed. (c) The Commandant (CG-5) must receive the request... decision on whether or not to approve the license application. (d) The Commandant (CG-5) will consider... the application process. (e) The Commandant (CG-5) may discuss the recommendation with...

  19. 33 CFR 148.108 - What if a Federal or State agency or other interested party requests additional information?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... must state briefly why the information is needed. (c) The Commandant (CG-5) must receive the request... decision on whether or not to approve the license application. (d) The Commandant (CG-5) will consider... the application process. (e) The Commandant (CG-5) may discuss the recommendation with...

  20. Space Takes Time: Concentration Dependent Output Codes from Primary Olfactory Networks Rapidly Provide Additional Information at Defined Discrimination Thresholds

    PubMed Central

    Daly, Kevin C.; Bradley, Samual; Chapman, Phillip D.; Staudacher, Erich M.; Tiede, Regina; Schachtner, Joachim

    2016-01-01

    As odor concentration increases, primary olfactory network representations expand in spatial distribution, temporal complexity and duration. However, the direct relationship between concentration dependent odor representations and the psychophysical thresholds of detection and discrimination is poorly understood. This relationship is absolutely critical as thresholds signify transition points whereby representations become meaningful to the organism. Here, we matched stimulus protocols for psychophysical assays and intracellular recordings of antennal lobe (AL) projection neurons (PNs) in the moth Manduca sexta to directly compare psychophysical thresholds and the output representations they elicit. We first behaviorally identified odor detection and discrimination thresholds across an odor dilution series for a panel of structurally similar odors. We then characterized spatiotemporal spiking patterns across a population of individually filled and identified AL PNs in response to those odors at concentrations below, at, and above identified thresholds. Using spatial and spatiotemporal based analyses we observed that each stimulus produced unique representations, even at sub-threshold concentrations. Mean response latency did not decrease and the percent glomerular activation did not increase with concentration until undiluted odor. Furthermore, correlations between spatial patterns for odor decreased, but only significantly with undiluted odor. Using time-integrated Euclidean distance (ED) measures, we determined that added spatiotemporal information was present at the discrimination but not detection threshold. This added information was evidenced by an increase in integrated distance between the sub-detection and discrimination threshold concentrations (of the same odor) that was not present in comparison of the sub-detection and detection threshold. After consideration of delays for information to reach the AL we find that it takes ~120–140 ms for the AL to

  1. Mechanistic Indicators of Childhood Asthma (MICA): piloting ...

    EPA Pesticide Factsheets

    Background: Modem methods in molecular biology and advanced computational tools show promise in elucidating complex interactions that occur between genes and environmental factors in diseases such as asthma; however appropriately designed studies are critical for these methods to reach their full potential. Objective: We used a case-control study to investigate whether genomic data (blood gene expression), viewed together with a spectrum of exposure effects and susceptibility markers (blood, urine and nail), can provide a mechanistic explanation for the increased susceptibility of asthmatics to ambient air pollutants. Methods: We studied 205 non-asthmatic and asthmatic children, (9-12 years of age) who participated in a clinical study in Detroit, Michigan. The study combines a traditional epidemiological design with an integrative approach to investigate the environmental exposure of children to indoor-outdoor air. The study includes measurements of internal dose (metals, allergen specific IgE, PAH and VOC metabolites) and clinical measures of health outcome (immunological, cardiovascular and respiratory). Results: Expected immunological indications of asthma have been obtained. In addition, initial results from our analyses point to the complex nature of childhood health and risk factors linked to metabolic syndrome (obesity, blood pressure and dyslipidemia). For example, 31% and 34% of the asthmatic MICA subjects were either overweight (BMI > 25) o

  2. Mechanistic pathway modeling for industrial biotechnology: challenging but worthwhile.

    PubMed

    Wiechert, Wolfgang; Noack, Stephan

    2011-10-01

    Mechanistic (also called kinetic) models quantitatively describe dynamic and steady states of biochemical pathways. They are based on network structure (stoichiometry), regulatory information (enzyme inhibitors and activators) and the corresponding reaction kinetics. Although this approach to understand and predict the behavior of biochemical networks has now been in use for almost half a century, its experimental foundation has dramatically changed in the data-rich age of systems biology. Large mechanistic models, ranging up to the genome scale, are now being built and lots of data are available to validate and test them. From the broad scope of possible modeling applications, this survey focuses on the recent developments and central problems of metabolic network modeling in the field of bioprocess development for industrial biotechnology.

  3. Providing additional information about the benefits of statins in a leaflet for patients with coronary heart disease: a qualitative study of the impact on attitudes and beliefs

    PubMed Central

    Dickinson, Rebecca; Raynor, David K; MacDonald, Jan

    2016-01-01

    Objective To explore the impact of providing additional information about the potential benefits of simvastatin in a patient leaflet on attitudes and beliefs. Design Interview-based study using a generic qualitative approach and framework analysis. Participants 21 participants receiving a prescription for simvastatin were recruited from a general practitioner practice (from a total of 120). 8 participants were women; the age range was 55–92. Intervention Participants were provided with leaflets showing one of 3 types of additional benefit information: (1) textual statement, (2) number needed to treat (NNT) or (3) natural frequency. Semistructured interviews explored patient's attitudes and beliefs. Results A descriptive narrative of preferences for format suggested patients prefer textual as opposed to numerical benefit information. Significant barriers to the acceptance of numerical benefit information included difficulty in understanding the numbers. Patients overestimated the benefits of statins and expressed surprise at the numerical information. Conclusions Textual information was preferred but numerical information, in particular in the form of a natural frequency, may help patients make judgements about their medicines. NNTs were found to be very difficult to understand. This raises the prospect that some patients might reject medicines because of disappointment with the perceived low benefits of their medicines. The self-reported impact on behaviour appeared minimal with reports of intentions to ‘do what the doctor tells me’. Further research is needed to explore the impact of such statements on people who are yet to be prescribed a statin. PMID:27913558

  4. A framework for recognizing mechanistic reasoning in student scientific inquiry

    NASA Astrophysics Data System (ADS)

    Russ, Rosemary S.

    A central ambition of science education reform is to help students develop abilities for scientific inquiry. Education research is thus rightly focused on defining what constitutes "inquiry" and developing tools for assessing it. There has been progress with respect to particular aspects of inquiry, namely student abilities for controlled experimentation and scientific argumentation. However, we suggest that in addition to these frameworks for assessing the structure of inquiry we need frameworks for analyzing the substance of that inquiry. In this work we draw attention to and evaluate the substance of student mechanistic reasoning. Both within the history and philosophy of science and within science education research, scientific inquiry is characterized in part as understanding the causal mechanisms that underlie natural phenomena. The challenge for science education, however, is that there has not been the same progress with respect to making explicit what constitutes mechanistic reasoning as there has been in making explicit other aspects of inquiry. This dissertation attempts to address this challenge. We adapt an account of mechanism in professional research science to develop a framework for reliably recognizing mechanistic reasoning in student discourse. The coding scheme articulates seven specific aspects of mechanistic reasoning and can be used to systematically analyze narrative data for patterns in student thinking. It provides a tool for detecting quality reasoning that may be overlooked by more traditional assessments. We apply the mechanism coding scheme to video and written data from a range of student inquiries, from large group discussions among first grade students to the individual problem solving of graduate students. While the primary result of this work is the coding scheme itself and the finding that it provides a reliable means of analyzing transcript data for evidence of mechanistic thinking, the rich descriptions we develop in each case

  5. EPA evaluation of the SYNERGY-1 fuel additive under Section 511 of the Motor Vehicle Information and Cost Savings Act. Technical report

    SciTech Connect

    Syria, S.L.

    1981-06-01

    This document announces the conclusions of the EPA evaluation of the 'SYNERGY-1' device under provisions of Section 511 of the Motor Vehicle Information and Cost Savings Act. This additive is intended to improve fuel economy and exhaust emission levels of two and four cycle gasoline fueled engines.

  6. Improve Quality of Life - additional criteria for health and social care information technology acceptance in an ageing world.

    PubMed

    Monteiro, Jorge

    2012-01-01

    Reversing the rising cost of health and social systems is needed in ageing developed and developing countries. A new model of ageing is advocated by the World Health Organization. This new model asks for more personal health accountability and a more integrated approach on care and preventive cure. Information systems and technologies can play an important role in supporting the changes needed in order to have better and more sustainable health and social care systems. Using value and results for patients as criteria by which systems are accepted by users and by organizations can contribute to a value based competition in health and social care systems. The unified theory of acceptance and use of technology is presented, and the pertinence of adding an extension to the theory in order capture Quality of Life improvements expectations is explored.

  7. Separate information required for nuclear and subnuclear localization: additional complexity in localizing an enzyme shared by mitochondria and nuclei.

    PubMed Central

    Rose, A M; Joyce, P B; Hopper, A K; Martin, N C

    1992-01-01

    The TRM1 gene of Saccharomyces cerevisiae codes for a tRNA modification enzyme, N2,N2-dimethylguanosine-specific tRNA methyltransferase (m2(2)Gtase), shared by mitochondria and nuclei. Immunofluorescent staining at the nuclear periphery demonstrates that m2(2)Gtase localizes at or near the nuclear membrane. In determining sequences necessary for targeting the enzyme to nuclei and mitochondria, we found that information required to deliver the enzyme to the nucleus is not sufficient for its correct subnuclear localization. We also determined that mislocalizing the enzyme from the nucleus to the cytoplasm does not destroy its biological function. This change in location was caused by altering a sequence similar to other known nuclear targeting signals (KKSKKKRC), suggesting that shared enzymes are likely to use the same import pathway as proteins that localize only to the nucleus. As with other well-characterized mitochondrial proteins, the mitochondrial import of the shared methyltransferase depends on amino-terminal amino acids, and removal of the first 48 amino acids prevents its import into mitochondria. While this truncated protein is still imported into nuclei, the immunofluorescent staining is uniform throughout rather than at the nuclear periphery, a staining pattern identical to that described for a fusion protein consisting of the first 213 amino acids of m2(2)Gtase in frame with beta-galactosidase. As both of these proteins together contain the entire m2(2)Gtase coding region, the information necessary for association with the nuclear periphery must be more complex than the short linear sequence necessary for nuclear localization. Images PMID:1448094

  8. Mechanistic Models for Soot Formation

    DTIC Science & Technology

    1992-07-02

    This data is plotted in Fig. 1 along with k for the reverse diels - alder reaction (obtained from detailed balancing and the rate data from Benson and...extrapolation of the retro diels - alder rate constant at lower temperatures, the overall activation energy is significantly higher and the pre-exponential is...has suggested that the acetylene addition processes may be related to the reverse diels -ader reaction of acetylene addition to CPD to form

  9. From the exposome to mechanistic understanding of chemical ...

    EPA Pesticide Factsheets

    BACKGROUND: Current definitions of the exposome expand beyond the initial idea to consider the totality of exposure and aim to relate to biological effects. While the exposome has been established for human health, its principles can be extended to include broader ecological issues. The assessment of exposure is tightly interlinked with hazard assessment. OBJECTIVES: We explore if mechanistic understanding of the causal links between exposure and adverse effects on human health and the environment can be improved by integrating the exposome approach with the adverse outcome pathway (AOP) concept - a framework to structure and organize the sequence of toxicological events from an initial molecular interaction of a chemical to an adverse outcome.METHODS: This review was informed by a Workshop organized by the Integrated Project EXPOSOME at the UFZ Helmholtz Centre for Environmental Research in Leipzig, Germany. DISCUSSION: The exposome encompasses all chemicals, including exogenous chemicals and endogenous compounds that are produced in response to external factors. By complementing the exposome research with the AOP concept, we can achieve a better mechanistic understanding, weigh the importance of various components of the exposome, and determine primary risk drivers. The ability to interpret multiple exposures and mixture effects at the mechanistic level requires a more holistic approach facilitated by the exposome concept.CONCLUSION: Incorporating the AOP conc

  10. Continually emerging mechanistic complexity of the multi-enzyme cellulosome complex.

    PubMed

    Smith, Steven P; Bayer, Edward A; Czjzek, Mirjam

    2017-04-06

    The robust plant cell wall polysaccharide-degrading properties of anaerobic bacteria are harnessed within elegant, marcomolecular assemblages called cellulosomes, in which proteins of complementary activities amass on scaffold protein networks. Research efforts have focused and continue to focus on providing detailed mechanistic insights into cellulosomal complex assembly, topology, and function. The accumulated information is expanding our fundamental understanding of the lignocellulosic biomass decomposition process and enhancing the potential of engineered cellulosomal systems for biotechnological purposes. Ongoing biochemical studies continue to reveal unexpected functional diversity within traditional cellulase families. Genomic, proteomic, and functional analyses have uncovered unanticipated cellulosomal proteins that augment the function of the native and designer cellulosomes. In addition, complementary structural and computational methods are continuing to provide much needed insights on the influence of cellulosomal interdomain linker regions on cellulosomal assembly and activity.

  11. Mechanistic species distribution modelling as a link between physiology and conservation

    PubMed Central

    Evans, Tyler G.; Diamond, Sarah E.; Kelly, Morgan W.

    2015-01-01

    Climate change conservation planning relies heavily on correlative species distribution models that estimate future areas of occupancy based on environmental conditions encountered in present-day ranges. The approach benefits from rapid assessment of vulnerability over a large number of organisms, but can have poor predictive power when transposed to novel environments and reveals little in the way of causal mechanisms that define changes in species distribution or abundance. Having conservation planning rely largely on this single approach also increases the risk of policy failure. Mechanistic models that are parameterized with physiological information are expected to be more robust when extrapolating distributions to future environmental conditions and can identify physiological processes that set range boundaries. Implementation of mechanistic species distribution models requires knowledge of how environmental change influences physiological performance, and because this information is currently restricted to a comparatively small number of well-studied organisms, use of mechanistic modelling in the context of climate change conservation is limited. In this review, we propose that the need to develop mechanistic models that incorporate physiological data presents an opportunity for physiologists to contribute more directly to climate change conservation and advance the field of conservation physiology. We begin by describing the prevalence of species distribution modelling in climate change conservation, highlighting the benefits and drawbacks of both mechanistic and correlative approaches. Next, we emphasize the need to expand mechanistic models and discuss potential metrics of physiological performance suitable for integration into mechanistic models. We conclude by summarizing other factors, such as the need to consider demography, limiting broader application of mechanistic models in climate change conservation. Ideally, modellers, physiologists and

  12. Mechanistic equations for membrane transport of multicomponent solutions.

    PubMed

    Suchanek, G

    2006-03-01

    In the present article, mechanistic equations for membrane transport of N + 1-component solutions have been derived. The major specific investigation result is the introduction - for ternary solutions - of two diffusion coefficients omega(d1) and omega(d2) for solutes, as well as two cross coefficients omega(d12) and omega(d21) for these solutes. The latter parameters may be treated as coefficients of interdiffusion. The expansion of the description of substance transport to include the N + 1-component solutions does not formulate any additional physical phenomena other than those which are formulated by the transport equations for three-component solutions.

  13. [Mechanistic examination of organometallic electron transfer reactions: Annual report, 1989

    SciTech Connect

    Not Available

    1989-12-31

    Our mechanistic examination of electron transfer reactions between organometallic complexes has required data from our stopped-flow infrared spectrophotometer that was constructed in the first year. Our research on organometallic electron transfer reaction mechanisms was recognized by an invitation to the Symposium on Organometallic Reaction Mechanisms at the National ACS meeting in Miami. We have obtained a reasonable understanding of the electron transfer reactions between metal cations and anions and between metal carbonyl anions and metal carbonyl dimers. In addition we have begun to obtain data on the outer sphere electron transfer between metal carbonyl anions and coordination complexes and on reactions involving cluster anions.

  14. Mechanistic Indicators of Childhood Asthma (MICA) Study

    EPA Science Inventory

    The Mechanistic Indicators of Childhood Asthma (MICA) Study has been designed to incorporate state-of-the-art technologies to examine the physiological and environmental factors that interact to increase the risk of asthmatic responses. MICA is primarily a clinically-bases obser...

  15. Reductive photocarboxylation of phenanthrene: A mechanistic investigation

    SciTech Connect

    Nikolaitchik, A.V.; Rodgers, M.A.J.; Neckers, D.C.

    1996-02-09

    Mechanistic aspects of photochemicl reactions between phenathrene and carbon dioxide while in the presence of N,N-dimethylaniline was studied. Five products were produced as characterized by NMR and GC-MS. The authors related changes in product yields to changes in reaction conditions. 31 refs., 6 figs., 3 tabs.

  16. Testing mechanistic models of growth in insects.

    PubMed

    Maino, James L; Kearney, Michael R

    2015-11-22

    Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg(-1)) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes.

  17. Exploring Organic Mechanistic Puzzles with Molecular Modeling

    ERIC Educational Resources Information Center

    Horowitz, Gail; Schwartz, Gary

    2004-01-01

    The molecular modeling was used to reinforce more general skills such as deducing and drawing reaction mechanisms, analyzing reaction kinetics and thermodynamics and drawing reaction coordinate energy diagrams. This modeling was done through the design of mechanistic puzzles, involving reactions not familiar to the students.

  18. Testing mechanistic models of growth in insects

    PubMed Central

    Maino, James L.; Kearney, Michael R.

    2015-01-01

    Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg−1) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes. PMID:26609084

  19. Bridging the boundaries between scientists and clinicians-mechanistic hypotheses and patient stories in risk assessment of drugs.

    PubMed

    Rocca, Elena

    2017-02-01

    The cultural divide between scientists and clinicians has been described as undermining the advance of medical science, by hindering the production of practice-relevant research and of research-informed clinical decisions. Here, I consider the field of post-marketing risk assessment of drugs as an example of strict interdependence between basic biomedical research, clinical research, and clinical evaluation and show how it would benefit from a closer collaboration between scientists and clinicians. The risk assessment of drugs after their marketing relies on spontaneous adverse effect reports to drug agencies and on peer-reviewed case reports. I emphasize the importance of qualitative analysis of such reports for the improvement of mechanistic understanding of harmful effects of drugs. I argue that mechanistic explanations of drug effects are at least as important as determination of their frequency, in order to establish causation. An ideal risk assessment, then, verifies not only the frequency of undesired effects but also why and how the harm happens. For this purpose, the frequency or novelty of the unintended outcome, although contextually indicative, should not determine the epistemic value of a report. Details about the context that generated an unexpected outcome, instead, can offer the chance of improving causal understanding about how the intervention works. This is illustrated through examples from medical research. Mechanistic understanding is a domain of joint collaboration among (1) clinicians, in charge of detailed, qualitative reporting of patient stories about side effects, (2) qualitative clinical researchers, in charge of analyzing clinical contexts or harmful effects and formulating explanatory hypotheses, and (3) basic biomedical researchers, in charge of verifying such hypotheses. In addition, direct information flow can on one side focus clinicians' attention on knowledge gaps about drugs/effects where more research is needed, while on the

  20. Trichloroethylene: Mechanistic, Epidemiologic and Other Supporting Evidence of Carcinogenic Hazard

    PubMed Central

    Rusyn, Ivan; Chiu, Weihsueh A.; Lash, Lawrence H.; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z.

    2013-01-01

    The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including from hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. Strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin's lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE. PMID:23973663

  1. Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard.

    PubMed

    Rusyn, Ivan; Chiu, Weihsueh A; Lash, Lawrence H; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z

    2014-01-01

    The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE.

  2. Observability analysis of biochemical process models as a valuable tool for the development of mechanistic soft sensors.

    PubMed

    Golabgir, Aydin; Hoch, Thomas; Zhariy, Mariya; Herwig, Christoph

    2015-01-01

    By enabling the estimation of difficult-to-measure target variables using available indirect measurements, mechanistic soft sensors have become important tools for various bioprocess monitoring and control scenarios. Despite promising higher process efficiencies and increased process understanding, widespread application of soft sensors has been stalled by uncertainty about the feasibility and reliability of their estimations given present process analytical constraints. Observability analysis can provide an indication of the possibility and reliability of soft sensor estimations by analyzing the structural properties of first-principle (mechanistic) models. In addition, it can provide a criteria for selection of suitable measurement methods with respect to their information content; thereby leading to successful implementation of soft sensors in bioprocess development and manufacturing environments. We demonstrate the utility of observability analysis for two classes of upstream bioprocesses: the processes involving growth and ethanol formation by Saccharomyces cerevisiae and the process of penicillin production by Penicillium chrysogenum. Results obtained from laboratory-scale cultivations in addition to in-silico experiments enable a comparison of theoretical aspects of observability analysis and the real-life performance of soft sensors. By taking the expected error of measurements provided to the soft sensor into account, an innovative scaling approach facilitates a higher degree of comparability of observability results among various measurement configurations and process conditions.

  3. Mechanistic fracture criteria for the failure of human cortical bone

    SciTech Connect

    Nalla, Ravi K.; Kinney, John H.; Ritchie, Robert O.

    2002-12-13

    A mechanistic understanding of fracture in human bone is critical to predicting fracture risk associated with age and disease. Despite extensive work, a mechanistic framework for describing how the underlying microstructure affects the failure mode in bone is lacking.

  4. New mechanistic interpretations for nitrone reactivity.

    PubMed

    Merino, Pedro; Tejero, Tomás; Delso, Ignacio; Matute, Rosa

    2017-03-22

    The reactivity of nitrones in cycloadditions and related reactions is revisited by introducing a topological perspective. In particular, the study of electron localization function (ELF) along a reaction pathway allows evaluating bond reorganization showing that in several cases the bonds are formed in a sequential way, the second one being formed once the first one is already formed. Both classical 1,3-dipolar cycloadditions and Mannich-type reactions revealed unexpected features often underestimated in classical mechanistic studies.

  5. [Underreporting of tuberculosis in the Information System on Notifiable Diseases (SINAN): primary default and case detection from additional data sources using probabilistic record linkage].

    PubMed

    Pinheiro, Rejane Sobrino; Andrade, Vanusa de Lemos; Oliveira, Gisele Pinto de

    2012-08-01

    This study aimed to analyze underreporting of tuberculosis (TB) cases in the Information System on Notifiable Diseases (SINAN), based on the following data sources: Mortality Information System (SIM), Registry and Follow-up Book for TB Case Treatment (LPATB), and Laboratory Registry Book (LRLAB). Probabilistic record linkage was used between the SIM (2007-2008) and SINAN (2002-2008). A search was conducted in LPATB and LRLAB (2007-2008) for cases not recorded in SINAN. There were 125 deaths, of which 44.8% were not recorded in SINAN. In LPATB, 58 cases (5.1%) were in treatment and were not reported in SINAN. LRLAB showed 32 smear-positive cases not reported to SINAN and without treatment, representing primary default. Addition of the retrieved cases, led to a 14.6% increase in the incidence rate in 2007 and 11.6% in 2008. Underreporting of deaths from or with TB in the Mortality Information System and primary default revealed difficulties in access to adequate and timely treatment, calling for rethinking of strategies to detect cases for timely treatment.

  6. A Mechanistic Study of Arsenic (III) Rejection by Reverse Osmosis and Nanofiltration Membranes

    ERIC Educational Resources Information Center

    Suzuki, Tasuma

    2009-01-01

    Reverse osmosis/nanofiltration (RO/NF) membranes are capable to provide an effective barrier for a wide range of contaminants (including disinfection by-products precursors) in a single treatment step. However, solute rejection mechanisms by RO/NF membranes are not well understood. The lack of mechanistic information arises from experimental…

  7. MECHANISTIC INFORMATION ON DISINFECTION BY-PRODUCTS FOR RISK ASSESSMENT

    EPA Science Inventory

    Colon cancer is the second most common cancer in people from developed countries, and populations exposed t o 50?g/L or more of trihalomethanes for at 1east 35 years have been estimated to be 1.5 times more likely to develop colon cancer. Trihalomethanes are one of the classes ...

  8. New web-based applications for mechanistic case diagramming.

    PubMed

    Dee, Fred R; Haugen, Thomas H; Kreiter, Clarence D

    2014-01-01

    The goal of mechanistic case diagraming (MCD) is to provide students with more in-depth understanding of cause and effect relationships and basic mechanistic pathways in medicine. This will enable them to better explain how observed clinical findings develop from preceding pathogenic and pathophysiological events. The pedagogic function of MCD is in relating risk factors, disease entities and morphology, signs and symptoms, and test and procedure findings in a specific case scenario with etiologic pathogenic and pathophysiological sequences within a flow diagram. In this paper, we describe the addition of automation and predetermined lists to further develop the original concept of MCD as described by Engelberg in 1992 and Guerrero in 2001. We demonstrate that with these modifications, MCD is effective and efficient in small group case-based teaching for second-year medical students (ratings of ~3.4 on a 4.0 scale). There was also a significant correlation with other measures of competency, with a 'true' score correlation of 0.54. A traditional calculation of reliability showed promising results (α =0.47) within a low stakes, ungraded environment. Further, we have demonstrated MCD's potential for use in independent learning and TBL. Future studies are needed to evaluate MCD's potential for use in medium stakes assessment or self-paced independent learning and assessment. MCD may be especially relevant in returning students to the application of basic medical science mechanisms in the clinical years.

  9. Real-time forecasting of infectious disease dynamics with a stochastic semi-mechanistic model.

    PubMed

    Funk, Sebastian; Camacho, Anton; Kucharski, Adam J; Eggo, Rosalind M; Edmunds, W John

    2016-12-16

    Real-time forecasts of infectious diseases can help public health planning, especially during outbreaks. If forecasts are generated from mechanistic models, they can be further used to target resources or to compare the impact of possible interventions. However, paremeterising such models is often difficult in real time, when information on behavioural changes, interventions and routes of transmission are not readily available. Here, we present a semi-mechanistic model of infectious disease dynamics that was used in real time during the 2013-2016 West African Ebola epidemic, and show fits to a Ebola Forecasting Challenge conducted in late 2015 with simulated data mimicking the true epidemic. We assess the performance of the model in different situations and identify strengths and shortcomings of our approach. Models such as the one presented here which combine the power of mechanistic models with the flexibility to include uncertainty about the precise outbreak dynamics may be an important tool in combating future outbreaks.

  10. Computer-assisted mechanistic structure-activity studies: application to diverse classes of chemical carcinogens.

    PubMed Central

    Loew, G H; Poulsen, M; Kirkjian, E; Ferrell, J; Sudhindra, B S; Rebagliati, M

    1985-01-01

    In the first part of this paper we have indicated how the techniques and capabilities of theoretical chemistry, together with experimental results, can be used in a mechanistic approach to structure-activity studies of toxicity. In the second part, we have illustrated how this computer-assisted approach has been used to identify and calculate causally related molecular indicators of relative carcinogenic activity in five classes of chemical carcinogens: polycyclic aromatic hydrocarbons and their methyl derivatives, aromatic amines, chloroethanes, chloroalkenes and dialkyl nitrosamines. In each class of chemicals studied, candidate molecular indicators have been identified that could be useful in predictive screening of unknown compounds. In addition, further insights into some mechanistic aspects of chemical carcinogenesis have been obtained. Finally, experiments have been suggested to both verify the usefulness of the indicators and test their mechanistic implications. PMID:3905382

  11. Fuel characteristics pertinent to the design of aircraft fuel systems, Supplement I : additional information on MIL-F-7914(AER) grade JP-5 fuel and several fuel oils

    NASA Technical Reports Server (NTRS)

    Barnett, Henry C; Hibbard, Robert R

    1953-01-01

    Since the release of the first NACA publication on fuel characteristics pertinent to the design of aircraft fuel systems (NACA-RM-E53A21), additional information has become available on MIL-F7914(AER) grade JP-5 fuel and several of the current grades of fuel oils. In order to make this information available to fuel-system designers as quickly as possible, the present report has been prepared as a supplement to NACA-RM-E53A21. Although JP-5 fuel is of greater interest in current fuel-system problems than the fuel oils, the available data are not as extensive. It is believed, however, that the limited data on JP-5 are sufficient to indicate the variations in stocks that the designer must consider under a given fuel specification. The methods used in the preparation and extrapolation of data presented in the tables and figures of this supplement are the same as those used in NACA-RM-E53A21.

  12. Mechanistic studies of carbon monoxide reduction

    SciTech Connect

    Geoffroy, G.L.

    1990-06-12

    The progress made during the current grant period (1 January 1988--1 April 1990) in three different areas of research is summarized. The research areas are: (1) oxidatively-induced double carbonylation reactions to form {alpha}-ketoacyl complexes and studies of the reactivity of the resulting compounds, (2) mechanistic studies of the carbonylation of nitroaromatics to form isocyanates, carbamates, and ureas, and (3) studies of the formation and reactivity of unusual metallacycles and alkylidene ligands supported on binuclear iron carbonyl fragments. 18 refs., 5 figs., 1 tab.

  13. Mechanistic facility safety and source term analysis

    SciTech Connect

    PLYS, M.G.

    1999-06-09

    A PC-based computer program was created for facility safety and source term analysis at Hanford The program has been successfully applied to mechanistic prediction of source terms from chemical reactions in underground storage tanks, hydrogen combustion in double contained receiver tanks, and proccss evaluation including the potential for runaway reactions in spent nuclear fuel processing. Model features include user-defined facility room, flow path geometry, and heat conductors, user-defined non-ideal vapor and aerosol species, pressure- and density-driven gas flows, aerosol transport and deposition, and structure to accommodate facility-specific source terms. Example applications are presented here.

  14. Composite Nanomechanics: A Mechanistic Properties Prediction

    NASA Technical Reports Server (NTRS)

    Chamis, Christos C.; Handler, Louis M.; Manderscheid, Jane M.

    2007-01-01

    A unique mechanistic theory is described to predict the properties of nanocomposites. The theory is based on composite micromechanics with progressive substructuring down to a nanoscale slice of a nanofiber where all the governing equations are formulated. These equations have been programmed in a computer code. That computer code is used to predict 25 properties of a mononanofiber laminate. The results are presented graphically and discussed with respect to their practical significance. Most of the results show smooth distributions. Results for matrix-dependent properties show bimodal through-the-thickness distribution with discontinuous changes from mode to mode.

  15. Composite Nanomechanics: A Mechanistic Properties Prediction

    NASA Technical Reports Server (NTRS)

    Chamis, Christos C.; Handler, Louis M.; Manderscheid, Jane M.

    2007-01-01

    A unique mechanistic theory is described to predict the properties of nanocomposites. The theory is based on composite micromechanics with progressive substructuring down to a nanoscale slice of a nanofiber where all the governing equations are formulated. These equations hav e been programmed in a computer code. That computer code is used to predict 25 properties of a mononanofiber laminate. The results are pr esented graphically and discussed with respect to their practical sig nificance. Most of the results show smooth distributions. Results for matrix-dependent properties show bimodal through-the-thickness distr ibution with discontinuous changes from mode to mode.

  16. Mechanistic determinants of biotherapeutics absorption following SC administration.

    PubMed

    Richter, Wolfgang F; Bhansali, Suraj G; Morris, Marilyn E

    2012-09-01

    The subcutaneous (SC) route is of growing interest for the administration of biotherapeutics. Key products on the biotherapeutic market such as insulins, but also several immunoglobulins or Fc-fusion proteins, are administered SC. Despite the importance of the SC route, the available knowledge about the processes involved in the SC absorption of biotherapeutics is limited. This review summarizes available information on the physiology of the SC tissue and on the pharmacokinetic processes after SC administration including "first pass catabolism" at the administration site as well as transport in the extracellular matrix of the SC tissue, followed by absorption into the blood circulation or the lymphatic system. Both monoclonal antibodies and other biotherapeutics are discussed. Determinants of absorption after SC administration are summarized including compound properties such as charge or molecular weight. Scale-up of animal data to humans is discussed, including the current shortcomings of empirical scaling approaches and the lack of suitable mechanistic approaches.

  17. From patterns to emerging processes in mechanistic urban ecology.

    PubMed

    Shochat, Eyal; Warren, Paige S; Faeth, Stanley H; McIntyre, Nancy E; Hope, Diane

    2006-04-01

    Rapid urbanization has become an area of crucial concern in conservation owing to the radical changes in habitat structure and loss of species engendered by urban and suburban development. Here, we draw on recent mechanistic ecological studies to argue that, in addition to altered habitat structure, three major processes contribute to the patterns of reduced species diversity and elevated abundance of many species in urban environments. These activities, in turn, lead to changes in animal behavior, morphology and genetics, as well as in selection pressures on animals and plants. Thus, the key to understanding urban patterns is to balance studying processes at the individual level with an integrated examination of environmental forces at the ecosystem scale.

  18. Appropriateness of mechanistic and non-mechanistic models for the application of ultrafiltration to mixed waste

    SciTech Connect

    Foust, Henry; Ghosehajra, Malay

    2007-07-01

    This study asks two questions: (1) How appropriate is the use of a basic filtration equation to the application of ultrafiltration of mixed waste, and (2) How appropriate are non-parametric models for permeate rates (volumes)? To answer these questions, mechanistic and non-mechanistic approaches are developed for permeate rates and volumes associated with an ultrafiltration/mixed waste system in dia-filtration mode. The mechanistic approach is based on a filtration equation which states that t/V vs. V is a linear relationship. The coefficients associated with this linear regression are composed of physical/chemical parameters of the system and based the mass balance equation associated with the membrane and associated developing cake layer. For several sets of data, a high correlation is shown that supports the assertion that t/V vs. V is a linear relationship. It is also shown that non-mechanistic approaches, i.e., the use of regression models to are not appropriate. One models considered is Q(p) = a*ln(Cb)+b. Regression models are inappropriate because the scale-up from a bench scale (pilot scale) study to full-scale for permeate rates (volumes) is not simply the ratio of the two membrane surface areas. (authors)

  19. Tear gas: an epidemiological and mechanistic reassessment

    PubMed Central

    Rothenberg, Craig; Achanta, Satyanarayana; Svendsen, Erik R.

