Porous media fracturing dynamics: stepwise crack advancement and fluid pressure oscillations

NASA Astrophysics Data System (ADS)

Cao, Toan D.; Hussain, Fazle; Schrefler, Bernhard A.

2018-02-01

We present new results explaining why fracturing in saturated porous media is not smooth and continuous but is a distinct stepwise process concomitant with fluid pressure oscillations. All exact solutions and almost all numerical models yield smooth fracture advancement and fluid pressure evolution, while recent experimental results, mainly from the oil industry, observation from geophysics and a very few numerical results for the quasi-static case indeed reveal the stepwise phenomenon. We summarize first these new experiments and these few numerical solutions for the quasi-static case. Both mechanical loading and pressure driven fractures are considered because their behaviours differ in the direction of the pressure jumps. Then we explore stepwise crack tip advancement and pressure fluctuations in dynamic fracturing with a hydro-mechanical model of porous media based on the Hybrid Mixture Theory. Full dynamic analyses of examples dealing with both hydraulic fracturing and mechanical loading are presented. The stepwise fracture advancement is confirmed in the dynamic setting as well as in the pressure fluctuations, but there are substantial differences in the frequency contents of the pressure waves in the two loading cases. Comparison between the quasi-static and fully dynamic solutions reveals that the dynamic response gives much more information such as the type of pressure oscillations and related frequencies and should be applied whenever there is a doubt about inertia forces playing a role - the case in most fracturing events. In the absence of direct relevant dynamic tests on saturated media some experimental results on dynamic fracture in dry materials, a fast hydraulic fracturing test and observations from geophysics confirm qualitatively the obtained results such as the type of pressure oscillations and the substantial difference in the behaviour under the two loading cases.

Stepwise sequential analysis of stable multiradicals formation in polyphenolic myricetin active OH groups throughout the antioxidant process to scavenge free radicals

NASA Astrophysics Data System (ADS)

Barzegar, Abolfazl; Rezaei-Sadabady, Rogaie

2017-10-01

Five galvinoxyl radicals (Grad) reduction by one polyphenolic myricetin (Myc, 3,3‧,4‧,5,5‧,7-Hexahydroxyflavone) molecule-using EPR method-demonstrated that each Myc should donate at least five H atoms resulted in multiradicals Myc5rad (5 Grad + 1Myc → 5 GH + 1 Myc5rad). The process that five H atoms donation occurs from different OH sites of Myc lead to appearing of five unpaired valence electrons of Myc5rad via two possible different mechanisms. First; concerted five H atoms donation from five different OH groups that directly results in Myc5rad radicals (Myc → Myc5rad). Second; the step-wise radical formation in five different OH groups of Myc (Myc → Mycrad → Myc2rad → Myc3rad → Myc4rad → Myc5rad). Computational DFT method was used to analyze all the six different OH groups of Myc which involved in free radical reactions for the purposes of clarification the stable multiradicals Myc5rad formation mechanism. The fast semi-empirical combined quantum method, AM1/DFT, as well as full DFT geometry optimization approaches of B3LYP functional DFT/DFT with different basis sets of 6-31G (d), 6-311 + G (d,p) and 6-311 + G (2d,2p) confirmed the stepwise H atom abstraction trend on the main three hydroxyl sites as 4‧-Orad → 4‧-Orad3-Orad → 4‧-Orad3-Orad-7Orad both in the gas and water phase. Spin delocalization over the entire Myc, adding the co-planarity, contributed to the stabilization of respective radical species. The excellent stability of Myc radicals should give an effective chain-breaking antioxidant activity for Myc in biological environment which is expected to have far fewer side effects. These findings may be useful to elucidate the radical scavenging mechanism of other flavonoids regarding to design novel antioxidants.

Electrochemical reduction of carbon fluorine bond in 4-fluorobenzonitrile Mechanistic analysis employing Marcus Hush quadratic activation-driving force relation

NASA Astrophysics Data System (ADS)

Muthukrishnan, A.; Sangaranarayanan, M. V.

2007-10-01

The reduction of carbon-fluorine bond in 4-fluorobenzonitrile in acetonitrile as the solvent, is analyzed using convolution potential sweep voltammetry and the dependence of the transfer coefficient on potential is investigated within the framework of Marcus-Hush quadratic activation-driving force theory. The validity of stepwise mechanism is inferred from solvent reorganization energy estimates as well as bond length calculations using B3LYP/6-31g(d) method. A novel method of estimating the standard reduction potential of the 4-fluorobenzonitrile in acetonitrile is proposed.

QM/MM nonadiabatic dynamics simulations on photoinduced Wolff rearrangements of 1,2,3-thiadiazole

NASA Astrophysics Data System (ADS)

Liu, Xiang-Yang; Fang, Ye-Guang; Xie, Bin-Bin; Fang, Wei-Hai; Cui, Ganglong

2017-06-01

The photoinduced rearrangement reaction mechanism of 1,2,3-thiadiazole remains experimentally elusive. Two possible mechanisms have been proposed to date. The first is a stepwise mechanism via a thiocarbene intermediate; the second is an excited-state concerted rearrangement mechanism. Herein we have adopted both the electronic structure calculations and nonadiabatic dynamics simulations to study the photoinduced rearrangement reactions of 1,2,3-thiadiazole in the S2, S1, and S0 states in solution. On the basis of QM(CASPT2)/MM [quantum mechanics(complete active space self-consistent field second-order perturbation theory)/molecular mechanics] calculations, we have found that (1) the thiocarbene intermediate is not stable; thus, the stepwise mechanism should be unfavorable; (2) the excited-state decay from the S2 via S1 to S0 state is ultrafast and completed within ca. 200 fs; therefore, both the S2 and S1 states should not have a long enough time for the excited-state rearrangements. Instead, we have computationally proposed a modified photoinduced rearrangement mechanism. Upon irradiation, the S2 state is first populated (114.0 kcal/mol), followed by an ultrafast S2 → S1 → S0 excited-state decay along the S-N bond fission, which eventually leads to a very "hot" intermediate with the S-N bond broken (18.3 kcal/mol). Then, thermal rearrangements to thioketene, thiirene, and ethynethiol occur in a concerted asynchronous way. This mechanistic scenario has been verified by full-dimensional trajectory-based nonadiabatic dynamics simulations at the QM(CASPT2)/MM level. Finally, our present computational work provides experimentally interesting mechanistic insights into the photoinduced rearrangement reactions of cyclic and acyclic diazo compounds.

Stepwise assembly of multiple Lin28 proteins on the terminal loop of let-7 miRNA precursors

PubMed Central

Desjardins, Alexandre; Bouvette, Jonathan; Legault, Pascale

2014-01-01

Lin28 inhibits the biogenesis of let-7 miRNAs through direct interactions with let-7 precursors. Previous studies have described seemingly inconsistent Lin28 binding sites on pre-let-7 RNAs. Here, we reconcile these data by examining the binding mechanism of Lin28 to the terminal loop of pre-let-7g (TL-let-7g) using biochemical and biophysical methods. First, we investigate Lin28 binding to TL-let-7g variants and short RNA fragments and identify three independent binding sites for Lin28 on TL-let-7g. We then determine that Lin28 assembles in a stepwise manner on TL-let-7g to form a stable 1:3 complex. We show that the cold-shock domain (CSD) of Lin28 is responsible for remodelling the terminal loop of TL-let-7g, whereas the NCp7-like domain facilitates the initial binding of Lin28 to TL-let-7g. This stable binding of multiple Lin28 molecules to the terminal loop of pre-let-7g extends to other precursors of the let-7 family, but not to other pre-miRNAs tested. We propose a model for stepwise assembly of the 1:1, 1:2 and 1:3 pre-let-7g/Lin28 complexes. Stepwise multimerization of Lin28 on pre-let-7 is required for maximum inhibition of Dicer cleavage for a least one member of the let-7 family and may be important for orchestrating the activity of the several factors that regulate let-7 biogenesis. PMID:24452802

Solvent effects on the excited-state double proton transfer mechanism in the 7-azaindole dimer: a TDDFT study with the polarizable continuum model.

PubMed

Yu, Xue-Fang; Yamazaki, Shohei; Taketsugu, Tetsuya

2017-08-30

Solvent effects on the excited-state double proton transfer (ESDPT) mechanism in the 7-azaindole (7AI) dimer were investigated using the time-dependent density functional theory (TDDFT) method. Excited-state potential energy profiles along the reaction paths in a locally excited (LE) state and a charge transfer (CT) state were calculated using the polarizable continuum model (PCM) to include the solvent effect. A series of non-polar and polar solvents with different dielectric constants were used to examine the polarity effect on the ESDPT mechanism. The present results suggest that in a non-polar solvent and a polar solvent with a small dielectric constant, ESDPT follows a concerted mechanism, similar to the case in the gas phase. In a polar solvent with a relatively large dielectric constant, however, ESDPT is likely to follow a stepwise mechanism via a stable zwitterionic intermediate in the LE state on the adiabatic potential energy surface, although inclusion of zero-point vibrational energy (ZPE) corrections again suggests the concerted mechanism. In the meantime, the stepwise reaction path involving the CT state with neutral intermediates is also examined, and is found to be less competitive than the concerted or stepwise path in the LE state in both non-polar and polar solvents. The present study provides a new insight into the experimental controversy of the ESDPT mechanism of the 7AI dimer in a solution.

Biochemical characterization of matrilysin. Activation conforms to the stepwise mechanisms proposed for other matrix metalloproteinases.

PubMed

Crabbe, T; Willenbrock, F; Eaton, D; Hynds, P; Carne, A F; Murphy, G; Docherty, A J

1992-09-15

The latent precursor of matrilysin (EC 3.4.24.23; punctuated metalloproteinase (PUMP) was purified from transfected mouse myeloma cell conditioned medium and was found to contain one zinc atom per molecule which was essential for catalytic activity. Promatrilysin could be activated to the same specific activity by (4-aminophenyl)mercuric acetate, trypsin, and incubation at elevated temperatures (heat activation). Active matrilysin hydrolyzed the fluorescent substrate 2,4-dinitrophenyl-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 at the Gly-Leu bond with a maximum value for kcat/Km of 1.3 x 10(4) M-1 s-1 at the pH optimum of 6.5 and pKa values of 4.60 and 8.65. Activity is inhibited by the tissue inhibitor of metalloproteinases-1 in a 1:1 stoichiometric interaction. Analysis by sodium dodecyl sulfate polyacrylamide gel electrophoresis in conjunction with N-terminal sequencing revealed that, as with all other matrix metalloproteinases similarly studied, promatrilysin activation was accompanied by the stepwise proteolytic removal of an M(r) 9000 propeptide from the N-terminus. The intermediates generated were dependent on the mode of activation used but, in all cases studied, activation terminated with an autocatalytic cleavage at E77-Y78 to yield the final M(r) 19,000 active matrilysin. From an analysis of the stability of the various intermediates, we propose that the sequence L13-K33 is particularly important in protecting the E77-Y78 site from autocatalytic cleavage, thereby maintaining the latency of the proenzyme.

Design and implementation of a novel mechanical testing system for cellular solids.

PubMed

Nazarian, Ara; Stauber, Martin; Müller, Ralph

2005-05-01

Cellular solids constitute an important class of engineering materials encompassing both man-made and natural constructs. Materials such as wood, cork, coral, and cancellous bone are examples of cellular solids. The structural analysis of cellular solid failure has been limited to 2D sections to illustrate global fracture patterns. Due to the inherent destructiveness of 2D methods, dynamic assessment of fracture progression has not been possible. Image-guided failure assessment (IGFA), a noninvasive technique to analyze 3D progressive bone failure, has been developed utilizing stepwise microcompression in combination with time-lapsed microcomputed tomographic imaging (microCT). This method allows for the assessment of fracture progression in the plastic region, where much of the structural deformation/energy absorption is encountered in a cellular solid. Therefore, the goal of this project was to design and fabricate a novel micromechanical testing system to validate the effectiveness of the stepwise IGFA technique compared to classical continuous mechanical testing, using a variety of engineered and natural cellular solids. In our analysis, we found stepwise compression to be a valid approach for IGFA with high precision and accuracy comparable to classical continuous testing. Therefore, this approach complements the conventional mechanical testing methods by providing visual insight into the failure propagation mechanisms of cellular solids. (c) 2005 Wiley Periodicals, Inc.

Kinetic Isotope Effects as a Probe for the Protonolysis Mechanism of Alkylmetal Complexes: VTST/MT Calculations Based on DFT Potential Energy Surfaces.

PubMed

Mai, Binh Khanh; Kim, Yongho

2016-10-03

Protonolysis by platinum or palladium complexes has been extensively studied because it is the microscopic reverse of the C-H bond activation reaction. The protonolysis of (COD)Pt II Me 2 , which exhibits abnormally large kinetic isotope effects (KIEs), is proposed to occur via a concerted pathway (S E 2 mechanism) with large tunneling. However, further investigation of KIEs for the protonolysis of ZnMe 2 and others led to a conclusion that there is no noticeable correlation between the mechanism and magnitude of KIE. In this study, we demonstrated that variational transition state theory including multidimensional tunneling (VTST/MT) could accurately predict KIEs and Arrhenius parameters of the protonolysis of alkylmetal complexes based on the potential energy surfaces generated by density functional theory. The predicted KIEs, E a D - E a H values, and A H /A D ratios for the protonolysis of (COD)Pt II Me 2 and Zn II Me 2 by TFA agreed very well with experimental values. The protonolysis of ZnMe 2 with the concerted pathway has a very flat potential energy surface, which produces a very small tunneling effect and therefore a small KIE. The predicted KIE for the stepwise protonolysis (S E (ox) mechanism) of (COD)Pt II Me 2 was much smaller than that of the concerted pathway, but greater than the KIE of the concerted protonolysis of ZnMe 2 . A large KIE, which entails a significant tunneling effect, could be used as an experimental probe of the concerted pathway. However, a normal or small KIE should not be used as an indicator of the stepwise mechanism, and the interplay between experiments and reliable theory including tunneling would be essential to uncover the mechanism correctly.

Tape transport mechanism

DOEpatents

Groh, Edward F.; McDowell, William; Modjeski, Norbert S.; Keefe, Donald J.; Groer, Peter

1979-01-01

A device is provided for transporting, in a stepwise manner, tape between a feed reel and takeup reel. An indexer moves across the normal path of the tape displacing it while the tape on the takeup reel side of the indexer is braked. After displacement, the takeup reel takes up the displaced tape while the tape on the feed reel side of the indexer is braked, providing stepwise tape transport in precise intervals determined by the amount of displacement caused by the indexer.