    2016-01-01

    Deployments of tear gas and pepper spray have rapidly increased worldwide. Large amounts of tear gas have been used in densely populated cities, including Cairo, Istanbul, Rio de Janeiro, Manama (Bahrain), and Hong Kong. In the United States, tear gas was used extensively during recent riots in Ferguson, Missouri. Whereas tear gas deployment systems have rapidly improved—with aerial drone systems tested and requested by law enforcement—epidemiological and mechanistic research have lagged behind and have received little attention. Case studies and recent epidemiological studies revealed that tear gas agents can cause lung, cutaneous, and ocular injuries, with individuals affected by chronic morbidities at high risk for complications. Mechanistic studies identified the ion channels TRPV1 and TRPA1 as targets of capsaicin in pepper spray, and of the tear gas agents chloroacetophenone, CS, and CR. TRPV1 and TRPA1 localize to pain‐sensing peripheral sensory neurons and have been linked to acute and chronic pain, cough, asthma, lung injury, dermatitis, itch, and neurodegeneration. In animal models, transient receptor potential inhibitors show promising effects as potential countermeasures against tear gas injuries. On the basis of the available data, a reassessment of the health risks of tear gas exposures in the civilian population is advised, and development of new countermeasures is proposed. PMID:27391380

  20. Tear gas: an epidemiological and mechanistic reassessment.

    PubMed

    Rothenberg, Craig; Achanta, Satyanarayana; Svendsen, Erik R; Jordt, Sven-Eric

    2016-08-01

    Deployments of tear gas and pepper spray have rapidly increased worldwide. Large amounts of tear gas have been used in densely populated cities, including Cairo, Istanbul, Rio de Janeiro, Manama (Bahrain), and Hong Kong. In the United States, tear gas was used extensively during recent riots in Ferguson, Missouri. Whereas tear gas deployment systems have rapidly improved-with aerial drone systems tested and requested by law enforcement-epidemiological and mechanistic research have lagged behind and have received little attention. Case studies and recent epidemiological studies revealed that tear gas agents can cause lung, cutaneous, and ocular injuries, with individuals affected by chronic morbidities at high risk for complications. Mechanistic studies identified the ion channels TRPV1 and TRPA1 as targets of capsaicin in pepper spray, and of the tear gas agents chloroacetophenone, CS, and CR. TRPV1 and TRPA1 localize to pain-sensing peripheral sensory neurons and have been linked to acute and chronic pain, cough, asthma, lung injury, dermatitis, itch, and neurodegeneration. In animal models, transient receptor potential inhibitors show promising effects as potential countermeasures against tear gas injuries. On the basis of the available data, a reassessment of the health risks of tear gas exposures in the civilian population is advised, and development of new countermeasures is proposed.

  1. Mechanistic Insight in the Function of Phosphite Additives for Protection of LiNi 0.5 Co 0.2 Mn 0.3 O 2 Cathode in High Voltage Li-Ion Cells

    SciTech Connect

    He, Meinan; Su, Chi-Cheung; Peebles, Cameron; Feng, Zhenxing; Connell, Justin G.; Liao, Chen; Wang, Yan; Shkrob, Ilya A.; Zhang, Zhengcheng

    2016-05-11

    Triethlylphosphite (TEP) and tris(2,2,2-trifluoroethyl) phosphite (TTFP) have been evaluated as electrolyte additives for high-voltage Li-ion battery cells using a Ni-rich layered cathode material LiNi0.5Co0.2Mn0.3O2 (NCM523) and the conventional carbonate electrolyte. The repeated charge/discharge cycling for cells containing 1 wt% of these additives was performed using an NCM523/graphite full cell operated at the voltage window from 3.0 to 4.6 V. During the initial charge process, these additives decompose on the cathode surface at a lower oxidation potential than the baseline electrolyte. Impedance spectroscopy and post-test analyses indicate the formation of protective coatings by both additives on the cathode surface that prevent oxidative breakdown of the electrolyte. However, only TTFP containing cells demonstrate the improved capacity retention and Coulombic efficiency. For TEP, the protective coating is also formed, but low Li+ ion mobility through the interphase layer results in inferior performance. These observations are rationalized through the inhibition of electrocatalytic centers present on the cathode surface and the formation of organophosphate deposits isolating the cathode surface from the electrolyte. The difference between the two phosphites clearly originates in the different properties of the resulting phosphate coatings, which may be in Li+ ion conductivity through such materials.

  2. Food additives

    PubMed Central

    Spencer, Michael

    1974-01-01

    Food additives are discussed from the food technology point of view. The reasons for their use are summarized: (1) to protect food from chemical and microbiological attack; (2) to even out seasonal supplies; (3) to improve their eating quality; (4) to improve their nutritional value. The various types of food additives are considered, e.g. colours, flavours, emulsifiers, bread and flour additives, preservatives, and nutritional additives. The paper concludes with consideration of those circumstances in which the use of additives is (a) justified and (b) unjustified. PMID:4467857

  3. BPI-ANCA Provides Additional Clinical Information to Anti-Pseudomonas Serology: Results from a Cohort of 117 Swedish Cystic Fibrosis Patients.

    PubMed

    Lindberg, Ulrika; Carlsson, Malin; Hellmark, Thomas; Segelmark, Mårten

    2015-01-01

    Patients with cystic fibrosis (CF) colonized with Pseudomonas aeruginosa (P. aeruginosa) have worse prognosis compared with patients who are not. BPI-ANCA is an anti-neutrophil cytoplasmic antibody against BPI (bactericidal/permeability increasing protein) correlating with P. aeruginosa colonization and adverse long time prognosis. Whether it provides additional information as compared to standard anti-P. aeruginosa serology tests is not known. 117 nontransplanted CF patients at the CF centre in Lund, Sweden, were followed prospectively for ten years. Bacterial colonisation was classified according to the Leeds criteria. IgA BPI-ANCA was compared with assays for antibodies against alkaline protease (AP), Elastase (ELA), and Exotoxin A (ExoA). Lung function and patient outcome, alive, lung transplanted, or dead, were registered. BPI-ANCA showed the highest correlation with lung function impairment with an r-value of 0.44. Forty-eight of the 117 patients were chronically colonized with P. aeruginosa. Twenty of these patients experienced an adverse outcome. Receiver operator curve (ROC) analysis revealed that this could be predicted by BPI-ANCA (AUC = 0.77), (p = 0.002) to a better degree compared with serology tests. BPI-ANCA correlates better with lung function impairment and long time prognosis than anti-P. aeruginosa serology and has similar ability to identify patients with chronic P. aeruginosa.

  4. Reaction Coordinates and Mechanistic Hypothesis Tests

    NASA Astrophysics Data System (ADS)

    Peters, Baron

    2016-05-01

    Reaction coordinates are integral to several classic rate theories that can (a) predict kinetic trends across conditions and homologous reactions, (b) extract activation parameters with a clear physical interpretation from experimental rates, and (c) enable efficient calculations of free energy barriers and rates. New trajectory-based rare events methods can provide rates directly from dynamical trajectories without a reaction coordinate. Trajectory-based frameworks can also generate ideal (but abstract) reaction coordinates such as committors and eigenfunctions of the master equation. However, rates and mechanistic insights obtained from trajectory-based methods and abstract coordinates are not readily generalized across simulation conditions or reaction families. We discuss methods for identifying physically meaningful reaction coordinates, including committor analysis, variational transition state theory, Kramers-Langer-Berezhkovskii-Szabo theory, and statistical inference methods that can use path sampling data to screen, mix, and optimize thousands of trial coordinates. Special focus is given to likelihood maximization and inertial likelihood maximization approaches.

  5. Mechanistic issues in asparagine synthetase catalysis.

    PubMed

    Richards, N G; Schuster, S M

    1998-01-01

    The enzymatic synthesis of asparagine is an ATP-dependent process that utilizes the nitrogen atom derived from either glutamine or ammonia. Despite a long history of kinetic and mechanistic investigation, there is no universally accepted catalytic mechanism for this seemingly straightforward carboxyl group activating enzyme, especially as regards those steps immediately preceding amide bond formation. This chapter considers four issues dealing with the mechanism: (a) the structural organization of the active site(s) partaking in glutamine utilization and aspartate activation; (b) the relationship of asparagine synthetase to other amidotransferases; (c) the way in which ATP is used to activate the beta-carboxyl group; and (d) the detailed mechanism by which nitrogen is transferred.

  6. Obesity, Diabetes and Cancer: A Mechanistic Perspective

    PubMed Central

    Cifarelli, V; Hursting, SD

    2016-01-01

    Nearly 35% of adults and 20% of children in the United States are obese, defined as having a body mass index (BMI) ≥ 30 kg/m2. Obesity is an established risk factor for many cancers, and obesity-associated metabolic perturbations often manifest in Type 2 diabetes mellitus and/or the metabolic syndrome. As part of the growth-promoting, proinflammatory microenvironment of the obese and/or diabetic state, crosstalk between macrophages, adipocytes, and epithelial cells occurs via metabolically-regulated hormones, cytokines, and other mediators to enhance cancer risk and/or progression. This review synthesizes the evidence on key biological mechanisms underlying the associations between obesity, diabetes and cancer, with particular emphasis on enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent mechanistic targets for disrupting the obesity-diabetes-cancer link, and several diabetes drugs, such as metformin and rosiglitazone, are being intensely studied for repurposing as cancer chemopreventive agents.

  7. Mechanistic interplay between ceramide and insulin resistance

    PubMed Central

    Reali, Federico; Morine, Melissa J.; Kahramanoğulları, Ozan; Raichur, Suryaprakash; Schneider, Hans-Christoph; Crowther, Daniel; Priami, Corrado

    2017-01-01

    Recent research adds to a growing body of literature on the essential role of ceramides in glucose homeostasis and insulin signaling, while the mechanistic interplay between various components of ceramide metabolism remains to be quantified. We present an extended model of C16:0 ceramide production through both the de novo synthesis and the salvage pathways. We verify our model with a combination of published models and independent experimental data. In silico experiments of the behavior of ceramide and related bioactive lipids in accordance with the observed transcriptomic changes in obese/diabetic murine macrophages at 5 and 16 weeks support the observation of insulin resistance only at the later phase. Our analysis suggests the pivotal role of ceramide synthase, serine palmitoyltransferase and dihydroceramide desaturase involved in the de novo synthesis and the salvage pathways in influencing insulin resistance versus its regulation. PMID:28112248

  8. Parameter and uncertainty estimation for mechanistic, spatially explicit epidemiological models

    NASA Astrophysics Data System (ADS)

    Finger, Flavio; Schaefli, Bettina; Bertuzzo, Enrico; Mari, Lorenzo; Rinaldo, Andrea

    2014-05-01

    Epidemiological models can be a crucially important tool for decision-making during disease outbreaks. The range of possible applications spans from real-time forecasting and allocation of health-care resources to testing alternative intervention mechanisms such as vaccines, antibiotics or the improvement of sanitary conditions. Our spatially explicit, mechanistic models for cholera epidemics have been successfully applied to several epidemics including, the one that struck Haiti in late 2010 and is still ongoing. Calibration and parameter estimation of such models represents a major challenge because of properties unusual in traditional geoscientific domains such as hydrology. Firstly, the epidemiological data available might be subject to high uncertainties due to error-prone diagnosis as well as manual (and possibly incomplete) data collection. Secondly, long-term time-series of epidemiological data are often unavailable. Finally, the spatially explicit character of the models requires the comparison of several time-series of model outputs with their real-world counterparts, which calls for an appropriate weighting scheme. It follows that the usual assumption of a homoscedastic Gaussian error distribution, used in combination with classical calibration techniques based on Markov chain Monte Carlo algorithms, is likely to be violated, whereas the construction of an appropriate formal likelihood function seems close to impossible. Alternative calibration methods, which allow for accurate estimation of total model uncertainty, particularly regarding the envisaged use of the models for decision-making, are thus needed. Here we present the most recent developments regarding methods for parameter and uncertainty estimation to be used with our mechanistic, spatially explicit models for cholera epidemics, based on informal measures of goodness of fit.

  9. From linked open data to molecular interaction: studying selectivity trends for ligands of the human serotonin and dopamine transporter† †The authors declare no competing interests. ‡ ‡Electronic supplementary information (ESI) available. See DOI: 10.1039/c6md00207b Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.

    PubMed Central

    Hellsberg, Eva; Viereck, Michael; Ecker, Gerhard F.

    2016-01-01

    Retrieval of congeneric and consistent SAR data sets for protein targets of interest is still a laborious task to do if no appropriate in-house data set is available. However, combining integrated open data sources (such as the Open PHACTS Discovery Platform) with workflow tools now offers the possibility of querying across multiple domains and tailoring the search to the given research question. Starting from two phylogenetically related protein targets of interest (the human serotonin and dopamine transporters), the whole chemical compound space was explored by implementing a scaffold-based clustering of compounds possessing biological measurements for both targets. In addition, potential hERG blocking liabilities were included. The workflow allowed studying the selectivity trends of scaffold series, identifying potentially harmful compound series, and performing SAR, docking studies and molecular dynamics (MD) simulations for a consistent data set of 56 cathinones. This delivered useful insights into driving determinants for hDAT selectivity over hSERT. With respect to the scaffold-based analyses it should be noted that the cathinone data set could be retrieved only when Murcko scaffold analyses were combined with similarity searches such as a common substructure search. PMID:27891211

  10. Food additives

    MedlinePlus

    ... or natural. Natural food additives include: Herbs or spices to add flavor to foods Vinegar for pickling ... Certain colors improve the appearance of foods. Many spices, as well as natural and man-made flavors, ...

  11. A windows based mechanistic subsidence prediction model for longwall mining

    SciTech Connect

    Begley, R.; Beheler, P.; Khair, A.W.

    1996-12-31

    The previously developed Mechanistic Subsidence Prediction Model (MSPM) has been incorporated into the graphical interface environment of MS Windows. MSPM has the unique capability of predicting maximum subsidence, angle of draw and the subsidence profile of a longwall panel at various locations for both the transverse and longitudinal orientations. The resultant enhanced model can be operated by individuals with little knowledge of subsidence prediction theories or little computer programming experience. In addition, predictions of subsidence can be made in a matter of seconds without the need to develop input data files or use the keyboard in some cases. The predictions are based upon the following input parameters: panel width, mining height, overburden depth, rock quality designation, and percent hard rock in the immediate roof, main roof and the entire overburden. The recently developed enhanced model has the capability to compare predictions in a graphical format for one half of the predicted subsidence profile based upon changes in input parameters easily and instantly on the same screen. In addition another screen can be obtained from a pull down menu where the operator can compare predictions for the entire subsidence profiles. This paper presents the background of the subsidence prediction model and the methodology of the enhanced model development. The paper also presents comparisons of subsidence predictions for several different sets of input parameters in addition to comparisons of the subsidence predictions with actual field data.

  12. Are Mechanistic and Statistical QSAR Approaches Really Different? MLR Studies on 158 Cycloalkyl-Pyranones.

    PubMed

    Bhhatarai, Barun; Garg, Rajni; Gramatica, Paola

    2010-07-12

    Two parallel approaches for quantitative structure-activity relationships (QSAR) are predominant in literature, one guided by mechanistic methods (including read-across) and another by the use of statistical methods. To bridge the gap between these two approaches and to verify their main differences, a comparative study of mechanistically relevant and statistically relevant QSAR models, developed on a case study of 158 cycloalkyl-pyranones, biologically active on inhibition (Ki ) of HIV protease, was performed. Firstly, Multiple Linear Regression (MLR) based models were developed starting from a limited amount of molecular descriptors which were widely proven to have mechanistic interpretation. Then robust and predictive MLR models were developed on the same set using two different statistical approaches unbiased of input descriptors. Development of models based on Statistical I method was guided by stepwise addition of descriptors while Genetic Algorithm based selection of descriptors was used for the Statistical II. Internal validation, the standard error of the estimate, and Fisher's significance test were performed for both the statistical models. In addition, external validation was performed for Statistical II model, and Applicability Domain was verified as normally practiced in this approach. The relationships between the activity and the important descriptors selected in all the models were analyzed and compared. It is concluded that, despite the different type and number of input descriptors, and the applied descriptor selection tools or the algorithms used for developing the final model, the mechanistical and statistical approach are comparable to each other in terms of quality and also for mechanistic interpretability of modelling descriptors. Agreement can be observed between these two approaches and the better result could be a consensus prediction from both the models.

  13. Territoriality and home-range dynamics in meerkats, Suricata suricatta: a mechanistic modelling approach.

    PubMed

    Bateman, Andrew W; Lewis, Mark A; Gall, Gabriella; Manser, Marta B; Clutton-Brock, Tim H

    2015-01-01

    Multiple approaches exist to model patterns of space use across species, among them resource selection analysis, statistical home-range modelling and mechanistic movement modelling. Mechanistic home-range models combine the benefits of these approaches, describing emergent territorial patterns based on fine-scale individual- or group-movement rules and incorporating interactions with neighbours and the environment. These models have not, to date, been extended to dynamic contexts. Using mechanistic home-range models, we explore meerkat (Suricata suricatta) territorial patterns, considering scent marking, direct group interactions and habitat selection. We also extend the models to accommodate dynamic aspects of meerkat territoriality (territory development and territory shift). We fit models, representing multiple working hypotheses, to data from a long-term meerkat study in South Africa, and we compare models using Akaike's and Bayesian Information Criteria. Our results identify important features of meerkat territorial patterns. Notably, larger groups do not seem to control larger territories, and groups apparently prefer dune edges along a dry river bed. Our model extensions capture instances in which 1) a newly formed group interacts more strongly with its parent groups over time and 2) a group moves its territory core out of aversive habitat. This extends our mechanistic modelling framework in previously unexplored directions.

  14. Predictive mechanistic bioenergetics to model habitat suitability of shellfish culture in coastal lakes

    NASA Astrophysics Data System (ADS)

    Rinaldi, A.; Montalto, V.; Manganaro, A.; Mazzola, A.; Mirto, S.; Sanfilippo, M.; Sarà, G.

    2014-05-01

    Quantitative tools based on mechanistic modelling of functional traits able to enhance the sustainability of aquaculture and most other human activities (i.e. reducing the likelihood of detrimental impacts optimising productions), are especially important factors in the decision to site aquaculture facilities in coastal lakes, ponds and lagoons and, in the case of detrimental impact, to adopt mitigation measures. We tested the ability of mechanistic functional trait based models to predict life history traits of cultivable shellfish in shallow coastal lakes. Dynamic Energy Budget (DEB) models were run to generate spatially explicit predictions of Mytilus galloprovincialis life history (LH) traits (e.g. body size and fecundity). Using fortnightly data of food supply and hourly data of body temperatures, and exploiting the power of mechanistic rules, we estimated the amount of faeces ejected by a fixed quantity of organisms cultivated in two shallow Southern Mediterranean (Sicily) lakes. These differed in terms of temperature and food density, implying large differences in life history traits of mussels in the two study areas. This information could help facilitate the selection of sites where environmental conditions are more suitable for aquaculture and contextually compatible with sustainability. The validation exercise obtained by comparing the predicted and observed data was nearly consistent. Therefore, a mechanistic functional traits-based model seems able to capture the link between habitat characteristics and functional traits of organisms, delineating the fundamental portion of an ecological niche, the possibility of predicting LH traits and potential ecological applications in the management of natural coastal resources.

  15. Intriguing mechanistic labyrinths in gold(i) catalysis

    PubMed Central

    Obradors, Carla

    2014-01-01

    Many mechanistically intriguing reactions have been developed in the last decade using gold(i) as catalyst. Here we review the main mechanistic proposals in gold-catalysed activation of alkynes and allenes, in which this metal plays a central role by stabilising a variety of complex cationic intermediates. PMID:24176910

  16. Infection and atherosclerosis: emerging mechanistic paradigms.

    PubMed

    Epstein, S E; Zhou, Y F; Zhu, J

    1999-07-27

    Although definitive proof of a causal role of infection contributing to atherogenesis is lacking, multiple investigations have demonstrated that infectious agents evoke cellular and molecular changes supportive of such a role. Moreover, both Chlamydia pneumoniae and cytomegalovirus exacerbate lesion development in animal models of atherosclerosis and restenosis. The fact that multiple pathogens have been associated with atherosclerosis implies that many "atherogenic" pathogens exist, and recent data suggest that the risk of atherosclerosis conveyed by infection relates to the number of atherogenic pathogens with which an individual is infected. It also is evident that variability in host susceptibility to the atherogenic effects of pathogens exists; this variability appears to be related at least in part to whether the host can generate an immune response that successfully controls pathogen inflammatory activity and in part to the specific pattern of immune response--humoral or cellular. The latter may relate to host capacity to control pathogen activity and to a pathogen-induced autoimmune component of the atherogenic process. Additional animal and human studies are necessary to further test the validity of the infection/atherosclerosis link and to provide more insight into the mechanisms by which infection may contribute to atherosclerosis, information critical for devising strategies to reduce or eliminate any contribution to atherosclerosis caused by infection.

  17. Mechanistically based mapping of human cardiac fibrillation

    PubMed Central

    Zaman, Junaid A. B.

    2016-01-01

    Abstract The mechanisms underpinning human cardiac fibrillation remain elusive. In his 1913 paper ‘On dynamic equilibrium in the heart’, Mines proposed that an activation wave front could propagate repeatedly in a circle, initiated by a stimulus in the vulnerable period. While the dynamics of activation and recovery are central to cardiac fibrillation, these physiological data are rarely used in clinical mapping. Fibrillation is a rapid irregular rhythm with spatiotemporal disorder resulting from two fundamental mechanisms – sources in preferred cardiac regions or spatially diffuse self‐sustaining activity, i.e. with no preferred source. On close inspection, however, this debate may also reflect mapping technique. Fibrillation is initiated from triggers by regional dispersion in repolarization, slow conduction and wavebreak, then sustained by non‐uniform interactions of these mechanisms. Notably, optical mapping of action potentials in atrial fibrillation (AF) show spiral wave sources (rotors) in nearly all studies including humans, while most traditional electrogram analyses of AF do not. Techniques may diverge in fibrillation because electrograms summate non‐coherent waves within an undefined field whereas optical maps define waves with a visually defined field. Also fibrillation operates at the limits of activation and recovery, which are well represented by action potentials while fibrillatory electrograms poorly represent repolarization. We conclude by suggesting areas for study that may be used, until such time as optical mapping is clinically feasible, to improve mechanistic understanding and therapy of human cardiac fibrillation. PMID:26607671

  18. Mechanistic simulation of line-edge roughness

    NASA Astrophysics Data System (ADS)

    Biafore, John J.; Smith, Mark D.; Robertson, Stewart A.; Graves, Trey

    2007-03-01

    Physically-based photoresist models, such as those in PROLITH, have been very successful in describing photolithography from a continuum standpoint. These models allow engineers to accurately predict the final resist CD on the wafer and to analyze process robustness. However, as the critical dimension continues to shrink, yield-limiting phenomena are observed that are related to the molecular nature and reaction kinetics of photoresist materials. An example of these phenomena is line-edge roughness (LER). In this paper, the origin of LER is hypothesized to be caused by fluctuations occurring in the initial position of the reactants, fluctuations during the exposure process (shot noise) and fluctuations occurring during thermally-induced reaction-diffusion (post-exposure bake). We have developed a lattice-based mechanistic simulator to better understand the stochastic nature of reactant initial position, the exposure step, the importance of the discrete nature of the reactants, the coupling to the deprotection kinetics and the deep complexity evident in the diffusion-limited acid-quencher reaction.

  19. Mechanistic Reactive Burn Modeling of Solid Explosives

    SciTech Connect

    Y.Horie; Y.Hamate; D.Greening

    2003-04-01

    This report describes a computational framework for reactive burn modeling of solid explosives and the development of a test case where physical mechanisms represent RDX or RDX-based materials. The report is a sequel to LA-13794-MS, ''A Unifying Framework for Hot Spots and the Ignition of Energetic Materials,'' where we proposed a new approach to the building of a general purpose model that captures the essential features of the three primary origins of hot-spot formation: void collapse, shear banding, friction. The purpose of the present report is to describe the continuing task of coupling the unifying hot-spot model to hydrodynamic calculations to develop a mechanistic reactive burn model. The key components of the coupling include energy localization, the growth of hot spots, overall hot-spot behavior, and a phase-averaged mixture equation of state (EOS) in a Mie-Grueneisen form. The nucleation and growth of locally heated regions is modeled by a phenomenological treatment as well as a statistical model based on an exponential size distribution. The Mie-Grueneisen form of the EOS is one of many possible choices and is not a critical selection for implementing the model. In this report, model calculations are limited to proof-of-concept illustrations for shock loading. Results include (1) shock ignition and growth-to-detonation, (2) double shock ignition, and (3) quenching and reignition. A comparative study of Pop-plots is discussed based on the statistical model.

  20. Potlining Additives

    SciTech Connect

    Rudolf Keller

    2004-08-10

    In this project, a concept to improve the performance of aluminum production cells by introducing potlining additives was examined and tested. Boron oxide was added to cathode blocks, and titanium was dissolved in the metal pool; this resulted in the formation of titanium diboride and caused the molten aluminum to wet the carbonaceous cathode surface. Such wetting reportedly leads to operational improvements and extended cell life. In addition, boron oxide suppresses cyanide formation. This final report presents and discusses the results of this project. Substantial economic benefits for the practical implementation of the technology are projected, especially for modern cells with graphitized blocks. For example, with an energy savings of about 5% and an increase in pot life from 1500 to 2500 days, a cost savings of $ 0.023 per pound of aluminum produced is projected for a 200 kA pot.

  1. Phosphazene additives

    DOEpatents

    Harrup, Mason K; Rollins, Harry W

    2013-11-26

    An additive comprising a phosphazene compound that has at least two reactive functional groups and at least one capping functional group bonded to phosphorus atoms of the phosphazene compound. One of the at least two reactive functional groups is configured to react with cellulose and the other of the at least two reactive functional groups is configured to react with a resin, such as an amine resin of a polycarboxylic acid resin. The at least one capping functional group is selected from the group consisting of a short chain ether group, an alkoxy group, or an aryloxy group. Also disclosed are an additive-resin admixture, a method of treating a wood product, and a wood product.

  2. The attention schema theory: a mechanistic account of subjective awareness.

    PubMed

    Graziano, Michael S A; Webb, Taylor W

    2015-01-01

    We recently proposed the attention schema theory, a novel way to explain the brain basis of subjective awareness in a mechanistic and scientifically testable manner. The theory begins with attention, the process by which signals compete for the brain's limited computing resources. This internal signal competition is partly under a bottom-up influence and partly under top-down control. We propose that the top-down control of attention is improved when the brain has access to a simplified model of attention itself. The brain therefore constructs a schematic model of the process of attention, the 'attention schema,' in much the same way that it constructs a schematic model of the body, the 'body schema.' The content of this internal model leads a brain to conclude that it has a subjective experience. One advantage of this theory is that it explains how awareness and attention can sometimes become dissociated; the brain's internal models are never perfect, and sometimes a model becomes dissociated from the object being modeled. A second advantage of this theory is that it explains how we can be aware of both internal and external events. The brain can apply attention to many types of information including external sensory information and internal information about emotions and cognitive states. If awareness is a model of attention, then this model should pertain to the same domains of information to which attention pertains. A third advantage of this theory is that it provides testable predictions. If awareness is the internal model of attention, used to help control attention, then without awareness, attention should still be possible but should suffer deficits in control. In this article, we review the existing literature on the relationship between attention and awareness, and suggest that at least some of the predictions of the theory are borne out by the evidence.

  3. Exploiting the Imidazolium Effect in Base-free Ammonium Enolate Generation: Synthetic and Mechanistic Studies.

    PubMed

    Young, Claire M; Stark, Daniel G; West, Thomas H; Taylor, James E; Smith, Andrew D

    2016-11-07

    N-Acyl imidazoles and catalytic isothiourea hydrochloride salts function as ammonium enolate precursors in the absence of base. Enantioselective Michael addition-cyclization reactions using different α,β-unsaturated Michael acceptors have been performed to form dihydropyranones and dihydropyridinones with high stereoselectivity. Detailed mechanistic studies using RPKA have revealed the importance of the "imidazolium" effect in ammonium enolate formation and have highlighted key differences with traditional base-mediated processes.

  4. Mechanistic insights from comparing intrinsic clearance values between human liver microsomes and hepatocytes to guide drug design.

    PubMed

    Di, Li; Keefer, Christopher; Scott, Dennis O; Strelevitz, Timothy J; Chang, George; Bi, Yi-An; Lai, Yurong; Duckworth, Jonathon; Fenner, Katherine; Troutman, Matthew D; Obach, R Scott

    2012-11-01

    Metabolic stability of drug candidates are often determined in both liver microsome and hepatocyte assays. Comparison of intrinsic clearance values between the two assays provides additional information to guide drug design. Intrinsic clearance values from human liver microsomes and hepatocytes were compared for a set of commercial drugs with known metabolic pathways and transporter characteristics. The results showed that for compounds that were predominately metabolized by CYP mediated mechanisms, the intrinsic clearance values from the two assays were comparable. For compounds with non-CYP pathways, such as UGT and AO, intrinsic clearance was faster in hepatocytes than in microsomes. Substrates of uptake or efflux transporters in this study did not have significant differences of intrinsic clearance between microsomes and hepatocytes, when uptake into the hepatocytes was not the rate-limiting step. When hepatic uptake was rate limiting, intrinsic clearance in microsomes was faster than that in hepatocytes, which was more prevalent for compounds with rapid metabolism. Low passive permeability can limit the exposure to drug molecules to the metabolizing enzymes in the hepatocytes in relationship to the rate of metabolism. The faster the rate of metabolism, the higher permeability is needed for molecule to enter the cells and not becoming rate-limiting. The findings are very useful for drug discovery programs to gain additional insights on mechanistic information to help drug design without added experiments. Follow-up studies can then be designed to address specific questions.

  5. Ligand interactions with galactose oxidase: mechanistic insights.

    PubMed Central

    Whittaker, M M; Whittaker, J W

    1993-01-01

    Interactions between galactose oxidase and small molecules have been explored using a combination of optical absorption, circular dichroism, and electron paramagnetic resonance (EPR) spectroscopies to detect complex formation and characterize the products. Anions bind directly to the cupric center in both active and inactive galactose oxidase, converting to complexes with optical and EPR spectra that are distinctly different from those of the starting aquo enzyme. Azide binding is coupled to stoichiometric proton uptake by the enzyme, reflecting the generation of a strong base (pKa > 9) in the active site anion adduct. At low temperature, the aquo enzyme converts to a form that exhibits the characteristic optical and EPR spectra of an anion complex, apparently reflecting deprotonation of the coordinated water. Anion binding results in a loss of the optical transition arising from coordinated tyrosine, implying displacement of the axial tyrosine ligand on forming the adduct. Nitric oxide binds to galactose oxidase, forming a specific complex exhibiting an unusual EPR spectrum with all g values below 2. The absence of Cu splitting in this spectrum and the observation that the cupric EPR signal from the active site metal ion is not significantly decreased in the complex suggest a nonmetal interaction site for NO in galactose oxidase. These results have been interpreted in terms of a mechanistic scheme where substrate binding displaces a tyrosinate ligand from the active site cupric ion, generating a base that may serve to deprotonate the coordinated hydroxyl group of the substrate, activating it for oxidation. The protein-NO interactions may probe a nonmetal O2 binding site in this enzyme. PMID:8386015

  6. Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

    PubMed Central

    Reddy, B. K. Kishore; Landge, Sudhir; Ravishankar, Sudha; Patil, Vikas; Shinde, Vikas; Tantry, Subramanyam; Kale, Manoj; Raichurkar, Anandkumar; Menasinakai, Sreenivasaiah; Mudugal, Naina Vinay; Ambady, Anisha; Ghosh, Anirban; Tunduguru, Ragadeepthi; Kaur, Parvinder; Singh, Ragini; Kumar, Naveen; Bharath, Sowmya; Sundaram, Aishwarya; Bhat, Jyothi; Sambandamurthy, Vasan K.; Björkelid, Christofer; Jones, T. Alwyn; Das, Kaveri; Bandodkar, Balachandra; Malolanarasimhan, Krishnan; Mukherjee, Kakoli

    2014-01-01

    Pantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme A (CoA) biosynthesis. In our earlier reports, we had established that the type I isoform encoded by the coaA gene is an essential pantothenate kinase in Mycobacterium tuberculosis, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of PanK inhibitors. The present report summarizes the synthesis and expansion efforts to understand the structure-activity relationships leading to the optimization of enzyme inhibition along with antimycobacterial activity. Additionally, we report the progression of two distinct classes of inhibitors, the triazoles, which are ATP competitors, and the biaryl acetic acids, with a mixed mode of inhibition. Cocrystallization studies provided evidence of these inhibitors binding to the enzyme. This was further substantiated with the biaryl acids having MIC against the wild-type M. tuberculosis strain and the subsequent establishment of a target link with an upshift in MIC in a strain overexpressing PanK. On the other hand, the ATP competitors had cellular activity only in a M. tuberculosis knockdown strain with reduced PanK expression levels. Additionally, in vitro and in vivo survival kinetic studies performed with a M. tuberculosis PanK (MtPanK) knockdown strain indicated that the target levels have to be significantly reduced to bring in growth inhibition. The dual approaches employed here thus established the poor vulnerability of PanK in M. tuberculosis. PMID:24687493

  7. A movie of the RNA polymerase nucleotide addition cycle.

    PubMed

    Brueckner, Florian; Ortiz, Julio; Cramer, Patrick

    2009-06-01

    During gene transcription, RNA polymerase (Pol) passes through repetitive cycles of adding a nucleotide to the growing mRNA chain. Here we obtained a movie of the nucleotide addition cycle by combining structural information on different functional states of the Pol II elongation complex (EC). The movie illustrates the two-step loading of the nucleoside triphosphate (NTP) substrate, closure of the active site for catalytic nucleotide incorporation, and the presumed two-step translocation of DNA and RNA, which is accompanied by coordinated conformational changes in the polymerase bridge helix and trigger loop. The movie facilitates teaching and a mechanistic analysis of transcription and can be downloaded from http://www.lmb.uni-muenchen.de/cramer/pr-materials.

  8. Mechanistic modeling of aberrant energy metabolism in human disease

    PubMed Central

    Sangar, Vineet; Eddy, James A.; Simeonidis, Evangelos; Price, Nathan D.

    2012-01-01

    Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based (CB) models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell. PMID:23112774

  9. A brief review of exercise, bipolar disorder, and mechanistic pathways

    PubMed Central

    Thomson, Daniel; Turner, Alyna; Lauder, Sue; Gigler, Margaret E.; Berk, Lesley; Singh, Ajeet B.; Pasco, Julie A.; Berk, Michael; Sylvia, Louisa

    2015-01-01

    Despite evidence that exercise has been found to be effective in the treatment of depression, it is unclear whether these data can be extrapolated to bipolar disorder. Available evidence for bipolar disorder is scant, with no existing randomized controlled trials having tested the impact of exercise on depressive, manic or hypomanic symptomatology. Although exercise is often recommended in bipolar disorder, this is based on extrapolation from the unipolar literature, theory and clinical expertise and not empirical evidence. In addition, there are currently no available empirical data on program variables, with practical implications on frequency, intensity and type of exercise derived from unipolar depression studies. The aim of the current paper is to explore the relationship between exercise and bipolar disorder and potential mechanistic pathways. Given the high rate of medical co-morbidities experienced by people with bipolar disorder, it is possible that exercise is a potentially useful and important intervention with regard to general health benefits; however, further research is required to elucidate the impact of exercise on mood symptomology. PMID:25788889

  10. Warming will affect phytoplankton differently: evidence through a mechanistic approach.

    PubMed

    Huertas, I Emma; Rouco, Mónica; López-Rodas, Victoria; Costas, Eduardo

    2011-12-07

    Although the consequences of global warming in aquatic ecosystems are only beginning to be revealed, a key to forecasting the impact on aquatic communities is an understanding of individual species' vulnerability to increased temperature. Despite their microscopic size, phytoplankton support about half of the global primary production, drive essential biogeochemical cycles and represent the basis of the aquatic food web. At present, it is known that phytoplankton are important targets and, consequently, harbingers of climate change in aquatic systems. Therefore, investigating the capacity of phytoplankton to adapt to the predicted warming has become a relevant issue. However, considering the polyphyletic complexity of the phytoplankton community, different responses to increased temperature are expected. We experimentally tested the effects of warming on 12 species of phytoplankton isolated from a variety of environments by using a mechanistic approach able to assess evolutionary adaptation (the so-called ratchet technique). We found different degrees of tolerance to temperature rises and an interspecific capacity for genetic adaptation. The thermal resistance level reached by each species is discussed in relation to their respective original habitats. Our study additionally provides evidence on the most resistant phytoplankton groups in a future warming scenario.

  11. Warming will affect phytoplankton differently: evidence through a mechanistic approach

    PubMed Central

    Huertas, I. Emma; Rouco, Mónica; López-Rodas, Victoria; Costas, Eduardo

    2011-01-01

    Although the consequences of global warming in aquatic ecosystems are only beginning to be revealed, a key to forecasting the impact on aquatic communities is an understanding of individual species' vulnerability to increased temperature. Despite their microscopic size, phytoplankton support about half of the global primary production, drive essential biogeochemical cycles and represent the basis of the aquatic food web. At present, it is known that phytoplankton are important targets and, consequently, harbingers of climate change in aquatic systems. Therefore, investigating the capacity of phytoplankton to adapt to the predicted warming has become a relevant issue. However, considering the polyphyletic complexity of the phytoplankton community, different responses to increased temperature are expected. We experimentally tested the effects of warming on 12 species of phytoplankton isolated from a variety of environments by using a mechanistic approach able to assess evolutionary adaptation (the so-called ratchet technique). We found different degrees of tolerance to temperature rises and an interspecific capacity for genetic adaptation. The thermal resistance level reached by each species is discussed in relation to their respective original habitats. Our study additionally provides evidence on the most resistant phytoplankton groups in a future warming scenario. PMID:21508031

  12. Kinetic and Mechanistic Investigations of Atom Abstraction Reactions

    NASA Astrophysics Data System (ADS)

    Stevens, Philip Stanford

    1990-01-01

    A discharge-flow system at 1-4 torr total pressure, employing resonance fluorescence detection of Br, Cl, O, H, N, and D, and laser magnetic resonance detection of OH and ClO, was used to measure the rate constants for a number of hydrogen and non-hydrogen atom abstraction reactions. The rate constants are examined within established reactivity trends in order to reveal the dominant forces governing the potential-energy surfaces. The activation energies for the F + rm H_2O/D_2O reactions are found to be smaller than that defined by the Evans-Polyani relationship between activation energy and exothermicity. The low activation energy and enhanced kinetic isotope effect for these reactions suggests that this deviation may be the result of quantum -mechanical tunneling. The rate constants for these and other heavy-light-heavy reactions are interpreted using transition-state theory and a one-dimensional tunneling model, in conjunction with ab initio calculations, to gain insight into the mechanism of these reactions. For the reactions of X + ClOCl to Products (X = Br, Cl, F, N), the rate constants correlate with the electron affinity of the radical, indicating that these mechanisms are dominated by electron transfer from ClOCl to X, similar to the reactivity of other non -hydrogen abstractions. The reactions of O and OH with ClOCl do not follow this trend, suggesting that electron transfer is not the only driving force in these reactions. These deviations are interpreted in terms of long-range attractive forces forming stable intermediates. The ClO + O_3 to ClOO + O_2 reaction has been proposed as an additional mechanism for ozone destruction within the antarctic vortex. Upper limits for the bimolecular rate constant for the ClO + O _3 reaction were measured directly between 233 and 413 K at 1-2 torr. The rate constants are several orders-of-magnitude smaller than estimated from the trend for non-hydrogen abstractions. From these results, it is concluded that this

  13. Application of Mechanistic Toxicology Data to Ecological Risk Assessments

    EPA Science Inventory

    The ongoing evolution of knowledge and tools in the areas of molecular biology, bioinformatics, and systems biology holds significant promise for reducing uncertainties associated with ecological risk assessment. As our understanding of the mechanistic basis of responses of organ...

  14. Mechanistic modelling of cancer: some reflections from software engineering and philosophy of science.

    PubMed

    Cañete-Valdeón, José M; Wieringa, Roel; Smallbone, Kieran

    2012-12-01

    There is a growing interest in mathematical mechanistic modelling as a promising strategy for understanding tumour progression. This approach is accompanied by a methodological change of making research, in which models help to actively generate hypotheses instead of waiting for general principles to become apparent once sufficient data are accumulated. This paper applies recent research from philosophy of science to uncover three important problems of mechanistic modelling which may compromise its mainstream application, namely: the dilemma of formal and informal descriptions, the need to express degrees of confidence and the need of an argumentation framework. We report experience and research on similar problems from software engineering and provide evidence that the solutions adopted there can be transferred to the biological domain. We hope this paper can provoke new opportunities for further and profitable interdisciplinary research in the field.

  15. Mechanistic modelling of cancer: some reflections from software engineering and philosophy of science

    NASA Astrophysics Data System (ADS)

    Cañete-Valdeón, José M.; Wieringa, Roel; Smallbone, Kieran

    2012-12-01

    There is a growing interest in mathematical mechanistic modelling as a promising strategy for understanding tumour progression. This approach is accompanied by a methodological change of making research, in which models help to actively generate hypotheses instead of waiting for general principles to become apparent once sufficient data are accumulated. This paper applies recent research from philosophy of science to uncover three important problems of mechanistic modelling which may compromise its mainstream application, namely: the dilemma of formal and informal descriptions, the need to express degrees of confidence and the need of an argumentation framework. We report experience and research on similar problems from software engineering and provide evidence that the solutions adopted there can be transferred to the biological domain. We hope this paper can provoke new opportunities for further and profitable interdisciplinary research in the field.

  16. Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI

    DTIC Science & Technology

    2015-10-01

    efficacy of veliparib and NAD as agents for suppressing inflammation and improving outcomes after traumatic brain injury. The animal models include...1 AWARD NUMBER: W81XWH-13-2-0091 TITLE: Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI PRINCIPAL INVESTIGATOR...COVERED 25 Sep 2014 - 24 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI 5b. GRANT

  17. Biophysical properties of presynaptic short-term plasticity in hippocampal neurons: insights from electrophysiology, imaging and mechanistic models

    PubMed Central

    Dutta Roy, Ranjita; Stefan, Melanie I.; Rosenmund, Christian

    2014-01-01

    Hippocampal neurons show different types of short-term plasticity (STP). Some exhibit facilitation of their synaptic responses and others depression. In this review we discuss presynaptic biophysical properties behind heterogeneity in STP in hippocampal neurons such as alterations in vesicle priming and docking, fusion, neurotransmitter filling and vesicle replenishment. We look into what types of information electrophysiology, imaging and mechanistic models have given about the time scales and relative impact of the different properties on STP with an emphasis on the use of mechanistic models as complementary tools to experimental procedures. Taken together this tells us that it is possible for a multitude of different mechanisms to underlie the same STP pattern, even though some are more important in specific cases, and that mechanistic models can be used to integrate the biophysical properties to see which mechanisms are more important in specific cases of STP. PMID:24904286

  18. A Top-Down Approach to Mechanistic Biological Modeling: Application to the Single-Chain Antibody Folding Pathway

    PubMed Central

    Hildebrandt, Scott; Raden, David; Petzold, Linda; Robinson, Anne Skaja; Doyle, Francis J.

    2008-01-01

    A top-down approach to mechanistic modeling of biological systems is presented and exemplified with the development of a hypothesis-driven mathematical model for single-chain antibody fragment (scFv) folding in Saccharomyces cerevisiae by mediators BiP and PDI. In this approach, model development starts with construction of the most basic mathematical model—typically consisting of predetermined or newly-elucidated biological behavior motifs—capable of reproducing desired biological behaviors. From this point, mechanistic detail is added incrementally and systematically, and the effects of each addition are evaluated. This approach follows the typical progression of experimental data availability in that higher-order, lumped measurements are often more prevalent initially than specific, mechanistic ones. It also necessarily provides the modeler with insight into the structural requirements and performance capabilities of the resulting detailed mechanistic model, which facilitates further analysis. The top-down approach to mechanistic modeling identified three such requirements and a branched dependency-degradation competition motif critical for the scFv folding model to reproduce experimentally observed scFv folding dependencies on BiP and PDI and increased production when both species are overexpressed and promoted straightforward prediction of parameter dependencies. It also prescribed modification of the guiding hypothesis to capture BiP and PDI synergy. PMID:18641066

  19. The ecological impacts of nighttime light pollution: a mechanistic appraisal.

    PubMed

    Gaston, Kevin J; Bennie, Jonathan; Davies, Thomas W; Hopkins, John

    2013-11-01

    The ecological impacts of nighttime light pollution have been a longstanding source of concern, accentuated by realized and projected growth in electrical lighting. As human communities and lighting technologies develop, artificial light increasingly modifies natural light regimes by encroaching on dark refuges in space, in time, and across wavelengths. A wide variety of ecological implications of artificial light have been identified. However, the primary research to date is largely focused on the disruptive influence of nighttime light on higher vertebrates, and while comprehensive reviews have been compiled along taxonomic lines and within specific research domains, the subject is in need of synthesis within a common mechanistic framework. Here we propose such a framework that focuses on the cross-factoring of the ways in which artificial lighting alters natural light regimes (spatially, temporally, and spectrally), and the ways in which light influences biological systems, particularly the distinction between light as a resource and light as an information source. We review the evidence for each of the combinations of this cross-factoring. As artificial lighting alters natural patterns of light in space, time and across wavelengths, natural patterns of resource use and information flows may be disrupted, with downstream effects to the structure and function of ecosystems. This review highlights: (i) the potential influence of nighttime lighting at all levels of biological organisation (from cell to ecosystem); (ii) the significant impact that even low levels of nighttime light pollution can have; and (iii) the existence of major research gaps, particularly in terms of the impacts of light at population and ecosystem levels, identification of intensity thresholds, and the spatial extent of impacts in the vicinity of artificial lights.

  20. Environmental Assessment for the Construction of an Addition to USSOCOM Command and Control Facility, an Information Technology Facility, and a Permanent Parking Lot MacDill AFB, Florida

    DTIC Science & Technology

    2004-01-01

    In addition, since the site is larger than one acre in area, a National Pollutant Discharge Elimination System (NPDES) Phase II Storm water...Clean Air Act (CAA), as amended in 1977 and 1990, provides the basis for regulating air pollution to the atmosphere. The United States Environmental...Protection Agency (USEPA) set air quality standards for six “criteria” pollutants : carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), sulfur

  1. MECHANISTIC CONSIDERATIONS FOR HUMAN RELEVANCE OF CANCER HAZARD OF DI(2-ETHYLHEXYL) PHTHALATE

    PubMed Central

    Rusyn, Ivan; Corton, J. Christopher

    2012-01-01

    Di(2-ethylhexyl) phthalate (DEHP) is a peroxisome proliferator agent that is widely used as a plasticizer to soften polyvinylchloride plastics and non-polymers. Both occupational (e.g., by inhalation during its manufacture and use as a plasticizer of polyvinylchloride) and environmental (medical devices, contamination of food, or intake from air, water and soil) routes of exposure to DEHP are of concern for human health. There is sufficient evidence for carcinogenicity of DEHP in the liver in both rats and mice; however, there is little epidemiological evidence on possible associations between exposure to DEHP and liver cancer in humans. Data are available to suggest that liver is not the only target tissue for DEHP-associated toxicity and carcinogenicity in both humans and rodents. The debate regarding human relevance of the findings in rats or mice has been informed by studies on the mechanisms of carcinogenesis of the peroxisome proliferator class of chemicals, including DEHP. Important additional mechanistic information became available in the past decade, including, but not limited to, sub-acute, sub-chronic and chronic studies with DEHP in peroxisome proliferator-activated receptor (PPAR) α-null mice, as well as experiments utilizing several transgenic mouse lines. Activation of PPARα and the subsequent downstream events mediated by this transcription factor represent an important mechanism of action for DEHP in rats and mice. However, additional data from animal models and studies in humans exposed to DEHP from the environment suggest that multiple molecular signals and pathways in several cell types in the liver, rather than a single molecular event, contribute to the cancer in rats and mice. In addition, the toxic and carcinogenic effects of DEHP are not limited to liver. The International Agency for Research on Cancer working group concluded that the human relevance of the molecular events leading to cancer elicited by DEHP in several target tissues (e

  2. Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate.

    PubMed

    Rusyn, Ivan; Corton, J Christopher

    2012-01-01

    Di(2-ethylhexyl) phthalate (DEHP) is a peroxisome proliferator agent that is widely used as a plasticizer to soften polyvinylchloride plastics and non-polymers. Both occupational (e.g., by inhalation during its manufacture and use as a plasticizer of polyvinylchloride) and environmental (medical devices, contamination of food, or intake from air, water and soil) routes of exposure to DEHP are of concern for human health. There is sufficient evidence for carcinogenicity of DEHP in the liver in both rats and mice; however, there is little epidemiological evidence on possible associations between exposure to DEHP and liver cancer in humans. Data are available to suggest that liver is not the only target tissue for DEHP-associated toxicity and carcinogenicity in both humans and rodents. The debate regarding human relevance of the findings in rats or mice has been informed by studies on the mechanisms of carcinogenesis of the peroxisome proliferator class of chemicals, including DEHP. Important additional mechanistic information became available in the past decade, including, but not limited to, sub-acute, sub-chronic and chronic studies with DEHP in peroxisome proliferator-activated receptor (PPAR) α-null mice, as well as experiments utilizing several transgenic mouse lines. Activation of PPARα and the subsequent downstream events mediated by this transcription factor represent an important mechanism of action for DEHP in rats and mice. However, additional data from animal models and studies in humans exposed to DEHP from the environment suggest that multiple molecular signals and pathways in several cell types in the liver, rather than a single molecular event, contribute to the cancer in rats and mice. In addition, the toxic and carcinogenic effects of DEHP are not limited to liver. The International Agency for Research on Cancer working group concluded that the human relevance of the molecular events leading to cancer elicited by DEHP in several target tissues (e

  3. Two new endemic species of Ameiva (Squamata: Teiidae) from the dry forest of northwestern Peru and additional information on Ameiva concolor Ruthven, 1924.

    PubMed

    Koch, Claudia; Venegas, Pablo J; Rödder, Dennis; Flecks, Morris; Böhme, Wolfgang

    2013-12-04

    We describe two new species of Ameiva Meyer, 1795 from the dry forest of the Northern Peruvian Andes. The new species Ameiva nodam sp. nov. and Ameiva aggerecusans sp. nov. share a divided frontal plate and are differentiated from each other and from their congeners based on genetic (12S and 16S rRNA genes) and morphological characteristics. A. nodam sp. nov. has dilated postbrachials, a maximum known snout-vent length of 101 mm, 10 longitudinal rows of ventral plates, 86-113 midbody granules, 25-35 lamellae under the fourth toe, and a color pattern with 5 longitudinal yellow stripes on the dorsum. Ameiva aggerecusans sp. nov. has not or only hardly dilated postbrachials, a maximum known snout-vent length of 99.3 mm, 10-12 longitudinal rows of ventral plates, 73-92 midbody granules, 31-39 lamellae under the fourth toe, and the females and juveniles of the species normally exhibit a cream-colored vertebral stripe on a dark dorsum ground color. We provide information on the intraspecific variation and distribution of A. concolor. Furthermore, we provide information on the environmental niches of the taxa and test for niche conservatism. 

  4. Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model.

    PubMed

    Harfoot, Michael B J; Newbold, Tim; Tittensor, Derek P; Emmott, Stephen; Hutton, Jon; Lyutsarev, Vassily; Smith, Matthew J; Scharlemann, Jörn P W; Purves, Drew W

    2014-04-01

    Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures.

  5. Emergent Global Patterns of Ecosystem Structure and Function from a Mechanistic General Ecosystem Model

    PubMed Central

    Emmott, Stephen; Hutton, Jon; Lyutsarev, Vassily; Smith, Matthew J.; Scharlemann, Jörn P. W.; Purves, Drew W.

    2014-01-01

    Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures. PMID:24756001

  6. A systematic approach for identifying and presenting mechanistic evidence in human health assessments

    PubMed Central

    Kushman, Mary E.; Kraft, Andrew D.; Guyton, Kathryn Z.; Chiu, Weihsueh A.; Makris, Susan L.; Rusyn, Ivan

    2013-01-01

    Clear documentation of literature search and presentation methodologies can improve transparency in chemical hazard assessments. We sought to improve clarity for the scientific support for cancer mechanisms of action using a systematic approach to literature retrieval, selection, and presentation of studies. The general question was “What are the mechanisms by which a chemical may cause carcinogenicity in the target tissue?” Di(2-ethylhexyl)phthalate was used as a case study chemical with a complex database of >3,000 publications. Relevant mechanistic events were identified from published reviews. The PubMed search strategy included relevant synonyms and wildcards for DEHP and its metabolites, mechanistic events, and species of interest. Tiered exclusion/inclusion criteria for study pertinence were defined, and applied to the retrieved literature. Manual curation was conducted for mechanistic events with large literature databases. Literature trees documented identification and selection of the literature evidence. The selected studies were summarized in evidence tables accompanied by succinct narratives. Primary publications were deposited into the Health and Environmental Research Online (http://hero.epa.gov/) database and identified by pertinence criteria and key terms to permit organized retrieval. This approach contributes to human health assessment by effectively managing a large volume of literature, improving transparency, and facilitating subsequent synthesis of information across studies. PMID:23959061

  7. Modeling systems-level dynamics: Understanding without mechanistic explanation in integrative systems biology.

    PubMed

    MacLeod, Miles; Nersessian, Nancy J

    2015-02-01

    In this paper we draw upon rich ethnographic data of two systems biology labs to explore the roles of explanation and understanding in large-scale systems modeling. We illustrate practices that depart from the goal of dynamic mechanistic explanation for the sake of more limited modeling goals. These processes use abstract mathematical formulations of bio-molecular interactions and data fitting techniques which we call top-down abstraction to trade away accurate mechanistic accounts of large-scale systems for specific information about aspects of those systems. We characterize these practices as pragmatic responses to the constraints many modelers of large-scale systems face, which in turn generate more limited pragmatic non-mechanistic forms of understanding of systems. These forms aim at knowledge of how to predict system responses in order to manipulate and control some aspects of them. We propose that this analysis of understanding provides a way to interpret what many systems biologists are aiming for in practice when they talk about the objective of a "systems-level understanding."

  8. Multiplex ligation-dependent probe amplification assay identifies additional copy number changes compared with R-band karyotype and provide more accuracy prognostic information in myelodysplastic syndromes

    PubMed Central

    Xu, Zefeng; Zhang, Yue; Liu, Jinqin; Li, Bing; Fang, Liwei; Zhang, Hongli; Pan, Lijuan; Hu, Naibo; Qu, Shiqiang; Cai, Wenyu; Ru, Kun; Jia, Yujiao; Huang, Gang; Xiao, Zhijian

    2017-01-01

    Cytogenetic analysis provides important diagnostic and prognostic information for patients with Myelodysplastic syndromes (MDS) and plays an essential role in the International Prognostic Scoring System (IPSS) and the revised International Prognostic Scoring System (IPSS-R). Multiplex ligation-dependent probe amplification (MLPA) assay is a recently developed technique to identify targeted cytogenetic aberrations in MDS patients. In the present study, we evaluated the results obtained using an MLPA assay in 437 patients with MDS to determine the efficacy of MLPA analysis. Using R-banding karyotyping, 45% (197/437) of MDS patients had chromosomal abnormalities, whereas MLPA analysis detected that 35% (153/437) of MDS cases contained at least one copy-number variations (CNVs) .2/5 individuals (40%) with R-band karyotype failures had trisomy 8 detected using only MLPA. Clonal cytogenetic abnormalities were detected in 20/235 (8.5%) MDS patients with a normal R-band karyotype, and 12/20 (60%) of those patients were reclassified into a higher-risk IPSS-R prognostic category. When sequencing and cytogenetics were combined, the fraction of patients with MDS-related oncogenic lesions increased to 87.3% (233/267 cases). MLPA analysis determined that the median OS of patients with a normal karyotype (n=218) was 65 months compared with 27 months in cases with an aberrant karyotype (P=0.002) in 240 patients with normal or failed karyotypes by R-banding karyotyping. The high-resolution MPLA assay is an efficient and reliable method that can be used in conjunction with R-band karyotyping to detect chromosomal abnormalities in patients with suspected MDS. MLPA may also provide more accurate prognostic information. PMID:27906673

  9. Simulating polar bear energetics during a seasonal fast using a mechanistic model.

    PubMed

    Mathewson, Paul D; Porter, Warren P

    2013-01-01

    In this study we tested the ability of a mechanistic model (Niche Mapper™) to accurately model adult, non-denning polar bear (Ursus maritimus) energetics while fasting during the ice-free season in the western Hudson Bay. The model uses a steady state heat balance approach, which calculates the metabolic rate that will allow an animal to maintain its core temperature in its particular microclimate conditions. Predicted weight loss for a 120 day fast typical of the 1990s was comparable to empirical studies of the population, and the model was able to reach a heat balance at the target metabolic rate for the entire fast, supporting use of the model to explore the impacts of climate change on polar bears. Niche Mapper predicted that all but the poorest condition bears would survive a 120 day fast under current climate conditions. When the fast extended to 180 days, Niche Mapper predicted mortality of up to 18% for males. Our results illustrate how environmental conditions, variation in animal properties, and thermoregulation processes may impact survival during extended fasts because polar bears were predicted to require additional energetic expenditure for thermoregulation during a 180 day fast. A uniform 3°C temperature increase reduced male mortality during a 180 day fast from 18% to 15%. Niche Mapper explicitly links an animal's energetics to environmental conditions and thus can be a valuable tool to help inform predictions of climate-related population changes. Since Niche Mapper is a generic model, it can make energetic predictions for other species threatened by climate change.

  10. Simulating Polar Bear Energetics during a Seasonal Fast Using a Mechanistic Model

    PubMed Central

    Mathewson, Paul D.; Porter, Warren P.

    2013-01-01

    In this study we tested the ability of a mechanistic model (Niche Mapper™) to accurately model adult, non-denning polar bear (Ursus maritimus) energetics while fasting during the ice-free season in the western Hudson Bay. The model uses a steady state heat balance approach, which calculates the metabolic rate that will allow an animal to maintain its core temperature in its particular microclimate conditions. Predicted weight loss for a 120 day fast typical of the 1990s was comparable to empirical studies of the population, and the model was able to reach a heat balance at the target metabolic rate for the entire fast, supporting use of the model to explore the impacts of climate change on polar bears. Niche Mapper predicted that all but the poorest condition bears would survive a 120 day fast under current climate conditions. When the fast extended to 180 days, Niche Mapper predicted mortality of up to 18% for males. Our results illustrate how environmental conditions, variation in animal properties, and thermoregulation processes may impact survival during extended fasts because polar bears were predicted to require additional energetic expenditure for thermoregulation during a 180 day fast. A uniform 3°C temperature increase reduced male mortality during a 180 day fast from 18% to 15%. Niche Mapper explicitly links an animal’s energetics to environmental conditions and thus can be a valuable tool to help inform predictions of climate-related population changes. Since Niche Mapper is a generic model, it can make energetic predictions for other species threatened by climate change. PMID:24019883

  11. Exploiting Bioprocessing Fluctuations to Elicit the Mechanistics of De Novo Lipogenesis in Yarrowia lipolytica

    PubMed Central

    Silverman, Andrew M.; Stephanopoulos, Gregory

    2017-01-01

    Despite substantial achievements in elucidating the metabolic pathways of lipogenesis, a mechanistic representation of lipid accumulation and degradation has not been fully attained to-date. Recent evidence suggests that lipid accumulation can occur through increases of either the cytosolic copy-number of lipid droplets (LDs), or the LDs size. However, the prevailing phenotype, or how such mechanisms pertain to lipid degradation remain poorly understood. To address this shortcoming, we employed the–recently discovered–innate bioprocessing fluctuations in Yarrowia lipolytica, and performed single-cell fluctuation analysis using optical microscopy and microfluidics that generate a quasi-time invariant microenvironment. We report that lipid accumulation at early stationary phase in rich medium is substantially more likely to occur through variations in the LDs copy-number, rather than the LDs size. Critically, these mechanistics are also preserved during lipid degradation, as well as upon exposure to a protein translation inhibitor. The latter condition additionally induced a lipid accumulation phase, accompanied by the downregulation of lipid catabolism. Our results enable an in-depth mechanistic understanding of lipid biogenesis, and expand longitudinal single-cell fluctuation analyses from gene regulation to metabolism. PMID:28052085

  12. Mechanistic Enzyme Models: Pyridoxal and Metal Ions.

    ERIC Educational Resources Information Center

    Hamilton, S. E.; And Others

    1984-01-01

    Background information, procedures, and results are presented for experiments on the pyridoxal/metal ion model system. These experiments illustrate catalysis through Schiff's base formation between aldehydes/ketones and primary amines, catalysis by metal ions, and the predictable manner in which metal ions inhibit or catalyze reactions. (JN)

  13. From formamide to purine: an energetically viable mechanistic reaction pathway.

    PubMed

    Wang, Jing; Gu, Jiande; Nguyen, Minh Tho; Springsteen, Greg; Leszczynski, Jerzy

    2013-02-28

    A step-by-step mechanistic pathway following the transformation of formamide to purine through a five-membered ring intermediate has been explored by density functional theory computations. The highlight of the mechanistic route detailed here is that the proposed pathway represents the simplest reaction pathway. All necessary reactants are generated from a single starting compound, formamide, through energetically viable reactions. Several important reaction steps are involved in this mechanistic route: formylation-dehydration, Leuckart reduction, five- and six-membered ring-closure, and deamination. On the basis of the study of noncatalytic pathways, catalytic water has been found to provide energetically viable step-by-step mechanistic pathways. Among these reaction steps, five-member ring-closure is the rate-determining step. The energy barrier (ca. 42 kcal/mol) of this rate-control step is somewhat lower than the rate-determining step (ca. 44 kcal/mol) for a pyrimidine-based pathway reported previously. The mechanistic pathway reported herein is less energetically demanding than for previously proposed routes to adenine.

  14. Mechanistic Understanding of Microbial Plugging for Improved Sweep Efficiency

    SciTech Connect

    Steven Bryant; Larry Britton

    2008-09-30

    Microbial plugging has been proposed as an effective low cost method of permeability reduction. Yet there is a dearth of information on the fundamental processes of microbial growth in porous media, and there are no suitable data to model the process of microbial plugging as it relates to sweep efficiency. To optimize the field implementation, better mechanistic and volumetric understanding of biofilm growth within a porous medium is needed. In particular, the engineering design hinges upon a quantitative relationship between amount of nutrient consumption, amount of growth, and degree of permeability reduction. In this project experiments were conducted to obtain new data to elucidate this relationship. Experiments in heterogeneous (layered) beadpacks showed that microbes could grow preferentially in the high permeability layer. Ultimately this caused flow to be equally divided between high and low permeability layers, precisely the behavior needed for MEOR. Remarkably, classical models of microbial nutrient uptake in batch experiments do not explain the nutrient consumption by the same microbes in flow experiments. We propose a simple extension of classical kinetics to account for the self-limiting consumption of nutrient observed in our experiments, and we outline a modeling approach based on architecture and behavior of biofilms. Such a model would account for the changing trend of nutrient consumption by bacteria with the increasing biomass and the onset of biofilm formation. However no existing model can explain the microbial preference for growth in high permeability regions, nor is there any obvious extension of the model for this observation. An attractive conjecture is that quorum sensing is involved in the heterogeneous bead packs.

  15. Addition of Cryoprotectant Significantly Alters the Epididymal Sperm Proteome

    PubMed Central

    Yoon, Sung-Jae; Rahman, Md Saidur; Kwon, Woo-Sung; Park, Yoo-Jin; Pang, Myung-Geol

    2016-01-01

    Although cryopreservation has been developed and optimized over the past decades, it causes various stresses, including cold shock, osmotic stress, and ice crystal formation, thereby reducing fertility. During cryopreservation, addition of cryoprotective agent (CPA) is crucial for protecting spermatozoa from freezing damage. However, the intrinsic toxicity and osmotic stress induced by CPA cause damage to spermatozoa. To identify the effects of CPA addition during cryopreservation, we assessed the motility (%), motion kinematics, capacitation status, and viability of epididymal spermatozoa using computer-assisted sperm analysis and Hoechst 33258/chlortetracycline fluorescence staining. Moreover, the effects of CPA addition were also demonstrated at the proteome level using two-dimensional electrophoresis. Our results demonstrated that CPA addition significantly reduced sperm motility (%), curvilinear velocity, viability (%), and non-capacitated spermatozoa, whereas straightness and acrosome-reacted spermatozoa increased significantly (p < 0.05). Ten proteins were differentially expressed (two decreased and eight increased) (>3 fold, p < 0.05) after CPA, whereas NADH dehydrogenase flavoprotein 2, f-actin-capping protein subunit beta, superoxide dismutase 2, and outer dense fiber protein 2 were associated with several important signaling pathways (p < 0.05). The present study provides a mechanistic basis for specific cryostresses and potential markers of CPA-induced stress. Therefore, these might provide information about the development of safe biomaterials for cryopreservation and basic ground for sperm cryopreservation. PMID:27031703

  16. Why did Jacques Monod make the choice of mechanistic determinism?

    PubMed

    Loison, Laurent

    2015-06-01

    The development of molecular biology placed in the foreground a mechanistic and deterministic conception of the functioning of macromolecules. In this article, I show that this conception was neither obvious, nor necessary. Taking Jacques Monod as a case study, I detail the way he gradually came loose from a statistical understanding of determinism to finally support a mechanistic understanding. The reasons of the choice made by Monod at the beginning of the 1950s can be understood only in the light of the general theoretical schema supported by the concept of mechanistic determinism. This schema articulates three fundamental notions for Monod, namely that of the rigidity of the sequence of the genetic program, that of the intrinsic stability of macromolecules (DNA and proteins), and that of the specificity of molecular interactions.

  17. Mechanistic simulation of the vertical soil organic matter profile

    NASA Astrophysics Data System (ADS)

    Braakhekke, M.; Beer, C.; Reichstein, M.; Hoosbeek, M.; Kruijt, B.; Kabat, P.

    2013-12-01

    Soil organic matter (SOM) constitutes a large global pool of carbon that may play a considerable role for future climate. The vertical distribution of SOM in the profile may be important due to depth-dependence of physical, chemical, and biological conditions, and links to physical processes such as heat and moisture transport. The aim of this thesis is to develop a dynamic and mechanistic representation of the vertical SOM profile that can be applied for large scale simulations as a part of global ecosystem and earth system models. A model structure called SOMPROF was developed that dynamically simulates the SOM profile based on above and below ground litter input, decomposition, bioturbation, and liquid phase transport. Furthermore, three organic surface horizons are explicitly represented. Since the organic matter transport processes have been poorly quantified in the past and are difficult to observe directly, the model was calibrated with a Bayesian approach for two contrasting temperate forest sites in Europe. Different types of data were included in the parameter estimation, including: organic carbon stocks and concentrations, respiration rates, and excess lead-210 activity. The calibrations yielded good fits to the observations, and showed that the two sites differ considerably with respect to the relevance of the different processes. These differences agree well with expectations based on local conditions. However, the results also demonstrate the difficulties arising from convolution of the processes. Several parameters are poorly constrained and for one of the sites, several distinct regions in parameter space exist that yield acceptable fit. In a subsequent study it was found that radiocarbon observations can offer much additional constraint on several parameters, most importantly on the turnover rate of the slowest SOM fraction. Additionally, for one site, a prognostic simulation until 2100 was performed using the resulting a posteriori parameter

  18. Diversity Takes Shape: Understanding the Mechanistic and Adaptive Basis of Bacterial Morphology

    PubMed Central

    2016-01-01

    The modern age of metagenomics has delivered unprecedented volumes of data describing the genetic and metabolic diversity of bacterial communities, but it has failed to provide information about coincident cellular morphologies. Much like metabolic and biosynthetic capabilities, morphology comprises a critical component of bacterial fitness, molded by natural selection into the many elaborate shapes observed across the bacterial domain. In this essay, we discuss the diversity of bacterial morphology and its implications for understanding both the mechanistic and the adaptive basis of morphogenesis. We consider how best to leverage genomic data and recent experimental developments in order to advance our understanding of bacterial shape and its functional importance. PMID:27695035

  19. Catalytic intermolecular amination of C-H bonds: method development and mechanistic insights.

    PubMed

    Fiori, Kristin Williams; Du Bois, J

    2007-01-24

    Reaction methodology for intermolecular C-H amination of benzylic and 3 degrees C-H bonds is described. This process uses the starting alkane as the limiting reagent, gives optically pure tetrasubstituted amines through stereospecific insertion into enantiomeric 3 degrees centers, displays high chemoselectivity for benzylic oxidation, and enables the facile preparation of isotopically enriched 15N-labeled compounds. Access to substituted amines, amino alcohols, and diamines is thereby made possible in a single transformation. Important information relevant to understanding the initial steps in the catalytic cycle, reaction chemoselectivity, the nature of the active oxidant, and pathways for catalyst inactivation has been gained through mechanistic analysis; these studies are also presented.

  20. NGSI student activities in open source information analysis in support of the training program of the U.S. DOE laboratories for the entry into force of the additional protocol

    SciTech Connect

    Sandoval, M Analisa; Uribe, Eva C; Sandoval, Marisa N; Boyer, Brian D; Stevens, Rebecca S

    2009-01-01

    In 2008 a joint team from Los Alamos National Laboratory (LANL) and Brookhaven National Laboratory (BNL) consisting of specialists in training of IAEA inspectors in the use of complementary access activities formulated a training program to prepare the U.S. Doe laboratories for the entry into force of the Additional Protocol. As a major part of the support of the activity, LANL summer interns provided open source information analysis to the LANL-BNL mock inspection team. They were a part of the Next Generation Safeguards Initiative's (NGSI) summer intern program aimed at producing the next generation of safeguards specialists. This paper describes how they used open source information to 'backstop' the LANL-BNL team's effort to construct meaningful Additional Protocol Complementary Access training scenarios for each of the three DOE laboratories, Lawrence Livermore National Laboratory, Idaho National Laboratory, and Oak Ridge National Laboratory.

  1. Parameterization of phosphine ligands reveals mechanistic pathways and predicts reaction outcomes

    NASA Astrophysics Data System (ADS)

    Niemeyer, Zachary L.; Milo, Anat; Hickey, David P.; Sigman, Matthew S.

    2016-06-01

    The mechanistic foundation behind the identity of a phosphine ligand that best promotes a desired reaction outcome is often non-intuitive, and thus has been addressed in numerous experimental and theoretical studies. In this work, multivariate correlations of reaction outcomes using 38 different phosphine ligands were combined with classic potentiometric analyses to study a Suzuki reaction, for which the site selectivity of oxidative addition is highly dependent on the nature of the phosphine. These studies shed light on the generality of hypotheses regarding the structural influence of different classes of phosphine ligands on the reaction mechanism(s), and deliver a methodology that should prove useful in future studies of phosphine ligands.