One- and Two-Photon Uncaging: Carbazole Fused o-Hydroxycinnamate Platform for Dual Release of Alcohols (Same or Different) with Real-Time Monitoring.

PubMed

Venkatesh, Yarra; Srivastava, Hemant Kumar; Bhattacharya, S; Mehra, Muneshwar; Datta, P K; Bandyopadhyay, S; Singh, N D Pradeep

2018-04-20

A one- and two-photon activated photoremovable protecting group (PRPG) was designed based on a carbazole fused o-hydroxycinnamate platform for the dual (same or different) release of alcohols. The mechanism for the dual release proceeds through a stepwise pathway and also monitors the first and second photorelease in real time by an increase in fluorescence intensity and color change, respectively. Further, its application in staining live neurons and ex vivo imaging with two-photon excitation is shown.

Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling

DOE PAGES

Ni, Lisheng; Zheng, Yonggang; Hara, Mayuko; ...

2015-06-24

The Mst–Lats kinase cascade is central to the Hippo tumor-suppressive pathway that controls organ size and tissue homeostasis. The adaptor protein Mob1 promotes Lats activation by Mst, but the mechanism remains unknown. Here, we show that human Mob1 binds to autophosphorylated docking motifs in active Mst2. This binding enables Mob1 phosphorylation by Mst2. Phosphorylated Mob1 undergoes conformational activation and binds to Lats1. We determine the crystal structures of phospho-Mst2–Mob1 and phospho-Mob1–Lats1 complexes, revealing the structural basis of both phosphorylation-dependent binding events. Further biochemical and functional analyses demonstrate that Mob1 mediates Lats1 activation through dynamic scaffolding and allosteric mechanisms. Thus, Mob1more » acts as a phosphorylation-regulated coupler of kinase activation by virtue of its ability to engage multiple ligands. We propose that stepwise, phosphorylation-triggered docking interactions of nonkinase elements enhance the specificity and robustness of kinase signaling cascades.« less

A statistical model for Windstorm Variability over the British Isles based on Large-scale Atmospheric and Oceanic Mechanisms

NASA Astrophysics Data System (ADS)

Kirchner-Bossi, Nicolas; Befort, Daniel J.; Wild, Simon B.; Ulbrich, Uwe; Leckebusch, Gregor C.

2016-04-01

Time-clustered winter storms are responsible for a majority of the wind-induced losses in Europe. Over last years, different atmospheric and oceanic large-scale mechanisms as the North Atlantic Oscillation (NAO) or the Meridional Overturning Circulation (MOC) have been proven to drive some significant portion of the windstorm variability over Europe. In this work we systematically investigate the influence of different large-scale natural variability modes: more than 20 indices related to those mechanisms with proven or potential influence on the windstorm frequency variability over Europe - mostly SST- or pressure-based - are derived by means of ECMWF ERA-20C reanalysis during the last century (1902-2009), and compared to the windstorm variability for the European winter (DJF). Windstorms are defined and tracked as in Leckebusch et al. (2008). The derived indices are then employed to develop a statistical procedure including a stepwise Multiple Linear Regression (MLR) and an Artificial Neural Network (ANN), aiming to hindcast the inter-annual (DJF) regional windstorm frequency variability in a case study for the British Isles. This case study reveals 13 indices with a statistically significant coupling with seasonal windstorm counts. The Scandinavian Pattern (SCA) showed the strongest correlation (0.61), followed by the NAO (0.48) and the Polar/Eurasia Pattern (0.46). The obtained indices (standard-normalised) are selected as predictors for a windstorm variability hindcast model applied for the British Isles. First, a stepwise linear regression is performed, to identify which mechanisms can explain windstorm variability best. Finally, the indices retained by the stepwise regression are used to develop a multlayer perceptron-based ANN that hindcasted seasonal windstorm frequency and clustering. Eight indices (SCA, NAO, EA, PDO, W.NAtl.SST, AMO (unsmoothed), EA/WR and Trop.N.Atl SST) are retained by the stepwise regression. Among them, SCA showed the highest linear coefficient, followed by SST in western Atlantic, AMO and NAO. The explanatory regression model (considering all time steps) provided a Coefficient of Determination (R^2) of 0.75. A predictive version of the linear model applying a leave-one-out cross-validation (LOOCV) shows an R2 of 0.56 and a relative RMSE of 4.67 counts/season. An ANN-based nonlinear hindcast model for the seasonal windstorm frequency is developed with the aim to improve the stepwise hindcast ability and thus better predict a time-clustered season over the case study. A 7 node-hidden layer perceptron is set, and the LOOCV procedure reveals a R2 of 0.71. In comparison to the stepwise MLR the RMSE is reduced a 20%. This work shows that for the British Isles case study, most of the interannual variability can be explained by certain large-scale mechanisms, considering also nonlinear effects (ANN). This allows to discern a time-clustered season from a non-clustered one - a key issue for applications e.g., in the (re)insurance industry.

Mild Aromatic Palladium-Catalyzed Protodecarboxylation: Kinetic Assessment of the Decarboxylative Palladation and the Protodepalladation Steps

PubMed Central

Dickstein, Joshua S.; Curto, John M.; Gutierrez, Osvaldo; Mulrooney, Carol A.; Kozlowski, Marisa C.

2013-01-01

Mechanism studies of a mild palladium catalyzed decarboxylation of aromatic carboxylic acids are described. In particular, reaction orders and activation parameters for the two stages of the transformation were determined. These studies guided development of a catalytic system capable of turnover. Further evidence reinforces that the second stage, protonation of the aryl palladium intermediate, is the rate-determining step of the reaction. The first step, decarboxylative palladation is proposed to occur through an intramolecular electrophilic palladation pathway, which is supported by computational and mechansim studies. In contrast to the reverse reaction (C-H insertion), the data support an electrophilic aromatic substitution mechanism involving a stepwise intramolecular protonation sequence for the protodepalladation portion of the reaction. PMID:23590518

Monotonous and stepwise character of deformation accumulation as a hierarchically organized process under high-temperature deformation of aluminum-magnesium alloy

NASA Astrophysics Data System (ADS)

Makarov, S. V.; Plotnikov, V. A.; Lysikov, M. V.

2017-12-01

Stepwise kinetics of deformation accumulation and monotonous and pulsed acoustic emission bear witness to the active role of acoustic emission in deformation processes. A standing acoustic wave in the region of deformation localization determines the effect of self-organization of dislocations on macroscopic scales around the natural resonator of the system.

Un-catalyzed peptide bond formation between two monomers of glycine, alanine, serine, threonine, and aspartic acid in gas phase: a density functional theory study

NASA Astrophysics Data System (ADS)

Bhunia, Snehasis; Singh, Ajeet; Ojha, Animesh K.

2016-05-01

In the present report, un-catalyzed peptide bond formation between two monomers of glycine (Gly), alanine (Ala), serine (Ser), threonine (Thr), and aspartic acid (Asp) has been investigated in gas phase via two steps reaction mechanism and concerted mechanism at B3LYP/6-31G(d,p) and M062X/6-31G(d,p) level of theories. The peptide bond is formed through a nucleophilic reaction via transition states, TS1 and TS2 in stepwise mechanism. The TS1 reveals formation of a new C-N bond while TS2 illustrate the formation of C=O bond. In case of concerted mechanism, C-N bond is formed by a single four-centre transition state (TS3). The energy barrier is used to explain the involvement of energy at each step of the reaction. The energy barrier (20-48 kcal/mol) is required for the transformation of reactant state R1 to TS1 state and intermediate state I1 to TS2 state. The large value of energy barrier is explained in terms of distortion and interaction energies for stepwise mechanism. The energy barrier of TS3 in concerted mechanism is very close to the energy barrier of the first transition state (TS1) of the stepwise mechanism for the formation of Gly-Gly and Ala-Ala di- peptide. However, in case of Ser-Ser, Thr-Thr and Asp-Asp di-peptide, the energy barrier of TS3 is relatively high than that of the energy barrier of TS1 calculated at B3LYP/6-31G(d,p) and M062X/6-31G(d,p) level of theories. In both the mechanisms, the value of energy barrier calculated at B3LYP/6-31G(d,p) level of theory is greater than that of the value calculated at M062X/6-31G(d,p) level of theory.

An Alternative Mechanism for the Methylation of Phosphoethanolamine Catalyzed by Plasmodium falciparum Phosphoethanolamine Methyltransferase*♦

PubMed Central

Saen-oon, Suwipa; Lee, Soon Goo; Jez, Joseph M.; Guallar, Victor

2014-01-01

The phosphobase methylation pathway catalyzed by the phosphoethanolamine methyltransferase in Plasmodium falciparum (PfPMT), the malaria parasite, offers an attractive target for anti-parasitic drug development. PfPMT methylates phosphoethanolamine (pEA) to phosphocholine for use in membrane biogenesis. Quantum mechanics and molecular mechanics (QM/MM) calculations tested the proposed reaction mechanism for methylation of pEA involving the previously identified Tyr-19–His-132 dyad, which indicated an energetically unfavorable mechanism. Instead, the QM/MM calculations suggested an alternative mechanism involving Asp-128. The reaction coordinate involves the stepwise transfer of a proton to Asp-128 via a bridging water molecule followed by a typical Sn2-type methyl transfer from S-adenosylmethionine to pEA. Functional analysis of the D128A, D128E, D128Q, and D128N PfPMT mutants shows a loss of activity with pEA but not with the final substrate of the methylation pathway. X-ray crystal structures of the PfPMT-D128A mutant in complex with S-adenosylhomocysteine and either pEA or phosphocholine reveal how mutation of Asp-128 disrupts a hydrogen bond network in the active site. The combined QM/MM, biochemical, and structural studies identify a key role for Asp-128 in the initial step of the phosphobase methylation pathway in Plasmodium and provide molecular insight on the evolution of multiple activities in the active site of the PMT. PMID:25288796

An alternative mechanism for the methylation of phosphoethanolamine catalyzed by Plasmodium falciparum phosphoethanolamine methyltransferase

DOE PAGES

Saen-oon, Suwipa; Lee, Soon Goo; Jez, Joseph M.; ...

2014-10-06

Here, the phosphobase methylation pathway catalyzed by the phosphoethanolamine methyltransferase in Plasmodium falciparum (PfPMT), the malaria parasite, offers an attractive target for anti-parasitic drug development. PfPMT methylates phosphoethanolamine (pEA) to phosphocholine for use in membrane biogenesis. Quantum mechanics and molecular mechanics (QM/MM) calculations tested the proposed reaction mechanism for methylation of pEA involving the previously identified Tyr-19–His-132 dyad, which indicated an energetically unfavorable mechanism. Instead, the QM/MM calculations suggested an alternative mechanism involving Asp-128. The reaction coordinate involves the stepwise transfer of a proton to Asp-128 via a bridging water molecule followed by a typical S n2-type methyl transfer frommore » S-adenosylmethionine to pEA. Functional analysis of the D128A, D128E, D128Q, and D128N PfPMT mutants shows a loss of activity with pEA but not with the final substrate of the methylation pathway. X-ray crystal structures of the PfPMT-D128A mutant in complex with S-adenosylhomocysteine and either pEA or phosphocholine reveal how mutation of Asp-128 disrupts a hydrogen bond network in the active site. The combined QM/MM, biochemical, and structural studies identify a key role for Asp-128 in the initial step of the phosphobase methylation pathway in Plasmodium and provide molecular insight on the evolution of multiple activities in the active site of the PMT.« less

An alternative mechanism for the methylation of phosphoethanolamine catalyzed by Plasmodium falciparum phosphoethanolamine methyltransferase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saen-oon, Suwipa; Lee, Soon Goo; Jez, Joseph M.

Here, the phosphobase methylation pathway catalyzed by the phosphoethanolamine methyltransferase in Plasmodium falciparum (PfPMT), the malaria parasite, offers an attractive target for anti-parasitic drug development. PfPMT methylates phosphoethanolamine (pEA) to phosphocholine for use in membrane biogenesis. Quantum mechanics and molecular mechanics (QM/MM) calculations tested the proposed reaction mechanism for methylation of pEA involving the previously identified Tyr-19–His-132 dyad, which indicated an energetically unfavorable mechanism. Instead, the QM/MM calculations suggested an alternative mechanism involving Asp-128. The reaction coordinate involves the stepwise transfer of a proton to Asp-128 via a bridging water molecule followed by a typical S n2-type methyl transfer frommore » S-adenosylmethionine to pEA. Functional analysis of the D128A, D128E, D128Q, and D128N PfPMT mutants shows a loss of activity with pEA but not with the final substrate of the methylation pathway. X-ray crystal structures of the PfPMT-D128A mutant in complex with S-adenosylhomocysteine and either pEA or phosphocholine reveal how mutation of Asp-128 disrupts a hydrogen bond network in the active site. The combined QM/MM, biochemical, and structural studies identify a key role for Asp-128 in the initial step of the phosphobase methylation pathway in Plasmodium and provide molecular insight on the evolution of multiple activities in the active site of the PMT.« less

A unified approach for EIT imaging of regional overdistension and atelectasis in acute lung injury.

PubMed

Gómez-Laberge, Camille; Arnold, John H; Wolf, Gerhard K

2012-03-01

Patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS) are vulnerable to ventilator-induced lung injury. Although this syndrome affects the lung heterogeneously, mechanical ventilation is not guided by regional indicators of potential lung injury. We used electrical impedance tomography (EIT) to estimate the extent of regional lung overdistension and atelectasis during mechanical ventilation. Techniques for tidal breath detection, lung identification, and regional compliance estimation were combined with the Graz consensus on EIT lung imaging (GREIT) algorithm. Nine ALI/ARDS patients were monitored during stepwise increases and decreases in airway pressure. Our method detected individual breaths with 96.0% sensitivity and 97.6% specificity. The duration and volume of tidal breaths erred on average by 0.2 s and 5%, respectively. Respiratory system compliance from EIT and ventilator measurements had a correlation coefficient of 0.80. Stepwise increases in pressure could reverse atelectasis in 17% of the lung. At the highest pressures, 73% of the lung became overdistended. During stepwise decreases in pressure, previously-atelectatic regions remained open at sub-baseline pressures. We recommend that the proposed approach be used in collaborative research of EIT-guided ventilation strategies for ALI/ARDS.

From shoot to leaf: step-wise shifts in meristem and KNOX1 activity correlate with the evolution of a unifoliate body plan in Gesneriaceae.

PubMed

Nishii, Kanae; Huang, Bing-Hong; Wang, Chun-Neng; Möller, Michael

2017-01-01

Typical dicots possess equal-sized cotyledons and leaf-bearing shoots topped with a shoot apical meristem (SAM), the source of lateral organs, and where KNOX1 homeobox genes act as key regulators. New World Gesneriaceae show typical cotyledons, whereas Old World Gesneriaceae show anisocotyly, the unequal post-germination growth of cotyledons, and include unifoliate (one-leaf) plants. One-leaf plants show an extremely reduced body plan: the adult above-ground photosynthetic tissue consisting of a single cotyledon, a macrocotyledon enlarged by the basal meristem (BM), but lacking a SAM. To investigate the origin and evolution of the BM and one-leaf plants, the meristem activity and KNOX1 SHOOTMERISTEMLESS (STM) expression in cotyledons and leaves were systematically studied by RT-PCR and in situ hybridization across the family Gesneriaceae, Jovellana in Calceolariaceae (sister family to Gesneriaceae), and Antirrhinum in Plantaginaceae, all families of order Lamiales (asterids), in comparison to Arabidopsis (Brassicales, rosids). In all examined Lamiales samples, unlike Arabidopsis, BM activity accompanied by STM expression was found in both cotyledons in early stages. Foliage leaves of Gesneriaceae and Jovellana also showed the correlation of BM and STM expression. An extension of BM activity was found following a phylogenetic trajectory towards one-leaf plants where it is active throughout the lifetime of the macrocotyledon. Our results suggest that KNOX1 involvement in early cotyledon expansion originated early on in the diversification of Lamiales and is proposed as the prerequisite for the evolution of vegetative diversity in Gesneriaceae. Step-wise morphological shifts, driven by transfers of meristematic activity, as evidenced by shifts in KNOX1 expression, may be one mechanism by which morphological diversity evolves in plants.

ISECG Global Exploration Roadmap: A Stepwise Approach to Deep Space Exploration

NASA Technical Reports Server (NTRS)

Martinez, Roland; Goodliff, Kandyce; Whitley, Ryan

2013-01-01

In 2011, ISECG released the Global Exploration Roadmap (GER), advancing the "Global Exploration Strategy: The Framework for Coordination" by articulating the perspectives of participating agencies on exploration goals and objectives, mission scenarios, and coordination of exploration preparatory activities. The GER featured a stepwise development and demonstration of capabilities ultimately required for human exploration of Mars. In 2013 the GER was updated to reflect the ongoing evolution of agency's exploration policies and plans, informed by individual agency and coordinated analysis activities that are relevant to various elements of the GER framework as well as coordinated stakeholder engagement activities. For this release of version 2 of the GER in the mid 2013 timeframe, a modified mission scenario is presented, more firmly reflecting the importance of a stepwise evolution of critical capabilities provided by multiple partners necessary for executing increasingly complex missions to multiple destinations and leading to human exploration of Mars. This paper will describe the updated mission scenario, the changes since the release of version 1, the mission themes incorporated into the scenario, and risk reduction for Mars missions provided by exploration at various destinations.

Rates and mechanism of fluoride and water exchange in UO(2)F(5)(3-) and [UO(2)F(4)(H(2)O)](2-) studied by NMR spectroscopy and wave function based methods.

PubMed

Vallet, Valérie; Wahlgren, Ulf; Szabó, Zoltán; Grenthe, Ingmar

2002-10-21

The reaction mechanism for the exchange of fluoride in UO(2)F(5)(3-) and UO(2)F(4)(H(2)O)(2-) has been investigated experimentally using (19)F NMR spectroscopy at -5 degrees C, by studying the line broadening of the free fluoride, UO(2)F(4)(2-)(aq) and UO(2)F(5)(3-), and theoretically using quantum chemical methods to calculate the activation energy for different pathways. The new experimental data allowed us to make a more detailed study of chemical equilibria and exchange mechanisms than in previous studies. From the integrals of the different individual peaks in the new NMR spectra, we obtained the stepwise stability constant K(5) = 0.60 +/- 0.05 M(-1) for UO(2)F(5)(3-). The theoretical results indicate that the fluoride exchange pathway of lowest activation energy, 71 kJ/mol, in UO(2)F(5)(3-) is water assisted. The pure dissociative pathway has an activation energy of 75 kJ/mol, while the associative mechanism can be excluded as there is no stable UO(2)F(6)(4-) intermediate. The quantum chemical calculations have been made at the SCF/MP2 levels, using a conductor-like polarizable continuum model (CPCM) to describe the solvent. The effects of different model assumptions on the activation energy have been studied. The activation energy is not strongly dependent on the cavity size or on interactions between the complex and Na(+) counterions. However, the solvation of the complex and the leaving fluoride results in substantial changes in the activation energy. The mechanism for water exchange in UO(2)F(4)(H(2)O)(2-) has also been studied. We could eliminate the associative mechanism, the dissociative mechanism had the lowest activation energy, 39 kJ/mol, while the interchange mechanism has an activation energy that is approximately 50 kJ/mol higher.

Stepwise hydrolysis to improve carbon releasing efficiency from sludge.

PubMed

Liu, Hongbo; Wang, Yuanyuan; Wang, Ling; Yu, Tiantian; Fu, Bo; Liu, He

2017-08-01

Based on thermal alkaline hydrolysis (TAH), a novel strategy of stepwise hydrolysis was developed to improve carbon releasing efficiency from waste activated sludge (WAS). By stepwise increasing hydrolysis intensity, conventional sludge hydrolysis (the control) was divided into four stages for separately recovering sludge carbon sources with different bonding strengths, namely stage 1 (60 °C, pH 6.0-8.0), stage 2 (80 °C, pH 6.0-8.0), stage 3 (80 °C, pH 10.0) and stage 4 (90 °C, pH 12.0). Results indicate stepwise hydrolysis could enhance the amount of released soluble chemical oxygen demand (SCOD) for almost 2 times, from 7200 to 14,693 mg/L, and the released carbon presented better biodegradability, with BOD/COD of 0.47 and volatile fatty acids (VFAs) yield of 0.37 g VFAs/g SCOD via anaerobic fermentation. Moreover, stepwise hydrolysis also improved the dewaterability of hydrolyzed sludge, capillary suction time (CST) reducing from 2500 to 1600 s. Economic assessment indicates stepwise hydrolysis shows less alkali demand and lower thermal energy consumption than those of the control. Furthermore, results of this study help support the concepts of improving carbon recovery in wastewater by manipulating WAS composition and the idea of classifiably recovering the nutrients in WAS. Copyright © 2017 Elsevier Ltd. All rights reserved.

In vivo stepwise multi-photon activation fluorescence imaging of melanin in human skin

NASA Astrophysics Data System (ADS)

Lai, Zhenhua; Gu, Zetong; Abbas, Saleh; Lowe, Jared; Sierra, Heidy; Rajadhyaksha, Milind; DiMarzio, Charles

2014-03-01

The stepwise multi-photon activated fluorescence (SMPAF) of melanin is a low cost and reliable method of detecting melanin because the activation and excitation can be a continuous-wave (CW) mode near infrared (NIR) laser. Our previous work has demonstrated the melanin SMPAF images in sepia melanin, mouse hair, and mouse skin. In this study, we show the feasibility of using SMPAF to detect melanin in vivo. in vivo melanin SMPAF images of normal skin and benign nevus are demonstrated. SMPAF images add specificity for melanin detection than MPFM images and CRM images. Melanin SMPAF is a promising technology to enable early detection of melanoma for dermatologists.

Advancing a Model-Validated Statistical Method for Decomposing the Key Oceanic Drivers of Regional Climate: Focus on Northern and Tropical African Climate Variability in the Community Earth System Model (CESM)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Fuyao; Yu, Yan; Notaro, Michael

This study advances the practicality and stability of the traditional multivariate statistical method, generalized equilibrium feedback assessment (GEFA), for decomposing the key oceanic drivers of regional atmospheric variability, especially when available data records are short. An advanced stepwise GEFA methodology is introduced, in which unimportant forcings within the forcing matrix are eliminated through stepwise selection. Method validation of stepwise GEFA is performed using the CESM, with a focused application to northern and tropical Africa (NTA). First, a statistical assessment of the atmospheric response to each primary oceanic forcing is carried out by applying stepwise GEFA to a fully coupled controlmore » run. Then, a dynamical assessment of the atmospheric response to individual oceanic forcings is performed through ensemble experiments by imposing sea surface temperature anomalies over focal ocean basins. Finally, to quantify the reliability of stepwise GEFA, the statistical assessment is evaluated against the dynamical assessment in terms of four metrics: the percentage of grid cells with consistent response sign, the spatial correlation of atmospheric response patterns, the area-averaged seasonal cycle of response magnitude, and consistency in associated mechanisms between assessments. In CESM, tropical modes, namely El Niño–Southern Oscillation and the tropical Indian Ocean Basin, tropical Indian Ocean dipole, and tropical Atlantic Niño modes, are the dominant oceanic controls of NTA climate. In complementary studies, stepwise GEFA is validated in terms of isolating terrestrial forcings on the atmosphere, and observed oceanic and terrestrial drivers of NTA climate are extracted to establish an observational benchmark for subsequent coupled model evaluation and development of process-based weights for regional climate projections.« less

Advancing a Model-Validated Statistical Method for Decomposing the Key Oceanic Drivers of Regional Climate: Focus on Northern and Tropical African Climate Variability in the Community Earth System Model (CESM)

DOE PAGES

Wang, Fuyao; Yu, Yan; Notaro, Michael; ...

2017-09-27

This study advances the practicality and stability of the traditional multivariate statistical method, generalized equilibrium feedback assessment (GEFA), for decomposing the key oceanic drivers of regional atmospheric variability, especially when available data records are short. An advanced stepwise GEFA methodology is introduced, in which unimportant forcings within the forcing matrix are eliminated through stepwise selection. Method validation of stepwise GEFA is performed using the CESM, with a focused application to northern and tropical Africa (NTA). First, a statistical assessment of the atmospheric response to each primary oceanic forcing is carried out by applying stepwise GEFA to a fully coupled controlmore » run. Then, a dynamical assessment of the atmospheric response to individual oceanic forcings is performed through ensemble experiments by imposing sea surface temperature anomalies over focal ocean basins. Finally, to quantify the reliability of stepwise GEFA, the statistical assessment is evaluated against the dynamical assessment in terms of four metrics: the percentage of grid cells with consistent response sign, the spatial correlation of atmospheric response patterns, the area-averaged seasonal cycle of response magnitude, and consistency in associated mechanisms between assessments. In CESM, tropical modes, namely El Niño–Southern Oscillation and the tropical Indian Ocean Basin, tropical Indian Ocean dipole, and tropical Atlantic Niño modes, are the dominant oceanic controls of NTA climate. In complementary studies, stepwise GEFA is validated in terms of isolating terrestrial forcings on the atmosphere, and observed oceanic and terrestrial drivers of NTA climate are extracted to establish an observational benchmark for subsequent coupled model evaluation and development of process-based weights for regional climate projections.« less

Multiple isotope effects with alternative dinucleotide substrates as a probe of the malic enzyme reaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weiss, P.M.; Urbauer, J.L.; Cleland, W.W.

1991-06-11

Deuterium isotope effects and {sup 13}C isotope effects with deuterium- and protium-labeled malate have been obtained for both NAD- and NADP-malic enzymes by using a variety of alternative dinucleotide substrates. With nicotinamide-containing dinucleotides as the oxidizing substrate, the {sup 13}C effect decreases when deuterated malate is the substrate compared to the value obtained with protium-labeled malate. These data are consistent with a stepwise chemical mechanism in which hydride transfer precedes decarboxylation of the oxalacetate intermediate as previously proposed. When dinucleotide substrates such as thio-NAD, 3-nicotinamide rings are used, the {sup 13}C effect increases when deuterated malate is the substrate comparedmore » to the value obtained with protium-labeled malate. These data, at face value, are consistent with a change in mechanism from stepwise to concerted for the oxidative decarboxylation portion of the mechanism. However, the increase in the deuterium isotope effect from 1.5 to 3 with a concomitant decrease in the {sup 13}C isotope effect from 1.034 to 1.003 as the dinucleotide substrate is changed suggests that the reaction may still be stepwise with the non-nicotinamide dinucleotides. A more likely explanation is that a {beta}-secondary {sup 13}C isotope effect accompanies hydride transfer as a result of hyperconjugation of the {beta}-carboxyl of malate as the transition state for the hydride transfer step is approached.« less

Experimental and theoretical study on activation of the C-H bond in pyridine by [M(m)]- (M = Cu, Ag, Au, m = 1-3).

PubMed

Liu, Xiao-Jing; Hamilton, I P; Han, Ke-Li; Tang, Zi-Chao

2010-09-21

Activation of the C-H bond of pyridine by [M(m)](-) (M = Cu, Ag, Au, m = 1-3) is investigated by experiment and theory. Complexes of coinage metal clusters and the pyridyl group, [M(m)-C(5)H(4)N](-), are produced from reactions between metal clusters formed by laser ablation of coinage metal samples and pyridine molecules seeded in argon carrier gas. We examine the structure and formation mechanism of these pyridyl-coinage metal complexes. Our study shows that C(5)H(4)N bonds to the metal clusters through a M-C sigma bond and [M(m)-C(5)H(4)N](-) is produced via a stepwise mechanism. The first step is a direct insertion reaction between [M(m)](-) and C(5)H(5)N with activation of the C-H bond to yield the intermediate [HM(m)-C(5)H(4)N](-). The second step is H atom abstraction by a neutral metal atom to yield [M(m)-C(5)H(4)N](-).

Computational QM/MM Study of the Reaction Mechanism of Human Glutathione S-Transferase A3-3

NASA Astrophysics Data System (ADS)

Calvaresi, Matteo; Stenta, Marco; Altoè, Piero; Bottoni, Andrea; Garavelli, Marco; Spinelli, Domenico

2007-12-01

Human Glutathione S-Transferase A3-3(hGSTA3-3) is the most efficient human steroid double-bond isomerase enzyme. It catalyzes the double bond isomerization of Δ5-androstene-3,17-dione (Δ5-AD) and Δ5-pregnene-3,20-dione (Δ5-PD). The isomerization products are the precursors of the steroid hormones testosterone and progesterone. We have carried out a QM/MM study to elucidate some interesting aspects of the enzyme catalytic mechanism. In particular, we have analyzed either a concerted or a stepwise reaction path. Moreover, we have attempted to rationalize the electrostatic effects on the catalytic activity of the residues surrounding the active site. Specifically, we have performed a "finger print" analysis to determine the electrostatic contribution of each aminoacid residue to the global electrostatic term, thus ranking the effect of the various aminoacids in the course of the reaction. In this way, we have highlighted the most important terms affecting the stabilization-destabilization of the enzyme.