  2. Nutraceuticals against Neurodegeneration: A Mechanistic Insight

    PubMed Central

    Dadhania, Vivekkumar P.; Trivedi, Priyanka P.; Vikram, Ajit; Tripathi, Durga Nand

    2016-01-01

    The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways. PMID:26725888

  3. Structural and mechanistic diversity of multidrug transporters.

    PubMed

    Mousa, Jarrod J; Bruner, Steven D

    2016-10-26

    Covering: 2009 to mid 2016Multidrug transporters are common and prevalent in all orders of life, having diverse functions from the removal of toxins, resistance to cytotoxins, and the transport of specific eluents. In addition, multidrug transporters pose a significant threat to modern medicine. Able to transport structurally diverse small molecule drugs, these transporters are implicated in antibiotic resistant strains of bacteria, as well as chemotherapeutic-resistance cancer cells. Although important in such resistance, a relatively small number of multidrug transporters have been structurally characterized, primarily due to the difficulty in purifying and crystallizing active membrane proteins and protein complexes. This review will cover recent structural breakthroughs in the past six years that have led to increased knowledge of the mechanisms of multidrug transporter chemistry, and the role of these transporters in exporting secondary metabolites.

  4. Twist-ing cell fate: mechanistic insights into the role of twist in lineage specification/differentiation and tumorigenesis.

    PubMed

    Cakouros, D; Raices, R M; Gronthos, S; Glackin, C A

    2010-08-15

    Bone marrow-derived mesenchymal stem cells (MSC), are multipotent cells that give rise to multiple lineages including osteoblasts, adipocytes, muscle, and fibroblasts. MSCs are useful for clinical applications such as cell therapy because they can be isolated from an individual and expanded for use in tissue repair, as well as other therapeutic applications, without immune rejection. However, one of the key problems in the use of MSCs for these applications is the efficiency of these cells to engraft and fully regenerate damaged tissues. Therefore, to optimize this process, a comprehensive understanding of the key regulators of MSCs self-renewal and maintenance are critical to the success of future cell therapy as well as other clinical applications. The basic helix loop helix transcription factor, Twist, plays a master regulatory role in all of these processes and, therefore, a thorough understanding of the mechanistic insights in the role of Twist in lineage specification/differentiation and tumorigenesis is vital to the success of future clinical applications for the therapeutic use of MSCs. In this article, we highlight the basic mechanisms and signaling pathways that are important to MSC fate, maintenance, and differentiation, as well as the critical role that Twist plays in these processes. In addition, we review the known literature suggesting a critical role for Twist in the generation of cancer stem cells, as this information may contribute to a broader understanding of stem cell biology and stem-cell-based therapeutics.

  5. A simple mechanistic model to interpret the effects of narcotics.

    PubMed

    Baas, J; Spurgeon, D; Broerse, M

    2015-01-01

    In this research we will show the advantages of using a time-independent dose metric in a mechanistic model to evaluate toxic effects for different narcotic compounds on different species. We will show how different already existing QSARs can be combined within a mechanistic framework to 1) make predictions of lethal thresholds; 2) show some limitations in the use of existing QSARs; 3) show how a mechanistic framework solves some conceptual problems in current approaches and 4) show how such a framework can be used to be of aid in an experimental setup in predicting the outcome of a survival experiment. The approach we chose is based on the simplest mechanistic model available, a scaled one-compartment model to describe uptake and elimination and hazard model to link the exposure to effects on survival. Within this theoretical framework a prediction for an internal threshold for effects on survival of 3 mmol/kg bw can be made, which should be similar for different species and independent of the partitioning characteristics of the toxicant. To demonstrate this, a threshold for 51 different species was derived, which indeed appeared to lie in a relatively small range, typically between 1 and 10 mmol/kg bw.

  6. Mechanistically Consistent Reduced Models of Synthetic Gene Networks

    PubMed Central

    Mier-y-Terán-Romero, Luis; Silber, Mary; Hatzimanikatis, Vassily

    2013-01-01

    Designing genetic networks with desired functionalities requires an accurate mathematical framework that accounts for the essential mechanistic details of the system. Here, we formulate a time-delay model of protein translation and mRNA degradation by systematically reducing a detailed mechanistic model that explicitly accounts for the ribosomal dynamics and the cleaving of mRNA by endonucleases. We exploit various technical and conceptual advantages that our time-delay model offers over the mechanistic model to probe the behavior of a self-repressing gene over wide regions of parameter space. We show that a heuristic time-delay model of protein synthesis of a commonly used form yields a notably different prediction for the parameter region where sustained oscillations occur. This suggests that such heuristics can lead to erroneous results. The functional forms that arise from our systematic reduction can be used for every system that involves transcription and translation and they could replace the commonly used heuristic time-delay models for these processes. The results from our analysis have important implications for the design of synthetic gene networks and stress that such design must be guided by a combination of heuristic models and mechanistic models that include all relevant details of the process. PMID:23663853

  7. DEVELOPMENT AND VALIDATION OF A MECHANISTIC GROUND SPRAYER MODEL

    EPA Science Inventory

    In the last ten years the Spray Drift Task Force (SDTF), U.S. Environmental Protection Agency (EPA), USDA Agricultural Research Service, and USDA Forest Service cooperated in the refinement and evaluation of a mechanistically-based aerial spray model (contained within AGDISP and ...

  8. MECHANISTIC AND SOURCE UNDERSTANDING OF PCDD/F FORMATION

    EPA Science Inventory

    The paper discusses mechanistic and source understanding of polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) formation. (NOTE: Considerable research effort has been expended over the last 15-plus years to understand how combustion sources result in formation of PCDDs/F...

  9. Does Mechanistic Thinking Improve Student Success in Organic Chemistry?

    ERIC Educational Resources Information Center

    Grove, Nathaniel P.; Cooper, Melanie M.; Cox, Elizabeth L.

    2012-01-01

    The use of the curved-arrow notation to depict electron flow during mechanistic processes is one of the most important representational conventions in the organic chemistry curriculum. Our previous research documented a disturbing trend: when asked to predict the products of a series of reactions, many students do not spontaneously engage in…

  10. Rearrangements of Allylic Sulfinates to Sulfones: A Mechanistic Study

    ERIC Educational Resources Information Center

    Ball, David B.; Mollard, Paul; Voigtritter, Karl R.; Ball, Jenelle L.

    2010-01-01

    Most current organic chemistry textbooks are organized by functional groups and those of us who teach organic chemistry use functional-group organization in our courses but ask students to learn organic chemistry from a mechanistic approach. To enrich and extend the chemical understanding and knowledge of pericyclic-type reactions for chemistry…

  11. Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation.

    PubMed

    Scotcher, Daniel; Jones, Christopher; Posada, Maria; Galetin, Aleksandra; Rostami-Hodjegan, Amin

    2016-09-01

    It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drug-drug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.

  12. Additives in plastics.

    PubMed Central

    Deanin, R D

    1975-01-01

    The polymers used in plastics are generally harmless. However, they are rarely used in pure form. In almost all commercial plastics, they are "compounded" with monomeric ingredients to improve their processing and end-use performance. In order of total volume used, these monomeric additives may be classified as follows: reinforcing fibers, fillers, and coupling agents; plasticizers; colorants; stabilizers (halogen stabilizers, antioxidants, ultraviolet absorbers, and biological preservatives); processing aids (lubricants, others, and flow controls); flame retardants, peroxides; and antistats. Some information is already available, and much more is needed, on potential toxicity and safe handling of these additives during processing and manufacture of plastics products. PMID:1175566

  13. Additives in plastics.

    PubMed

    Deanin, R D

    1975-06-01

    The polymers used in plastics are generally harmless. However, they are rarely used in pure form. In almost all commercial plastics, they are "compounded" with monomeric ingredients to improve their processing and end-use performance. In order of total volume used, these monomeric additives may be classified as follows: reinforcing fibers, fillers, and coupling agents; plasticizers; colorants; stabilizers (halogen stabilizers, antioxidants, ultraviolet absorbers, and biological preservatives); processing aids (lubricants, others, and flow controls); flame retardants, peroxides; and antistats. Some information is already available, and much more is needed, on potential toxicity and safe handling of these additives during processing and manufacture of plastics products.

  14. 24 CFR 1710.116 - Additional information.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the right to exercise, any control over the Association because of voting rights or placement of... any of the following general areas: Lot marketing and advertising, rendering of lot services, and...

  15. 12 CFR 1010.116 - Additional information.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... developer exercise, or have the right to exercise, any control over the Association because of voting rights... environment, land sales, securities sales, construction or sale of homes or home improvements, consumer fraud... subdivision. (d) Resale or exchange program. (1) Are there restrictions which might hinder lot owners in...

  16. 24 CFR 1710.116 - Additional information.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... URBAN DEVELOPMENT (INTERSTATE LAND SALES REGISTRATION PROGRAM) LAND REGISTRATION Reporting Requirements..., when will it be formed? Who is responsible for its formation? (2) Does the developer exercise, or have the right to exercise, any control over the Association because of voting rights or placement...

  17. 24 CFR 1710.116 - Additional information.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... land but only the right to use it for a certain period of time.” (f) Equal opportunity in lot sales... the right to exercise, any control over the Association because of voting rights or placement of... Statements of Record and amendments need not be listed.) (2) Has the developer, the owner of the land,...

  18. 303d Impaired Waters Additional Information

    EPA Pesticide Factsheets

    For ATTAINS 303(d) geospatial data, the Table of Available Cycles in the RAD lists the most recent ATTAINS cycle for which GIS data are available for each state. Page includes a fact sheet and pollution category summary document.

  19. 24 CFR 1710.216 - Additional information.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... of any membership agreement or similar document. (b) Price range, type of sales and marketing. (1... marketing to be used for the subdivision. The description should include, but need not be limited to... will be furnished transportation from distant cities to the subdivision; (iv) Whether mass...

  20. Mechanistic Insights of Vitamin D Anticancer Effects.

    PubMed

    Ma, Yingyu; Johnson, Candace S; Trump, Donald L

    2016-01-01

    Vitamin D is a secosteroid hormone that regulates many biological functions in addition to its classical role in maintaining calcium homeostasis and bone metabolism. Vitamin D deficiency appears to predispose individuals to increased risk of developing a number of cancers. Compelling epidemiological and experimental evidence supports a role for vitamin D in cancer prevention and treatment in many types of cancers. Preclinical studies show that 1,25D3, the active metabolite of vitamin D, and its analogs have antitumor effects in vitro and in vivo through multiple mechanisms including the induction of cell cycle arrest, apoptosis, differentiation and the suppression of inflammation, angiogenesis, invasion, and metastasis. 1,25D3 also potentiates the effect of chemotherapeutic agents and other agents in the combination treatment. In this review, the antitumor effects of 1,25D3 and the potential underlying mechanisms will be discussed. The current findings support the application of 1,25D3 in cancer prevention and treatment.

  1. Structural neurobiology: missing link to a mechanistic understanding of neural computation.

    PubMed

    Denk, Winfried; Briggman, Kevin L; Helmstaedter, Moritz

    2012-02-22

    High-resolution, comprehensive structural information is often the final arbiter between competing mechanistic models of biological processes, and can serve as inspiration for new hypotheses. In molecular biology, definitive structural data at atomic resolution are available for many macromolecules; however, information about the structure of the brain is much less complete, both in scope and resolution. Several technical developments over the past decade, such as serial block-face electron microscopy and trans-synaptic viral tracing, have made the structural biology of neural circuits conceivable: we may be able to obtain the structural information needed to reconstruct the network of cellular connections for large parts of, or even an entire, mouse brain within a decade or so. Given that the brain's algorithms are ultimately encoded by this network, knowing where all of these connections are should, at the very least, provide the data needed to distinguish between models of neural computation.

  2. Selenium in thioredoxin reductase: a mechanistic perspective.

    PubMed

    Lacey, Brian M; Eckenroth, Brian E; Flemer, Stevenson; Hondal, Robert J

    2008-12-02

    Most high M(r) thioredoxin reductases (TRs) have the unusual feature of utilizing a vicinal disulfide bond (Cys(1)-Cys(2)) which forms an eight-membered ring during the catalytic cycle. Many eukaryotic TRs have replaced the Cys(2) position of the dyad with the rare amino acid selenocysteine (Sec). Here we demonstrate that Cys- and Sec-containing TRs are distinguished by the importance each class of enzymes places on the eight-membered ring structure in the catalytic cycle. This hypothesis was explored by studying the truncated enzyme missing the C-terminal ring structure in conjunction with oxidized peptide substrates to investigate the reduction and opening of this dyad. The peptide substrates were identical in sequence to the missing part of the enzyme, containing either a disulfide or selenylsulfide linkage, but were differentiated by the presence (cyclic) and absence (acyclic) of the ring structure. The ratio of these turnover rates informs that the ring is only of modest importance for the truncated mouse mitochondrial Sec-TR (ring/no ring = 32), while the ring structure is highly important for the truncated Cys-TRs from Drosophila melanogaster and Caenorhabditis elegans (ring/no ring > 1000). All three enzymes exhibit a similar dependence upon leaving group pK(a) as shown by the use of the acyclic peptides as substrates. These two factors can be reconciled for Cys-TRs if the ring functions to simultaneously allow for attack by a nearby thiolate while correctly positioning the leaving group sulfur atom to accept a proton from the enzymic general acid. For Sec-TRs the ring is unimportant because the lower pK(a) of the selenol relative to a thiol obviates its need to be protonated upon S-Se bond scission and permits physical separation of the selenol and the general acid. Further study of the biochemical properties of the truncated Cys and Sec TR enzymes demonstrates that the chemical advantage conferred on the eukaryotic enzyme by a selenol is the ability to

  3. MECHANISTIC STUDIES OF IMPROVED FOAM EOR PROCESSES

    SciTech Connect

    William R. Rossen

    2004-06-14

    The objective of this research is to widen the application of foam to enhanced oil recovery (EOR) by investigating fundamental mechanisms of foams in porous media. This research will lay the groundwork for more applied research on foams for improved sweep efficiency in miscible gas, steam and surfactant-based EOR. Task 1 investigates the pore-scale interactions between foam bubbles and polymer molecules. Task 2 examines the mechanisms of gas trapping, and interaction between gas trapping and foam effectiveness. Task 3 investigates mechanisms of foam generation in porous media. Significant progress was made during this period on all three Tasks. Regarding Task 1, we continued comparisons of foam behavior in sandpacks with and without polymer and oil. As in our previous results, decane was moderately destabilizing to foam. Xanthan polymer did not stabilize foam in the presence of decane in this case. Rather, it appears to have destabilized foam, so that pressure gradient decreased in spite of the increase in aqueous-phase viscosity. Research on Task 2 included the first shake-down experiments with our new apparatus for gas-phase tracer tests for direct measurement of trapped-gas saturation with foam. In addition, we began to analyze CT images of gas-phase tracer in foam displacements, which offers an independent measure of trapped-gas fraction and insights into the roles of convection of tracer in flowing gas and diffusion into trapped gas. Research on Task 3 included foam generation experiments in heterogeneous sandpacks and beadpacks and modeling of discontinuous changes in state such as foam generation. The experiments found the same three regimes (coarse foam, strong foam, and intermediate regime) in heterogeneous sandpacks previously identified in homogeneous porous media. One implication is that there may be a minimum flow rate required for foam generation in even heterogeneous porous media. The dynamics in SAG foam processes in heterogeneous media are complex

  4. Carbenic vs. ionic mechanistic pathway in reaction of cyclohexanone with bromoform.

    PubMed

    Vitnik, Vesna D; Vitnik, Zeljko J; Juranić, Ivan O

    2012-10-01

    The extensive computation study was done to elucidate the mechanism of formation dibromoepoxide from cyclohexanone and bromoform. In this reaction, the formation of dihaloepoxide 2 is postulated as a key step that determines the distribution and stereochemistry of products. Two mechanistic paths of reaction were investigated: the addition of dibromocarbene to carbonyl group of ketone, and the addition of tribromomethyl carbanion to the same (C=O) group. The mechanisms for the addition reactions of dibromocarbenes and tribromomethyl carbanions with cyclohexanone have been investigated using ab initio HF/6-311++G** and MP2/6-311+G* level of theory. Solvent effects on these reactions have been explored by calculations which included a continuum polarizable conductor model (CPCM) for the solvent (H₂O). The calculations showed that both mechanisms are possible and are exothermic, but have markedly different activation energies.

  5. Clinical and Mechanistic Drivers of Acute Traumatic Coagulopathy

    PubMed Central

    Cohen, Mitchell Jay; Kutcher, Matt; Redick, Britt; Nelson, Mary; Call, Mariah; Knudson, M Margaret; Schreiber, Martin A; Bulger, Eileen M; Muskat, Peter; Alarcon, Louis H; Myers, John G; Rahbar, Mohammad H; Brasel, Karen J; Phelan, Herb A; del Junco, Deborah J; Fox, Erin E; Wade, Charles E; Holcomb, John B; Cotton, Bryan A; Matijevic, Nena

    2013-01-01

    Background Acute Traumatic Coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma. Methods Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data. Results There were 1198 patients with laboratory results of whom 41.6% were coagulopathic. Using International Normalized Ratio (INR)≥1.3, 41.6% (448) of patients were coagulopathic while 20.5% (214) were coagulopathic using partial thromboplastin time (PTT)≥35. Coagulopathy was primarily associated with a combination of an ISS>15 and a BD<−6 (P<.05). Regression modeling for INR-based coagulopathy shows that pre-hospital crystalloid (odds ratio (OR)=1.05), Injury Severity Score (ISS, OR=1.03), Glasgow Coma Scale (OR=0.93), heart rate (OR=1.08), systolic blood pressure (OR=0.96), base deficit (BD, OR=0.92) and temperature (OR=0.84) were significant predictors of coagulopathy (all P<.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all P<.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p<.04). Similar results were found for PTT-defined coagulopathy. Conclusions ATC is associated with depletion of factors I, II, V, VII, VIII, IX and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of

  6. Ring Substituent Effects on the Thiol Addition and Hydrolysis Reactions of N-Arylmaleimides.

    PubMed

    Chen, Yingche; Tsao, Kelvin; De Francesco, Élise; Keillor, Jeffrey W

    2015-12-18

    Maleimide groups are used extensively in bioconjugation reactions, but limited kinetic information is available regarding their thiol addition and hydrolysis reactions. We prepared a series of fluorogenic coumarin maleimide derivatives that differ by the substituent on their maleimide C═C bond. Fluorescence-based kinetic studies of the reaction with β-mercaptoethanol (BME) yielded the second-order rate constants (k2), while pH-rate studies from pH 7 to 9 gave base-catalyzed hydrolysis rate constants (kOH). Linear free-energy relationships were studied through the correlation of log k2 and log kOH to both electronic (σ(+)) and steric (Es(norm)) parameters of the C═C substituent. These correlations revealed the thiol addition reaction is primarily sensitive to the electronic effects, while steric effects dominate the hydrolysis reaction. These mechanistic studies provide the basis for the design of novel bioconjugation reactants or fluorogenic labeling agents.

  7. Mechanistic investigation of a hemostatic keratin biomaterial

    NASA Astrophysics Data System (ADS)

    Rahmany, Maria Bahawdory

    Traumatic injury leads to more productive years lost than heart disease, cancer and stroke combined. Trauma is often accompanied and complicated by uncontrolled bleeding. Human hair keratin biomaterials have demonstrated efficacy in controlling hemorrhage in both small and large animal models; however little is known about the mechanism by which these proteins aid in blood clotting. Inspection of the amino acid sequence of known keratins shows the presence of several cellular binding motifs, suggesting a possible mechanism and potentially eliminating the need to functionalize the material's surface for cellular interaction. In addition to small animal studies, the hemostatic activity of keratin hydrogels was explored through porcine hemorrhage models representing both a high flow and low flow bleed. In both studies, keratin hydrogels appeared to lead to a significant reduction in blood loss. The promising results from these in vivo studies provided the motivation for this project. The objective of this dissertation work was to assess the mechanism of action of a hemostatic keratin biomaterial, and more broadly assess the biomaterial-cellular interaction(s). It is our hypothesis that keratin biomaterials have the capacity to specifically interact with cells and lead to propagation of intracellular signaling pathway, specifically contributing to hemostasis. Through application of biochemical and molecular tools, we demonstrate here that keratin biomaterials contribute to hemostasis through two probable mechanisms; integrin mediated platelet adhesion and increased fibrin polymerization. Platelets are the major cell type involved in coagulation both by acting as a catalytic surface for the clotting cascade and adhering to extracellular matrix (ECM) proteins providing a soft platelet plug. Because keratin biomaterials have structural and biochemical characteristics similar to ECM proteins, we utilized several adhesion assays to investigate platelet adhesion to keratin

  8. Mechanistic variables can enhance predictive models of endotherm distributions: The American pika under current, past, and future climates

    USGS Publications Warehouse

    Mathewson, Paul; Moyer-Horner, Lucas; Beever, Erik; Briscoe, Natalie; Kearney, Michael T; Yahn, Jeremiah; Porter, Warren P.

    2017-01-01

    How climate constrains species’ distributions through time and space is an important question in the context of conservation planning for climate change. Despite increasing awareness of the need to incorporate mechanism into species distribution models (SDMs), mechanistic modeling of endotherm distributions remains limited in this literature. Using the American pika (Ochotona princeps) as an example, we present a framework whereby mechanism can be incorporated into endotherm SDMs. Pika distribution has repeatedly been found to be constrained by warm temperatures, so we used Niche Mapper, a mechanistic heat-balance model, to convert macroclimate data to pika-specific surface activity time in summer across the western United States. We then explored the difference between using a macroclimate predictor (summer temperature) and using a mechanistic predictor (predicted surface activity time) in SDMs. Both approaches accurately predicted pika presences in current and past climate regimes. However, the activity models predicted 8–19% less habitat loss in response to annual temperature increases of ~3–5 °C predicted in the region by 2070, suggesting that pikas may be able to buffer some climate change effects through behavioral thermoregulation that can be captured by mechanistic modeling. Incorporating mechanism added value to the modeling by providing increased confidence in areas where different modeling approaches agreed and providing a range of outcomes in areas of disagreement. It also provided a more proximate variable relating animal distribution to climate, allowing investigations into how unique habitat characteristics and intraspecific phenotypic variation may allow pikas to exist in areas outside those predicted by generic SDMs. Only a small number of easily obtainable data are required to parameterize this mechanistic model for any endotherm, and its use can improve SDM predictions by explicitly modeling a widely applicable direct physiological effect

  9. Mechanistic variables can enhance predictive models of endotherm distributions: the American pika under current, past, and future climates.

    PubMed

    Mathewson, Paul D; Moyer-Horner, Lucas; Beever, Erik A; Briscoe, Natalie J; Kearney, Michael; Yahn, Jeremiah M; Porter, Warren P

    2017-03-01

    How climate constrains species' distributions through time and space is an important question in the context of conservation planning for climate change. Despite increasing awareness of the need to incorporate mechanism into species distribution models (SDMs), mechanistic modeling of endotherm distributions remains limited in this literature. Using the American pika (Ochotona princeps) as an example, we present a framework whereby mechanism can be incorporated into endotherm SDMs. Pika distribution has repeatedly been found to be constrained by warm temperatures, so we used Niche Mapper, a mechanistic heat-balance model, to convert macroclimate data to pika-specific surface activity time in summer across the western United States. We then explored the difference between using a macroclimate predictor (summer temperature) and using a mechanistic predictor (predicted surface activity time) in SDMs. Both approaches accurately predicted pika presences in current and past climate regimes. However, the activity models predicted 8-19% less habitat loss in response to annual temperature increases of ~3-5 °C predicted in the region by 2070, suggesting that pikas may be able to buffer some climate change effects through behavioral thermoregulation that can be captured by mechanistic modeling. Incorporating mechanism added value to the modeling by providing increased confidence in areas where different modeling approaches agreed and providing a range of outcomes in areas of disagreement. It also provided a more proximate variable relating animal distribution to climate, allowing investigations into how unique habitat characteristics and intraspecific phenotypic variation may allow pikas to exist in areas outside those predicted by generic SDMs. Only a small number of easily obtainable data are required to parameterize this mechanistic model for any endotherm, and its use can improve SDM predictions by explicitly modeling a widely applicable direct physiological effect

  10. A dynamic and mechanistic model of PCB bioaccumulation in the European hake ( Merluccius merluccius)

    NASA Astrophysics Data System (ADS)

    Bodiguel, Xavier; Maury, Olivier; Mellon-Duval, Capucine; Roupsard, François; Le Guellec, Anne-Marie; Loizeau, Véronique

    2009-08-01

    Bioaccumulation is difficult to document because responses differ among chemical compounds, with environmental conditions, and physiological processes characteristic of each species. We use a mechanistic model, based on the Dynamic Energy Budget (DEB) theory, to take into account this complexity and study factors impacting accumulation of organic pollutants in fish through ontogeny. The bioaccumulation model proposed is a comprehensive approach that relates evolution of hake PCB contamination to physiological information about the fish, such as diet, metabolism, reserve and reproduction status. The species studied is the European hake ( Merluccius merluccius, L. 1758). The model is applied to study the total concentration and the lipid normalised concentration of 4 PCB congeners in male and female hakes from the Gulf of Lions (NW Mediterranean sea) and the Bay of Biscay (NE Atlantic ocean). Outputs of the model compare consistently to measurements over the life span of fish. Simulation results clearly demonstrate the relative effects of food contamination, growth and reproduction on the PCB bioaccumulation in hake. The same species living in different habitats and exposed to different PCB prey concentrations exhibit marked difference in the body accumulation of PCBs. At the adult stage, female hakes have a lower PCB concentration compared to males for a given length. We successfully simulated these sex-specific PCB concentrations by considering two mechanisms: a higher energy allocation to growth for females and a transfer of PCBs from the female to its eggs when allocating lipids from reserve to eggs. Finally, by its mechanistic description of physiological processes, the model is relevant for other species and sets the stage for a mechanistic understanding of toxicity and ecological effects of organic contaminants in marine organisms.

  11. Mechanistic model for catalytic recombination during aerobraking maneuvers

    NASA Technical Reports Server (NTRS)

    Willey, Ronald J.

    1989-01-01

    Several mechanistic models are developed to predict recombination coefficients for use in heat shield design for reusable surface insulation (RSI) on aerobraking vehicles such as space shuttles. The models are applied over a temperature range of 300 to 1800 K and a stagnation pressure range of 0 to 3,000 Pa. A four parameter model in temperature was found to work best; however, several models (including those with atom concentrations at the surface) were also investigated. Mechanistic models developed with atom concentration terms may be applicable when sufficient data becomes available. The requirement is shown for recombination experiments in the 300 to 1000 K and 1500 to 1850 K temperature range, with deliberate concentration variations.

  12. Validating Mechanistic Sorption Model Parameters and Processes for Reactive Transport in Alluvium

    SciTech Connect

    Zavarin, M; Roberts, S K; Rose, T P; Phinney, D L

    2002-05-02

    The laboratory batch and flow-through experiments presented in this report provide a basis for validating the mechanistic surface complexation and ion exchange model we use in our hydrologic source term (HST) simulations. Batch sorption experiments were used to examine the effect of solution composition on sorption. Flow-through experiments provided for an analysis of the transport behavior of sorbing elements and tracers which includes dispersion and fluid accessibility effects. Analysis of downstream flow-through column fluids allowed for evaluation of weakly-sorbing element transport. Secondary Ion Mass Spectrometry (SIMS) analysis of the core after completion of the flow-through experiments permitted the evaluation of transport of strongly sorbing elements. A comparison between these data and model predictions provides additional constraints to our model and improves our confidence in near-field HST model parameters. In general, cesium, strontium, samarium, europium, neptunium, and uranium behavior could be accurately predicted using our mechanistic approach but only after some adjustment was made to the model parameters. The required adjustments included a reduction in strontium affinity for smectite, an increase in cesium affinity for smectite and illite, a reduction in iron oxide and calcite reactive surface area, and a change in clinoptilolite reaction constants to reflect a more recently published set of data. In general, these adjustments are justifiable because they fall within a range consistent with our understanding of the parameter uncertainties. These modeling results suggest that the uncertainty in the sorption model parameters must be accounted for to validate the mechanistic approach. The uncertainties in predicting the sorptive behavior of U-1a and UE-5n alluvium also suggest that these uncertainties must be propagated to nearfield HST and large-scale corrective action unit (CAU) models.

  13. Group Sparse Additive Models

    PubMed Central

    Yin, Junming; Chen, Xi; Xing, Eric P.

    2016-01-01

    We consider the problem of sparse variable selection in nonparametric additive models, with the prior knowledge of the structure among the covariates to encourage those variables within a group to be selected jointly. Previous works either study the group sparsity in the parametric setting (e.g., group lasso), or address the problem in the nonparametric setting without exploiting the structural information (e.g., sparse additive models). In this paper, we present a new method, called group sparse additive models (GroupSpAM), which can handle group sparsity in additive models. We generalize the ℓ1/ℓ2 norm to Hilbert spaces as the sparsity-inducing penalty in GroupSpAM. Moreover, we derive a novel thresholding condition for identifying the functional sparsity at the group level, and propose an efficient block coordinate descent algorithm for constructing the estimate. We demonstrate by simulation that GroupSpAM substantially outperforms the competing methods in terms of support recovery and prediction accuracy in additive models, and also conduct a comparative experiment on a real breast cancer dataset.

  14. Millifluidics for Chemical Synthesis and Time-resolved Mechanistic Studies

    PubMed Central

    Krishna, Katla Sai; Biswas, Sanchita; Navin, Chelliah V.; Yamane, Dawit G.; Miller, Jeffrey T.; Kumar, Challa S.S.R.

    2013-01-01

    Procedures utilizing millifluidic devices for chemical synthesis and time-resolved mechanistic studies are described by taking three examples. In the first, synthesis of ultra-small copper nanoclusters is described. The second example provides their utility for investigating time resolved kinetics of chemical reactions by analyzing gold nanoparticle formation using in situ X-ray absorption spectroscopy. The final example demonstrates continuous flow catalysis of reactions inside millifluidic channel coated with nanostructured catalyst. PMID:24327099

  15. INTEGRATED CHEMICAL INFORMATION TECHNOLOGIES ...

    EPA Pesticide Factsheets

    A central regulatory mandate of the Environmental Protection Agency, spanning many Program Offices and issues, is to assess the potential health and environmental risks of large numbers of chemicals released into the environment, often in the absence of relevant test data. Models for predicting potential adverse effects of chemicals based primarily on chemical structure play a central role in prioritization and screening strategies yet are highly dependent and conditional upon the data used for developing such models. Hence, limits on data quantity, quality, and availability are considered by many to be the largest hurdles to improving prediction models in diverse areas of toxicology. Generation of new toxicity data for additional chemicals and endpoints, development of new high-throughput, mechanistically relevant bioassays, and increased generation of genomics and proteomics data that can clarify relevant mechanisms will all play important roles in improving future SAR prediction models. The potential for much greater immediate gains, across large domains of chemical and toxicity space, comes from maximizing the ability to mine and model useful information from existing toxicity data, data that represent huge past investment in research and testing expenditures. In addition, the ability to place newer “omics” data, data that potentially span many possible domains of toxicological effects, in the broader context of historical data is the means for opti

  16. Bird Migration Under Climate Change - A Mechanistic Approach Using Remote Sensing

    NASA Technical Reports Server (NTRS)

    Smith, James A.; Blattner, Tim; Messmer, Peter

    2010-01-01

    The broad-scale reductions and shifts that may be expected under climate change in the availability and quality of stopover habitat for long-distance migrants is an area of increasing concern for conservation biologists. Researchers generally have taken two broad approaches to the modeling of migration behaviour to understand the impact of these changes on migratory bird populations. These include models based on causal processes and their response to environmental stimulation, "mechanistic models", or models that primarily are based on observed animal distribution patterns and the correlation of these patterns with environmental variables, i.e. "data driven" models. Investigators have applied the latter technique to forecast changes in migration patterns with changes in the environment, for example, as might be expected under climate change, by forecasting how the underlying environmental data layers upon which the relationships are built will change over time. The learned geostatstical correlations are then applied to the modified data layers.. However, this is problematic. Even if the projections of how the underlying data layers will change are correct, it is not evident that the statistical relationships will remain the same, i.e. that the animal organism may not adapt its' behaviour to the changing conditions. Mechanistic models that explicitly take into account the physical, biological, and behaviour responses of an organism as well as the underlying changes in the landscape offer an alternative to address these shortcomings. The availability of satellite remote sensing observations at multiple spatial and temporal scales, coupled with advances in climate modeling and information technologies enable the application of the mechanistic models to predict how continental bird migration patterns may change in response to environmental change. In earlier work, we simulated the impact of effects of wetland loss and inter-annual variability on the fitness of

  17. Water-soluble NHC-Cu catalysts: applications in click chemistry, bioconjugation and mechanistic analysis.

    PubMed

    Díaz Velázquez, Heriberto; Ruiz García, Yara; Vandichel, Matthias; Madder, Annemieke; Verpoort, Francis

    2014-12-14

    Copper(I)-catalyzed 1,3-dipolar cycloaddition of azides and terminal alkynes (CuAAC), better known as "click" reaction, has triggered the use of 1,2,3-triazoles in bioconjugation, drug discovery, materials science and combinatorial chemistry. Here we report a new series of water-soluble catalysts based on N-heterocyclic carbene (NHC)-Cu complexes which are additionally functionalized with a sulfonate group. The complexes show superior activity towards CuAAC reactions and display a high versatility, enabling the production of triazoles with different substitution patterns. Additionally, successful application of these complexes in bioconjugation using unprotected peptides acting as DNA binding domains was achieved for the first time. Mechanistic insight into the reaction mechanism is obtained by means of state-of-the-art first principles calculations.

  18. Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling.

    PubMed

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-11-01

    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses.

  19. The autism puzzle: challenging a mechanistic model on conceptual and historical grounds

    PubMed Central

    2013-01-01

    Although clinicians and researchers working in the field of autism are generally not concerned with philosophical categories of kinds, a model for understanding the nature of autism is important for guiding research and clinical practice. Contemporary research in the field of autism is guided by the depiction of autism as a scientific object that can be identified with systematic neuroscientific investigation. This image of autism is compatible with a permissive account of natural kinds: the mechanistic property cluster (MPC) account of natural kinds, recently proposed as the model for understanding psychiatric disorders. Despite the heterogeneity, multicausality and fuzzy boundaries that complicate autism research, a permissive account of natural kinds (MPC kinds) provides prescriptive guidance for the investigation of objective causal mechanisms that should inform nosologists in their attempt to carve autism’s boundaries at its natural joints. However, this essay will argue that a mechanistic model of autism is limited since it disregards the way in which autism relates to ideas about what kind of behavior is abnormal. As historical studies and definitions of autism show, normative issues concerning disability, impairment and societal needs have been and still are inextricably linked to how we recognize and understand autism. The current search for autism’s unity in neurobiological mechanisms ignores the values, social norms and various perspectives on mental pathology that play a significant role in 'the thing called autism’. Autism research needs to engage with these issues in order to achieve more success in the effort to become clinically valuable. PMID:24207065

  20. Combining solvent isotope effects with substrate isotope effects in mechanistic studies of alcohol and amine oxidation by enzymes.