Discussion of the Investigation Method on the Reaction Kinetics of Metallurgical Reaction Engineering

NASA Astrophysics Data System (ADS)

Du, Ruiling; Wu, Keng; Zhang, Jiazhi; Zhao, Yong

Reaction kinetics of metallurgical physical chemistry which was successfully applied in metallurgy (as ferrous metallurgy, non-ferrous metallurgy) became an important theoretical foundation for subject system of traditional metallurgy. Not only the research methods were very perfect, but also the independent structures and systems of it had been formed. One of the important tasks of metallurgical reaction engineering was the simulation of metallurgical process. And then, the mechanism of reaction process and the conversion time points of different control links should be obtained accurately. Therefore, the research methods and results of reaction kinetics in metallurgical physical chemistry were not very suitable for metallurgical reaction engineering. In order to provide the definite conditions of transmission, reaction kinetics parameters and the conversion time points of different control links for solving the transmission and reaction equations in metallurgical reaction engineering, a new method for researching kinetics mechanisms in metallurgical reaction engineering was proposed, which was named stepwise attempt method. Then the comparison of results between the two methods and the further development of stepwise attempt method were discussed in this paper. As a new research method for reaction kinetics in metallurgical reaction engineering, stepwise attempt method could not only satisfy the development of metallurgical reaction engineering, but also provide necessary guarantees for establishing its independent subject system.

Down's Syndrome and Leukemia: Mechanism of Additional Chromosomal Abnormalities

ERIC Educational Resources Information Center

And Others; Goh, Kong-oo

1978-01-01

Chromosomal abnormalities, some appearing in a stepwise clonal evoluation, were found in five Down's syndrome patients (35 weeks to 12 years old), four with acute leukemia and one with abnormal regulation of leukopoiesis. (Author/SBH)

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

PubMed

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

2013-10-14

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

Selective anaerobic oxidation of methane enables direct synthesis of methanol.

PubMed

Sushkevich, Vitaly L; Palagin, Dennis; Ranocchiari, Marco; van Bokhoven, Jeroen A

2017-05-05

Direct functionalization of methane in natural gas remains a key challenge. We present a direct stepwise method for converting methane into methanol with high selectivity (~97%) over a copper-containing zeolite, based on partial oxidation with water. The activation in helium at 673 kelvin (K), followed by consecutive catalyst exposures to 7 bars of methane and then water at 473 K, consistently produced 0.204 mole of CH 3 OH per mole of copper in zeolite. Isotopic labeling confirmed water as the source of oxygen to regenerate the zeolite active centers and renders methanol desorption energetically favorable. On the basis of in situ x-ray absorption spectroscopy, infrared spectroscopy, and density functional theory calculations, we propose a mechanism involving methane oxidation at Cu II oxide active centers, followed by Cu I reoxidation by water with concurrent formation of hydrogen. Copyright © 2017, American Association for the Advancement of Science.

Effect of ionization on the oxidation kinetics of aluminum nanoparticles

NASA Astrophysics Data System (ADS)

Zheng, Yao-Ting; He, Min; Cheng, Guang-xu; Zhang, Zaoxiao; Xuan, Fu-Zhen; Wang, Zhengdong

2018-03-01

Molecular dynamics simulation (MD) of the observed stepwise oxidation of core-shell structured Al/Al2O3 nanoparticles is presented. Different from the metal ion hopping process in the Cabrera-Mott model, which is assumed to occur only at a certain distance from the oxide layer, the MD simulation shows that Al atoms jump over various interfacial gaps directly under the thermal driving force. The energy barrier for Al ionization is found to be increased along with the enlargement of interfacial gap. A mechanism of competition between thermal driving force and ionization potential barrier is proposed in the interpretation of stepwise oxidation behavior.

Stepwise crystallization and the layered distribution in crystallization kinetics of ultra-thin poly(ethylene terephthalate) film

NASA Astrophysics Data System (ADS)

Zuo, Biao; Xu, Jianquan; Sun, Shuzheng; Liu, Yue; Yang, Juping; Zhang, Li; Wang, Xinping

2016-06-01

Crystallization is an important property of polymeric materials. In conventional viewpoint, the transformation of disordered chains into crystals is usually a spatially homogeneous process (i.e., it occurs simultaneously throughout the sample), that is, the crystallization rate at each local position within the sample is almost the same. Here, we show that crystallization of ultra-thin poly(ethylene terephthalate) (PET) films can occur in the heterogeneous way, exhibiting a stepwise crystallization process. We found that the layered distribution of glass transition dynamics of thin film modifies the corresponding crystallization behavior, giving rise to the layered distribution of the crystallization kinetics of PET films, with an 11-nm-thick surface layer having faster crystallization rate and the underlying layer showing bulk-like behavior. The layered distribution in crystallization kinetics results in a particular stepwise crystallization behavior during heating the sample, with the two cold-crystallization temperatures separated by up to 20 K. Meanwhile, interfacial interaction is crucial for the occurrence of the heterogeneous crystallization, as the thin film crystallizes simultaneously if the interfacial interaction is relatively strong. We anticipate that this mechanism of stepwise crystallization of thin polymeric films will allow new insight into the chain organization in confined environments and permit independent manipulation of localized properties of nanomaterials.

Stepwise crystallization and the layered distribution in crystallization kinetics of ultra-thin poly(ethylene terephthalate) film

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zuo, Biao, E-mail: chemizuo@zstu.edu.cn, E-mail: wxinping@yahoo.com; Xu, Jianquan; Sun, Shuzheng

2016-06-21

Crystallization is an important property of polymeric materials. In conventional viewpoint, the transformation of disordered chains into crystals is usually a spatially homogeneous process (i.e., it occurs simultaneously throughout the sample), that is, the crystallization rate at each local position within the sample is almost the same. Here, we show that crystallization of ultra-thin poly(ethylene terephthalate) (PET) films can occur in the heterogeneous way, exhibiting a stepwise crystallization process. We found that the layered distribution of glass transition dynamics of thin film modifies the corresponding crystallization behavior, giving rise to the layered distribution of the crystallization kinetics of PET films,more » with an 11-nm-thick surface layer having faster crystallization rate and the underlying layer showing bulk-like behavior. The layered distribution in crystallization kinetics results in a particular stepwise crystallization behavior during heating the sample, with the two cold-crystallization temperatures separated by up to 20 K. Meanwhile, interfacial interaction is crucial for the occurrence of the heterogeneous crystallization, as the thin film crystallizes simultaneously if the interfacial interaction is relatively strong. We anticipate that this mechanism of stepwise crystallization of thin polymeric films will allow new insight into the chain organization in confined environments and permit independent manipulation of localized properties of nanomaterials.« less

Effect of Stepwise Doping on Lifetime and Efficiency of Blue and White Phosphorescent Organic Light Emitting Diodes.

PubMed

Lee, Song Eun; Lee, Ho Won; Lee, Seok Jae; Koo, Ja-ryong; Lee, Dong Hyung; Yang, Hyung Jin; Kim, Hye Jeong; Yoon, Seung Soo; Kim, Young Kwan

2015-02-01

We investigated a light emission mechanism of blue phosphorescent organic light emitting diodes (PHOLEDs), using a stepwise doping profile of 2, 8, and 14 wt.% within the emitting layer (EML). We fabricated several blue PHOLEDs with phosphorescent blue emitter iridium(III) bis[(4,6-difluorophenyl)-pyridinato-N,C2]picolinate doped in N,N'-dicarbazolyl-3,5-benzene as a p-type host material. A blue PHOLED with the highest doping concentration as part of the EML close to an electron transporting layer showed a maximum luminous efficiency of 20.74 cd/A, and a maximum external quantum efficiency of 10.52%. This can be explained by effective electron injection through a highly doped EML side. Additionally, a white OLED based on the doping profile was fabricated with two thin red EMLs within a blue EML maintaining a thickness of 30 nm for the entire EML. Keywords: Blue Phosphorescent Organic Light Emitting Diodes, Stepwise Doping Structure, Charge Trapping Effect.

Analysis of blood flow in the long posterior ciliary artery of the cat.

PubMed

Koss, M C

1999-03-01

Experiments were undertaken to use a new technique for direct on-line measurement of blood flow in the long posterior ciliary artery (LPCA) in cats and to evaluate possible physiological mechanisms controlling blood flow in the vascular beds perfused by this artery. Blood flow in the temporal LPCA was measured on a continuous basis using ultrasonic flowmetry in anesthetized cats. Effects of acute sectioning of the sympathetic nerve and changes in LPCA and cerebral blood flows in response to altered levels of inspired CO2 and O2 were tested in some animals. In others, the presence of vascular autoregulatory mechanisms in response to stepwise elevations of intraocular pressure was studied. Blood flow in the temporal LPCA averaged 0.58+/-0.03 ml/min in 45 cats anesthetized with pentobarbital. Basal LPCA blood flow was not altered by acute sectioning of the sympathetic nerve or by changes in low levels of inspired CO2 and O2, although 10% CO2 caused a modest increase. Stepwise elevations of intraocular pressure resulted in comparable stepwise decreases of LPCA blood flow, with perfusion pressure declining in a linear manner throughout the perfusion-pressure range. Ultrasonic flowmetry seems to be a useful tool for continuous on-line measurement of LPCA blood flow in the cat eye. Blood flow to vascular beds perfused by this artery does not seem to be under sympathetic neural control and is refractory to modest alterations of blood gas levels of CO2 and O2. Blood vessels perfused by the LPCA show no clear autoregulatory mechanisms.

Proton-Coupled Electron Transfer in a Strongly Coupled Photosystem II-Inspired Chromophore–Imidazole–Phenol Complex: Stepwise Oxidation and Concerted Reduction

DOE PAGES

Manbeck, Gerald F.; Fujita, Etsuko; Concepcion, Javier J.

2016-08-18

Proton-coupled electron-transfer (PCET) reactions were studied in acetonitrile for a Photosystem II (PSII) inspired [Ru(bpy) 2(phen-imidazole-Ph(OH)( tBu) 2)] 2+, in which Ru(III) generated by a flash-quench sequence oxidizes the appended phenol and the proton is transferred to the hydrogen bonded imidazole base. In contrast to related systems, the donor and acceptor are strongly coupled, as indicated by the shift in the Ru III/IIcouple upon phenol oxidation, and intramolecular oxidation of the phenol by Ru(III) is energetically favorable by both stepwise or concerted pathways. The phenol oxidation occurs via a stepwise ET-PT mechanism with k ET = 2.7 × 10 7more » s ₋1 and a kinetic isotope effect (KIE) of 0.99 ± 0.03. The electron transfer reaction was characterized as adiabatic with λ DA = 1.16 eV and 280 < H DA < 540 cm ₋1 consistent with strong electronic coupling and slow solvent dynamics. Reduction of the phenoxyl radical by the quencher radical was examined as the analogue of the redox reaction between the PSII tyrosyl radical and the oxygen evolving complex (OEC). In our PSII-inspired complex, the recombination reaction activation energy is < 2 kcal mol ₋1. In conclusion, the reaction is nonadiabatic (V PCET ~ 22 cm ₋1 (H) and 49 cm ₋1 (D)), concerted, and exhibits an unexpected inverse KIE of 0.55 that is attributed to greater overlap of the reactant vibronic ground state with the OD vibronic states of the proton acceptor due to the smaller quantum spacing of the deuterium vibrational levels.« less

Computational Studies on the Synthesis of β-Lactams via [2+2] Thermal Cycloadditions

NASA Astrophysics Data System (ADS)

Arrieta, Ana; Lecea, Begoña; Cossío, Fernando P.

The main computational studies on the formation of β-lactams through [2+2] cycloadditions published during 1992-2008 are reported with special emphasis on the mechanistic and selectivity aspects of these reactions. Disconnection of the N1-C2 and C3-C4 bonds of the azetidin-2-one ring leads to the reaction between ketenes and imines. Computational and experimental results point to a stepwise mechanism for this reaction. The first step consists of a nucleophilic attack of the iminic nitrogen on the sp-hybridized carbon atom of the ketene. The zwitterionic intermediate thus formed yields the corresponding β-lactam by means of a four-electron conrotatoty electrocyclization. The steroecontrol and the periselectivity of the reaction support this two-step mechanism. The [2+2] cycloaddition between isocyanates and alkenes takes place via a concerted (but asynchronous) mechanism that can be interpreted in terms of a [π2s + (π2s + π2s)] interaction between both reactants. Both the regio and the stereochemistry observed are compatible with this computational model. However, the combination of solvent and substituent effects can result in a stepwise mechanism.

Development of a heat-processing method for koji to enhance its antioxidant activity.

PubMed

Okutsu, Kayu; Yoshizaki, Yumiko; Takamine, Kazunori; Tamaki, Hisanori; Ito, Kiyoshi; Sameshima, Yoshihiro

2012-03-01

We developed a heat-processing method to enhance the antioxidant activity of koji. The superoxide anion scavenging activity (SOSA) and oxygen radical absorbance capacity (ORAC) of heat-processed koji (HP-koji) at 55 °C for 7 days were 4.9 times and 4.2 times, respectively, those of unheated koji. These results showed that heat processing effectively enhances the antioxidant activity of koji. Analysis of the antioxidant activities of koji subjected to a range of temperatures (45-75 °C) revealed that the SOSA is enhanced by heating at higher temperatures, which might be catalyzed by Maillard reaction, whereas the ORAC was enhanced by heating at lower temperatures, which might be catalyzed by an enzymatic reaction. Assuming these enhancements in antioxidant activities are contributed by both Maillard and enzyme reactions, we hypothesized that the antioxidant activity of HP-koji could be more effectively amplified by heating at a higher temperature after the progression of the enzymatic reaction at a moderate temperature. Therefore, we evaluated the effect of heating of koji in a stepwise manner, first at 55 °C for 2 days and then at 75 °C for 5days. The antioxidant activities of stepwise-heated HP-koji were higher than those of koji heated at either 55 °C or 75 °C. The SOSA and ORAC of stepwise-heated HP-koji were 94 times and 6 times, respectively, those of unheated koji. This result suggests that enzymatic reaction followed by Maillard reaction can effectively enhance the antioxidant activity of HP-koji. Thus, we developed a novel heat-processing method to enhance the antioxidant activity of koji. Copyright © 2011 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

GaN growth via HVPE on SiC/Si substrates: growth mechanisms

NASA Astrophysics Data System (ADS)

Sharofidinov, Sh Sh; Redkov, A. V.; Osipov, A. V.; Kukushkin, S. A.

2017-11-01

The article focuses on the study of GaN thin film growth via chloride epitaxy on SiC/Si hybrid substrate. SiC buffer layer was grown by a method of substitution of atoms, which allows one to reduce impact of mechanical stress therein on subsequent growth of III-nitride films. It is shown, that change in GaN growth conditions leads to change in its growth mechanism. Three mechanisms: epitaxial, spiral and stepwise growth are considered and mechanical stresses are estimated via Raman spectroscopy.

Phenylalanine ammonia lyase catalyzed synthesis of amino acids by an MIO-cofactor independent pathway.

PubMed

Lovelock, Sarah L; Lloyd, Richard C; Turner, Nicholas J

2014-04-25

Phenylalanine ammonia lyases (PALs) belong to a family of 4-methylideneimidazole-5-one (MIO) cofactor dependent enzymes which are responsible for the conversion of L-phenylalanine into trans-cinnamic acid in eukaryotic and prokaryotic organisms. Under conditions of high ammonia concentration, this deamination reaction is reversible and hence there is considerable interest in the development of PALs as biocatalysts for the enantioselective synthesis of non-natural amino acids. Herein the discovery of a previously unobserved competing MIO-independent reaction pathway, which proceeds in a non-stereoselective manner and results in the generation of both L- and D-phenylalanine derivatives, is described. The mechanism of the MIO-independent pathway is explored through isotopic-labeling studies and mutagenesis of key active-site residues. The results obtained are consistent with amino acid deamination occurring by a stepwise E1 cB elimination mechanism. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis of radiolabelled aryl azides from diazonium salts: experimental and computational results permit the identification of the preferred mechanism.

PubMed

Joshi, Sameer M; de Cózar, Abel; Gómez-Vallejo, Vanessa; Koziorowski, Jacek; Llop, Jordi; Cossío, Fernando P

2015-05-28

Experimental and computational studies on the formation of aryl azides from the corresponding diazonium salts support a stepwise mechanism via acyclic zwitterionic intermediates. The low energy barriers associated with both transition structures are compatible with very fast and efficient processes, thus making this method suitable for the chemical synthesis of radiolabelled aryl azides.

Stepwise Loop Insertion Strategy for Active Site Remodeling to Generate Novel Enzyme Functions.

PubMed

Hoque, Md Anarul; Zhang, Yong; Chen, Liuqing; Yang, Guangyu; Khatun, Mst Afroza; Chen, Haifeng; Hao, Liu; Feng, Yan

2017-05-19

The remodeling of active sites to generate novel biocatalysts is an attractive and challenging task. We developed a stepwise loop insertion strategy (StLois), in which randomized residue pairs are inserted into active site loops. The phosphotriesterase-like lactonase from Geobacillus kaustophilus (GkaP-PLL) was used to investigate StLois's potential for changing enzyme function. By inserting six residues into active site loop 7, the best variant ML7-B6 demonstrated a 16-fold further increase in catalytic efficiency toward ethyl-paraoxon compared with its initial template, that is a 609-fold higher, >10 7 fold substrate specificity shift relative to that of wild-type lactonase. The remodeled variants displayed 760-fold greater organophosphate hydrolysis activity toward the organophosphates parathion, diazinon, and chlorpyrifos. Structure and docking computations support the source of notably inverted enzyme specificity. Considering the fundamental importance of active site loops, the strategy has potential for the rapid generation of novel enzyme functions by loop remodeling.

Feet deformities are correlated with impaired balance and postural stability in seniors over 75

PubMed Central

Puszczalowska-Lizis, Ewa; Bujas, Przemyslaw; Omorczyk, Jaroslaw; Jandzis, Slawomir

2017-01-01

Objective Understanding the factors and mechanisms that determine balance in seniors appears vital in terms of their self-reliance and overall safety. The study aimed to determine the relationship between the features of feet structure and the indicators of postural stability in the elderly. Methods The study group comprised 80 seniors (41F, 39M; aged 75–85 years). CQ-ST podoscope and the CQ-Stab 2P two-platform posturograph were used as primary research tools. The data were analyzed based on Spearman’s rank correlation and forward stepwise regression. Results Analysis of forward stepwise regression identified the left foot length in females and Clarke’s angle of the left foot in men as significant and independent predictors of postural up to 30% of the variance of dependent variables. Conclusions Longer feet provide older women with better stability, whereas in men, the lowering of the longitudinal arch results in postural deterioration. In the elderly, the left lower limb shows greater activity in the stabilizing processes in the standing position than the right one. In gerontological rehabilitation special attention should be paid to the individually tailored, gender-specific treatment, with a view to enhancing overall safety and quality of seniors’ lives. PMID:28877185

Novel Investigation on Nanostructured Multilayer and Functionally Graded Ni-P Electroless Coatings on Stainless Steel

NASA Astrophysics Data System (ADS)

Anvari, S. R.; Monirvaghefi, S. M.; Enayati, M. H.

2015-06-01

In this study, step-wise multilayer and functionally graded Ni-P coatings were deposited with electroless in which the content of phosphorus and nickel would be changed gradually and step-wise through the thickness of the coatings, respectively. To compare the properties of these coatings with Ni-P single-layer coatings, three types of coatings with different phosphorus contents were deposited. Heat treatment of coatings was performed at 400 °C for 1 h. The microstructure and phase transformation of coatings were characterized by SEM/EDS, TEM, and XRD. The mechanical properties of coatings were studied by nanoindentation test. According to the results of the single-layer coatings, low P coating had the maximum hardness and also the ratio of hardness ( H) to elasticity modulus ( E) for the mentioned coating was maximum. In addition, low and medium P coatings had crystalline and semi-crystalline structure, respectively. The mentioned coatings had <111> texture and after heat treatment their texture didn't change. While high P coating had amorphous structure, after heat treatment it changed to crystalline structure with <100> texture for nickel grains. Furthermore, the results showed that functionally graded and step-wise multilayer coatings were deposited successfully by using the same initial bath and changing the temperature and pH during deposition. Nanoindentation test results showed that the hardness of the mentioned coatings changed from 670 Hv near the substrate to 860 Hv near the top surface of coatings. For functionally graded coating the hardness profile had gradual changes, while step-wise multilayer coating had step-wise hardness profile. After heat treatment trend of hardness profiles was changed, so that near the substrate, hardness was measured 1400 Hv and changed to 1090 Hv at the top coat.

Reaction mechanism of the acidic hydrolysis of highly twisted amides: Rate acceleration caused by the twist of the amide bond.

PubMed

Mujika, Jon I; Formoso, Elena; Mercero, Jose M; Lopez, Xabier

2006-08-03

We present an ab initio study of the acid hydrolysis of a highly twisted amide and a planar amide analogue. The aim of these studies is to investigate the effect that the twist of the amide bond has on the reaction barriers and mechanism of acid hydrolysis. Concerted and stepwise mechanisms were investigated using density functional theory and polarizable continuum model calculations. Remarkable differences were observed between the mechanism of twisted and planar amide, due mainly to the preference for N-protonation of the former and O-protonation of the latter. In addition, we were also able to determine that the hydrolytic mechanism of the twisted amide will be pH dependent. Thus, there is a preference for a stepwise mechanism with formation of an intermediate in the acid hydrolysis, whereas the neutral hydrolysis undergoes a concerted-type mechanism. There is a nice agreement between the characterized intermediate and available X-ray data and a good agreement with the kinetically estimated rate acceleration of hydrolysis with respect to analogous undistorted amide compounds. This work, along with previous ab initio calculations, describes a complex and rich chemistry for the hydrolysis of highly twisted amides as a function of pH. The theoretical data provided will allow for a better understanding of the available kinetic data of the rate acceleration of amides upon twisting and the relation of the observed rate acceleration with intrinsic differential reactivity upon loss of amide bond resonance.

Isotope Effects and Mechanism of the Asymmetric BOROX Brønsted Acid Catalyzed Aziridination Reaction

PubMed Central

Vetticatt, Mathew J.; Desai, Aman A.; Wulff, William D.

2013-01-01

The mechanism of the chiral VANOL-BOROX Brønsted acid catalyzed aziridination reaction of imines and ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and theoretical calculations. A stepwise mechanism where reversible formation of a diazonium ion intermediate precedes rate-limiting ring-closure to form the cis-aziridine is implicated. A revised model for the origin of enantio- and diastereoselectivity is proposed based on relative energies of the ring closing transition structures. PMID:23687986

Structural and biochemical characterization of MCAT from photosynthetic microorganism Synechocystis sp. PCC 6803 reveal its stepwise catalytic mechanism.

PubMed

Liu, Yinghui; Feng, Yanbin; Wang, Yayue; Li, Xia; Cao, Xupeng; Xue, Song

2015-02-13

Malonyl-coenzyme A: acyl-carrier protein transacylase (MCAT) catalyzes the transfer of malonyl group from malonyl-CoA to the holo-acyl carrier protein (Holo-ACP), yielding malonyl-ACP. The overall reaction has been extensively studied in heterotrophic microorganisms, while its mechanism in photosynthetic autotrophs as well as the stepwise reaction information remains unclear. Here the 2.42 Å crystal structure of MCAT from photosynthetic microorganism Synechocystis sp. PCC 6803 is presented. It demonstrates that Arg113, Ser88 and His188 constitute catalytic triad. The second step involved ACP-MCAT-malonyl intermediate is speed-limited instead of the malonyl-CoA-MCAT intermediate in the first step. Therefore His87, Arg113 and Ser88 render different contributions for the two intermediates. Additionally, S88T mutant initializes the reaction by H87 deprotonating S88T which is different from the wild type. Copyright © 2015 Elsevier Inc. All rights reserved.

Work Done by Titin Protein Folding Assists Muscle Contraction.

PubMed

Rivas-Pardo, Jaime Andrés; Eckels, Edward C; Popa, Ionel; Kosuri, Pallav; Linke, Wolfgang A; Fernández, Julio M

2016-02-16

Current theories of muscle contraction propose that the power stroke of a myosin motor is the sole source of mechanical energy driving the sliding filaments of a contracting muscle. These models exclude titin, the largest protein in the human body, which determines the passive elasticity of muscles. Here, we show that stepwise unfolding/folding of titin immunoglobulin (Ig) domains occurs in the elastic I band region of intact myofibrils at physiological sarcomere lengths and forces of 6-8 pN. We use single-molecule techniques to demonstrate that unfolded titin Ig domains undergo a spontaneous stepwise folding contraction at forces below 10 pN, delivering up to 105 zJ of additional contractile energy, which is larger than the mechanical energy delivered by the power stroke of a myosin motor. Thus, it appears inescapable that folding of titin Ig domains is an important, but as yet unrecognized, contributor to the force generated by a contracting muscle. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Isotope effect studies of the chemical mechanism of nicotinamide adenine dinucleotide malic enzyme from Crassula

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grissom, C.B.; Willeford, O.; Wedding, R.T.

1987-05-05

The /sup 13/C primary kinetic isotope effect on the decarboxylation of malate by nicotinamide adenine dinucleotide malic enzyme from Crassula argentea is 1.0199 +/- 0.0006 with proteo L-malate-2-H and 1.0162 +/- 0.0003 with malate-2-d. The primary deuterium isotope effect is 1.45 +/- 0.10 on V/K and 1.93 +/- 0.13 on V/sub max/. This indicates a stepwise conversion of malate to pyruvate and CO/sub 2/ with hydride transfer preceding decarboxylation, thereby suggesting a discrete oxaloacetate intermediate. This is in agreement with the stepwise nature of the chemical mechanism of other malic enzymes despite the Crassula enzyme's inability to reduce or decarboxylatemore » oxaloacetate. Differences in morphology and allosteric regulation between enzymes suggest specialization of the Crassula malic enzyme for the physiology of crassulacean and acid metabolism while maintaining the catalytic events founds in malic enzymes from animal sources.« less

One-Step and Stepwise Magnification of a BOBBED LETHAL Chromosome in DROSOPHILA MELANOGASTER

PubMed Central

Endow, Sharyn A.; Komma, Donald J.

1986-01-01

Bobbed lethal (bbl) chromosomes carry too few ribosomal genes for homozygous flies to be viable. Reversion of bbl chromosomes to bb or nearly bb + occurs under magnifying conditions at a low frequency in a single generation. These reversions occur too rapidly to be accounted for by single unequal sister chromatid exchanges and seem unlikely to be due to multiple sister strand exchanges within a given cell lineage. Analysis of several one-step revertants indicates that they are X-Y recombinant chromosomes which probably arise from X-Y recombination at bb. The addition of ribosomal genes from the Y chromosome to the bbl chromosome explains the more rapid reversion of the bbl chromosome than is permitted by single events of unequal sister chromatid exchange. Analysis of stepwise bbl magnified chromosomes, which were selected over a period of 4–9 magnifying generations, shows ribosomal gene patterns that are closely similar to each other. Similarity in rDNA pattern among stepwise magnified products of the same parental chromosome is consistent with reversion by a mechanism of unequal sister strand exchange. PMID:3095184

Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci

PubMed Central

Noordermeer, Daan; Leleu, Marion; Schorderet, Patrick; Joye, Elisabeth; Chabaud, Fabienne; Duboule, Denis

2014-01-01

Hox genes are essential regulators of embryonic development. Their step-wise transcriptional activation follows their genomic topology and the various states of activation are subsequently memorized into domains of progressively overlapping gene products. We have analyzed the 3D chromatin organization of Hox clusters during their early activation in vivo, using high-resolution circular chromosome conformation capture. Initially, Hox clusters are organized as single chromatin compartments containing all genes and bivalent chromatin marks. Transcriptional activation is associated with a dynamic bi-modal 3D organization, whereby the genes switch autonomously from an inactive to an active compartment. These local 3D dynamics occur within a framework of constitutive interactions within the surrounding Topological Associated Domains, indicating that this regulation process is mostly cluster intrinsic. The step-wise progression in time is fixed at various body levels and thus can account for the chromatin architectures previously described at a later stage for different anterior to posterior levels. DOI: http://dx.doi.org/10.7554/eLife.02557.001 PMID:24843030

Reaction mechanism of guanidinoacetate methyltransferase, concerted or step-wise.