    PubMed

    Fitzpatrick, Paul F

    2015-11-01

    Oxidation of alcohols and amines is catalyzed by multiple families of flavin- and pyridine nucleotide-dependent enzymes. Measurement of solvent isotope effects provides a unique mechanistic probe of the timing of the cleavage of the OH and NH bonds, necessary information for a complete description of the catalytic mechanism. The inherent ambiguities in interpretation of solvent isotope effects can be significantly decreased if isotope effects arising from isotopically labeled substrates are measured in combination with solvent isotope effects. The application of combined solvent and substrate (mainly deuterium) isotope effects to multiple enzymes is described here to illustrate the range of mechanistic insights that such an approach can provide. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment.

  1. Mechanistic micro-structural theory of soft tissues growth and remodeling: tissues with unidirectional fibers.

    PubMed

    Lanir, Yoram

    2015-04-01

    A new mechanistic theory was developed for soft tissues growth and remodeling (G&R). The theory considers tissues with unidirectional fibers. It is based on the loading-dependent local turnover events of each constituent and on the resulting evolution of the tissue micro-structure, the tissue dimensions and its mechanical properties. The theory incorporates the specific mechanical properties and turnover kinetics of each constituent, thereby establishing a general framework which can serve for future integration of additional mechanisms involved in G&R. The feasibility of the theory was examined by considering a specific realization of tissues with one fibrous constituent (collagen fibers), assuming a specific loading-dependent first-order fiber's turnover kinetics and the fiber's deposition characteristics. The tissue was subjected to a continuous constant rate growth. Model parameters were adopted from available data. The resulting predictions show qualitative agreement with a number of well-known features of tissues including the fibers' non-uniform recruitment density distribution, the associated tissue convex nonlinear stress-stretch relationship, and the development of tissue pre-stretch and pre-stress states. These results show that mechanistic micro-structural modeling of soft tissue G&R based on first principles can successfully capture the evolution of observed tissues' structure and size, and of their associated mechanical properties.

  2. On a novel mechanistic model for simultaneous enzymatic hydrolysis of cellulose and hemicellulose considering morphology.

    PubMed

    Zhang, Yang; Xu, Bingqian; Zhou, Wen

    2014-09-01

    We develop a novel and general modeling framework for enzymatic hydrolysis of cellulose and hemicellulose simultaneously. Our mechanistic model, for the first time, takes into consideration explicitly the time evolution of morphologies of intertwining cellulose and hemicelluloses within substrate during enzymatic hydrolysis. This morphology evolution is driven by hydrolytic chain fragmentation and solubilization, which is, in return, profoundly affected by the substrate morphology. We represent the substrate morphology as a randomly distributed smallest accessible compartments (SACs) which are described by geometric functions to track total volume and exposed surface substrate materials, including both cellulose and hemicelluloses. Our morphology-plus-kinetics approach then couple the time-dependent morphology with chain fragmentation and solubilization resulted from enzymatic reactions between various bonds in cellulose and hemicelluloses and a mixture (i.e., endo-, exo-, and oligomer- acting) of cellulases and hemicellulases. In addition, we propose an advanced and generalized site concentration formalism that considers different polysaccharide chain types and different monomer unit types on chains. The resulting ODE system has a substantially reduced size compared to conventional chain concentration formalism. We present numerical simulation results under real enzymatic hydrolysis experimental conditions from literature. The comparisons between the simulation results and the experiment measurements demonstrate effectiveness and wide applicability of the proposed mechanistic model.

  3. Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: expansion of substrate scope and mechanistic studies.

    PubMed

    Lee, Doris; Williamson, Caitlin L; Chan, Lina; Taylor, Mark S

    2012-05-16

    Synthetic and mechanistic aspects of the diarylborinic acid-catalyzed regioselective monofunctionalization of 1,2- and 1,3-diols are presented. Diarylborinic acid catalysis is shown to be an efficient and general method for monotosylation of pyranoside derivatives bearing three secondary hydroxyl groups (7 examples, 88% average yield). In addition, the scope of the selective acylation, sulfonylation, and alkylation is extended to 1,2- and 1,3-diols not derived from carbohydrates (28 examples); the efficiency, generality, and operational simplicity of this method are competitive with those of state-of-the-art protocols including the broadly applied organotin-catalyzed or -mediated reactions. Mechanistic details of the organoboron-catalyzed processes are explored using competition experiments, kinetics, and catalyst structure-activity relationships. These experiments are consistent with a mechanism in which a tetracoordinate borinate complex reacts with the electrophilic species in the turnover-limiting step of the catalytic cycle.

  4. Ferritin Diversity: Mechanistic Studies, Disease Implications, and Materials Chemistry

    NASA Astrophysics Data System (ADS)

    Hilton, Robert J.

    2011-07-01

    The study of ferritin includes a rich history of discoveries and scientific progress. Initially, the composition of ferritin was determined. Soon, it was shown that ferritin is a spherical, hollow protein. Eventually, over several decades of research, the structure and some function of this interesting protein was elucidated. However, the ferritin field was not completely satisfied. Today, for example, researchers are interested in refining the details of ferritin function, in discovering the role of ferritin in a variety of diseases, and in using ferritin for materials chemistry applications. The work presented in this dissertation highlights the progress that we have made in each of these three areas: (1) Mechanistic studies: The buffer used during horse spleen ferritin iron loading significantly influences the mineralization process and the quantity of iron deposited in ferritin. The ferrihydrite core of ferritin is crystalline and ordered when iron is loaded into ferritin in the presence of imidazole buffer. On the other hand, when iron is loaded into ferritin in the presence of MOPS buffer, the ferrihydrite core is less crystalline and less ordered, and a smaller amount of total iron is loaded in ferritin. We also show that iron can be released from the ferritin core in a non-reductive manner. The rate of Fe3+ release from horse spleen ferritin was measured using the Fe3+-specific chelator desferoxamine. We show that iron release occurs by three kinetic events. (2) Disease studies: In order to better understand iron disruption during disease states, we performed in vitro assays that mimicked chronic kidney disease. We tested the hypothesis that elevated levels of serum phosphate interrupted normal iron binding by transferrin and ferritin. Results show that phosphate competes for iron, forming an iron(III)-phosphate complex that is inaccessible to either transferrin or ferritin. Ferritin samples separated from the iron(III)-phosphate complex shows that as the

  5. Mechanistic species distribution modeling reveals a niche shift during invasion.

    PubMed

    Chapman, Daniel S; Scalone, Romain; Štefanić, Edita; Bullock, James M

    2017-04-02

    Niche shifts of non-native plants can occur when they colonize novel climatic conditions. However, the mechanistic basis for niche shifts during invasion is poorly understood and has rarely been captured within species distribution models. We quantified the consequence of between-population variation in phenology for invasion of common ragweed (Ambrosia artemisiifolia L.) across Europe. Ragweed is of serious concern because of its harmful effects as a crop weed and because of its impact on public health as a major aeroallergen. We developed a forward mechanistic species distribution model based on responses of ragweed development rates to temperature and photoperiod. The model was parameterized and validated from the literature and by re-analyzing data from a reciprocal common garden experiment in which native and invasive populations were grown within and beyond the current invaded range. It could therefore accommodate between-population variation in the physiological requirements for flowering, and predict the potentially-invaded ranges of individual populations. Northern-origin populations that were established outside the generally-accepted climate envelope of the species had lower thermal requirements for bud development, suggesting local adaptation of phenology had occurred during the invasion. The model predicts that this will extend the potentially-invaded range northwards and increase the average suitability across Europe by 90% in the current climate and 20% in the future climate. Therefore, trait variation observed at the population scale can trigger a climatic niche shift at the biogeographic scale. For ragweed, earlier flowering phenology in established northern populations could allow the species to spread beyond its current invasive range, substantially increasing its risk to agriculture and public health. Mechanistic species distribution models offer the possibility to represent niche shifts by varying the traits and niche responses of individual

  6. Randomized pilot study and qualitative evaluation of a clinical decision support system for brain tumour diagnosis based on SV ¹H MRS: evaluation as an additional information procedure for novice radiologists.

    PubMed

    Sáez, Carlos; Martí-Bonmatí, Luis; Alberich-Bayarri, Angel; Robles, Montserrat; García-Gómez, Juan M

    2014-02-01

    The results of a randomized pilot study and qualitative evaluation of the clinical decision support system Curiam BT are reported. We evaluated the system's feasibility and potential value as a radiological information procedure complementary to magnetic resonance (MR) imaging to assist novice radiologists in diagnosing brain tumours using MR spectroscopy (1.5 and 3.0T). Fifty-five cases were analysed at three hospitals according to four non-exclusive diagnostic questions. Our results show that Curiam BT improved the diagnostic accuracy in all the four questions. Additionally, we discuss the findings of the users' feedback about the system, and the further work to optimize it for real environments and to conduct a large clinical trial.

  7. A statistical approach based on substitution of macronutrients provides additional information to models analyzing single dietary factors in relation to type 2 diabetes in danish adults: the Inter99 study.

    PubMed

    Faerch, Kristine; Lau, Cathrine; Tetens, Inge; Pedersen, Oluf Borbye; Jørgensen, Torben; Borch-Johnsen, Knut; Glümer, Charlotte

    2005-05-01

    Most studies analyzing diet-disease relations focus on single dietary factors rather than combining different nutrients into the same statistical model. The objective of this study was to identify dietary factors associated with the probability of having diabetes identified by screening (SDM) in Danish men and women aged 30-60 y. A specific objective was to examine whether an alternative statistical approach could provide additional information to already existing statistical approaches used in nutritional epidemiology. Baseline data from the Danish population-based Inter99 study were used. The dietary intake of 262 individuals with SDM was compared with that of 4627 individuals with normal glucose tolerance (NGT) using 2 different types of multiple logistic regression models adjusted for potential confounders. The first model included single dietary factors, whereas the second model was based on substitution of macronutrients. In the models with single dietary factors, high intakes of carbohydrates, dietary fiber, and coffee were inversely associated with SDM (P < 0.01), whereas high intakes of total fat and saturated fat were positively associated with SDM (P < 0.05). A modest U-shaped association was found between alcohol consumption and SDM (P = 0.10) [corrected] Results from the substitution model showed that when 3% of energy (En%) as carbohydrate replaced 3 En% fat or alcohol, the probability of having SDM decreased by 9 and 10%, respectively (P < 0.01) [corrected] No other macronutrient substitutions resulted in significant associations. Hence, the statistical approach based on substitution of macronutrients provided additional information to the model analyzing single dietary factors.

  8. Mechanistic modeling of CHF in forced-convection subcooled boiling

    SciTech Connect

    Podowski, M.Z.; Alajbegovic, A.; Kurul, N.; Drew, D.A.; Lahey, R.T. Jr.

    1997-05-01

    Because of the complexity of phenomena governing boiling heat transfer, the approach to solve practical problems has traditionally been based on experimental correlations rather than mechanistic models. The recent progress in computational fluid dynamics (CFD), combined with improved experimental techniques in two-phase flow and heat transfer, makes the use of rigorous physically-based models a realistic alternative to the current simplistic phenomenological approach. The objective of this paper is to present a new CFD model for critical heat flux (CHF) in low quality (in particular, in subcooled boiling) forced-convection flows in heated channels.

  9. Opioid receptors: Structural and mechanistic insights into pharmacology and signaling

    PubMed Central

    Shang, Yi; Filizola, Marta

    2015-01-01

    Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G protein-coupled receptors has been conducted over the past two decades to discover ligands with higher specificity and diminished side effects, currently used opioid therapeutics remain suboptimal. Luckily, recent advances in structural biology of opioid receptors provide unprecedented insights into opioid receptor pharmacology and signaling. We review here a few recent studies that have used the crystal structures of opioid receptors as a basis for revealing mechanistic details of signal transduction mediated by these receptors, and for the purpose of drug discovery. PMID:25981301

  10. Opioid receptors: Structural and mechanistic insights into pharmacology and signaling.

    PubMed

    Shang, Yi; Filizola, Marta

    2015-09-15

    Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G protein-coupled receptors has been conducted over the past two decades to discover ligands with higher specificity and diminished side effects, currently used opioid therapeutics remain suboptimal. Luckily, recent advances in structural biology of opioid receptors provide unprecedented insights into opioid receptor pharmacology and signaling. We review here a few recent studies that have used the crystal structures of opioid receptors as a basis for revealing mechanistic details of signal transduction mediated by these receptors, and for the purpose of drug discovery.

  11. Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

    SciTech Connect

    Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

    2005-07-26

    A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

  12. Selective Synthesis of Cyclic Carbonate by Salalen-Aluminum Complexes and Mechanistic Studies.

    PubMed

    Cozzolino, Mariachiara; Rosen, Tomer; Goldberg, Israel; Mazzeo, Mina; Lamberti, Marina

    2017-03-22

    Salalen-aluminum complexes were synthesized and used as catalysts in the reactions of CO2 with different epoxides. The reaction of cyclohexene oxide and CO2 was thoroughly investigated. In particular, the effect of the reaction conditions (nature and equivalents of the co-catalyst, CO2 pressure, and temperature) and of the ligands (substituents on the ancillary ligand, nature of the labile ligand, and nature of the nitrogen-donor atoms) on the results of this reaction was studied. The cycloaddition reaction of CO2 with terminal epoxides bearing different functional groups was realized. Moreover, NMR mechanistic studies provided information on the catalytic cycle. Interestingly, the characterization of an intermediate species in the mechanism of the reaction of cyclohexene oxide with CO2 , catalyzed by one of the salalen-aluminum complexes, was accomplished.

  13. Pathophysiology of white-nose syndrome in bats: a mechanistic model linking wing damage to mortality

    USGS Publications Warehouse

    Warnecke, Lisa; Turner, James M.; Bollinger, Trent K.; Misra, Vikram; Cryan, Paul M.; Blehert, David S.; Wibbelt, Gudrun; Willis, Craig K.R.

    2013-01-01

    White-nose syndrome is devastating North American bat populations but we lack basic information on disease mechanisms. Altered blood physiology owing to epidermal invasion by the fungal pathogen Geomyces destructans (Gd) has been hypothesized as a cause of disrupted torpor patterns of affected hibernating bats, leading to mortality. Here, we present data on blood electrolyte concentration, haematology and acid–base balance of hibernating little brown bats, Myotis lucifugus, following experimental inoculation with Gd. Compared with controls, infected bats showed electrolyte depletion (i.e. lower plasma sodium), changes in haematology (i.e. increased haematocrit and decreased glucose) and disrupted acid–base balance (i.e. lower CO2 partial pressure and bicarbonate). These findings indicate hypotonic dehydration, hypovolaemia and metabolic acidosis. We propose a mechanistic model linking tissue damage to altered homeostasis and morbidity/mortality.

  14. Desmosomes in the heart: a review of clinical and mechanistic analyses.

    PubMed

    Patel, Dipal M; Green, Kathleen J

    2014-06-01

    Desmosomes have long been appreciated as intercellular junctions that are vital for maintaining the structural integrity of stratified epithelia. More recent clinical investigations of patients with diseases such as arrhythmogenic cardiomyopathy have further highlighted the importance of desmosomes in cardiac tissue, where they help to maintain coordination of cardiac myocytes. Here, we review clinical and mechanistic studies that provide insight into the functions of desmosomal proteins in skin and heart during homeostasis and in disease. While intercellular junctions are organized differently in cardiac and epithelial tissues, studies conducted in epithelial systems may inform our understanding of cardiac desmosomes. We explore traditional and non-traditional roles of desmosomal proteins, ranging from adhesive capacities to nuclear functions. Finally, we discuss how these studies can guide future investigations focused on determining the molecular mechanisms by which desmosomal mutations promote the development of cardiac diseases.

  15. Organolanthanide-catalyzed imine hydrogenation. Scope, selectivity, mechanistic observations, and unusual byproducts

    SciTech Connect

    Obora, Yasushi; Ohta, Tetsuo; Stern, C.L.; Marks, T.J.

    1997-04-23

    This paper reports a catalytic, synthetic, and molecular structure study of the Cp{prime}{sub 2}Ln/Me{sub 2}SiCp{double_prime}{sub 2}Ln-catalyzed (Cp{prime} = {eta}{sup 5}-Me{sub 5}C{sub 5}; Cp{double_prime} = {eta}{sup 5}-Me{sub 4}C{sub 5}) hydrogenation of acyclic imines to yield the corresponding amines, using well-defined precatalysts and focusing on scope, selectivity, mechanistic observations, and the information nature of several unusual organolanthanide byproducts. The results demonstrate that the rates are modest and roughly comparable to those mediated by a chiral titanocene. 49 refs., 4 figs., 5 tabs.

  16. A structural classification of carbohydrate epimerases: From mechanistic insights to practical applications.

    PubMed

    Van Overtveldt, Stevie; Verhaeghe, Tom; Joosten, Henk-Jan; van den Bergh, Tom; Beerens, Koen; Desmet, Tom

    2015-12-01

    In recent years, carbohydrate epimerases have attracted a lot of attention as efficient biocatalysts that can convert abundant sugars (e.g.d-fructose) directly into rare counterparts (e.g.d-psicose). Despite increased research activities, no review about these enzymes has been published in more than a decade, meaning that their full potential is hard to appreciate. Here, we present an overview of all known carbohydrate epimerases based on a classification in structural families, which links every substrate specificity to a well-defined reaction mechanism. The mechanism can even be predicted for enzymes that have not yet been characterized or that lack structural information. In this review, the different families are discussed in detail, both structurally and mechanistically, with special reference to recent examples in the literature. Furthermore, the value of understanding the reaction mechanism will be illustrated by making the link to possible application and engineering targets.

  17. Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research.

    PubMed

    Ainsbury, Elizabeth A; Barnard, Stephen; Bright, Scott; Dalke, Claudia; Jarrin, Miguel; Kunze, Sarah; Tanner, Rick; Dynlacht, Joseph R; Quinlan, Roy A; Graw, Jochen; Kadhim, Munira; Hamada, Nobuyuki

    The lens of the eye has long been considered as a radiosensitive tissue, but recent research has suggested that the radiosensitivity is even greater than previously thought. The 2012 recommendation of the International Commission on Radiological Protection (ICRP) to substantially reduce the annual occupational equivalent dose limit for the ocular lens has now been adopted in the European Union and is under consideration around the rest of the world. However, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological, mechanistic evidence at doses <2Gy. This paper aims to present a review of recently published information on the biological and mechanistic aspects of cataracts induced by exposure to ionizing radiation (IR). The data were compiled by assessing the pertinent literature in several distinct areas which contribute to the understanding of IR induced cataracts, information regarding lens biology and general processes of cataractogenesis. Results from cellular and tissue level studies and animal models, and relevant human studies, were examined. The main focus was the biological effects of low linear energy transfer IR, but dosimetry issues and a number of other confounding factors were also considered. The results of this review clearly highlight a number of gaps in current knowledge. Overall, while there have been a number of recent advances in understanding, it remains unknown exactly how IR exposure contributes to opacification. A fuller understanding of how exposure to relatively low doses of IR promotes induction and/or progression of IR-induced cataracts will have important implications for prevention and treatment of this disease, as well as for the field of radiation protection.

  18. Descriptive vs. mechanistic network models in plant development in the post-genomic era.

    PubMed

    Davila-Velderrain, J; Martinez-Garcia, J C; Alvarez-Buylla, E R

    2015-01-01

    Network modeling is now a widespread practice in systems biology, as well as in integrative genomics, and it constitutes a rich and diverse scientific research field. A conceptually clear understanding of the reasoning behind the main existing modeling approaches, and their associated technical terminologies, is required to avoid confusions and accelerate the transition towards an undeniable necessary more quantitative, multidisciplinary approach to biology. Herein, we focus on two main network-based modeling approaches that are commonly used depending on the information available and the intended goals: inference-based methods and system dynamics approaches. As far as data-based network inference methods are concerned, they enable the discovery of potential functional influences among molecular components. On the other hand, experimentally grounded network dynamical models have been shown to be perfectly suited for the mechanistic study of developmental processes. How do these two perspectives relate to each other? In this chapter, we describe and compare both approaches and then apply them to a given specific developmental module. Along with the step-by-step practical implementation of each approach, we also focus on discussing their respective goals, utility, assumptions, and associated limitations. We use the gene regulatory network (GRN) involved in Arabidopsis thaliana Root Stem Cell Niche patterning as our illustrative example. We show that descriptive models based on functional genomics data can provide important background information consistent with experimentally supported functional relationships integrated in mechanistic GRN models. The rationale of analysis and modeling can be applied to any other well-characterized functional developmental module in multicellular organisms, like plants and animals.

  19. Optimization of biopharmaceutical downstream processes supported by mechanistic models and artificial neural networks.

    PubMed

    Pirrung, Silvia M; van der Wielen, Luuk A M; van Beckhoven, Ruud F W C; van de Sandt, Emile J A X; Eppink, Michel H M; Ottens, Marcel

    2017-01-05

    Downstream process development is a major area of importance within the field of bioengineering. During the design of such a downstream process, important decisions have to be made regarding the type of unit operations as well as their sequence and their operating conditions. Current computational approaches addressing these issues either show a high level of simplification or struggle with computational speed. Therefore, this article presents a new approach that combines detailed mechanistic models and speed-enhancing artificial neural networks. This approach was able to simultaneously optimize a process with three different chromatographic columns toward yield with a minimum purity of 99.9%. The addition of artificial neural networks greatly accelerated this optimization. Due to high computational speed, the approach is easily extendable to include more unit operations. Therefore, it can be of great help in the acceleration of downstream process development. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 2017.

  20. Synthetic and Mechanistic Studies of Strained Heterocycle Opening Reactions Mediated by Zirconium(IV) Imido Complexes

    PubMed Central

    Blum, Suzanne A.; Rivera, Vicki A.; Ruck, Rebecca T.; Michael, Forrest E.; Bergman, Robert G.

    2005-01-01

    The reactions of the bis(cyclopentadienyl)(tert-butylimido)zirconium complex (Cp2Zr=N-t-Bu)(THF) (1) with epoxides, aziridines, and episulfides were investigated. Heterocycles without accessible β-hydrogens undergo insertion/protonation of the C–X bond to produce 1,2-amino alcohols (X = O) and 1,2-diamines (X = NR), whereas heterocycles with accessible β-hydrogens undergo elimination/protonation to produce allylic alcohols (X = O) and allylic sulfides (X = S). Mechanistic investigations support a stepwise pathway with zwitterionic intermediates for the first reaction class and a concerted pathway for the second reaction class. Additionally, the feasibility of chirality transfer from the planar-chiral ebthi (ebthi = ethylenebis(tetrahydroindenyl)) ligand was demonstrated with a chiral analogue, (ebthi)-Zr=NAr(THF) (Ar = 2,6-dimethylphenyl), 2, through the diastereoselective ring opening of meso epoxides. PMID:16508693

  1. Combating Pathogenic Microorganisms Using Plant-Derived Antimicrobials: A Minireview of the Mechanistic Basis

    PubMed Central

    Upadhyaya, Indu; Kollanoor-Johny, Anup

    2014-01-01

    The emergence of antibiotic resistance in pathogenic bacteria has led to renewed interest in exploring the potential of plant-derived antimicrobials (PDAs) as an alternative therapeutic strategy to combat microbial infections. Historically, plant extracts have been used as a safe, effective, and natural remedy for ailments and diseases in traditional medicine. Extensive research in the last two decades has identified a plethora of PDAs with a wide spectrum of activity against a variety of fungal and bacterial pathogens causing infections in humans and animals. Active components of many plant extracts have been characterized and are commercially available; however, research delineating the mechanistic basis of their antimicrobial action is scanty. This review highlights the potential of various plant-derived compounds to control pathogenic bacteria, especially the diverse effects exerted by plant compounds on various virulence factors that are critical for pathogenicity inside the host. In addition, the potential effect of PDAs on gut microbiota is discussed. PMID:25298964

  2. A Three-Stage Mechanistic Model for Ammonia Borane Dehydrogenation by Shvo’s Catalyst

    PubMed Central

    Lu, Zhiyao; Conley, Brian L.; Williams, Travis J.

    2012-01-01

    We propose a mechanistic model for three-stage dehydrogenation of ammonia borane (AB) catalyzed by Shvo’s cyclopentadienone-ligated ruthenium complex. We provide evidence for a plausible mechanism for catalyst deactivation, the transition from fast catalysis to slow catalysis, and relate those findings to the invention of a second-generation catalyst that does not suffer from the same deactivation chemistry. The primary mechanism of catalyst deactivation is borazine-mediated hydroboration of the ruthenium species that is the active oxidant in the fast catalysis case. This transition is characterized by a change in the rate law for the reaction and changes in the apparent resting state of the catalyst. Also, in this slow catalysis situation, we see an additional intermediate in the sequence of boron, nitrogen species, aminodiborane. This occurs with concurrent generation of NH3, which itself does not strongly affect the rate of AB dehydrogenation. PMID:23335832

  3. Modeling of batch sorber system: kinetic, mechanistic, and thermodynamic modeling

    NASA Astrophysics Data System (ADS)

    Mishra, Vishal

    2016-09-01

    The present investigation has dealt with the biosorption of copper and zinc ions on the surface of egg-shell particles in the liquid phase. Various rate models were evaluated to elucidate the kinetics of copper and zinc biosorptions, and the results indicated that the pseudo-second-order model was more appropriate than the pseudo-first-order model. The curve of the initial sorption rate versus the initial concentration of copper and zinc ions also complemented the results of the pseudo-second-order model. Models used for the mechanistic modeling were the intra-particle model of pore diffusion and Bangham's model of film diffusion. The results of the mechanistic modeling together with the values of pore and film diffusivities indicated that the preferential mode of the biosorption of copper and zinc ions on the surface of egg-shell particles in the liquid phase was film diffusion. The results of the intra-particle model showed that the biosorption of the copper and zinc ions was not dominated by the pore diffusion, which was due to macro-pores with open-void spaces present on the surface of egg-shell particles. The thermodynamic modeling reproduced the fact that the sorption of copper and zinc was spontaneous, exothermic with the increased order of the randomness at the solid-liquid interface.

  4. Noncanonical IFN Signaling: Mechanistic Linkage of Genetic and Epigenetic Events

    PubMed Central

    Ahmed, Chulbul M.

    2016-01-01

    The canonical model of cytokine signaling via the JAK/STAT pathway dominates our view of signal transduction but provides no insight into the significance of the simultaneous presence of activated JAKs and STATs in the nucleus of cells treated with cytokines. Such a mechanistic shortcoming challenges the usefulness of the model in its present form. Focusing on the interferon (IFN) cytokines, we have developed a noncanonical model of IFN signaling that naturally connects activated JAKs and STATs at or near response elements of genes that are activated by the IFNs. Specifically, cells treated with IFNγ showed association of activated STAT1α and JAK2 at the GAS element of genes activated by IFNγ. For IFNα treated cells, the association involved activated STAT1α and TYK2 JAK kinase at the ISRE promoter. The power of the noncanonical model is that it provides mechanistic insight into specific gene activation at the level of the associated epigenetics, akin to that of steroid/steroid receptor signaling. PMID:28077919

  5. From Data Patterns to Mechanistic Models in Acute Critical Illness

    PubMed Central

    Aerts, Jean-Marie; Haddad, Wassim M.; An, Gary; Vodovotz, Yoram

    2014-01-01

    The complexity of the physiologic and inflammatory response in acute critical illness has stymied the accurate diagnosis and development of therapies. The Society for Complex Acute Illness was formed a decade ago with the goal of leveraging multiple complex systems approaches in order to address this unmet need. Two main paths of development have characterized the Society’s approach: i) data pattern analysis, either defining the diagnostic/prognostic utility of complexity metrics of physiological signals or multivariate analyses of molecular and genetic data, and ii) mechanistic mathematical and computational modeling, all being performed with an explicit translational goal. Here, we summarize the progress to date on each of these approaches, along with pitfalls inherent in the use of each approach alone. We suggest that the next decade holds the potential to merge these approaches, connecting patient diagnosis to treatment via mechanism-based dynamical system modeling and feedback control, and allowing extrapolation from physiologic signals to biomarkers to novel drug candidates. As a predicate example, we focus on the role of data-driven and mechanistic models in neuroscience, and the impact that merging these modeling approaches can have on general anesthesia. PMID:24768566

  6. Photosynthetic water oxidation vs. mitochondrial oxygen reduction: distinct mechanistic parallels.

    PubMed

    Silverstein, Todd P

    2011-08-01

    The photosynthetic oxygen evolving complex (PSII-OEC) and the mitochondrial cytochrome c oxidase (CcO) not only catalyze anti-parallel reactions (the OEC oxidizes water to dioxygen, whereas CcO reduces dioxygen to water), they also share a number of uncanny molecular and mechanistic similarities. Both feature a redox-active polymetallic cluster that includes a key tyrosine, and both utilize a two-phase mechanism. In one phase the polymetallic cluster undergoes four sequential one-electron transfers: In the PSII-OEC, four successive photooxidations of the photosystem II reaction center P680 (to P680(+)) allows acceptance of 4 × 1e- from the Mn(4)Ca cluster; in CcO, four reduced cytochrome c Fe(2+) cations donate 4 × 1e- to the bimetallic center. In the second phase for each enzyme, the polymetallic cluster undergoes a single four-electron transfer with the O(2)/2 H(2)O redox couple. Intriguing mechanistic similarities between these two complex redox enzymes first delineated over a decade ago by Hoganson/Proshlyakov/Babcock et al. are updated and expanded in this article.

  7. The coefficient of restitution of pressurized balls: a mechanistic model

    NASA Astrophysics Data System (ADS)

    Georgallas, Alex; Landry, Gaëtan

    2016-01-01

    Pressurized, inflated balls used in professional sports are regulated so that their behaviour upon impact can be anticipated and allow the game to have its distinctive character. However, the dynamics governing the impacts of such balls, even on stationary hard surfaces, can be extremely complex. The energy transformations, which arise from the compression of the gas within the ball and from the shear forces associated with the deformation of the wall, are examined in this paper. We develop a simple mechanistic model of the dependence of the coefficient of restitution, e, upon both the gauge pressure, P_G, of the gas and the shear modulus, G, of the wall. The model is validated using the results from a simple series of experiments using three different sports balls. The fits to the data are extremely good for P_G > 25 kPa and consistent values are obtained for the value of G for the wall material. As far as the authors can tell, this simple, mechanistic model of the pressure dependence of the coefficient of restitution is the first in the literature. *%K Coefficient of Restitution, Dynamics, Inflated Balls, Pressure, Impact Model

  8. Advancements in the mechanistic understanding of the copper-catalyzed azide-alkyne cycloaddition.

    PubMed

    Berg, Regina; Straub, Bernd F

    2013-12-02

    The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most broadly applicable and easy-to-handle reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I) alkyne and acetylide complexes. Following an introductory section on common catalyst systems in CuAAC reactions, this review will highlight experimental and computational studies from early proposals to very recent and more sophisticated investigations, which deliver more detailed insights into the CuAAC's catalytic cycle and the species involved. As diverging mechanistic views are presented in articles, books and online resources, we intend to present the research efforts in this field during the past decade and finally give an up-to-date picture of the currently accepted dinuclear mechanism of CuAAC. Additionally, we hope to inspire research efforts on the development of molecularly defined copper(I) catalysts with defined structural characteristics, whose main advantage in contrast to the regularly used precatalyst reagent mixtures is twofold: on the one hand, the characteristics of molecularly defined, well soluble catalysts can be tuned according to the particular requirements of the experiment; on the other hand, the understanding of the CuAAC reaction mechanism can be further advanced by kinetic studies and the isolation and characterization of key intermediates.

  9. Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

    PubMed Central

    2013-01-01

    Summary The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most broadly applicable and easy-to-handle reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I) alkyne and acetylide complexes. Following an introductory section on common catalyst systems in CuAAC reactions, this review will highlight experimental and computational studies from early proposals to very recent and more sophisticated investigations, which deliver more detailed insights into the CuAAC’s catalytic cycle and the species involved. As diverging mechanistic views are presented in articles, books and online resources, we intend to present the research efforts in this field during the past decade and finally give an up-to-date picture of the currently accepted dinuclear mechanism of CuAAC. Additionally, we hope to inspire research efforts on the development of molecularly defined copper(I) catalysts with defined structural characteristics, whose main advantage in contrast to the regularly used precatalyst reagent mixtures is twofold: on the one hand, the characteristics of molecularly defined, well soluble catalysts can be tuned according to the particular requirements of the experiment; on the other hand, the understanding of the CuAAC reaction mechanism can be further advanced by kinetic studies and the isolation and characterization of key intermediates. PMID:24367437

  10. Stereochemistry of enzymatic water addition to C=C bonds.

    PubMed

    Chen, Bi-Shuang; Otten, Linda G; Hanefeld, Ulf

    2015-01-01

    Water addition to carbon-carbon double bonds using hydratases is attracting great interest in biochemistry. Most of the known hydratases are involved in primary metabolism and to a lesser extent in secondary metabolism. New hydratases have recently been added to the toolbox, both from natural sources or artificial metalloenzymes. In order to comprehensively understand how the hydratases are able to catalyse the water addition to carbon-carbon double bonds, this review will highlight the mechanistic and stereochemical studies of the enzymatic water addition to carbon-carbon double bonds, focusing on the syn/anti-addition and stereochemistry of the reaction.

  11. Backtracking behaviour in lost ants: an additional strategy in their navigational toolkit.

    PubMed

    Wystrach, Antoine; Schwarz, Sebastian; Baniel, Alice; Cheng, Ken

    2013-10-22

    Ants use multiple sources of information to navigate, but do not integrate all this information into a unified representation of the world. Rather, the available information appears to serve three distinct main navigational systems: path integration, systematic search and the use of learnt information--mainly via vision. Here, we report on an additional behaviour that suggests a supplemental system in the ant's navigational toolkit: 'backtracking'. Homing ants, having almost reached their nest but, suddenly displaced to unfamiliar areas, did not show the characteristic undirected headings of systematic searches. Instead, these ants backtracked in the compass direction opposite to the path that they had just travelled. The ecological function of this behaviour is clear as we show it increases the chances of returning to familiar terrain. Importantly, the mechanistic implications of this behaviour stress an extra level of cognitive complexity in ant navigation. Our results imply: (i) the presence of a type of 'memory of the current trip' allowing lost ants to take into account the familiar view recently experienced, and (ii) direct sharing of information across different navigational systems. We propose a revised architecture of the ant's navigational toolkit illustrating how the different systems may interact to produce adaptive behaviours.

  12. p53 and rapamycin are additive

    PubMed Central

    Campisi, Judith; Huang, Jing; Jones, Diane; Dodds, Sherry G.; Williams, Charnae; Hubbard, Gene; Livi, Carolina B.; Gao, Xiaoli; Weintraub, Susan; Curiel, Tyler; Sharp, Z. Dave; Hasty, Paul

    2015-01-01

    Mechanistic target of rapamycin (mTOR) is a kinase found in a complex (mTORC1) that enables macromolecular synthesis and cell growth and is implicated in cancer etiology. The rapamycin-FK506 binding protein 12 (FKBP12) complex allosterically inhibits mTORC1. In response to stress, p53 inhibits mTORC1 through a separate pathway involving cell signaling and amino acid sensing. Thus, these different mechanisms could be additive. Here we show that p53 improved the ability of rapamycin to: 1) extend mouse life span, 2) suppress ionizing radiation (IR)-induced senescence-associated secretory phenotype (SASP) and 3) increase the levels of amino acids and citric acid in mouse embryonic stem (ES) cells. This additive effect could have implications for cancer treatment since rapamycin and p53 are anti-oncogenic. PMID:26158292

  13. A new mechanistic framework to predict OCS fluxes in soils

    NASA Astrophysics Data System (ADS)

    Sauze, Joana; Ogee, Jérôme; Launois, Thomas; Kesselmeier, Jürgen; Van Diest, Heidi; Wingate, Lisa

    2015-04-01

    A better description of the amplitude of photosynthetic and respiratory gross CO2 fluxes at large scales is needed to improve our predictions of the current and future global CO2 cycle. Carbonyl sulfide (COS) is the most abundant sulphur gas in the atmosphere and has been proposed as a new tracer of gross photosynthesis, as the uptake of COS from the atmosphere is dominated by the activity of carbonic anhydrase (CA), an enzyme abundant in leaves that also catalyses CO2 hydration during photosynthesis. However, soils also exchange COS with the atmosphere and there is growing evidence that this flux must also be accounted for in atmospheric budgets. In this context a new mechanistic description of soil-atmosphere COS exchange is clearly needed. Soils can take up COS from the atmosphere as the soil biota also contain CA, and COS emissions from soils have also been reported in agricultural fields or anoxic soils. Previous studies have also shown that soil COS fluxes present an optimum soil water content and soil temperature. Here we propose a new mechanistic framework to predict the fluxes of COS between the soils and the atmosphere. We describe the COS soil budget by a first-order reaction-diffusion-production equation, assuming that the hydrolysis of COS by CA is total and irreversible. To describe COS diffusion through the soil matrix, we use different formulations of soil air-filled pore space and temperature, depending on the turbulence level above the soil surface. Using this model we are able to explain the observed presence of an optimum temperature for soil COS uptake and show how this optimum can shift to cooler temperatures in the presence of soil COS emissions. Our model can also explain the observed optimum with soil moisture content previously described in the literature (e.g. Van Diest & Kesselmeier, 2008) as a result of diffusional constraints on COS hydrolysis. These diffusional constraints are also responsible for the response of COS uptake to soil

  14. Conservative or reactive? Mechanistic chemical perspectives on organic matter stability

    NASA Astrophysics Data System (ADS)

    Koch, Boris

    2016-04-01

    Carbon fixation by terrestrial and marine primary production has a fundamental seasonal effect on the atmospheric carbon content and it profoundly contributes to long-term carbon storage in form of organic matter (OM) in soils, water, and sediments. The efficacy of this sequestration process strongly depends on the degree of OM persistence. Therefore, one of the key issues in dissolved and particulate OM research is to assess the stability of reservoirs and to quantify their contribution to global carbon fluxes. Incubation experiments are helpful to assess OM stability during the first, early diagenetic turnover induced by sunlight or microbes. However, net carbon fluxes within the global carbon cycle also act on much longer time scales, which are not amenable in experiments. It is therefore critical to improve our mechanistic understanding to be able to assess potential future changes in the organic matter cycle. This session contribution highlights some achievements and open questions in the field. An improved mechanistic understanding of OM turnover particularly depends on the molecular characterization of biogeochemical processes and their kinetics: (i) in soils and sediments, aggregation/disaggregation of OM is primarily controlled by its molecular composition. Hence, the chemical composition determines the transfer of organic carbon from the large particulate to the small dissolved organic matter reservoir - an important substrate for microbial metabolism. (ii) In estuaries, dissolved organic carbon gradients usually suggest conservative behavior, whereas molecular-level studies reveal a substantial chemical modification of terrestrial DOM along the land-ocean interface. (iii) In the ocean, previous studies have shown that the recalcitrance of OM depends on bulk concentration and energy yield. However, ultrahigh resolution mass spectrometry in combination with radiocarbon analyses also emphasized that stability is tightly connected to molecular composition

  15. Mechanistic models of plant seed dispersal by wind in heterogeneous landscapes

    NASA Astrophysics Data System (ADS)

    Trakhtenbrot, A.; Katul, G. G.; Nathan, R.

    2010-12-01

    Seed dispersal, and especially long-distance dispersal (LDD), is a key process in plant population survival, colonization, and gene flow. Its importance is amplified by the man-induced habitat fragmentation, climate change and invasions of exotic species. Mechanistic seed dispersal models are central to quantitative prediction of dispersal patterns and understanding their underlying mechanisms. For wind dispersal, most current mechanistic models assume homogenous environment. Although both topography and sharp transitions in vegetation stature profoundly affect wind flow, accounting for these effects via simplified models remains a vexing research problem. Such simplified models are needed to inform ecosystem managers about consequences of landscape fragmentation. We modified the Coupled Eulerian-Lagrangian closure (CELC) mechanistic dispersal model to represent scenarios of wind flow over a sharp transition from short to tall vegetation or over forested hilly terrain, and predicted the resulting dispersal distances and direction. We parameterized the wind and vegetation factors using measurements taken on a hill with short height Mediterranean shrubland and pine forest vegetation at Mt. Pithulim, Israel. For the short-to-tall vegetation transition scenario, the main feature of the modeled wind field is an exponential decay of the mean horizontal wind velocity, assuming that the mean momentum equation simplifies to a balance between the advective acceleration and the drag force terms. As a consequence of the incompressibility condition, this exponential decay leads to strong upward mean vertical velocity component. We found that for seed release downwind of the edge, the simulated median (short) and 99-th percentile (long) distances were longer than those for the homogeneous tall vegetation scenario. For seed release upwind of the edge the effect on dispersal distance was more complex and depended on the release height and he seed terminal velocity of the seeds

  16. Mechanistic characterization of chloride interferences in electrothermal atomization systems

    USGS Publications Warehouse

    Shekiro, J.M.; Skogerboe, R.K.; Taylor, H.E.

    1988-01-01

    A computer-controlled spectrometer with a photodiode array detector has been used for wavelength and temperature resolved characterization of the vapor produced by an electrothermal atomizer. The system has been used to study the chloride matrix interference on the atomic absorption spectrometric determination of manganese and copper. The suppression of manganese and copper atom populations by matrix chlorides such as those of calcium and magnesium is due to the gas-phase formation of an analyte chloride species followed by the diffusion of significant fractions of these species from the atom cell prior to completion of the atomization process. The analyte chloride species cannot be formed when matrix chlorides with metal-chloride bond dissociation energies above those of the analyte chlorides are the principal entitles present. The results indicate that multiple wavelength spectrometry used to obtain temperature-resolved spectra is a viable tool in the mechanistic characterization of interference effects observed with electrothermal atomization systems. ?? 1988 American Chemical Society.

  17. Atrial Fibrillation and Hypertension: Mechanistic, Epidemiologic, and Treatment Parallels.

    PubMed

    Ogunsua, Adedotun A; Shaikh, Amir Y; Ahmed, Mohamed; McManus, David D

    2015-01-01

    Atrial fibrillation (AF) is an increasingly prevalent condition and the most common sustained arrhythmia encountered in ambulatory and hospital practice. Several clinical risk factors for AF include age, sex, valvular heart disease, obesity, sleep apnea, heart failure, and hypertension (HTN). Of all the risk factors, HTN is the most commonly encountered condition in patients with incident AF. Hypertension is associated with a 1.8-fold increase in the risk of developing new-onset AF and a 1.5-fold increase in the risk of progression to permanent AF. Hypertension predisposes to cardiac structural changes that influence the development of AF such as atrial remodeling. The renin angiotensin aldosterone system has been demonstrated to be a common mechanistic link in the pathogenesis of HTN and AF. Importantly, HTN is one of the few modifiable AF risk factors, and guideline-directed management of HTN may reduce the incidence of AF.

  18. Enhancer function: mechanistic and genome-wide insights come together.

    PubMed

    Plank, Jennifer L; Dean, Ann

    2014-07-03

    Enhancers establish spatial or temporal patterns of gene expression that are critical for development, yet our understanding of how these DNA cis-regulatory elements function from a distance to increase transcription of their target genes and shape the cellular transcriptome has been gleaned primarily from studies of individual genes or gene families. High-throughput sequencing studies place enhancer-gene interactions within the 3D context of chromosome folding, inviting a new look at enhancer function and stimulating provocative new questions. Here, we integrate these whole-genome studies with recent mechanistic studies to illuminate how enhancers physically interact with target genes, how enhancer activity is regulated during development, and the role of noncoding RNAs transcribed from enhancers in their function.

  19. Mechanistic modeling confronts the complexity of molecular cell biology.

    PubMed

    Phair, Robert D

    2014-11-05

    Mechanistic modeling has the potential to transform how cell biologists contend with the inescapable complexity of modern biology. I am a physiologist-electrical engineer-systems biologist who has been working at the level of cell biology for the past 24 years. This perspective aims 1) to convey why we build models, 2) to enumerate the major approaches to modeling and their philosophical differences, 3) to address some recurrent concerns raised by experimentalists, and then 4) to imagine a future in which teams of experimentalists and modelers build-and subject to exhaustive experimental tests-models covering the entire spectrum from molecular cell biology to human pathophysiology. There is, in my view, no technical obstacle to this future, but it will require some plasticity in the biological research mind-set.

  20. A mechanistic interpretation of the resonant wave-particle interaction

    NASA Astrophysics Data System (ADS)

    Chim, Chi Yung; O'Neil, Thomas M.

    2016-05-01

    This paper provides a simple mechanistic interpretation of the resonant wave-particle interaction of Landau. For the simple case of a Langmuir wave in a Vlasov plasma, the non-resonant electrons satisfy an oscillator equation that is driven resonantly by the bare electric field from the resonant electrons, and in the case of wave damping, this complex driver field is of a phase to reduce the oscillation amplitude. The wave-particle resonant interaction also occurs in waves governed by 2D E × B drift dynamics, such as a diocotron wave. In this case, the bare electric field from the resonant electrons causes E × B drift motion back in the core plasma, reducing the amplitude of the wave.

  1. Mechanistic model for void distribution in flashing flow

    SciTech Connect

    Riznic, J.; Ishii, M.; Afgan, N.

    1987-01-01

    A problem of discharging of an initially subcooled liquid from a high pressure condition into a low pressure environment is quite important in several industrial systems such as nuclear reactors and chemical reactors. A new model for the flashing process is proposed here based on the wall nucleation theory, bubble growth model and drift-flux bubble transport model. In order to calculate the bubble number density, the bubble number transport equation with a distributed source from the wall nucleation sites is used. The model predictions in terms of the void fraction are compared to Moby Dick and BNL experimental data. It shows that satisfactory agreements could be obtained from the present model without any floating parameter to be adjusted with data. This result indicates that, at least for the experimental conditions considered here, the mechanistic prediction of the flashing phenomenon is possible based on the present wall nucleation based model. 43 refs., 4 figs.

  2. Micelle confined mechanistic pathway for 4-nitrophenol reduction.

    PubMed

    Roy, Anindita; Debnath, Biplab; Sahoo, Ramkrishna; Aditya, Teresa; Pal, Tarasankar

    2017-05-01

    The model 4-nitrophenol reduction has been carried out by different groups in presence of metallic or even non-metallic catalyst elaborating different mechanistic aspects. In the present investigation, we have thoroughly studied the hydrogenation of 4-nitrophenol in a completely metal free homogeneous condition. The introduction of a non-fluorescent probe unequivocally generates a fluorescent molecule that indirectly justifies the anion radical stabilization in the micelle. The reduction mechanism under metal-free condition was proposed and the concept of stabilization of anion radical transition state of 4-nitrophenol at the positively charged Stern layer of anionic micelle was established. The plausible reduction mechanism has also enlightened the graphene-like conducting property of Stern layer of the homogeneous micellar system. Furthermore, the confinement effect for catalysis has also been authenticated by supporting experimental evidences. The borrowed concept of catalysis in confinement drives the catalytic study to a new era of catalysis.

  3. Calorie restriction and cancer prevention: a mechanistic perspective

    PubMed Central

    2013-01-01

    Calorie restriction (CR) is one of the most potent broadly acting dietary interventions for inducing weight loss and for inhibiting cancer in experimental models. Translation of the mechanistic lessons learned from research on CR to cancer prevention strategies in human beings is important given the high prevalence of excess energy intake, obesity, and metabolic syndrome in many parts of the world and the established links between obesity-associated metabolic perturbations and increased risk or progression of many types of cancer. This review synthesizes findings on the biological mechanisms underlying many of the anticancer effects of CR, with emphasis on the impact of CR on growth factor signaling pathways, inflammation, cellular and systemic energy homeostasis pathways, vascular perturbations, and the tumor microenvironment. These CR-responsive pathways and processes represent targets for translating CR research into effective cancer prevention strategies in human beings. PMID:24280167

  4. Assembly Line Polyketide Synthases: Mechanistic Insights and Unsolved Problems

    PubMed Central

    2015-01-01

    Two hallmarks of assembly line polyketide synthases have motivated an interest in these unusual multienzyme systems, their stereospecificity and their capacity for directional biosynthesis. In this review, we summarize the state of knowledge regarding the mechanistic origins of these two remarkable features, using the 6-deoxyerythronolide B synthase as a prototype. Of the 10 stereocenters in 6-deoxyerythronolide B, the stereochemistry of nine carbon atoms is directly set by ketoreductase domains, which catalyze epimerization and/or diastereospecific reduction reactions. The 10th stereocenter is established by the sequential action of three enzymatic domains. Thus, the problem has been reduced to a challenge in mainstream enzymology, where fundamental gaps remain in our understanding of the structural basis for this exquisite stereochemical control by relatively well-defined active sites. In contrast, testable mechanistic hypotheses for the phenomenon of vectorial biosynthesis are only just beginning to emerge. Starting from an elegant theoretical framework for understanding coupled vectorial processes in biology [Jencks, W. P. (1980) Adv. Enzymol. Relat. Areas Mol. Biol. 51, 75–106], we present a simple model that can explain assembly line polyketide biosynthesis as a coupled vectorial process. Our model, which highlights the important role of domain–domain interactions, not only is consistent with recent observations but also is amenable to further experimental verification and refinement. Ultimately, a definitive view of the coordinated motions within and between polyketide synthase modules will require a combination of structural, kinetic, spectroscopic, and computational tools and could be one of the most exciting frontiers in 21st Century enzymology. PMID:24779441

  5. Toxic Neuropathies: Mechanistic Insights Based On A Chemical Perspective

    PubMed Central

    LoPachin, Richard M.; Gavin, Terrence

    2014-01-01

    2,5-Hexanedione (HD) and acrylamide (ACR) are considered to be prototypical among chemical toxicants that cause central-peripheral axonopathies characterized by distal axon swelling and degeneration. Because the demise of distal regions was assumed to be causally related to the onset of neurotoxicity, substantial effort was devoted to deciphering the respective mechanisms. Continued research, however, revealed that expression of the presumed hallmark morphological features was dependent upon the daily rate of toxicant exposure. Indeed, many studies reported that the corresponding axonopathic changes were late developing effects that occurred independent of behavioral and/or functional neurotoxicity. This suggested that the toxic axonopathy classification might be based on epiphenomena related to dose-rate. Therefore, the goal of this mini-review is to discuss how quantitative morphometric analyses and the establishment of dose-dependent relationships helped distinguish primary, mechanistically relevant toxicant effects from non-specific consequences. Perhaps more importantly, we will discuss how knowledge of neurotoxicant chemical nature can guide molecular-level research toward a better, more rational understanding of mechanism. Our discussion will focus on HD, the neurotoxic γ-diketone metabolite of the industrial solvents n-hexane and methyl-n-butyl ketone. Early investigations suggested that HD caused giant neurofilamentous axonal swellings and eventual degeneration in CNS and PNS. However, as our review will point out, this interpretation underwent several iterations as the understanding of γ-diketone chemistry improved and more quantitative experimental approaches were implemented. The chemical concepts and design strategies discussed in this mini-review are broadly applicable to the mechanistic studies of other chemicals (e.g., n-propyl bromine, methyl methacrylate) that cause toxic neuropathies. PMID:25218479

  6. Beneficial effects of melatonin on bovine oocytes maturation: a mechanistic approach.

    PubMed

    Tian, XiuZhi; Wang, Feng; He, ChangJiu; Zhang, Lu; Tan, DunXian; Reiter, Russel J; Xu, Jing; Ji, PengYun; Liu, GuoShi

    2014-10-01

    This study was performed to investigate the effect of melatonin on bovine oocyte maturation and subsequent embryonic development in vitro. The endogenous melatonin concentration in bovine follicular fluid is approximately 10(-11) M. To examine the potential beneficial effects of melatonin on bovine oocyte maturation in vitro, germinal vesicle (GV) oocytes were incubated with different concentrations of melatonin (10(-11), 10(-9), 10(-7), 10(-5), 10(-3) M). Melatonin supplementation at suitable concentrations significantly promoted oocyte maturation. The development of embryos and the mean cell number/blastocyst produced after in vitro fertilization were remarkably improved. The most effective melatonin concentrations obtained from the studies ranged from 10(-9) to 10(-7) M. The expression of melatonin receptor MT1 and MT2 genes was identified in cumulus cells, granulosa cells, and oocytes using reverse transcription PCR, immunofluorescence, and Western blot. The mechanistic studies show that the beneficial effects of melatonin on bovine oocyte maturation are mediated via melatonin membrane receptors as the melatonin receptor agonist (IIK7) promotes this effect while the melatonin receptor antagonist (luzindole) blocks this action. Mechanistic explorations revealed that melatonin supplementation during bovine oocyte maturation significantly up-regulated the expressions of oocyte maturation-associated genes (GDF9, MARF1, and DNMT1a) and cumulus cells expansion-related gene (PTX3, HAS1/2) and that LHR1/2, EGFR are involved in signal transduction and epigenetic reprogramming. The results obtained from the studies provide new information regarding the mechanisms by which melatonin promotes bovine oocyte maturation in vitro and provide an important reference for in vitro embryo production of bovine and the human-assisted reproductive technology.

  7. Simvastatin and dipentyl phthalate lower testosterone production and exhibit dose additive effects on the fetal testis via distinct mechanistic pathways

    EPA Science Inventory

    Sex differentiation of the mammalian reproductive tract is a highly regulated process that is driven, in part, by fetal testosterone (T) production. In utero exposure to phthalate esters (PE) during sex differentiation can result in reproductive tract malformations in rats. PE al...

  8. Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes: A Mechanistic Study.

    PubMed

    Laurell Nash, Anna; Hertzberg, Robin; Wen, Ye-Qian; Dahlgren, Björn; Brinck, Tore; Moberg, Christina

    2016-03-07

    A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

  9. A mechanistic study of manganese(iii) acetate-mediated phosphonyl group additions to [60]- and [70]-fullerenes: the oxidative-ion-transfer mechanism vs. free radical addition.

    PubMed

    Tumanskii, Boris L; Sabirov, Denis S; Lyakhovetsky, Yury I

    2016-11-14

    The phosphonylation of C60 with HP(O)(OAlk)2 and Mn(OAc)3·2H2O has been considered to occur via a free radical (FR) path involving intermediate radicals ˙P(O)(OAlk)2. The present study provides evidence in support of another mechanism for the reactions, oxidative-ion-transfer (OIT). The mechanism involves the change of an acetate group in Mn(OAc)3 for the phosphonate group and oxidation of C60 by the Mn(OAc)2P(O)(OAlk)2 formed to a pair: (C60˙(+), Mn(OAc)2P(O)(OAlk)2˙(-)) followed by the transfer of the phosphonate anion to give the monophposphonylfullerenyl radical. It undergoes reversible dimerization. The polyaddition occurs analogously. Moreover, the compounds Mn(OAc)2P(O)(OAlk)2 (Alk = Et and i-Pr) obtained make novel reagents for phosphonylation of fullerenes working by the OIT mechanism. The reactions of C60 in benzene with equimolar amounts of Mn(OAc)2P(O)(OPr-i)2 or Hg[P(O)(OPr-i)2]2 which is known as working by the FR mechanism since it produces radical ˙P(O)(OPr-i)2 under UV-irradiation, furnished the same radical ˙C60P(O)(OPr-i)2. However, at a 20-fold molar excess of the reagent toward C60, a single derivative C60[P(O)(OPr-i)2]4 and a mixture of derivatives bearing between two and eight phosphonyls were obtained in the former and latter cases, respectively. With C70, the change of the mechanism produced a change in the regioselectivity: 5 and 3 isomers of ˙C70P(O)(OPr-i)2 were obtained, respectively. DFT-calculations provided the hyperfine coupling (hfc) constants of the isomers and explained the regioselectivity change.

  10. Investigation of intervertebral disc degeneration using multivariate FTIR spectroscopic imaging† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c5fd00160a Click here for additional data file.

    PubMed Central

    Peeters, Mirte; Detiger, Suzanne E. L.; Helder, Marco N.; Smit, Theo H.; Le Maitre, Christine L.; Sammon, Chris

    2016-01-01

    Traditionally tissue samples are analysed using protein or enzyme specific stains on serial sections to build up a picture of the distribution of components contained within them. In this study we investigated the potential of multivariate curve resolution-alternating least squares (MCR-ALS) to deconvolute 2nd derivative spectra of Fourier transform infrared (FTIR) microscopic images measured in transflectance mode of goat and human paraffin embedded intervertebral disc (IVD) tissue sections, to see if this methodology can provide analogous information to that provided by immunohistochemical stains and bioassays but from a single section. MCR-ALS analysis of non-degenerate and enzymatically in vivo degenerated goat IVDs reveals five matrix components displaying distribution maps matching histological stains for collagen, elastin and proteoglycan (PG), as well as immunohistochemical stains for collagen type I and II. Interestingly, two components exhibiting characteristic spectral and distribution profiles of proteoglycans were found, and relative component/tissue maps of these components (labelled PG1 and PG2) showed distinct distributions in non-degenerate versus mildly degenerate goat samples. MCR-ALS analysis of human IVD sections resulted in comparable spectral profiles to those observed in the goat samples, highlighting the inter species transferability of the presented methodology. Multivariate FTIR image analysis of a set of 43 goat IVD sections allowed the extraction of semi-quantitative information from component/tissue gradients taken across the IVD width of collagen type I, collagen type II, PG1 and PG2. Regional component/tissue parameters were calculated and significant correlations were found between histological grades of degeneration and PG parameters (PG1: p = 0.0003, PG2: p < 0.0001); glycosaminoglycan (GAG) content and PGs (PG1: p = 0.0055, PG2: p = 0.0001); and MRI T2* measurements and PGs (PG1: p = 0.0021, PG2: p < 0.0001). Additionally

  11. Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers

    SciTech Connect

    Matheis, Katja A.; Com, Emmanuelle; Gautier, Jean-Charles; Guerreiro, Nelson; Brandenburg, Arnd; Gmuender, Hans; Sposny, Alexandra; Hewitt, Philip; Amberg, Alexander; Boernsen, Olaf; Riefke, Bjoern; Hoffmann, Dana; Mally, Angela; Kalkuhl, Arno; Suter, Laura; Dieterle, Frank; Staedtler, Frank

    2011-04-15

    The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with 'omics' data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.

  12. 27 CFR 5.33 - Additional requirements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... English, and for products bottled for consumption within Puerto Rico the required information may be... cannot be removed without thorough application of water or other solvents. (f) Additional information...

  13. 27 CFR 5.33 - Additional requirements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... English, and for products bottled for consumption within Puerto Rico the required information may be... cannot be removed without thorough application of water or other solvents. (f) Additional information...

  14. 27 CFR 5.33 - Additional requirements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... English, and for products bottled for consumption within Puerto Rico the required information may be... cannot be removed without thorough application of water or other solvents. (f) Additional information...

  15. 27 CFR 5.33 - Additional requirements.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... English, and for products bottled for consumption within Puerto Rico the required information may be... cannot be removed without thorough application of water or other solvents. (f) Additional information...

  16. 27 CFR 5.33 - Additional requirements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... English, and for products bottled for consumption within Puerto Rico the required information may be... cannot be removed without thorough application of water or other solvents. (f) Additional information...

  17. Development of a mechanistic model for forced convection subcooled boiling

    NASA Astrophysics Data System (ADS)

    Shaver, Dillon R.

    The focus of this work is on the formulation, implementation, and testing of a mechanistic model of subcooled boiling. Subcooled boiling is the process of vapor generation on a heated wall when the bulk liquid temperature is still below saturation. This is part of a larger effort by the US DoE's CASL project to apply advanced computational tools to the simulation of light water reactors. To support this effort, the formulation of the dispersed field model is described and a complete model of interfacial forces is formulated. The model has been implemented in the NPHASE-CMFD computer code with a K-epsilon model of turbulence. The interfacial force models are built on extensive work by other authors, and include novel formulations of the turbulent dispersion and lift forces. The complete model of interfacial forces is compared to experiments for adiabatic bubbly flows, including both steady-state and unsteady conditions. The same model is then applied to a transient gas/liquid flow in a complex geometry of fuel channels in a sodium fast reactor. Building on the foundation of the interfacial force model, a mechanistic model of forced-convection subcooled boiling is proposed. This model uses the heat flux partitioning concept and accounts for condensation of bubbles attached to the wall. This allows the model to capture the enhanced heat transfer associated with boiling before the point of net generation of vapor, a phenomenon consistent with existing experimental observations. The model is compared to four different experiments encompassing flows of light water, heavy water, and R12 at different pressures, in cylindrical channels, an internally heated annulus, and a rectangular channel. The experimental data includes axial and radial profiles of both liquid temperature and vapor volume fraction, and the agreement can be considered quite good. The complete model is then applied to simulations of subcooled boiling in nuclear reactor subchannels consistent with the

  18. A new mechanistic framework to predict OCS fluxes from soils

    NASA Astrophysics Data System (ADS)

    Ogée, Jérôme; Sauze, Joana; Kesselmeier, Jürgen; Genty, Bernard; Van Diest, Heidi; Launois, Thomas; Wingate, Lisa

    2016-04-01

    Estimates of photosynthetic and respiratory fluxes at large scales are needed to improve our predictions of the current and future global CO2 cycle. Carbonyl sulfide (OCS) is the most abundant sulfur gas in the atmosphere and has been proposed as a new tracer of photosynthetic gross primary productivity (GPP), as the uptake of OCS from the atmosphere is dominated by the activity of carbonic anhydrase (CA), an enzyme abundant in leaves that also catalyses CO2 hydration during photosynthesis. However soils also exchange OCS with the atmosphere, which complicates the retrieval of GPP from atmospheric budgets. Indeed soils can take up large amounts of OCS from the atmosphere as soil microorganisms also contain CA, and OCS emissions from soils have been reported in agricultural fields or anoxic soils. To date no mechanistic framework exists to describe this exchange of OCS between soils and the atmosphere, but empirical results, once upscaled to the global scale, indicate that OCS consumption by soils dominates OCS emission and its contribution to the atmospheric budget is large, at about one third of the OCS uptake by vegetation, also with a large uncertainty. Here, we propose a new mechanistic model of the exchange of OCS between soils and the atmosphere that builds on our knowledge of soil CA activity from CO2 oxygen isotopes. In this model the OCS soil budget is described by a first-order reaction-diffusion-production equation, assuming that the hydrolysis of OCS by CA is total and irreversible. Using this model we are able to explain the observed presence of an optimum temperature for soil OCS uptake and show how this optimum can shift to cooler temperatures in the presence of soil OCS emission. Our model can also explain the observed optimum with soil moisture content previously described in the literature as a result of diffusional constraints on OCS hydrolysis. These diffusional constraints are also responsible for the response of OCS uptake to soil weight and

  19. Station Blackout: A case study in the interaction of mechanistic and probabilistic safety analysis

    SciTech Connect

    Curtis Smith; Diego Mandelli; Cristian Rabiti

    2013-11-01

    The ability to better characterize and quantify safety margins is important to improved decision making about nuclear power plant design, operation, and plant life extension. As research and development (R&D) in the light-water reactor (LWR) Sustainability (LWRS) Program and other collaborative efforts yield new data, sensors, and improved scientific understanding of physical processes that govern the aging and degradation of plant SSCs needs and opportunities to better optimize plant safety and performance will become known. The purpose of the Risk Informed Safety Margin Characterization (RISMC) Pathway R&D is to support plant decisions for risk-informed margin management with the aim to improve economics, reliability, and sustain safety of current NPPs. In this paper, we describe the RISMC analysis process illustrating how mechanistic and probabilistic approaches are combined in order to estimate a safety margin. We use the scenario of a “station blackout” wherein offsite power and onsite power is lost, thereby causing a challenge to plant safety systems. We describe the RISMC approach, illustrate the station blackout modeling, and contrast this with traditional risk analysis modeling for this type of accident scenario.

  20. Exploring novel mechanistic insights in Alzheimer’s disease by assessing reliability of protein interactions

    PubMed Central

    Malhotra, Ashutosh; Younesi, Erfan; Sahadevan, Sudeep; Zimmermann, Joerg; Hofmann-Apitius, Martin

    2015-01-01

    Protein interaction networks are widely used in computational biology as a graphical means of representing higher-level systemic functions in a computable form. Although, many algorithms exist that seamlessly collect and measure protein interaction information in network models, they often do not provide novel mechanistic insights using quantitative criteria. Measuring information content and knowledge representation in network models about disease mechanisms becomes crucial particularly when exploring new target candidates in a well-defined functional context of a potential disease mechanism. To this end, we have developed a knowledge-based scoring approach that uses literature-derived protein interaction features to quantify protein interaction confidence. Thereby, we introduce the novel concept of knowledge cliffs, regions of the interaction network where a significant gap between high scoring and low scoring interactions is observed, representing a divide between established and emerging knowledge on disease mechanism. To show the application of this approach, we constructed and assessed reliability of a protein-protein interaction model specific to Alzheimer’s disease, which led to screening, and prioritization of four novel protein candidates. Evaluation of the identified candidates showed that two of them are already followed in clinical trials for testing potential AD drugs. PMID:26346705

  1. Cobalt-Catalyzed C(sp(2))-H Borylation: Mechanistic Insights Inspire Catalyst Design.

    PubMed

    Obligacion, Jennifer V; Semproni, Scott P; Pappas, Iraklis; Chirik, Paul J

    2016-08-24

    A comprehensive study into the mechanism of bis(phosphino)pyridine (PNP) cobalt-catalyzed C-H borylation of 2,6-lutidine using B2Pin2 (Pin = pinacolate) has been conducted. The experimentally observed rate law, deuterium kinetic isotope effects, and identification of the catalyst resting state support turnover limiting C-H activation from a fully characterized cobalt(I) boryl intermediate. Monitoring the catalytic reaction as a function of time revealed that borylation of the 4-position of the pincer in the cobalt catalyst was faster than arene borylation. Cyclic voltammetry established the electron withdrawing influence of 4-BPin, which slows the rate of C-H oxidative addition and hence overall catalytic turnover. This mechanistic insight inspired the next generation of 4-substituted PNP cobalt catalysts with electron donating and sterically blocking methyl and pyrrolidinyl substituents that exhibited increased activity for the C-H borylation of unactivated arenes. The rationally designed catalysts promote effective turnover with stoichiometric quantities of arene substrate and B2Pin2. Kinetic studies on the improved catalyst, 4-(H)2BPin, established a change in turnover limiting step from C-H oxidative addition to C-B reductive elimination. The iridium congener of the optimized cobalt catalyst, 6-(H)2BPin, was prepared and crystallographically characterized and proved inactive for C-H borylation, a result of the high kinetic barrier for reductive elimination from octahedral Ir(III) complexes.

  2. Circadian rhythms and addiction: Mechanistic insights and future directions

    PubMed Central

    Logan, Ryan W.; Williams, Wilbur P.; McClung, Colleen A.

    2014-01-01

    Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes, may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction, and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction. PMID:24731209

  3. Diffusion theory in biology: a relic of mechanistic materialism.

    PubMed

    Agutter, P S; Malone, P C; Wheatley, D N

    2000-01-01

    Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of diffusion theory will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theory's evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metalbolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science.

  4. Mechanistic Perspectives of Maslinic Acid in Targeting Inflammation

    PubMed Central

    Yap, Wei Hsum; Lim, Yang Mooi

    2015-01-01

    Chronic inflammation drives the development of various pathological diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and cancer. The arachidonic acid pathway represents one of the major mechanisms for inflammation. Prostaglandins (PGs) are lipid products generated from arachidonic acid by the action of cyclooxygenase (COX) enzymes and their activity is blocked by nonsteroidal anti-inflammatory drugs (NSAIDS). The use of natural compounds in regulation of COX activity/prostaglandins production is receiving increasing attention. In Mediterranean diet, olive oil and table olives contain significant dietary sources of maslinic acid. Maslinic acid is arising as a safe and novel natural pentacyclic triterpene which has protective effects against chronic inflammatory diseases in various in vivo and in vitro experimental models. Understanding the anti-inflammatory mechanism of maslinic acid is crucial for its development as a potential dietary nutraceutical. This review focuses on the mechanistic action of maslinic acid in regulating the inflammation pathways through modulation of the arachidonic acid metabolism including the nuclear factor-kappa B (NF-κB)/COX-2 expression, upstream protein kinase signaling, and phospholipase A2 enzyme activity. Further investigations may provide insight into the mechanism of maslinic acid in regulating the molecular targets and their associated pathways in response to specific inflammatory stimuli. PMID:26491566

  5. A mechanistic stochastic framework for regulating bacterial cell division

    PubMed Central

    Ghusinga, Khem Raj; Vargas-Garcia, Cesar A.; Singh, Abhyudai

    2016-01-01

    How exponentially growing cells maintain size homeostasis is an important fundamental problem. Recent single-cell studies in prokaryotes have uncovered the adder principle, where cells add a fixed size (volume) from birth to division, irrespective of their size at birth. To mechanistically explain the adder principle, we consider a timekeeper protein that begins to get stochastically expressed after cell birth at a rate proportional to the volume. Cell-division time is formulated as the first-passage time for protein copy numbers to hit a fixed threshold. Consistent with data, the model predicts that the noise in division timing increases with size at birth. Intriguingly, our results show that the distribution of the volume added between successive cell-division events is independent of the newborn cell size. This was dramatically seen in experimental studies, where histograms of the added volume corresponding to different newborn sizes collapsed on top of each other. The model provides further insights consistent with experimental observations: the distribution of the added volume when scaled by its mean becomes invariant of the growth rate. In summary, our simple yet elegant model explains key experimental findings and suggests a mechanism for regulating both the mean and fluctuations in cell-division timing for controlling size. PMID:27456660

  6. AIR POLLUTION, INFLAMMATION AND PRETERM BIRTH: A POTENTIAL MECHANISTIC LINK

    PubMed Central

    Vadillo-Ortega, Felipe; Osornio-Vargas, Alvaro; Buxton, Miatta A.; Sánchez, Brisa N.; Rojas-Bracho, Leonora; Viveros-Alcaráz, Martin; Castillo-Castrejón, Marisol; Beltrán-Montoya, Jorge; Brown, Daniel G.; O´Neill, Marie S.