PubMed

Zhang, Xiaodong; Bruice, Thomas C

2006-10-31

We describe a quantum mechanics/molecular mechanics investigation of the guanidinoacetate methyltransferase catalyzed reaction, which shows that proton transfer from guanidinoacetate (GAA) to Asp-134 and methyl transfer from S-adenosyl-L-methionine (AdoMet) to GAA are concerted. By self-consistent-charge density functional tight binding/molecular mechanics, the bond lengths in the concerted mechanism's transition state are 1.26 A for both the OD1 (Asp-134)-H(E) (GAA) and H(E) (GAA)-N(E) (GAA) bonds, and 2.47 and 2.03 A for the S8 (AdoMet)-C9 (AdoMet) and C9 (AdoMet)-N(E) (GAA) bonds, respectively. The potential-energy barrier (DeltaE++) determined by single-point B3LYP/6-31+G*//MM is 18.9 kcal/mol. The contributions of the entropy (-TDeltaS++) and zero-point energy corrections Delta(ZPE)++ by normal mode analysis are 2.3 kcal/mol and -1.7 kcal/mol, respectively. Thus, the activation enthalpy of this concerted mechanism is predicted to be DeltaH++ = DeltaE++ plus Delta(ZPE)++ = 17.2 kcal/mol. The calculated free-energy barrier for the concerted mechanism is DeltaG++ = 19.5 kcal/mol, which is in excellent agreement with the value of 19.0 kcal/mol calculated from the experimental rate constant (3.8 +/- 0.2.min(-1)).

From peripheral to central: the role of ERK signaling pathway in acupuncture analgesia.

PubMed

Park, Ji-Yeun; Park, Jongbae J; Jeon, Songhee; Doo, Ah-Reum; Kim, Seung-Nam; Lee, Hyangsook; Chae, Younbyoung; Maixner, William; Lee, Hyejung; Park, Hi-Joon

2014-05-01

Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. We assume that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. To determine possible bio-candidates involved in the mechanisms of acupuncture and investigate the role of such bio-candidates in the analgesic effects of acupuncture, we conducted 2 stepwise experiments. First, a genome-wide microarray of the isolated skin layer at the GB34-equivalent acupoint of C57BL/6 mice 1 hour after acupuncture found that a total of 236 genes had changed and that extracellular signal-regulated kinase (ERK) activation was the most prominent bio-candidate. Second, in mouse pain models using formalin and complete Freund adjuvant, we found that acupuncture attenuated the nociceptive behavior and the mechanical allodynia; these effects were blocked when ERK cascade was interrupted by the mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) inhibitor U0126 (.8 μg/μL). Based on these results, we suggest that ERK phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia. This article presents the novel evidence of the local molecular signaling in acupuncture analgesia by demonstrating that ERK activation in the skin layer contributes to the analgesic effect of acupuncture in a mouse pain model. This work improves our understanding of the scientific basis underlying acupuncture analgesia. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Handheld Tissue Hardness Meters for Assessing the Mechanical Properties of Skeletal Muscle: A Feasibility Study.

PubMed

Chino, Kentaro; Takahashi, Hideyuki

2016-09-01

The purpose of this study was to examine the feasibility of using handheld tissue hardness meters to assess the mechanical properties of skeletal muscle. This observational study included 33 healthy men (age, 22.4 ± 4.4 years) and 33 healthy women (age, 23.7 ± 4.2 years). Participants were placed in a supine position, and tissue hardness overlying the rectus femoris and the shear modulus of the muscle were measured on the right side of the body at 50% thigh length. In the same position, subcutaneous adipose tissue thickness and muscle thickness were measured using B-mode ultrasonography. To examine the associations of subcutaneous adipose tissue thickness, muscle thickness, and muscle shear modulus with tissue hardness, linear regression using a stepwise bidirectional elimination approach was performed. Stepwise linear regression revealed that subcutaneous adipose tissue thickness (r = -0.38, P = .002) and muscle shear modulus (r = 0.27, P = .03) were significantly associated with tissue hardness. Significant associations among adipose tissue thickness, muscle shear modulus, and tissue hardness show the limitations and feasibility of handheld tissue hardness meters for assessing the mechanical properties of skeletal muscles. Copyright © 2016. Published by Elsevier Inc.

Self-Concept and Participation in School Activities Reanalyzed.

ERIC Educational Resources Information Center

Winne, Philip H.; Walsh, John

1980-01-01

Yarworth and Gauthier (EJ 189 606) examined whether self-concept variables enhanced predictions about students' participation in school activities, using unstructured stepwise regression techniques. A reanalysis of their data using hierarchial regression models tested their hypothesis more appropriately, and uncovered multicollinearity and…

Isolation and characterization of Chinese standard fulvic acid sub-fractions separated from forest soil by stepwise elution with pyrophosphate buffer.

PubMed

Bai, Yingchen; Wu, Fengchang; Xing, Baoshan; Meng, Wei; Shi, Guolan; Ma, Yan; Giesy, John P

2015-03-04

XAD-8 adsorption technique coupled with stepwise elution using pyrophosphate buffers with initial pH values of 3, 5, 7, 9, and 13 was developed to isolate Chinese standard fulvic acid (FA) and then separated the FA into five sub-fractions: FApH3, FApH5, FApH7, FApH9 and FApH13, respectively. Mass percentages of FApH3-FApH13 decreased from 42% to 2.5%, and the recovery ratios ranged from 99.0% to 99.5%. Earlier eluting sub-fractions contained greater proportions of carboxylic groups with greater polarity and molecular mass, and later eluting sub-fractions had greater phenolic and aliphatic content. Protein-like components, as well as amorphous and crystalline poly(methylene)-containing components were enriched using neutral and basic buffers. Three main mechanisms likely affect stepwise elution of humic components from XAD-8 resin with pyrophosphate buffers including: 1) the carboxylic-rich sub-fractions are deprotonated at lower pH values and eluted earlier, while phenolic-rich sub-fractions are deprotonated at greater pH values and eluted later. 2) protein or protein-like components can be desorbed and eluted by use of stepwise elution as progressively greater pH values exceed their isoelectric points. 3) size exclusion affects elution of FA sub-fractions. Successful isolation of FA sub-fractions will benefit exploration of the origin, structure, evolution and the investigation of interactions with environmental contaminants.

Isolation and Characterization of Chinese Standard Fulvic Acid Sub-fractions Separated from Forest Soil by Stepwise Elution with Pyrophosphate Buffer

PubMed Central

Bai, Yingchen; Wu, Fengchang; Xing, Baoshan; Meng, Wei; Shi, Guolan; Ma, Yan; Giesy, John P.

2015-01-01

XAD-8 adsorption technique coupled with stepwise elution using pyrophosphate buffers with initial pH values of 3, 5, 7, 9, and 13 was developed to isolate Chinese standard fulvic acid (FA) and then separated the FA into five sub-fractions: FApH3, FApH5, FApH7, FApH9 and FApH13, respectively. Mass percentages of FApH3-FApH13 decreased from 42% to 2.5%, and the recovery ratios ranged from 99.0% to 99.5%. Earlier eluting sub-fractions contained greater proportions of carboxylic groups with greater polarity and molecular mass, and later eluting sub-fractions had greater phenolic and aliphatic content. Protein-like components, as well as amorphous and crystalline poly(methylene)-containing components were enriched using neutral and basic buffers. Three main mechanisms likely affect stepwise elution of humic components from XAD-8 resin with pyrophosphate buffers including: 1) the carboxylic-rich sub-fractions are deprotonated at lower pH values and eluted earlier, while phenolic-rich sub-fractions are deprotonated at greater pH values and eluted later. 2) protein or protein-like components can be desorbed and eluted by use of stepwise elution as progressively greater pH values exceed their isoelectric points. 3) size exclusion affects elution of FA sub-fractions. Successful isolation of FA sub-fractions will benefit exploration of the origin, structure, evolution and the investigation of interactions with environmental contaminants. PMID:25735451

Ensemble cryo-EM elucidates the mechanism of translation fidelity

PubMed Central

Loveland, Anna B.; Demo, Gabriel; Grigorieff, Nikolaus; Korostelev, Andrei A.

2017-01-01

SUMMARY Faithful gene translation depends on accurate decoding, whose structural mechanism remains a matter of debate. Ribosomes decode mRNA codons by selecting cognate aminoacyl-tRNAs delivered by EF-Tu. We present high-resolution structural ensembles of ribosomes with cognate or near-cognate aminoacyl-tRNAs delivered by EF-Tu. Both cognate and near-cognate tRNA anticodons explore the A site of an open 30S subunit, while inactive EF-Tu is separated from the 50S subunit. A transient conformation of decoding-center nucleotide G530 stabilizes the cognate codon-anticodon helix, initiating step-wise “latching” of the decoding center. The resulting 30S domain closure docks EF-Tu at the sarcin-ricin loop of the 50S subunit, activating EF-Tu for GTP hydrolysis and ensuing aminoacyl-tRNA accommodation. By contrast, near-cognate complexes fail to induce the G530 latch, thus favoring open 30S pre-accommodation intermediates with inactive EF-Tu. This work unveils long-sought structural differences between the pre-accommodation of cognate and near-cognate tRNA that elucidate the mechanism of accurate decoding. PMID:28538735

Cooling-induced contraction in ovine airways smooth muscle.

PubMed

Mustafa, S M; Pilcher, C W; Williams, K I

1999-02-01

The mechanism of cold-induced bronchoconstriction is poorly understood. This prompted the present study whose aim was to determine the step-wise direct effect of cooling on smooth muscle of isolated ovine airways and analyse the role of calcium in the mechanisms involved. Isolated tracheal strips and bronchial segments were suspended in organ baths containing Krebs' solution for isometric tension recording. Tissue responses during stepwise cooling from 37 to 5 degrees C were examined. Cooling induced a rapid and reproducible contraction proportional to cooling temperature in ovine tracheal and bronchial preparations which was epithelium-independent. On readjustment to 37 degrees C the tone returned rapidly to basal level. Maximum contraction was achieved at a temperature of 5 degrees C for trachea and 15 degrees C for bronchiole. Cooling-induced contractions (CIC) was resistant to tetrodotoxin (1; 10 micrometer), and not affected by the muscarinic antagonist atropine (1 micrometer) or the alpha-adrenergic antagonist phentolamine (1 micrometer), or the histamine H1-antagonist mepyramine (1 micrometer) or indomethacin (1 micrometer). Ca2+ antagonists (nifedipine and verapamil) and Mn2+ raised tracheal but not bronchiolar tone and augmented CIC. Incubation in Ca2+-free, EGTA-containing Krebs' solution for 5 min had no effect on CIC, although it significantly reduced KCl-induced contraction by up to 75%. Cooling inhibited Ca2+ influx measured using 45Ca2+ uptake. Caffeine (100 micrometer) significantly inhibited CIC. The results show that cooling-induced contractions do not appear to involve activation of nerve endings, all surface reception systems or Ca2+ influx. However, CIC is mainly dependent on release of intracellular Ca2+. Copyright 1999 The Italian Pharmacological Society.

Stereoselective Degradation and Molecular Ecological Mechanism of Chiral Pesticides Beta-Cypermethrin in Soils with Different pH Values.

PubMed

Yang, Zhong-Hua; Ji, Guo-Dong

2015-12-15

For decades, pesticides have been widely used for agricultural activities around the world, and the environmental problems caused by these compounds have raised widespread concern. However, the different enantioselective behaviors of chiral pesticide enantiomers are often ignored. Here, the selective degradation patterns and mechanisms of chiral pesticide enantiomers were successfully investigated for the first time in the soils of three cultivation areas with different pH values. Beta-cypermethrin was chosen as the target analyte. We found that the degradation rates of the four isomers of beta-cypermethrin were different. We used stepwise regression equations between degradation rates and functional genes to quantitatively study their relationships. Quantitative response analysis revealed that different isomers have different equations even under identical conditions. The results of path analysis showed that a single functional gene can make different direct and indirect contributions to the degradation of different isomers. Finally, the high-throughput technology was used to analysis the genome of the three tested soils and then compared the main microbial communities in them. We have successfully devised a method to investigate the molecular biological mechanisms of the selective degradation behavior of chiral compounds, thus enabling us to better understand these mechanisms.

[Age-related dynamics of the maximum oxygen consumption associated with different regimens of locomotor activity].

PubMed

Miakotnykh, V V; Khodasevich, L S; Ermakov, B A

2011-01-01

This study included a total of 234 practically healthy men at the age from 40 to 69 years differing in the regimen of daily locomotor activity. They were divided into 4 groups, each comprised of subjects ranged by age with a ten-year interval. Group 1 included former high-level athletes continuing active physical training, group 2 was comprised of former high-level athletes living a sedentary life style, group 3 consisted of subjects regularly engaged in health-giving physical exercises, and group 4 included subjects who were never engaged in physical exercises. The energy consumption by the members of all four groups was estimated when they were undergoing a stepwise increasing workload on the veloergometer measured with the help of a computerized diagnostic system. The results of the study indicate that the high oxygen consumption at a limiting load in the former high-level athletes is associated with the significant economization of basal metabolism and the reduction of oxygen consumption at rest. This mechanism accounts for the possibility to retain adequate physical activity of the organism up to the age of 70 years.

Development of an in vitro culture method for stepwise differentiation of mouse embryonic stem cells and induced pluripotent stem cells into mature osteoclasts.

PubMed

Nishikawa, Keizo; Iwamoto, Yoriko; Ishii, Masaru

2014-05-01

The development of methods for differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cell (iPSCs) into functional cells have helped to analyze the mechanism regulating cellular processes and to explore cell-based assays for drug discovery. Although several reports have demonstrated methods for differentiation of mouse ESCs into osteoclast-like cells, it remains unclear whether these methods are applicable for differentiation of iPSCs to osteoclasts. In this study, we developed a simple method for stepwise differentiation of mouse ESCs and iPSCs into bone-resorbing osteoclasts based upon a monoculture approach consisting of three steps. First, based on conventional hanging-drop methods, embryoid bodies (EBs) were produced from mouse ESCs or iPSCs. Second, EBs were cultured in medium supplemented with macrophage colony-stimulating factor (M-CSF), and differentiated to osteoclast precursors, which expressed CD11b. Finally, ESC- or iPSC-derived osteoclast precursors stimulated with receptor activator of nuclear factor-B ligand (RANKL) and M-CSF formed large multinucleated osteoclast-like cells that expressed tartrate-resistant acid phosphatase and were capable of bone resorption. Molecular analysis showed that the expression of osteoclast marker genes such as Nfatc1, Ctsk, and Acp5 are increased in a RANKL-dependent manner. Thus, our procedure is simple and easy and would be helpful for stem cell-based bone research.

Stabilization of Two Radicals with One Metal: A Stepwise Coupling Model for Copper-Catalyzed Radical–Radical Cross-Coupling

PubMed Central

Qi, Xiaotian; Zhu, Lei; Bai, Ruopeng; Lan, Yu

2017-01-01

Transition metal-catalyzed radical–radical cross-coupling reactions provide innovative methods for C–C and C–heteroatom bond construction. A theoretical study was performed to reveal the mechanism and selectivity of the copper-catalyzed C–N radical–radical cross-coupling reaction. The concerted coupling pathway, in which a C–N bond is formed through the direct nucleophilic addition of a carbon radical to the nitrogen atom of the Cu(II)–N species, is demonstrated to be kinetically unfavorable. The stepwise coupling pathway, which involves the combination of a carbon radical with a Cu(II)–N species before C–N bond formation, is shown to be probable. Both the Mulliken atomic spin density distribution and frontier molecular orbital analysis on the Cu(II)–N intermediate show that the Cu site is more reactive than that of N; thus, the carbon radical preferentially react with the metal center. The chemoselectivity of the cross-coupling is also explained by the differences in electron compatibility of the carbon radical, the nitrogen radical and the Cu(II)–N intermediate. The higher activation free energy for N–N radical–radical homo-coupling is attributed to the mismatch of Cu(II)–N species with the nitrogen radical because the electrophilicity for both is strong. PMID:28272407

Influence of probe pressure on diffuse reflectance spectra of human skin measured in vivo

NASA Astrophysics Data System (ADS)

Popov, Alexey P.; Bykov, Alexander V.; Meglinski, Igor V.

2017-11-01

Mechanical pressure superficially applied on the human skin surface by a fiber-optic probe influences the spatial distribution of blood within the cutaneous tissues. Upon gradual load of weight on the probe, a stepwise increase in the skin reflectance spectra is observed. The decrease in the load follows the similar inverse staircase-like tendency. The observed stepwise reflectance spectra changes are due to, respectively, sequential extrusion of blood from the topical cutaneous vascular beds and their filling afterward. The obtained results are confirmed by Monte Carlo modeling. This implies that pressure-induced influence during the human skin diffuse reflectance spectra measurements in vivo should be taken into consideration, in particular, in the rapidly developing area of wearable gadgets for real-time monitoring of various human body parameters.

Runaway electron generation as possible trigger for enhancement of magnetohydrodynamic plasma activity and fast changes in runaway beam behavior

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pankratov, I. M., E-mail: pankratov@kipt.kharkov.ua, E-mail: rjzhou@ipp.ac.cn; Zhou, R. J., E-mail: pankratov@kipt.kharkov.ua, E-mail: rjzhou@ipp.ac.cn; Hu, L. Q.

2015-07-15

Peculiar phenomena were observed during experiments with runaway electrons: rapid changes in the synchrotron spot and its intensity that coincided with stepwise increases in the electron cyclotron emission (ECE) signal (cyclotron radiation of suprathermal electrons). These phenomena were initially observed in TEXTOR (Tokamak Experiment for Technology Oriented Research), where these events only occurred in the current decay phase or in discharges with thin stable runaway beams at a q = 1 drift surface. These rapid changes in the synchrotron spot were interpreted by the TEXTOR team as a fast pitch angle scattering event. Recently, similar rapid changes in the synchrotron spot andmore » its intensity that coincided with stepwise increases in the non-thermal ECE signal were observed in the EAST (Experimental Advanced Superconducting Tokamak) runaway discharge. Runaway electrons were located around the q = 2 rational magnetic surface (ring-like runaway electron beam). During the EAST runaway discharge, stepwise ECE signal increases coincided with enhanced magnetohydrodynamic (MHD) activity. This behavior was peculiar to this shot. In this paper, we show that these non-thermal ECE step-like jumps were related to the abrupt growth of suprathermal electrons induced by bursting electric fields at reconnection events during this MHD plasma activity. Enhancement of the secondary runaway electron generation also occurred simultaneously. Local changes in the current-density gradient appeared because of local enhancement of the runaway electron generation process. These current-density gradient changes are considered to be a possible trigger for enhancement of the MHD plasma activity and the rapid changes in runaway beam behavior.« less

Runaway electron generation as possible trigger for enhancement of magnetohydrodynamic plasma activity and fast changes in runaway beam behavior

NASA Astrophysics Data System (ADS)

Pankratov, I. M.; Zhou, R. J.; Hu, L. Q.

2015-07-01

Peculiar phenomena were observed during experiments with runaway electrons: rapid changes in the synchrotron spot and its intensity that coincided with stepwise increases in the electron cyclotron emission (ECE) signal (cyclotron radiation of suprathermal electrons). These phenomena were initially observed in TEXTOR (Tokamak Experiment for Technology Oriented Research), where these events only occurred in the current decay phase or in discharges with thin stable runaway beams at a q = 1 drift surface. These rapid changes in the synchrotron spot were interpreted by the TEXTOR team as a fast pitch angle scattering event. Recently, similar rapid changes in the synchrotron spot and its intensity that coincided with stepwise increases in the non-thermal ECE signal were observed in the EAST (Experimental Advanced Superconducting Tokamak) runaway discharge. Runaway electrons were located around the q = 2 rational magnetic surface (ring-like runaway electron beam). During the EAST runaway discharge, stepwise ECE signal increases coincided with enhanced magnetohydrodynamic (MHD) activity. This behavior was peculiar to this shot. In this paper, we show that these non-thermal ECE step-like jumps were related to the abrupt growth of suprathermal electrons induced by bursting electric fields at reconnection events during this MHD plasma activity. Enhancement of the secondary runaway electron generation also occurred simultaneously. Local changes in the current-density gradient appeared because of local enhancement of the runaway electron generation process. These current-density gradient changes are considered to be a possible trigger for enhancement of the MHD plasma activity and the rapid changes in runaway beam behavior.

Observing cellulose biosynthesis and membrane translocation in crystallo

PubMed Central

Morgan, Jacob L.W.; McNamara, Joshua T.; Fischer, Michael; Rich, Jamie; Chen, Hong-Ming; Withers, Stephen G.; Zimmer, Jochen

2016-01-01

Many biopolymers, including polysaccharides, must be translocated across at least one membrane to reach their site of biological function. Cellulose is a linear glucose polymer synthesized and secreted by a membrane-integrated cellulose synthase. In crystallo enzymology with the catalytically-active bacterial cellulose synthase BcsA-B complex reveals structural snapshots of a complete cellulose biosynthesis cycle, from substrate binding to polymer translocation. Substrate and product-bound structures of BcsA provide the basis for substrate recognition and demonstrate the stepwise elongation of cellulose. Furthermore, the structural snapshots show that BcsA translocates cellulose via a ratcheting mechanism involving a “finger helix” that contacts the polymer's terminal glucose. Cooperating with BcsA's gating loop, the finger helix moves ‘up’ and ‘down’ in response to substrate binding and polymer elongation, respectively, thereby pushing the elongated polymer into BcsA’s transmembrane channel. This mechanism is validated experimentally by tethering BcsA's finger helix, which inhibits polymer translocation but not elongation. PMID:26958837

Graphene Nanopores for Protein Sequencing.

PubMed

Wilson, James; Sloman, Leila; He, Zhiren; Aksimentiev, Aleksei

2016-07-19

An inexpensive, reliable method for protein sequencing is essential to unraveling the biological mechanisms governing cellular behavior and disease. Current protein sequencing methods suffer from limitations associated with the size of proteins that can be sequenced, the time, and the cost of the sequencing procedures. Here, we report the results of all-atom molecular dynamics simulations that investigated the feasibility of using graphene nanopores for protein sequencing. We focus our study on the biologically significant phenylalanine-glycine repeat peptides (FG-nups)-parts of the nuclear pore transport machinery. Surprisingly, we found FG-nups to behave similarly to single stranded DNA: the peptides adhere to graphene and exhibit step-wise translocation when subject to a transmembrane bias or a hydrostatic pressure gradient. Reducing the peptide's charge density or increasing the peptide's hydrophobicity was found to decrease the translocation speed. Yet, unidirectional and stepwise translocation driven by a transmembrane bias was observed even when the ratio of charged to hydrophobic amino acids was as low as 1:8. The nanopore transport of the peptides was found to produce stepwise modulations of the nanopore ionic current correlated with the type of amino acids present in the nanopore, suggesting that protein sequencing by measuring ionic current blockades may be possible.

Ruthenium(II) Complexes Containing Lutidine-Derived Pincer CNC Ligands: Synthesis, Structure, and Catalytic Hydrogenation of C-N bonds.

PubMed

Hernández-Juárez, Martín; López-Serrano, Joaquín; Lara, Patricia; Morales-Cerón, Judith P; Vaquero, Mónica; Álvarez, Eleuterio; Salazar, Verónica; Suárez, Andrés

2015-05-11

A series of Ru complexes containing lutidine-derived pincer CNC ligands have been prepared by transmetalation with the corresponding silver-carbene derivatives. Characterization of these derivatives shows both mer and fac coordination of the CNC ligands depending on the wingtips of the N-heterocyclic carbene fragments. In the presence of tBuOK, the Ru-CNC complexes are active in the hydrogenation of a series of imines. In addition, these complexes catalyze the reversible hydrogenation of phenantridine. Detailed NMR spectroscopic studies have shown the capability of the CNC ligand to be deprotonated and get involved in ligand-assisted activation of dihydrogen. More interestingly, upon deprotonation, the Ru-CNC complex 5 e(BF4 ) is able to add aldimines to the metal-ligand framework to yield an amido complex. Finally, investigation of the mechanism of the hydrogenation of imines has been carried out by means of DFT calculations. The calculated mechanism involves outer-sphere stepwise hydrogen transfer to the C-N bond assisted either by the pincer ligand or a second coordinated H2 molecule. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Elevated STAT3 Signaling-Mediated Upregulation of MMP-2/9 Confers Enhanced Invasion Ability in Multidrug-Resistant Breast Cancer Cells

PubMed Central

Zhang, Fei; Wang, Zhiyong; Fan, Yanling; Xu, Qiao; Ji, Wei; Tian, Ran; Niu, Ruifang

2015-01-01

The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling pathways during development of drug resistance may increase invasive potential of multidrug-resistant (MDR) cancer cells. However, the accurate mechanism of this process is largely undefined. In this study, to better understand the associated molecular pathways responsible for cancer progression induced by drug resistance, a MDR human breast cancer cell line SK-BR-3/EPR with P-glycoprotein overexpression was established using stepwise long-term exposure to increasing concentration of epirubicin. The SK-BR-3/EPR cell line exhibited decreased cell proliferative activity, but enhanced cell invasive capacity. We showed that the expression of metastasis-related matrix metalloproteinase (MMP)-2/9 was elevated in SK-BR-3/EPR cells. Moreover, SK-BR-3/EPR cells showed elevated activation of STAT3. Activation of STAT3 signaling is responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of MMP-2/9. STAT3 is a well-known oncogene and is frequently implicated in tumorigenesis and chemotherapeutic resistance. Our findings augment insight into the mechanism underlying the functional association between MDR and cancer invasiveness. PMID:26501276

Stepwise oxygenations of toluene and 4-nitrotoluene by a fungal peroxygenase

Treesearch

Matthias Kinne; Christian Zeisig; Rene Ullrich; Gernot Kayser; Kenneth E. Hammel; Martin Hofrichter

2010-01-01

Fungal peroxygenases have recently been shown to catalyze remarkable oxidation reactions. The present study addresses the mechanism of benzylic oxygenations catalyzed by the extracellular peroxygenase of the argic basidiomycete Agrocybe aegerita. The peroxygenase oxidized toluene and 4-nitrotoluene via the corresponding alcohols and aldehydes to give benzoic acids. The...

Electromagnetically Operated Counter

DOEpatents

Goldberg, H D; Goldberg, M I

1951-12-18

An electromagnetically operated counter wherein signals to be counted are applied to cause stepwise rotation of a rotatable element which is connected to a suitable register. The mechanism involved consists of a rotatable armature having three spaced cores of magnetic material and a pair of diametrically opposed electromagnets with a suitable pulsing circuit to actuate the magnets.

The step-wise pathway of septin hetero-octamer assembly in budding yeast.

PubMed

Weems, Andrew; McMurray, Michael

2017-05-25

Septin proteins bind guanine nucleotides and form rod-shaped hetero-oligomers. Cells choose from a variety of available septins to assemble distinct hetero-oligomers, but the underlying mechanism was unknown. Using a new in vivo assay, we find that a stepwise assembly pathway produces the two species of budding yeast septin hetero-octamers: Cdc11/Shs1-Cdc12-Cdc3-Cdc10-Cdc10-Cdc3-Cdc12-Cdc11/Shs1. Rapid GTP hydrolysis by monomeric Cdc10 drives assembly of the core Cdc10 homodimer. The extended Cdc3 N terminus autoinhibits Cdc3 association with Cdc10 homodimers until prior Cdc3-Cdc12 interaction. Slow hydrolysis by monomeric Cdc12 and specific affinity of Cdc11 for transient Cdc12•GTP drive assembly of distinct trimers, Cdc11-Cdc12-Cdc3 or Shs1-Cdc12-Cdc3. Decreasing the cytosolic GTP:GDP ratio increases the incorporation of Shs1 vs Cdc11, which alters the curvature of filamentous septin rings. Our findings explain how GTP hydrolysis controls septin assembly, and uncover mechanisms by which cells construct defined septin complexes.

Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing

NASA Astrophysics Data System (ADS)

Wülfing, Christoph; Purtic, Bozidar; Klem, Jennifer; Schatzle, John D.

2003-06-01

Cytolytic killing is a major effector mechanism in the elimination of virally infected and tumor cells. The innate cytolytic effectors, natural killer (NK) cells, and the adaptive effectors, cytotoxic T cells (CTL), despite differential immune recognition, both use the same lytic mechanism, cytolytic granule release. Using live cell video fluorescence microscopy in various primary cell models of NK cell and CTL killing, we show here that on tight target cell contact, a majority of the NK cells established cytoskeletal polarity required for effective lytic function slowly or incompletely. In contrast, CTLs established cytoskeletal polarity rapidly. In addition, NK cell killing was uniquely sensitive to minor interference with cytoskeletal dynamics. We propose that the stepwise NK cell cytoskeletal polarization constitutes a series of checkpoints in NK cell killing. In addition, the use of more deliberate progression to effector function to compensate for inferior immune recognition specificity provides a mechanistic explanation for how the same effector function can be used in the different functional contexts of the innate and adaptive immune response.

Reaction mechanism of guanidinoacetate methyltransferase, concerted or step-wise

PubMed Central

Zhang, Xiaodong; Bruice, Thomas C.