    2014-01-01

    Preterm birth is a public health issue of global significance, which may result in mortality during the perinatal period or may lead to major health and financial consequences due to lifelong impacts. Even though several risk factors for preterm birth have been identified, prevention efforts have failed to halt the increasing rates of preterm birth. Epidemiological studies have identified air pollution as an emerging potential risk factor for preterm birth. However, many studies were limited by study design and inadequate exposure assessment. Due to the ubiquitous nature of ambient air pollution and the potential public health significance of any role in causing preterm birth, a novel focus investigating possible causal mechanisms influenced by air pollution is therefore a global health priority. We hypothesize that air pollution may act together with other biological factors to induce systemic inflammation and influence the duration of pregnancy. Evaluation and testing of this hypothesis is currently being conducted in a prospective cohort study in Mexico City and will provide an understanding of the pathways that mediate the effects of air pollution on preterm birth. The important public health implication is that crucial steps in this mechanistic pathway can potentially be acted on early in pregnancy to reduce the risk of preterm birth. PMID:24382337

  7. Mechanistic perspectives on cancer chemoprevention/chemotherapeutic effects of thymoquinone.

    PubMed

    Kundu, Juthika; Chun, Kyung-Soo; Aruoma, Okezie I; Kundu, Joydeb Kumar

    2014-10-01

    The bioactive natural products (plant secondary metabolites) are widely known to possess therapeutic value for the prevention and treatment of various chronic diseases including cancer. Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone; TQ), a monoterpene present in black cumin seeds, exhibits pleiotropic pharmacological activities including antioxidant, anti-inflammatory, antidiabetic and antitumor effects. TQ inhibits experimental carcinogenesis in a wide range of animal models and has been shown to arrest the growth of various cancer cells in culture as well as xenograft tumors in vivo. The mechanistic basis of anticancer effects of TQ includes the inhibition of carcinogen metabolizing enzyme activity and oxidative damage of cellular macromolecules, attenuation of inflammation, induction of cell cycle arrest and apoptosis in tumor cells, blockade of tumor angiogenesis, and suppression of migration, invasion and metastasis of cancer cells. TQ shows synergistic and/or potentiating anticancer effects when combined with clinically used chemotherapeutic agents. At the molecular level, TQ targets various components of intracellular signaling pathways, particularly a variety of upstream kinases and transcription factors, which are aberrantly activated during the course of tumorigenesis.

  8. Rapid Discrimination Among Putative Mechanistic Models of Biochemical Systems

    PubMed Central

    Lomnitz, Jason G.; Savageau, Michael A.

    2016-01-01

    An overarching goal in molecular biology is to gain an understanding of the mechanistic basis underlying biochemical systems. Success is critical if we are to predict effectively the outcome of drug treatments and the development of abnormal phenotypes. However, data from most experimental studies is typically noisy and sparse. This allows multiple potential mechanisms to account for experimental observations, and often devising experiments to test each is not feasible. Here, we introduce a novel strategy that discriminates among putative models based on their repertoire of qualitatively distinct phenotypes, without relying on knowledge of specific values for rate constants and binding constants. As an illustration, we apply this strategy to two synthetic gene circuits exhibiting anomalous behaviors. Our results show that the conventional models, based on their well-characterized components, cannot account for the experimental observations. We examine a total of 40 alternative hypotheses and show that only 5 have the potential to reproduce the experimental data, and one can do so with biologically relevant parameter values. PMID:27578053

  9. Mechanistic evaluation of virus clearance by depth filtration.

    PubMed

    Venkiteshwaran, Adith; Fogle, Jace; Patnaik, Purbasa; Kowle, Ron; Chen, Dayue

    2015-01-01

    Virus clearance by depth filtration has not been well-understood mechanistically due to lack of quantitative data on filter charge characteristics and absence of systematic studies. It is generally believed that both electrostatic interactions and sized based mechanical entrapment contribute to virus clearance by depth filtration. In order to establish whether the effectiveness of virus clearance correlates with the charge characteristics of a given depth filter, a counter-ion displacement technique was employed to determine the ionic capacity for several depth filters. Two depth filters (Millipore B1HC and X0HC) with significant differences in ionic capacities were selected and evaluated for their ability to eliminate viruses. The high ionic capacity X0HC filter showed complete porcine parvovirus (PPV) clearance (eliminating the spiked viruses to below the limit of detection) under low conductivity conditions (≤2.5 mS/cm), achieving a log10 reduction factor (LRF) of > 4.8. On the other hand, the low ionic capacity B1HC filter achieved only ∼2.1-3.0 LRF of PPV clearance under the same conditions. These results indicate that parvovirus clearance by these two depth filters are mainly achieved via electrostatic interactions between the filters and PPV. When much larger xenotropic murine leukemia virus (XMuLV) was used as the model virus, complete retrovirus clearance was obtained under all conditions evaluated for both depth filters, suggesting the involvement of mechanisms other than just electrostatic interactions in XMuLV clearance.

  10. Simplified mechanistic models of gene regulation for analysis and design

    PubMed Central

    Hancock, Edward J.; Stan, Guy-Bart; Arpino, James A. J.; Papachristodoulou, Antonis

    2015-01-01

    Simplified mechanistic models of gene regulation are fundamental to systems biology and essential for synthetic biology. However, conventional simplified models typically have outputs that are not directly measurable and are based on assumptions that do not often hold under experimental conditions. To resolve these issues, we propose a ‘model reduction’ methodology and simplified kinetic models of total mRNA and total protein concentration, which link measurements, models and biochemical mechanisms. The proposed approach is based on assumptions that hold generally and include typical cases in systems and synthetic biology where conventional models do not hold. We use novel assumptions regarding the ‘speed of reactions’, which are required for the methodology to be consistent with experimental data. We also apply the methodology to propose simplified models of gene regulation in the presence of multiple protein binding sites, providing both biological insights and an illustration of the generality of the methodology. Lastly, we show that modelling total protein concentration allows us to address key questions on gene regulation, such as efficiency, burden, competition and modularity. PMID:26063825

  11. Mechanistic explanation, cognitive systems demarcation, and extended cognition.

    PubMed

    van Eck, Dingmar; Looren de Jong, Huib

    2016-10-01

    Approaches to the Internalism-Externalism controversy in the philosophy of mind often involve both (broadly) metaphysical and explanatory considerations. Whereas originally most emphasis seems to have been placed on metaphysical concerns, recently the explanation angle is getting more attention. Explanatory considerations promise to offer more neutral grounds for cognitive systems demarcation than (broadly) metaphysical ones. However, it has been argued that explanation-based approaches are incapable of determining the plausibility of internalist-based conceptions of cognition vis-à-vis externalist ones. On this perspective, improved metaphysics is the route along which to solve the Internalist-Externalist stalemate. In this paper we challenge this claim. Although we agree that explanation-orientated approaches have indeed so far failed to deliver solid means for cognitive system demarcation, we elaborate a more promising explanation-oriented framework to address this issue. We argue that the mutual manipulability account of constitutive relevance in mechanisms, extended with the criterion of 'fat-handedness', is capable of plausibly addressing the cognitive systems demarcation problem, and thus able to decide on the explanatory traction of Internalist vs. Externalist conceptions, on a case-by-case basis. Our analysis also highlights why some other recent mechanistic takes on the problem of cognitive systems demarcation have been unsuccessful. We illustrate our claims with a case on gestures and learning.

  12. A mechanistic physicochemical model of carbon dioxide transport in blood.

    PubMed

    O'Neill, David P; Robbins, Peter A

    2017-02-01

    A number of mathematical models have been produced that, given the Pco2 and Po2 of blood, will calculate the total concentrations for CO2 and O2 in blood. However, all these models contain at least some empirical features, and thus do not represent all of the underlying physicochemical processes in an entirely mechanistic manner. The aim of this study was to develop a physicochemical model of CO2 carriage by the blood to determine whether our understanding of the physical chemistry of the major chemical components of blood together with their interactions is sufficiently strong to predict the physiological properties of CO2 carriage by whole blood. Standard values are used for the ionic composition of the blood, the plasma albumin concentration, and the hemoglobin concentration. All Km values required for the model are taken from the literature. The distribution of bicarbonate, chloride, and H(+) ions across the red blood cell membrane follows that of a Gibbs-Donnan equilibrium. The system of equations that results is solved numerically using constraints for mass balance and electroneutrality. The model reproduces the phenomena associated with CO2 carriage, including the magnitude of the Haldane effect, very well. The structural nature of the model allows various hypothetical scenarios to be explored. Here we examine the effects of 1) removing the ability of hemoglobin to form carbamino compounds; 2) allowing a degree of Cl(-) binding to deoxygenated hemoglobin; and 3) removing the chloride (Hamburger) shift. The insights gained could not have been obtained from empirical models.

  13. Bioavailability and Pharmacokinetics of Genistein: Mechanistic Studies on its ADME

    PubMed Central

    Yang, Zhen; Kulkarni, Kaustubh; Zhu, Wei; Hu, Ming

    2014-01-01

    Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches. PMID:22583407

  14. Mechanistic insight into sonochemical biodiesel synthesis using heterogeneous base catalyst.

    PubMed

    Choudhury, Hanif A; Chakma, Sankar; Moholkar, Vijayanand S

    2014-01-01

    The beneficial effect of ultrasound on transesterification reaction is well known. Heterogeneous (or solid) catalysts for biodiesel synthesis have merit that they do not contaminate the byproduct of glycerol. In this paper, we have attempted to identify the mechanistic features of ultrasound-enhanced biodiesel synthesis with the base-catalyst of CaO. A statistical design of experiments (Box-Behnken) was used to identify the influence of temperature, alcohol to oil molar ratio and catalyst loading on transesterification yield. The optimum values of these parameters for the highest yield were identified through Response Surface Method (with a quadratic model) and ANOVA. These values are: temperature=62 °C, molar ratio=10:1 and catalyst loading=6 wt.%. The activation energy was determined as 82.3 kJ/mol, which is higher than that for homogeneous catalyzed system (for both acidic and basic catalyst). The experimental results have been analyzed vis-à-vis simulations of cavitation bubble dynamics. Due to 3-phase heterogeneity of the system, the yield was dominated by intrinsic kinetics, and the optimum temperature for the highest yield was close to boiling point of methanol. At this temperature, the influence of cavitation bubbles (in terms of both sonochemical and sonophysical effect) is negligible, and ultrasonic micro-streaming provided necessary convection in the system. The influence of all parameters on the reaction system was found to be strongly inter-dependent.

  15. Refined pipe theory for mechanistic modeling of wood development.

    PubMed

    Deckmyn, Gaby; Evans, Sam P; Randle, Tim J

    2006-06-01

    We present a mechanistic model of wood tissue development in response to changes in competition, management and climate. The model is based on a refinement of the pipe theory, where the constant ratio between sapwood and leaf area (pipe theory) is replaced by a ratio between pipe conductivity and leaf area. Simulated pipe conductivity changes with age, stand density and climate in response to changes in allocation or pipe radius, or both. The central equation of the model, which calculates the ratio of carbon (C) allocated to leaves and pipes, can be parameterized to describe the contrasting stem conductivity behavior of different tree species: from constant stem conductivity (functional homeostasis hypothesis) to height-related reduction in stem conductivity with age (hydraulic limitation hypothesis). The model simulates the daily growth of pipes (vessels or tracheids), fibers and parenchyma as well as vessel size and simulates the wood density profile and the earlywood to latewood ratio from these data. Initial runs indicate the model yields realistic seasonal changes in pipe radius (decreasing pipe radius from spring to autumn) and wood density, as well as realistic differences associated with the competitive status of trees (denser wood in suppressed trees).

  16. MECHANISTIC AND BIOLOGICAL ASPECTS OF HELICASE ACTION ON DAMAGED DNA

    PubMed Central

    Suhasini, Avvaru N.; Brosh, Robert M.

    2010-01-01

    Helicases catalytically unwind structured nucleic acids in a nucleoside-triphosphate-dependent and directionally specific manner, and are essential for virtually all aspects of nucleic acid metabolism. ATPase-driven helicases which translocate along nucleic acids play a role in damage recognition or unwinding of a DNA tract containing the lesion. Although classical biochemical experiments provided evidence that bulky covalent adducts inhibit DNA unwinding catalyzed by certain DNA helicases in a strand-specific manner (i.e. , block to DNA unwinding restricted to adduct residence in the strand the helicase translocates), recent studies suggest more complex arrangements that may depend on the helicase under study, its assembly in a protein complex, and the type of structural DNA perturbation. Moreover, base and sugar phosphate backbone modifications exert effects on DNA helicases that suggest specialized tracking mechanisms. As a component of the replication stress response, the single-stranded DNA binding protein Replication Protein A (RPA) may serve to enable eukaryotic DNA helicases to overcome certain base lesions. Helicases play important roles in DNA damage signaling which also involve their partnership with RPA. In this review, we will discuss our current understanding of mechanistic and biological aspects of helicase action on damaged DNA. PMID:20574162

  17. Mechanistic solutions to the opening of the Gulf of Mexico

    USGS Publications Warehouse

    Schouten, Hans; Klitgord, Kim D.

    1994-01-01

    Two mechanistic models-which are unlike the traditional plate-tectonic landfill models used for most proposed Pangea reconstructions of the Yucatán block-relate the Mesozoic opening of the Gulf of Mexico directly to the movement of the North and South American plates: (1) a previous piggyback model in which Yucatán moves with South America out of the western gulf and (2) a new edge-driven model in which the motion of the Yucatán block is caused by forces applied to its margins by the movement of the North and South American plates. In the second model, Yucatán moves out of the northern Gulf of Mexico as a gear or roller bearing. On the basis of magnetic edge anomalies around the gulf, this edge-driven model predicts that from the Bathonian to Tithonian (~170 to ~50 Ma), Yucatán was rotated ~60° counterclockwise as a rigid block between North and South America with rift propagation and extension occurring simultaneously in the Gulf of Mexico and Yucatán Basin.

  18. Neutron structure and mechanistic studies of diisopropyl fluorophosphatase (DFPase)

    SciTech Connect

    Chen, Julian C.-H.; Mustyakimov, Marat; Schoenborn, Benno P.; Langan, Paul; Blum, Marc-Michael

    2010-11-01

    The structure and mechanism of diisopropyl fluorophosphatase (DFPase) have been studied using a variety of methods, including isotopic labelling, X-ray crystallography and neutron crystallography. The neutron structure of DFPase, mechanistic studies and subsequent rational design efforts are described. Diisopropyl fluorophosphatase (DFPase) is a calcium-dependent phosphotriesterase that acts on a variety of highly toxic organophosphorus compounds that act as inhibitors of acetylcholinesterase. The mechanism of DFPase has been probed using a variety of methods, including isotopic labelling, which demonstrated the presence of a phosphoenzyme intermediate in the reaction mechanism. In order to further elucidate the mechanism of DFPase and to ascertain the protonation states of the residues and solvent molecules in the active site, the neutron structure of DFPase was solved at 2.2 Å resolution. The proposed nucleophile Asp229 is deprotonated, while the active-site solvent molecule W33 was identified as water and not hydroxide. These data support a mechanism involving direct nucleophilic attack by Asp229 on the substrate and rule out a mechanism involving metal-assisted water activation. These data also allowed for the re-engineering of DFPase through rational design to bind and productively orient the more toxic S{sub P} stereoisomers of the nerve agents sarin and cyclosarin, creating a modified enzyme with enhanced overall activity and significantly increased detoxification properties.

  19. Mechanistic modelling of the drying behaviour of single pharmaceutical granules.

    PubMed

    Mortier, Séverine Thérèse F C; De Beer, Thomas; Gernaey, Krist V; Vercruysse, Jurgen; Fonteyne, Margot; Remon, Jean Paul; Vervaet, Chris; Nopens, Ingmar

    2012-04-01

    The trend to move towards continuous production processes in pharmaceutical applications enhances the necessity to develop mechanistic models to understand and control these processes. This work focuses on the drying behaviour of a single wet granule before tabletting, using a six-segmented fluidised bed drying system, which is part of a fully continuous from-powder-to-tablet manufacturing line. The drying model is based on a model described by Mezhericher et al. and consists of two submodels. In the first drying phase (submodel 1), the surface water evaporates, while in the second drying phase (submodel 2), the water inside the granule evaporates. The second submodel contains an empirical power coefficient, β. A sensitivity analysis was performed to study the influence of parameters on the moisture content of single pharmaceutical granules, which clearly points towards the importance of β on the drying behaviour. Experimental data with the six-segmented fluidised bed dryer were collected to calibrate β. An exponential dependence on the drying air temperature was found. Independent experiments were done for the validation of the drying model.

  20. Mechanistic understanding of monosaccharide-air flow battery electrochemistry

    NASA Astrophysics Data System (ADS)

    Scott, Daniel M.; Tsang, Tsz Ho; Chetty, Leticia; Aloi, Sekotilani; Liaw, Bor Yann

    Recently, an inexpensive monosaccharide-air flow battery configuration has been demonstrated to utilize a strong base and a mediator redox dye to harness electrical power from the partial oxidation of glucose. Here the mechanistic understanding of glucose oxidation in this unique glucose-air power source is further explored by acid-base titration experiments, 13C NMR, and comparison of results from chemically different redox mediators (indigo carmine vs. methyl viologen) and sugars (fructose vs. glucose) via studies using electrochemical techniques. Titration results indicate that gluconic acid is the main product of the cell reaction, as supported by evidence in the 13C NMR spectra. Using indigo carmine as the mediator dye and fructose as the energy source, an abiotic cell configuration generates a power density of 1.66 mW cm -2, which is greater than that produced from glucose under similar conditions (ca. 1.28 mW cm -2). A faster transition from fructose into the ene-diol intermediate than from glucose likely contributed to this difference in power density.

  1. Mechanistic Enzymology of the Radical SAM Enzyme DesII.

    PubMed

    Ruszczycky, Mark W; Liu, Hung-Wen

    2015-04-01

    DesII is a member of the radical SAM family of enzymes that catalyzes radical-mediated transformations of TDP-4-amino-4,6-didexoy-D-glucose as well as other sugar nucleotide diphosphates. Like nearly all radical SAM enzymes, the reactions begin with the reductive homolysis of SAM to produce a 5'-deoxyadenosyl radical which is followed by regiospecific hydrogen atom abstraction from the substrate. What happens next, however, depends on the nature of the substrate radical so produced. In the case of the biosynthetically relevant substrate, a radical-mediated deamination ensues; however, when this amino group is replaced with a hydroxyl, one instead observes dehydrogenation. The factors that govern the fate of the initially generated substrate radical as well as the mechanistic details underlying these transformations have been a key focus of research into the chemistry of DesII. This review will discuss recent discoveries pertaining to the enzymology of DesII, how it may relate to understanding other radical-mediated lyases and dehydrogenases and the working hypotheses currently being investigated regarding the mechanism of DesII catalysis.

  2. A mechanistic stochastic framework for regulating bacterial cell division.

    PubMed

    Ghusinga, Khem Raj; Vargas-Garcia, Cesar A; Singh, Abhyudai

    2016-07-26

    How exponentially growing cells maintain size homeostasis is an important fundamental problem. Recent single-cell studies in prokaryotes have uncovered the adder principle, where cells add a fixed size (volume) from birth to division, irrespective of their size at birth. To mechanistically explain the adder principle, we consider a timekeeper protein that begins to get stochastically expressed after cell birth at a rate proportional to the volume. Cell-division time is formulated as the first-passage time for protein copy numbers to hit a fixed threshold. Consistent with data, the model predicts that the noise in division timing increases with size at birth. Intriguingly, our results show that the distribution of the volume added between successive cell-division events is independent of the newborn cell size. This was dramatically seen in experimental studies, where histograms of the added volume corresponding to different newborn sizes collapsed on top of each other. The model provides further insights consistent with experimental observations: the distribution of the added volume when scaled by its mean becomes invariant of the growth rate. In summary, our simple yet elegant model explains key experimental findings and suggests a mechanism for regulating both the mean and fluctuations in cell-division timing for controlling size.

  3. Anti-fibro-hepatocarcinogenic Chinese herbal medicines: A mechanistic overview

    PubMed Central

    Boye, Alex; Yang, Yan; Asenso, James; Wei, Wei

    2016-01-01

    Chinese herbal medicine (CHM) is an integral component of complementary/alternative medicine and it is increasingly becoming the preferred therapeutic modality for the treatment of liver fibrosis and hepatocellular carcinoma (HCC) worldwide. Accordingly, the World Health Organization (WHO) has attested to the popularity and efficacy of indigenous herbal therapies including CHM as a first line of treatment for some diseases including liver disorders. However, the WHO and drug discovery experts have always recommended that use of indigenous herbal remedies must go hand-in-hand with the requisite mechanistic elucidation so as to constitute a system of verification of efficacy within the ethnobotanical context of use. Although many CHM experts have advanced knowledge on CHM, nonetheless, more enlightenment is needed, particularly mechanisms of action of CHMs on fibro-hepato-carcinogenesis. We, herein, provide in-depth mechanisms of the action of CHMs which have demonstrated anti-fibro-hepatocarcinogenic effects, in pre-clinical and clinical studies as published in PubMed and other major scientific databases. Specifically, the review brings out the important signaling pathways, and their downstream targets which are modulated at multi-level by various anti-fibro-hepatocarcinogenic CHMs. PMID:27366355

  4. Mechanistic rationales for targeting interleukin-17A in spondyloarthritis.

    PubMed

    Raychaudhuri, Siba P; Raychaudhuri, Smriti K

    2017-03-08

    The term spondyloarthritis (SpA) is used to describe a group of inflammatory autoimmune diseases, including ankylosing spondylitis and psoriatic arthritis, with common genetic risk factors and clinical features. SpA is clinically distinct from rheumatoid arthritis and typically affects the spine, sacroiliac joints, entheses, and, less commonly, peripheral joints. Although the pathogenesis of SpA is not fully understood, recent findings have identified the interleukin (IL)-17 pathway as a key mediator of disease pathogenesis. Clinical evidence for the efficacy of IL-17A inhibition by biologic agents was initially shown in patients with chronic plaque psoriasis, another autoimmune disease mediated by the IL-17 pathway. Subsequently, similar positive efficacy for inhibition of IL-17A was seen in patients with ankylosing spondylitis and psoriatic arthritis. Inhibition of IL-17A may also improve cardiovascular and metabolic comorbidities often found in patients with SpA because studies have linked these disorders to the IL-17 pathway. In this review, we will examine key preclinical studies that demonstrated the mechanistic role of IL-17A in the development SpA and discuss how these observations were translated into clinical practice.

  5. Mechanistic Investigation on ROS Resistance of Phosphorothioated DNA

    PubMed Central

    Wu, Tingting; Huang, Qiang; Wang, Xiao-Lei; Shi, Ting; Bai, Linquan; Liang, Jingdan; Wang, Zhijun; Deng, Zixin; Zhao, Yi-Lei

    2017-01-01

    Phosphorothioated DNA (PT-DNA) exhibits a mild anti-oxidant property both in vivo and in vitro. It was found that 8-OHdG and ROS levels were significantly lower in dnd+ (i.e. S+) E. coli., compared to a dnd− (i.e. S−) strain. Furthermore, different from traditional antioxidants, phosphorothioate compound presents an unexpectedly high capacity to quench hydroxyl radical. Oxidative product analysis by liquid chromatography-mass spectrometry and quantum mechanistic computation supported its unique anti-oxidant characteristic of the hydroxyl selectivity: phosphorothioate donates an electron to either hydroxyl radical or guanine radical derived from hydroxyl radical, leading to a PS• radical; a complex of PS• radical and OH− (i.e. the reductive product of hydroxyl radical) releases a highly reductive HS• radical, which scavenges more equivalents of oxidants in the way to high-covalent sulphur compounds such as sulphur, sulphite and sulphate. The PS-PO conversion (PS and PO denote phosphorus-sulphur and phosphorus-oxygen compounds, respectively) made a switch of extremely oxidative OH• to highly reductive HS• species, endowing PT-DNA with the observed high capacity in hydroxyl-radical neutralization. This plausible mechanism provides partial rationale as to why bacteria develop the resource-demanding PT modification on guanine-neighboring phosphates in genome. PMID:28216673

  6. Mechanistic modeling of broth temperature in outdoor photobioreactors.

    PubMed

    Béchet, Quentin; Shilton, Andy; Fringer, Oliver B; Muñoz, Raul; Guieysse, Benoit

    2010-03-15

    This study presents the first mechanistic model describing broth temperature in column photobioreactors as a function of static (location, reactor geometry) and dynamic (light irradiance, air temperature, wind velocity) parameters. Based on a heat balance on the liquid phase the model predicted temperature in a pneumatically agitated column photobioreactor (1 m(2) illuminated area, 0.19 m internal diameter, 50 L gas-free cultivation broth) operated outdoor in Singapore to an accuracy of 2.4 °C at the 95% confidence interval over the entire data set used (104 measurements from 7 different batches). Solar radiation (0 to 200 W) and air convection (-30 to 50 W)were the main contributors to broth temperature change. The model predicted broth temperature above 40 °C will be reached during summer months in the same photobioreactor operated in California, a value well over the maximum temperature tolerated by most commercial algae species. Accordingly, 18,000 and 5500 GJ year(-1) ha(-1) of heat energy must be removed to maintain broth temperature at or below 25 and 35 °C, respectively, assuming a reactor density of one reactor per square meter. Clearly, the significant issue of temperature control must be addressed when evaluating the technical feasibility, costs, and sustainability of large-scale algae production.

  7. Circadian rhythms and addiction: mechanistic insights and future directions.

    PubMed

    Logan, Ryan W; Williams, Wilbur P; McClung, Colleen A

    2014-06-01

    Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug-induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction.

  8. Early Mechanistic Events in Biotin Dissociation from Streptavidin

    SciTech Connect

    Hyre, D. E.

    2002-01-01

    The streptavidin-biotin system has provided a unique opportunity to investigate the molecular details of ligand dissociation pathways. An underlying mechanistic question is whether ligand dissociation proceeds with a relatively ordered process of bond breaking and ligand escape. Here we report a joint computational and crystallographic study of the earliest events in biotin dissociation. In molecular dynamics potential of mean force simulations, a water molecule from a defined access channel intercalated into the hydrogen bond between Asp 128 and biotin, bridging them and stabilizing an intermediate state. In forced biotin dissociation simulations, this event led to subsequent bond breaking steps and ligand escape. In equilibrium simulations, the water molecule was sometimes observed to move back to the access channel with re-formation of the biotin hydrogen bond. Analysis of streptavidin crystal structures revealed a close overlap of crystallographically defined and simulated waters in the water access channel. These results suggest that biotin dissociation is initiated by stochastic coupling of water entry with lengthening of a specific biotin hydrogen-bonding interaction.

  9. Equation-free mechanistic ecosystem forecasting using empirical dynamic modeling

    PubMed Central

    Ye, Hao; Beamish, Richard J.; Glaser, Sarah M.; Grant, Sue C. H.; Hsieh, Chih-hao; Richards, Laura J.; Schnute, Jon T.; Sugihara, George

    2015-01-01

    It is well known that current equilibrium-based models fall short as predictive descriptions of natural ecosystems, and particularly of fisheries systems that exhibit nonlinear dynamics. For example, model parameters assumed to be fixed constants may actually vary in time, models may fit well to existing data but lack out-of-sample predictive skill, and key driving variables may be misidentified due to transient (mirage) correlations that are common in nonlinear systems. With these frailties, it is somewhat surprising that static equilibrium models continue to be widely used. Here, we examine empirical dynamic modeling (EDM) as an alternative to imposed model equations and that accommodates both nonequilibrium dynamics and nonlinearity. Using time series from nine stocks of sockeye salmon (Oncorhynchus nerka) from the Fraser River system in British Columbia, Canada, we perform, for the the first time to our knowledge, real-data comparison of contemporary fisheries models with equivalent EDM formulations that explicitly use spawning stock and environmental variables to forecast recruitment. We find that EDM models produce more accurate and precise forecasts, and unlike extensions of the classic Ricker spawner–recruit equation, they show significant improvements when environmental factors are included. Our analysis demonstrates the strategic utility of EDM for incorporating environmental influences into fisheries forecasts and, more generally, for providing insight into how environmental factors can operate in forecast models, thus paving the way for equation-free mechanistic forecasting to be applied in management contexts. PMID:25733874

  10. Mechanistic studies of malonic acid-mediated in situ acylation.

    PubMed

    Chandra, Koushik; Naoum, Johnny N; Roy, Tapta Kanchan; Gilon, Chaim; Gerber, R Benny; Friedler, Assaf

    2015-09-01

    We have previously introduced an easy to perform, cost-effective and highly efficient acetylation technique for solid phase synthesis (SPPS). Malonic acid is used as a precursor and the reaction proceeds via a reactive ketene that acetylates the target amine. Here we present a detailed mechanistic study of the malonic acid-mediated acylation. The influence of reaction conditions, peptide sequence and reagents was systematically studied. Our results show that the methodology can be successfully applied to different types of peptides and nonpeptidic molecules irrespective of their structure, sequence, or conformation. Using alkyl, phenyl, and benzyl malonic acid, we synthesized various acyl peptides with almost quantitative yields. The ketenes obtained from the different malonic acid derived precursors were characterized by in situ (1) H-NMR. The reaction proceeded in short reaction times and resulted in excellent yields when using uronium-based coupling agents, DIPEA as a base, DMF/DMSO/NMP as solvents, Rink amide/Wang/Merrifield resins, temperature of 20°C, pH 8-12 and 5 min preactivation at inert atmosphere. The reaction was unaffected by Lewis acids, transition metal ions, surfactants, or salt. DFT studies support the kinetically favorable concerted mechanism for CO2 and ketene formation that leads to the thermodynamically stable acylated products. We conclude that the malonic acid-mediated acylation is a general method applicable to various target molecules.

  11. A global scale mechanistic model of the photosynthetic capacity

    NASA Astrophysics Data System (ADS)

    Ali, A. A.; Xu, C.; Rogers, A.; Fisher, R. A.; Wullschleger, S. D.; McDowell, N. G.; Massoud, E. C.; Vrugt, J. A.; Muss, J. D.; Fisher, J. B.; Reich, P. B.; Wilson, C. J.

    2015-08-01

    Although plant photosynthetic capacity as determined by the maximum carboxylation rate (i.e., Vc, max25) and the maximum electron transport rate (i.e., Jmax25) at a reference temperature (generally 25 °C) is known to vary substantially in space and time in response to environmental conditions, it is typically parameterized in Earth system models (ESMs) with tabulated values associated to plant functional types. In this study, we developed a mechanistic model of leaf utilization of nitrogen for assimilation (LUNA V1.0) to predict the photosynthetic capacity at the global scale under different environmental conditions, based on the optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The LUNA model was able to reasonably well capture the observed patterns of photosynthetic capacity in view that it explained approximately 55 % of the variation in observed Vc, max25 and 65 % of the variation in observed Jmax25 across the globe. Our model simulations under current and future climate conditions indicated that Vc, max25 could be most affected in high-latitude regions under a warming climate and that ESMs using a fixed Vc, max25 or Jmax25 by plant functional types were likely to substantially overestimate future global photosynthesis.

  12. A global scale mechanistic model of the photosynthetic capacity

    NASA Astrophysics Data System (ADS)

    Xu, C.; Ali, A. A.; Fisher, R.; Wullschleger, S. D.; Rogers, A.; McDowell, N. G.; Wilson, C. J.

    2015-12-01

    Although plant photosynthetic capacity as determined by the maximum carboxylation rate (i.e., Vc,max25) and the maximum electron transport rate (i.e., Jmax25) at a reference temperature (generally 25oC) is known to vary substantially in space and time in response to environmental conditions, it is typically parameterized in Earth system models (ESMs) with tabulated values associated to plant functional types. In this study, we developed a mechanistic model of leaf utilization of nitrogen for assimilation (LUNA V1.0) to predict the photosynthetic capacity at the global scale under different environmental conditions, based on the optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The LUNA model was able to reasonably well capture the observed patterns of photosynthetic capacity in view that it explained approximately 55% of the variation in observed Vc,max25 and 65% of the variation in observed Jmax25 across the globe. Our model simulations under current and future climate conditions indicated that Vc,max25 could be most affected in high-latitude regions under a warming climate and that ESMs using a fixed Vc,max25 or Jmax25 by plant functional types were likely to substantially overestimate future global photosynthesis.

  13. Mechanistic insights into acyclovir-polyethylene glycol 20000 binary dispersions

    PubMed Central

    Venkateskumar, Krishnamoorthy; Parasuraman, Subramani; Gunasunderi, Raju; Sureshkumar, Krishnan; Nayak, M. Muralidhar; Shah, Syed Adnan Ali; Kassen, Khoo; Kai, Heng Wei

    2016-01-01

    Objective: The objective of this study is to provide a mechanistic insight into solubility enhancement and dissolution of acyclovir (ACY) by polyethylene glycol20000 (PEG20000). Materials and Methods: Solid dispersions with differing ratios of drug (ACY) and carrier (PEG20000) were prepared and evaluated by phase solubility, in vitro release studies, kinetic analysis, in situ perfusion, and in vitro permeation studies. Solid state characterization was also done by Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FT-IR) analysis and surface morphology was assessed by Polarizing Microscopic Image (PMI) analysis, Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), and Nuclear Magnetic Resonance (NMR) analysis. Results: Thermodynamic parameters proved the solubilization effect of carrier. The aqueous solubility and dissolution of ACY were increased in all samples. Formation of solid solution, crystallinity reduction, and absence of interaction between drug and carrier was proved by XRD, DSC, and FTIR analysis. The particle size reduction and change in surface morphology were confirmed by SEM and AFM and analysis. The permeation coefficient and amount of drug diffused was higher in samples as compared to ACY. The stability was high in dispersions, and it was proved by NMR analysis. Conclusion: The mechanical insights into the enhancement of solubility and dissolution could be used as a platform to improve the aqueous solubility for other poor water soluble drugs. PMID:28123988

  14. Mechanistic aspects of photooxidation of polyhydroxylated molecules on metal oxides.

    SciTech Connect

    Shkrob, I. A.; Marin, T. M.; Sevilla, M. D.; Chemerisov, S.

    2011-03-24

    Polyhydroxylated molecules, including natural carbohydrates, are known to undergo photooxidation on wide-gap transition-metal oxides irradiated by ultraviolet light. In this study, we examine mechanistic aspects of this photoreaction on aqueous TiO{sub 2}, {alpha}-FeOOH, and {alpha}-Fe{sub 2}O{sub 3} particles using electron paramagnetic resonance (EPR) spectroscopy and site-selective deuteration. We demonstrate that the carbohydrates are oxidized at sites involved in the formation of oxo bridges between the chemisorbed carbohydrate molecule and metal ions at the oxide surface. This bridging inhibits the loss of water (which is the typical reaction of the analogous free radicals in bulk solvent) promoting instead a rearrangement that leads to elimination of the formyl radical. For natural carbohydrates, the latter reaction mainly involves carbon-1, whereas the main radical products of the oxidation are radical arising from H atom loss centered on carbon-1, -2, and -3 sites. Photoexcited TiO{sub 2} oxidizes all of the carbohydrates and polyols, whereas {alpha}-FeOOH oxidizes some of the carbohydrates, and {alpha}-Fe{sub 2}O{sub 3} is unreactive. These results serve as a stepping stone for understanding the photochemistry on mineral surfaces of more complex biomolecules such as nucleic acids.

  15. Mechanistic Differences Leading to Infectious and Sterile Inflammation.

    PubMed

    Behnia, Faranak; Sheller, Samantha; Menon, Ramkumar

    2016-05-01

    Inflammation is a physiologic component of pregnancy and parturition. Overwhelming intrauterine inflammatory load promotes quiescent feto-maternal tissues into a contractile phenotype. Like inflammation, oxidative stress is an inevitable component of both pregnancy and parturition. Pathologic activation of host innate immune response to adverse pregnancy conditions can lead to premature activation of inflammatory and oxidative stress. Inflammation and oxidative stress markers seen with both sterile and infectious inflammation are often similar; therefore, it is difficult to understand causality of conditions like spontaneous preterm birth. This review demonstrates potential mechanistic pathways of activation of sterile and infectious inflammation. We demonstrate the activation of two unique pathways of inflammation by factors that are well-documented proxies for oxidative stress (cigarette smoke extract) and infection (lipopolysaccharide). Sterile inflammation seen after exposure to an oxidative stress inducer is due to cellular elemental damage resulting in p38 mitogen-activated protein kinase (MAPK) induced cellular senescence. Infectious inflammation is through activation of transcription factor NF-κB and independent of oxidative stress-associated damages and p38 MAPK-induced senescence. Understanding the differences in the inflammatory pathway activation by various risk factors is important to design better screening, diagnostic and intervention strategies to reduce the risks of adverse pregnancy outcomes.

  16. Physical activity and its mechanistic effects on prostate cancer.

    PubMed

    Wekesa, A; Harrison, M; Watson, R W

    2015-09-01

    Beneficial effects of physical activity have been illustrated in numerous aspects of health. With the increasing incidence of prostate cancer and changes in physical activity of men, understanding the link between the two has important implications for changing this cancer burden. Both positive and negative associations between physical activity and prostate cancer have been previously demonstrated in observational epidemiological studies. Elucidating the biological mechanisms would lead to a better understanding of how physical activity influences the progression of prostate cancer. This review was undertaken to: (1) identify evidence in literature that demonstrates the effects of physical activity on skeletal muscle secretomes, (2) indicate the plausible signaling pathways these proteins might activate, and (3) identify evidence in literature that demonstrates the roles of the signaling pathways in prostate cancer progression and regression. We also discuss proposed biological mechanisms and signaling pathways by which physical activity may prevent the development and progression of prostate cancer. We discuss proteins involved in the normal and aberrant growth and development of the prostate gland that may be affected by physical activity. We further identify future directions for research, including a better understanding of the biological mechanisms, the need to standardize physical activity and identify mechanistic end points of physical activity that can then be correlated with outcomes.

  17. Mechanistic modeling of destratification in cryogenic storage tanks using ultrasonics.

    PubMed

    Jagannathan, T K; Mohanan, Srijith; Nagarajan, R

    2014-01-01

    Stratification is one of the main causes for vaporization of cryogens and increase of tank pressure during cryogenic storage. This leads subsequent problems such as cavitation in cryo-pumps, reduced length of storage time. Hence, it is vital to prevent stratification to improve the cost efficiency of storage systems. If stratified layers exist inside the tank, they have to be removed by suitable methods without venting the vapor. Sonication is one such method capable of keeping fluid layers mixed. In the present work, a mechanistic model for ultrasonic destratification is proposed and validated with destratification experiments done in water. Then, the same model is used to predict the destratification characteristics of cryogenic liquids such as liquid nitrogen (LN₂), liquid hydrogen (LH₂) and liquid ammonia (LNH₃). The destratification parameters are analysed for different frequencies of ultrasound and storage pressures by considering continuous and pulsed modes of ultrasonic operation. From the results, it is determined that use of high frequency ultrasound (low-power/continuous; high-power/pulsing) or low frequency ultrasound (continuous operation with moderate power) can both be effective in removing stratification.

  18. Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse.

    PubMed

    Agarwal, Vinayak; Miles, Zachary D; Winter, Jaclyn M; Eustáquio, Alessandra S; El Gamal, Abrahim A; Moore, Bradley S

    2017-01-20

    Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution. Biosynthetic halogenation reactions range from simple aromatic substitutions to stereoselective C-H functionalizations on remote carbon centers and can initiate the formation of simple to complex ring structures. Dehalogenating enzymes, on the other hand, are best known for removing halogen atoms from man-made organohalogens, yet also function naturally, albeit rarely, in metabolic pathways. This review details the scope and mechanism of nature's halogenation and dehalogenation enzymatic strategies, highlights gaps in our understanding, and posits where new advances in the field might arise in the near future.

  19. A Mechanistic Link between Olfaction and Autism Spectrum Disorder.

    PubMed

    Rozenkrantz, Liron; Zachor, Ditza; Heller, Iris; Plotkin, Anton; Weissbrod, Aharon; Snitz, Kobi; Secundo, Lavi; Sobel, Noam

    2015-07-20

    Internal action models (IAMs) are brain templates for sensory-motor coordination underlying diverse behaviors. An emerging theory suggests that impaired IAMs are a common theme in autism spectrum disorder (ASD). However, whether impaired IAMs occur across sensory systems and how they relate to the major phenotype of ASD, namely impaired social communication, remains unclear. Olfaction relies on an IAM known as the sniff response, where sniff magnitude is automatically modulated to account for odor valence. To test the failed IAM theory in olfaction, we precisely measured the non-verbal non-task-dependent sniff response concurrent with pleasant and unpleasant odors in 36 children--18 with ASD and 18 matched typically developing (TD) controls. We found that whereas TD children generated a typical adult-like sniff response within 305 ms of odor onset, ASD children had a profoundly altered sniff response, sniffing equally regardless of odor valance. This difference persisted despite equal reported odor perception and allowed for 81% correct ASD classification based on the sniff response alone (binomial, p < 0.001). Moreover, increasingly aberrant sniffing was associated with increasingly severe ASD (r = -0.75, p < 0.001), specifically with social (r = -0.72, p < 0.001), but not motor (r < -0.38, p > 0.18), impairment. These results uncover a novel ASD marker implying a mechanistic link between the underpinnings of olfaction and ASD and directly linking an impaired IAM with impaired social abilities.

  20. Air pollution, inflammation and preterm birth: a potential mechanistic link.

    PubMed

    Vadillo-Ortega, Felipe; Osornio-Vargas, Alvaro; Buxton, Miatta A; Sánchez, Brisa N; Rojas-Bracho, Leonora; Viveros-Alcaráz, Martin; Castillo-Castrejón, Marisol; Beltrán-Montoya, Jorge; Brown, Daniel G; O'Neill, Marie S

    2014-02-01

    Preterm birth is a public health issue of global significance, which may result in mortality during the perinatal period or may lead to major health and financial consequences due to lifelong impacts. Even though several risk factors for preterm birth have been identified, prevention efforts have failed to halt the increasing rates of preterm birth. Epidemiological studies have identified air pollution as an emerging potential risk factor for preterm birth. However, many studies were limited by study design and inadequate exposure assessment. Due to the ubiquitous nature of ambient air pollution and the potential public health significance of any role in causing preterm birth, a novel focus investigating possible causal mechanisms influenced by air pollution is therefore a global health priority. We hypothesize that air pollution may act together with other biological factors to induce systemic inflammation and influence the duration of pregnancy. Evaluation and testing of this hypothesis is currently being conducted in a prospective cohort study in Mexico City and will provide an understanding of the pathways that mediate the effects of air pollution on preterm birth. The important public health implication is that crucial steps in this mechanistic pathway can potentially be acted on early in pregnancy to reduce the risk of preterm birth.

  1. Mechanistic investigation of beta-galactosidase-activated MR contrast agents.

    PubMed

    Urbanczyk-Pearson, Lauren M; Femia, Frank J; Smith, Jeffrey; Parigi, Giacomo; Duimstra, Joseph A; Eckermann, Amanda L; Luchinat, Claudio; Meade, Thomas J

    2008-01-07

    We report a mechanistic investigation of an isomeric series of beta-galactosidase-activated magnetic resonance contrast agents. Our strategy focuses on the synthesis of macrocyclic caged-complexes that coordinatively saturate a chelated lanthanide. Enzyme cleavage of the complex results in an open coordination site available for water that creates a detectable MR contrast agent. The complexes consist of a DO3A Gd(III) chelator modified with a galactopyranose at the N-10 position of the macrocycle. We observed significant differences in relaxometric properties and coordination geometry that can be correlated to subtle variations of the linker between the macrocycle and the galactopyranose. After synthesis and purification of the R, S, and racemic mixtures of complexes 1 and 3 and measurement of the hydration number, water residence lifetime, and longitudinal relaxation rates, we propose mechanisms for water exclusion from the lanthanide in the precleavage state. While the stereochemistry of the linker does not influence the agents' properties, the mechanism of water exclusion for each isomer is significantly influenced by the position of modification. Data for one series with a methyl group substituted on the sugar-macrocycle linker at the alpha-position suggests a steric mechanism where the galactopyranose sugar blocks water from the Gd(III) center. In contrast, our observations for a second series with methyl substitution at the beta position of the sugar-macrocycle linker are consistent with a mechanism in which a bidentate anion occupies two available coordination sites of Gd(III) in the precleavage state.

  2. Environmental perception and epigenetic memory: mechanistic insight through FLC

    PubMed Central

    Berry, Scott; Dean, Caroline

    2015-01-01

    Chromatin plays a central role in orchestrating gene regulation at the transcriptional level. However, our understanding of how chromatin states are altered in response to environmental and developmental cues, and then maintained epigenetically over many cell divisions, remains poor. The floral repressor gene FLOWERING LOCUS C (FLC) in Arabidopsis thaliana is a useful system to address these questions. FLC is transcriptionally repressed during exposure to cold temperatures, allowing studies of how environmental conditions alter expression states at the chromatin level. FLC repression is also epigenetically maintained during subsequent development in warm conditions, so that exposure to cold may be remembered. This memory depends on molecular complexes that are highly conserved among eukaryotes, making FLC not only interesting as a paradigm for understanding biological decision-making in plants, but also an important system for elucidating chromatin-based gene regulation more generally. In this review, we summarize our understanding of how cold temperature induces a switch in the FLC chromatin state, and how this state is epigenetically remembered. We also discuss how the epigenetic state of FLC is reprogrammed in the seed to ensure a requirement for cold exposure in the next generation. Significance Statement FLOWERING LOCUS C (FLC) regulation provides a paradigm for understanding how chromatin can be modulated to determine gene expression in a developmental context. This review describes our current mechanistic understanding of how FLC expression is genetically specified and epigenetically regulated throughout the plant life cycle, and how this determines plant life-history strategy. PMID:25929799

  3. Additive Similarity Trees

    ERIC Educational Resources Information Center

    Sattath, Shmuel; Tversky, Amos

    1977-01-01

    Tree representations of similarity data are investigated. Hierarchical clustering is critically examined, and a more general procedure, called the additive tree, is presented. The additive tree representation is then compared to multidimensional scaling. (Author/JKS)

  4. Diverse Data Sets Can Yield Reliable Information through Mechanistic Modeling: Salicylic Acid Clearance.

    PubMed

    Raymond, G M; Bassingthwaighte, J B

    This is a practical example of a powerful research strategy: putting together data from studies covering a diversity of conditions can yield a scientifically sound grasp of the phenomenon when the individual observations failed to provide definitive understanding. The rationale is that defining a realistic, quantitative, explanatory hypothesis for the whole set of studies, brings about a "consilience" of the often competing hypotheses considered for individual data sets. An internally consistent conjecture linking multiple data sets simultaneously provides stronger evidence on the characteristics of a system than does analysis of individual data sets limited to narrow ranges of conditions. Our example examines three very different data sets on the clearance of salicylic acid from humans: a high concentration set from aspirin overdoses; a set with medium concentrations from a research study on the influences of the route of administration and of sex on the clearance kinetics, and a set on low dose aspirin for cardiovascular health. Three models were tested: (1) a first order reaction, (2) a Michaelis-Menten (M-M) approach, and (3) an enzyme kinetic model with forward and backward reactions. The reaction rates found from model 1 were distinctly different for the three data sets, having no commonality. The M-M model 2 fitted each of the three data sets but gave a reliable estimates of the Michaelis constant only for the medium level data (Km = 24±5.4 mg/L); analyzing the three data sets together with model 2 gave Km = 18±2.6 mg/L. (Estimating parameters using larger numbers of data points in an optimization increases the degrees of freedom, constraining the range of the estimates). Using the enzyme kinetic model (3) increased the number of free parameters but nevertheless improved the goodness of fit to the combined data sets, giving tighter constraints, and a lower estimated Km = 14.6±2.9 mg/L, demonstrating that fitting diverse data sets with a single model improves confidence in the results. This modeling effort is also an example of reproducible science available at html://www.physiome.org/jsim/models/webmodel/NSR/SalicylicAcidClearance.

  5. Diverse Data Sets Can Yield Reliable Information through Mechanistic Modeling: Salicylic Acid Clearance

    PubMed Central

    Raymond, G. M.; Bassingthwaighte, J. B.

    2016-01-01

    This is a practical example of a powerful research strategy: putting together data from studies covering a diversity of conditions can yield a scientifically sound grasp of the phenomenon when the individual observations failed to provide definitive understanding. The rationale is that defining a realistic, quantitative, explanatory hypothesis for the whole set of studies, brings about a “consilience” of the often competing hypotheses considered for individual data sets. An internally consistent conjecture linking multiple data sets simultaneously provides stronger evidence on the characteristics of a system than does analysis of individual data sets limited to narrow ranges of conditions. Our example examines three very different data sets on the clearance of salicylic acid from humans: a high concentration set from aspirin overdoses; a set with medium concentrations from a research study on the influences of the route of administration and of sex on the clearance kinetics, and a set on low dose aspirin for cardiovascular health. Three models were tested: (1) a first order reaction, (2) a Michaelis-Menten (M-M) approach, and (3) an enzyme kinetic model with forward and backward reactions. The reaction rates found from model 1 were distinctly different for the three data sets, having no commonality. The M-M model 2 fitted each of the three data sets but gave a reliable estimates of the Michaelis constant only for the medium level data (Km = 24±5.4 mg/L); analyzing the three data sets together with model 2 gave Km = 18±2.6 mg/L. (Estimating parameters using larger numbers of data points in an optimization increases the degrees of freedom, constraining the range of the estimates). Using the enzyme kinetic model (3) increased the number of free parameters but nevertheless improved the goodness of fit to the combined data sets, giving tighter constraints, and a lower estimated Km = 14.6±2.9 mg/L, demonstrating that fitting diverse data sets with a single model improves confidence in the results. This modeling effort is also an example of reproducible science available at html://www.physiome.org/jsim/models/webmodel/NSR/SalicylicAcidClearance PMID:27308260

  6. Drug-induced liver injury: Advances in mechanistic understanding that will inform risk management.

    PubMed

    Mosedale, M; Watkins, P B

    2016-11-09

    Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.

  7. Pd-catalyzed carbonylative α-arylation of aryl bromides: scope and mechanistic studies.

    PubMed

    Nielsen, Dennis U; Lescot, Camille; Gøgsig, Thomas M; Lindhardt, Anders T; Skrydstrup, Troels

    2013-12-23

    Reaction conditions for the three-component synthesis of aryl 1,3-diketones are reported applying the palladium-catalyzed carbonylative α-arylation of ketones with aryl bromides. The optimal conditions were found by using a catalytic system derived from [Pd(dba)2] (dba=dibenzylideneacetone) as the palladium source and 1,3-bis(diphenylphosphino)propane (DPPP) as the bidentate ligand. These transformations were run in the two-chamber reactor, COware, applying only 1.5 equivalents of carbon monoxide generated from the CO-releasing compound, 9-methylfluorene-9-carbonyl chloride (COgen). The methodology proved adaptable to a wide variety of aryl and heteroaryl bromides leading to a diverse range of aryl 1,3-diketones. A mechanistic investigation of this transformation relying on 31P and 13C NMR spectroscopy was undertaken to determine the possible catalytic pathway. Our results revealed that the combination of [Pd(dba)2] and DPPP was only reactive towards 4-bromoanisole in the presence of the sodium enolate of propiophenone suggesting that a [Pd(dppp)(enolate)] anion was initially generated before the oxidative-addition step. Subsequent CO insertion into an [Pd(Ar)(dppp)(enolate)] species provided the 1,3-diketone. These results indicate that a catalytic cycle, different from the classical carbonylation mechanism proposed by Heck, is operating. To investigate the effect of the dba ligand, the Pd0 precursor, [Pd(η3-1-PhC3H4)(η5-C5H5)], was examined. In the presence of DPPP, and in contrast to [Pd(dba)2], its oxidative addition with 4-bromoanisole occurred smoothly providing the [PdBr(Ar)(dppp)] complex. After treatment with CO, the acyl complex [Pd(CO)Br(Ar)(dppp)] was generated, however, its treatment with the sodium enolate led exclusively to the acylated enol in high yield. Nevertheless, the carbonylative α-arylation of 4-bromoanisole with either catalytic or stoichiometric [Pd(η3-1-PhC3H4)(η5-C5H5)] over a short reaction time, led to the 1,3-diketone product

  8. Polyimide processing additives

    NASA Technical Reports Server (NTRS)

    Pratt, J. R.; St. Clair, T. L.; Burks, H. D.; Stoakley, D. M.

    1987-01-01

    A method has been found for enhancing the melt flow of thermoplastic polyimides during processing. A high molecular weight 422 copoly(amic acid) or copolyimide was fused with approximately 0.05 to 5 pct by weight of a low molecular weight amic acid or imide additive, and this melt was studied by capillary rheometry. Excellent flow and improved composite properties on graphite resulted from the addition of a PMDA-aniline additive to LARC-TPI. Solution viscosity studies imply that amic acid additives temporarily lower molecular weight and, hence, enlarge the processing window. Thus, compositions containing the additive have a lower melt viscosity for a longer time than those unmodified.

  9. [Food additives and healthiness].

    PubMed

    Heinonen, Marina

    2014-01-01

    Additives are used for improving food structure or preventing its spoilage, for example. Many substances used as additives are also naturally present in food. The safety of additives is evaluated according to commonly agreed principles. If high concentrations of an additive cause adverse health effects for humans, a limit of acceptable daily intake (ADI) is set for it. An additive is a risk only when ADI is exceeded. The healthiness of food is measured on the basis of nutrient density and scientifically proven effects.

  10. Ozonation of piperidine, piperazine and morpholine: Kinetics, stoichiometry, product formation and mechanistic considerations.

    PubMed

    Tekle-Röttering, Agnes; Jewell, Kevin S; Reisz, Erika; Lutze, Holger V; Ternes, Thomas A; Schmidt, Winfried; Schmidt, Torsten C

    2016-01-01

    Piperidine, piperazine and morpholine as archetypes for secondary heterocyclic amines, a structural unit that is often present in pharmaceuticals (e.g., ritalin, cetirizine, timolol, ciprofloxacin) were investigated in their reaction with ozone. In principle the investigated compounds can be degraded with ozone in a reasonable time, based on their high reaction rate constants with respect to ozone (1.9 × 10(4)-2.4 × 10(5) M(-1) s(-1)). However, transformation is insufficient (13-16%), most likely due to a chain reaction, which decomposes ozone. This conclusion is based on OH scavenging experiments, leading to increased compound transformation (18-27%). The investigated target compounds are similar in their kinetic and stoichiometric characteristics. However, the mechanistic considerations based on product formation indicate various reaction pathways. Piperidine reacts with ozone via a nonradical addition reaction to N-hydroxypiperidine (yield: 92% with and 94% without scavenging, with respect to compound transformation). However, piperazine degradation with ozone does not lead to N-hydroxypiperazine. In the morpholine/ozone reaction, N-hydroxymorpholine was identified. Additional oxidation pathways in all cases involved the formation of OH with high yields. One important pathway of piperazine and morpholine by ozonation could be the formation of C-centered radicals after ozone or OH radical attack. Subsequently, O2 addition forms unstable peroxyl radicals, which in one pathway loose superoxide radicals by generating a carbon-centered cation. Subsequent hydrolysis of the carbon-centered cation leads to formaldehyde, whereby ozonation of the N-hydroxy products can proceed in the same way and in addition give rise to hydroxylamine. A second pathway of the short-lived peroxyl radicals could be a dimerization to form short-lived tetraoxides, which cleave by forming hydrogen peroxide. All three products have been found.

  11. Kinetic and mechanistic studies of allicin as an antioxidant.

    PubMed

    Okada, Youji; Tanaka, Kaoru; Sato, Eisuke; Okajima, Haruo

    2006-11-21

    We have undertaken a detailed study of the antioxidant activity of allicin, one of the main thiosulfinates in garlic, in order to obtain quantitative information on it as a chain-breaking antioxidant. The antioxidant actions of allicin against the oxidation of cumene and methyl linoleate (ML) in chlorobenzene were studied in detail using HPLC. The hydroperoxides formed during the course of the inhibited oxidation of ML were analyzed as their corresponding alcohols by HPLC, and it is apparent that an allylic hydrogen atom of the allicin is responsible for the antioxidant activity. Furthermore, it is clear that the radical-scavenging reactions of allicin proceed via a one-step hydrogen atom transfer based on the results of the reaction with 2,2-diphenyl-1-picrylhydrazyl (DPPH) in the presence of Mg2+ and calculation of the ionization potential value. In addition, we determined the stoichiometric factor (n), the number of peroxyl radicals trapped by one antioxidant molecule, of allicin by measuring the reactivity toward DPPH in chlorobenzene, and the value of n for allicin was about 1.0. Therefore, we measured the rate constants, k(inh), for the reaction of allicin with peroxyl radicals during the induction period of the cumene and the ML oxidation. As a result, we found that allicin reacts with peroxyl radicals derived from cumene and ML with the rate constants k(inh) = 2.6 x 10(3) M(-1)s(-1) and 1.6 x 10(5) M(-1)s(-1) in chlorobenzene, respectively. Our results demonstrate for the first time reliable quantitative kinetic data and the antioxidative mechanism of allicin as an antioxidant.

  12. Impacts of mechanistic changes on HOx formation and recycling in the oxidation of isoprene

    NASA Astrophysics Data System (ADS)

    Archibald, A. T.; Cooke, M. C.; Utembe, S. R.; Shallcross, D. E.; Derwent, R. G.; Jenkin, M. E.

    2010-09-01

    Recently reported model-measurement discrepancies for the concentrations of the HOx radical species (OH and HO2) in locations characterized by high emission rates of isoprene have indicated possible deficiencies in the representation of OH recycling and formation in isoprene mechanisms currently employed in numerical models; particularly at low levels of NOx. Using version 3.1 of the Master Chemical Mechanism (MCM v3.1) as a base mechanism, the sensitivity of the system to a number of detailed mechanistic changes is examined for a wide range of NOx levels, using a simple box model. The studies consider sensitivity tests in relation to three general areas for which experimental and/or theoretical evidence has been reported in the peer-reviewed literature, as follows: (1) implementation of propagating channels for the reactions of HO2 with acyl and β-oxo peroxy radicals with HO2, with support from a number of studies; (2) implementation of the OH-catalysed conversion of isoprene-derived hydroperoxides to isomeric epoxydiols, as characterised by Paulot et al.~(2009a); and (3) implementation of a mechanism involving respective 1,5 and 1,6 H atom shift isomerisation reactions of the β-hydroxyalkenyl and cis-δ-hydroxyalkenyl peroxy radical isomers, formed from the sequential addition of OH and O2 to isoprene, based on the theoretical study of Peeters et al. (2009). All the considered mechanistic changes lead to simulated increases in the concentrations of OH, with (1) and (2) resulting in respective increases of up to about 7% and 16%, depending on the level of NOx. (3) is found to have potentially much greater impacts, with enhancements in OH concentrations of up to a factor of about 3.3, depending on the level of NOx, provided the (crucial) rapid photolysis of the hydroperoxy-methyl-butenal products of the cis-δ-hydroxyalkenyl peroxy radical isomerisation reactions is represented, as also postulated by Peeters et al.~(2009). Additional tests suggest that the

  13. Mechanistic Investigation of Toxaphene Induced Mouse Liver Tumors.

    PubMed

    Wang, Zemin; Neal, Barbara H; Lamb, James C; Klaunig, James E

    2015-10-01

    Chronic exposure to toxaphene resulted in an increase in liver tumors in B6C3F1 mice. This study was performed to investigate the mode of action of toxaphene induced mouse liver tumors. Following an initial 14 day dietary dose range-finding study in male mice, a mechanistic study (0, 3, 32, and 320 ppm toxaphene in diet for 7, 14, and 28 days of treatment) was performed to examine the potential mechanisms of toxaphene induced mouse liver tumors. Toxaphene induced a significant increase in expression of constitutive androstane receptor (CAR) target genes (Cyp2b10, Cyp3a11) at 32 and 320 ppm toxaphene. aryl hydrocarbon receptor (AhR) target genes (Cyp1a1 and Cyp1a2) were slightly increased in expression at the highest toxaphene dose (320 ppm). No increase in peroxisome proliferator-activated receptor alpha activity or related genes was seen following toxaphene treatment. Lipid peroxidation was seen following treatment with 320 ppm toxaphene. These changes correlated with increases in hepatic DNA synthesis. To confirm the role of CAR in this mode of action, CAR knockout mice (CAR(-/-)) treated with toxaphene confirmed that the induction of CAR responsive genes seen in wild-type mice was abolished following treatment with toxaphene for 14 days. These findings, taken together with previously reported studies, support the mode of action of toxaphene induced mouse liver tumors is through a nongenotoxic mechanism involving primarily a CAR-mediated processes that results in an increase in cell proliferation in the liver, promotes the clonal expansion of preneoplastic lesions leading to adenoma formation.

  14. Metabolic diseases and pro- and prebiotics: Mechanistic insights.

    PubMed

    Nakamura, Yukiko K; Omaye, Stanley T

    2012-06-19

    Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual's behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars) can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4). Long-term intake of diets high in fats and meats appear to induce chronic systemic low-grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS) sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes), chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases.

  15. Toward a mechanistic modeling of nitrogen limitation on vegetation dynamics

    SciTech Connect

    Xu, Chonggang; Fisher, Rosie; Wullschleger, Stan D; Wilson, Cathy; Cai, Michael; McDowell, Nathan

    2012-01-01

    Nitrogen is a dominant regulator of vegetation dynamics, net primary production, and terrestrial carbon cycles; however, most ecosystem models use a rather simplistic relationship between leaf nitrogen content and photosynthetic capacity. Such an approach does not consider how patterns of nitrogen allocation may change with differences in light intensity, growing-season temperature and CO{sub 2} concentration. To account for this known variability in nitrogen-photosynthesis relationships, we develop a mechanistic nitrogen allocation model based on a trade-off of nitrogen allocated between growth and storage, and an optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The developed model is able to predict the acclimation of photosynthetic capacity to changes in CO{sub 2} concentration, temperature, and radiation when evaluated against published data of V{sub c,max} (maximum carboxylation rate) and J{sub max} (maximum electron transport rate). A sensitivity analysis of the model for herbaceous plants, deciduous and evergreen trees implies that elevated CO{sub 2} concentrations lead to lower allocation of nitrogen to carboxylation but higher allocation to storage. Higher growing-season temperatures cause lower allocation of nitrogen to carboxylation, due to higher nitrogen requirements for light capture pigments and for storage. Lower levels of radiation have a much stronger effect on allocation of nitrogen to carboxylation for herbaceous plants than for trees, resulting from higher nitrogen requirements for light capture for herbaceous plants. As far as we know, this is the first model of complete nitrogen allocation that simultaneously considers nitrogen allocation to light capture, electron transport, carboxylation, respiration and storage, and the responses of each to altered environmental conditions. We expect this model could potentially improve our confidence in simulations of carbon-nitrogen interactions

  16. Metabolic diseases and pro- and prebiotics: Mechanistic insights

    PubMed Central

    2012-01-01

    Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual’s behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars) can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4). Long-term intake of diets high in fats and meats appear to induce chronic systemic low-grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS) sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes), chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases. PMID:22713169

  17. Human endotoxemia: a model for mechanistic insight and therapeutic targeting.

    PubMed

    Lowry, Stephen F

    2005-12-01

    The diversity of phenotypic manifestations, comorbidities, and therapeutic algorithms in patients with severe inflammation have confounded efforts to translate mechanistic insights from the bench top to the bedside. This dilemma has negatively impacted upon many therapeutic interventions that exhibited seemingly well-reasoned preclinical portfolios. Prudence urges the assessment of potent immunoregulatory therapies, wherever possible, in models that replicate the clinical phenotype absent overt manifestations of genetically or environmentally modified processes. The healthy human model of endotoxin administration (systemic or endobronchial) provides such an opportunity and has been used to great advantage for gaining insight into mechanisms of disease and for determination of therapeutic signal strength. When thoughtfully interpreted, the model may provide proof of principle as well as lessen the unpredictability of clinical responses. Although the broad characteristics of this model are well described in the literature, it is recognized that this model does not fully replicate the magnitude of initial inflammatory stress nor the latent spectrum of inflammation/sepsis-inducible organ system pathologies. Nevertheless, the similarities between the early, transient clinical phenotype, inducible physiochemical change, and biochemical pathway activation of this model to the early hyperdynamic phase of resuscitated injury and infection are striking. Rational testing of a therapeutic mechanism requires a quantifiable and reproducibly altered marker of the hypothetical mechanism. Given the modest nature of endotoxin induced insult, interventions that demonstrate target specific efficacy in conjunction with attenuated phenotype responses are more likely to exhibit efficacy within lower risk patient populations. By contrast, the model cannot predict clinical efficacy among higher risk patients nor in those who have endured extended periods of inflammatory stress.

  18. Mechanistic kinetic models of enzymatic cellulose hydrolysis-a review.

    PubMed

    Jeoh, Tina; Cardona, Maria J; Karuna, Nardrapee; Mudinoor, Akshata R; Nill, Jennifer

    2017-02-28

    Bioconversion of lignocellulose forms the basis for renewable, advanced biofuels, and bioproducts. Mechanisms of hydrolysis of cellulose by cellulases have been actively studied for nearly 70 years with significant gains in understanding of the cellulolytic enzymes. Yet, a full mechanistic understanding of the hydrolysis reaction has been elusive. We present a review to highlight new insights gained since the most recent comprehensive review of cellulose hydrolysis kinetic models by Bansal et al. () Biotechnol Adv 27:833-848. Recent models have taken a two-pronged approach to tackle the challenge of modeling the complex heterogeneous reaction-an enzyme-centric modeling approach centered on the molecularity of the cellulase-cellulose interactions to examine rate limiting elementary steps and a substrate-centric modeling approach aimed at capturing the limiting property of the insoluble cellulose substrate. Collectively, modeling results suggest that at the molecular-scale, how rapidly cellulases can bind productively (complexation) and release from cellulose (decomplexation) is limiting, while the overall hydrolysis rate is largely insensitive to the catalytic rate constant. The surface area of the insoluble substrate and the degrees of polymerization of the cellulose molecules in the reaction both limit initial hydrolysis rates only. Neither enzyme-centric models nor substrate-centric models can consistently capture hydrolysis time course at extended reaction times. Thus, questions of the true reaction limiting factors at extended reaction times and the role of complexation and decomplexation in rate limitation remain unresolved. Biotechnol. Bioeng. 2017;9999: 1-16. © 2017 Wiley Periodicals, Inc.

  19. Mechanistic basis of infertility of mouse intersubspecific hybrids

    PubMed Central

    Bhattacharyya, Tanmoy; Gregorova, Sona; Mihola, Ondrej; Anger, Martin; Sebestova, Jaroslava; Denny, Paul; Simecek, Petr; Forejt, Jiri

    2013-01-01

    According to the Dobzhansky–Muller model, hybrid sterility is a consequence of the independent evolution of related taxa resulting in incompatible genomic interactions of their hybrids. The model implies that the incompatibilities evolve randomly, unless a particular gene or nongenic sequence diverges much faster than the rest of the genome. Here we propose that asynapsis of heterospecific chromosomes in meiotic prophase provides a recurrently evolving trigger for the meiotic arrest of interspecific F1 hybrids. We observed extensive asynapsis of chromosomes and disturbance of the sex body in >95% of pachynemas of Mus m. musculus × Mus m. domesticus sterile F1 males. Asynapsis was not preceded by a failure of double-strand break induction, and the rate of meiotic crossing over was not affected in synapsed chromosomes. DNA double-strand break repair was delayed or failed in unsynapsed autosomes, and misexpression of chromosome X and chromosome Y genes was detected in single pachynemas and by genome-wide expression profiling. Oocytes of F1 hybrid females showed the same kind of synaptic problems but with the incidence reduced to half. Most of the oocytes with pachytene asynapsis were eliminated before birth. We propose the heterospecific pairing of homologous chromosomes as a preexisting condition of asynapsis in interspecific hybrids. The asynapsis may represent a universal mechanistic basis of F1 hybrid sterility manifested by pachytene arrest. It is tempting to speculate that a fast-evolving subset of the noncoding genomic sequence important for chromosome pairing and synapsis may be the culprit. PMID:23329330

  20. Conceptualising population health: from mechanistic thinking to complexity science.

    PubMed

    Jayasinghe, Saroj

    2011-01-20

    The mechanistic interpretation of reality can be traced to the influential work by René Descartes and Sir Isaac Newton. Their theories were able to accurately predict most physical phenomena relating to motion, optics and gravity. This paradigm had at least three principles and approaches: reductionism, linearity and hierarchy. These ideas appear to have influenced social scientists and the discourse on population health. In contrast, Complexity Science takes a more holistic view of systems. It views natural systems as being 'open', with fuzzy borders, constantly adapting to cope with pressures from the environment. These are called Complex Adaptive Systems (CAS). The sub-systems within it lack stable hierarchies, and the roles of agency keep changing. The interactions with the environment and among sub-systems are non-linear interactions and lead to self-organisation and emergent properties. Theoretical frameworks such as epi+demos+cracy and the ecosocial approach to health have implicitly used some of these concepts of interacting dynamic sub-systems. Using Complexity Science we can view population health outcomes as an emergent property of CAS, which has numerous dynamic non-linear interactions among its interconnected sub-systems or agents. In order to appreciate these sub-systems and determinants, one should acquire a basic knowledge of diverse disciplines and interact with experts from different disciplines. Strategies to improve health should be multi-pronged, and take into account the diversity of actors, determinants and contexts. The dynamic nature of the system requires that the interventions are constantly monitored to provide early feedback to a flexible system that takes quick corrections.