2006-01-01

We describe a quantum mechanics/molecular mechanics investigation of the guanidinoacetate methyltransferase catalyzed reaction, which shows that proton transfer from guanidinoacetate (GAA) to Asp-134 and methyl transfer from S-adenosyl-l-methionine (AdoMet) to GAA are concerted. By self-consistent-charge density functional tight binding/molecular mechanics, the bond lengths in the concerted mechanism's transition state are 1.26 Å for both the OD1 (Asp-134)–HE (GAA) and HE (GAA)–NE (GAA) bonds, and 2.47 and 2.03 Å for the S8 (AdoMet)–C9 (AdoMet) and C9 (AdoMet)–NE (GAA) bonds, respectively. The potential-energy barrier (ΔE‡) determined by single-point B3LYP/6–31+G*//MM is 18.9 kcal/mol. The contributions of the entropy (−TΔS‡) and zero-point energy corrections Δ(ZPE)‡ by normal mode analysis are 2.3 kcal/mol and −1.7 kcal/mol, respectively. Thus, the activation enthalpy of this concerted mechanism is predicted to be ΔH‡ = ΔE‡ + Δ(ZPE)‡ = 17.2 kcal/mol. The calculated free-energy barrier for the concerted mechanism is ΔG‡ = 19.5 kcal/mol, which is in excellent agreement with the value of 19.0 kcal/mol calculated from the experimental rate constant (3.8 ± 0.2·min−1). PMID:17053070

The Alkaline Hydrolysis of Sulfonate Esters: Challenges in Interpreting Experimental and Theoretical Data

PubMed Central

2013-01-01

Sulfonate ester hydrolysis has been the subject of recent debate, with experimental evidence interpreted in terms of both stepwise and concerted mechanisms. In particular, a recent study of the alkaline hydrolysis of a series of benzene arylsulfonates (Babtie et al., Org. Biomol. Chem.10, 2012, 8095) presented a nonlinear Brønsted plot, which was explained in terms of a change from a stepwise mechanism involving a pentavalent intermediate for poorer leaving groups to a fully concerted mechanism for good leaving groups and supported by a theoretical study. In the present work, we have performed a detailed computational study of the hydrolysis of these compounds and find no computational evidence for a thermodynamically stable intermediate for any of these compounds. Additionally, we have extended the experimental data to include pyridine-3-yl benzene sulfonate and its N-oxide and N-methylpyridinium derivatives. Inclusion of these compounds converts the Brønsted plot to a moderately scattered but linear correlation and gives a very good Hammett correlation. These data suggest a concerted pathway for this reaction that proceeds via an early transition state with little bond cleavage to the leaving group, highlighting the care that needs to be taken with the interpretation of experimental and especially theoretical data. PMID:24279349

Quantitative analysis of the thermal requirements for stepwise physical dormancy-break in seeds of the winter annual Geranium carolinianum (Geraniaceae)

PubMed Central

Gama-Arachchige, N. S.; Baskin, J. M.; Geneve, R. L.; Baskin, C. C.

2013-01-01

Background and Aims Physical dormancy (PY)-break in some annual plant species is a two-step process controlled by two different temperature and/or moisture regimes. The thermal time model has been used to quantify PY-break in several species of Fabaceae, but not to describe stepwise PY-break. The primary aims of this study were to quantify the thermal requirement for sensitivity induction by developing a thermal time model and to propose a mechanism for stepwise PY-breaking in the winter annual Geranium carolinianum. Methods Seeds of G. carolinianum were stored under dry conditions at different constant and alternating temperatures to induce sensitivity (step I). Sensitivity induction was analysed based on the thermal time approach using the Gompertz function. The effect of temperature on step II was studied by incubating sensitive seeds at low temperatures. Scanning electron microscopy, penetrometer techniques, and different humidity levels and temperatures were used to explain the mechanism of stepwise PY-break. Key Results The base temperature (Tb) for sensitivity induction was 17·2 °C and constant for all seed fractions of the population. Thermal time for sensitivity induction during step I in the PY-breaking process agreed with the three-parameter Gompertz model. Step II (PY-break) did not agree with the thermal time concept. Q10 values for the rate of sensitivity induction and PY-break were between 2·0 and 3·5 and between 0·02 and 0·1, respectively. The force required to separate the water gap palisade layer from the sub-palisade layer was significantly reduced after sensitivity induction. Conclusions Step I and step II in PY-breaking of G. carolinianum are controlled by chemical and physical processes, respectively. This study indicates the feasibility of applying the developed thermal time model to predict or manipulate sensitivity induction in seeds with two-step PY-breaking processes. The model is the first and most detailed one yet developed for sensitivity induction in PY-break. PMID:23456728

Mechanism of quinolone resistance in anaerobic bacteria.

PubMed

Oh, H; Edlund, C

2003-06-01

Several recently developed quinolones have excellent activity against a broad range of aerobic and anaerobic bacteria and are thus potential drugs for the treatment of serious anaerobic and mixed infections. Resistance to quinolones is increasing worldwide, but is still relatively infrequent among anaerobes. Two main mechanisms, alteration of target enzymes (gyrase and topoisomerase IV) caused by chromosomal mutations in encoding genes, or reduced intracellular accumulation due to increased efflux of the drug, are associated with quinolone resistance. These mechanisms have also been found in anaerobic species. High-level resistance to the newer broad-spectrum quinolones often requires stepwise mutations in target genes. The increasing emergence of resistance among anaerobes may be a consequence of previous widespread use of quinolones, which may have enriched first-step mutants in the intestinal tract. Quinolone resistance in the Bacteroides fragilis group strains is strongly correlated with amino acid substitutions at positions 82 and 86 in GyrA (equivalent to positions 83 and 87 of Escherichia coli). Several studies have indicated that B. fragilis group strains possess efflux pump systems that actively expel quinolones, leading to resistance. DNA gyrase seems also to be the primary target for quinolones in Clostridium difficile, since amino acid substitutions in GyrA and GyrB have been detected in resistant strains. To what extent other mechanisms, such as mutational events in other target genes or alterations in outer-membrane proteins, contribute to resistance among anaerobes needs to be further investigated.

Slow Starter Enzymes: Role of Active Site Architecture in the Catalytic Control in the Biosynthesis of Taxadiene by Taxadiene Synthase.

PubMed

Ansbacher, Tamar; Freud, Yehoshua; Major, Dan Thomas

2018-05-23

Taxadiene synthase (TXS) catalyzes the formation of the natural product Taxa-4(5),11(12)-diene (henceforth Taxadiene). Taxadiene is the precursor in the formation of Taxol, which is an important natural anti-cancer agent. In the current study, we present a detailed mechanistic view of the biosynthesis of Taxadiene by TXS, using a hybrid quantum mechanics-molecular mechanics potential in conjunction with free energy simulation methods. The obtained free energy landscape displays initial endergonic steps followed by a step-wise downhill profile, which is an emerging free energy fingerprint for type I terpene synthases. We identify an active site Trp residue (W753) as a key feature of the TXS active site architecture and propose that this residue stabilized intermediate cations via -cation interactions. To validate our proposed active TXS model, we examine a previously reported W753H mutation, which leads to exclusive formation of the side product, cembrene A. The simulations of the W753H mutant show that in the mutant structure, the His side-chain is in perfect position to deprotonate the cembrenyl cation en route to cembrene formation, and that this abortive deprotonation is an energetically facile process. Based on the current model, we propose that an analogous mutation of Y841 to His could possibly lead to verticillane. The current simulations stress the importance of precise positioning of key active site residues in stabilizing intermediate carbocations. In view of the great pharmaceutical importance of taxadiene, a detailed understanding of the TXS mechanism can provide important clues towards a synthetic strategy for taxol manufacturing.

Mechanisms of the Knoevenagel hetero Diels-Alder sequence in multicomponent reactions to dihydropyrans: experimental and theoretical investigations into the role of water.

PubMed

Frapper, Gilles; Bachmann, Christian; Gu, Yanlong; Coval De Sousa, Rodolphe; Jérôme, François

2011-01-14

The role of water in a multicomponent domino reaction (MCR) involving styrene, 2,4-pentanedione, and formaldehyde was studied. Whereas anhydrous conditions produced no reaction, the MCR successfully proceeded in the presence of water, affording the targeted dihydropyran derivatives with good yield. The mechanism of this MCR (Knoevenagel hetero Diels-Alder sequence) was studied with and without explicit water molecules using the SMD continuum solvation model in combination with the B3LYP density functional and the 6-311++G** basis set to compute the water and acetone (aprotic organic solvent) solution Gibbs free energies. In the Knoevenagel step, we found that water acted as a proton relay to favor the formation of more flexible six-membered ring transition state structures both in concerted (direct H(2)O elimination) and stepwise (keto-enol tautomerization and dehydration) pathways. The inclusion of a water molecule in our model resulted in a significant decrease (-8.5 kcal mol(-1)ΔG(water)(‡)) of the direct water elimination activation barrier. Owing to the presence of water, all chemical steps involved in the MCR mechanism had activation free energies barriers lower than 39 kcal mol(-1) at 25 °C in aqueous solvent (<21 kcal mol(-1) ZPE corrected electronic energies barriers). Consequently, the MCR proceeded without the assistance of any catalyst.

Teaching the Absorption of Light Colours Using an Artificial Rainbow

ERIC Educational Resources Information Center

Yurumezoglu, Kemal; Isik, Hakan; Arikan, Gizem; Kabay, Gozde

2015-01-01

This paper presents an experimental activity based on the absorption of light colours by pigments. The activity is constructed using a stepwise design and offers an opportunity for students and teachers to compare and generalize the interactions between light and pigment colours. The light colours composing an artificial rainbow produced in the…

Scholarly Networking among Business Students: Structured Discussion Board Activity and Academic Outcomes

ERIC Educational Resources Information Center

Walker, Kristen; Curren, Mary T.; Kiesler, Tina; Lammers, H. Bruce; Goldenson, Jamie

2013-01-01

The authors' intent was to show the effect of student discussion board activity on academic outcomes, after accounting for past academic performance. Data were collected from 516 students enrolled in a junior-level required business course. Controlling for students' grade point average, stepwise regression showed a significant…

Stepwise Splitting Growth and Pseudocapacitive Properties of Hierarchical Three-Dimensional Co3O4 Nanobooks

PubMed Central

Chen, Huilong; Lu, Shuang; Gong, Feilong; Liu, Huanzhen; Li, Feng

2017-01-01

Three-dimensional hierarchical Co3O4 nanobooks have been synthesized successfully on a large scale by calcining orthorhombic Co(CO3)0.5(OH)·0.11H2O precursors with identical morphologies. Based on the influence of reaction time and urea concentration on the nanostructures of the precursors, a stepwise splitting growth mechanism can be proposed to understand the formation of the 3D nanobooks. The 3D Co3O4 nanobooks exhibit excellent pseudocapacitive performances with specific capacitances of 590, 539, 476, 453, and 421 F/g at current densities of 0.5, 1, 2, 4, and 8 A/g, respectively. The devices can retain ca. 97.4% of the original specific capacitances after undergoing charge–discharge cycle tests 1000 times continuously at 4 A/g. PMID:28394297

Development and implementation of the Caribbean Laboratory Quality Management Systems Stepwise Improvement Process (LQMS-SIP) Towards Accreditation.

PubMed

Alemnji, George; Edghill, Lisa; Guevara, Giselle; Wallace-Sankarsingh, Sacha; Albalak, Rachel; Cognat, Sebastien; Nkengasong, John; Gabastou, Jean-Marc

2017-01-01

Implementing quality management systems and accrediting laboratories in the Caribbean has been a challenge. We report the development of a stepwise process for quality systems improvement in the Caribbean Region. The Caribbean Laboratory Stakeholders met under a joint Pan American Health Organization/US Centers for Disease Control and Prevention initiative and developed a user-friendly framework called 'Laboratory Quality Management System - Stepwise Improvement Process (LQMS-SIP) Towards Accreditation' to support countries in strengthening laboratory services through a stepwise approach toward fulfilling the ISO 15189: 2012 requirements. This approach consists of a three-tiered framework. Tier 1 represents the minimum requirements corresponding to the mandatory criteria for obtaining a licence from the Ministry of Health of the participating country. The next two tiers are quality improvement milestones that are achieved through the implementation of specific quality management system requirements. Laboratories that meet the requirements of the three tiers will be encouraged to apply for accreditation. The Caribbean Regional Organisation for Standards and Quality hosts the LQMS-SIP Secretariat and will work with countries, including the Ministry of Health and stakeholders, including laboratory staff, to coordinate and implement LQMS-SIP activities. The Caribbean Public Health Agency will coordinate and advocate for the LQMS-SIP implementation. This article presents the Caribbean LQMS-SIP framework and describes how it will be implemented among various countries in the region to achieve quality improvement.

Stepwise pumping approach to improve free phase light hydrocarbon recovery from unconfined aquifers

NASA Astrophysics Data System (ADS)

Cooper, Grant S.; Peralta, Richard C.; Kaluarachchi, Jagath J.

1995-04-01

A stepwise, time-varying pumping approach is developed to improve free phase oil recovery of light non-aqueous phase liquids (LNAPL) from a homogeneous, unconfined aquifer. Stepwise pumping is used to contain the floating oil plume and obtain efficient free oil recovery. The graphical plots. The approach uses ARMOS ©, an areal two-dimensional multiphase flow, finite-element simulation model. Systematic simulations of free oil area changes to pumping rates are analyzed. Pumping rates are determined that achieve LNAPL plume containment at different times (i.e. 90, 180 and 360 days) for a planning period of 360 days. These pumping rates are used in reverse order as a stepwise (monotonically increasing) pumping strategy. This stepwise pumping strategy is analyzed further by performing additional simulations at different pumping rates for the last pumping period. The final stepwise pumping strategy is varied by factors of -25% and +30% to evaluate sensitivity in the free oil recovery process. Stepwise pumping is compared to steady pumping rates to determine the best free oil recovery strategy. Stepwise pumping is shown to improve oil recovery by increasing recoveredoil volume (11%) and decreasing residual oil (15%) when compared with traditional steady pumping strategies. The best stepwise pumping strategy recovers more free oil by reducing the amount of residual oil left in the system due to pumping drawdown. This stepwise pumping pproach can be used to enhance free oil recovery and provide for cost-effective design and management of LNAPL cleanup.

Kinome signaling through regulated protein-protein interactions in normal and cancer cells.

PubMed

Pawson, Tony; Kofler, Michael

2009-04-01

The flow of molecular information through normal and oncogenic signaling pathways frequently depends on protein phosphorylation, mediated by specific kinases, and the selective binding of the resulting phosphorylation sites to interaction domains present on downstream targets. This physical and functional interplay of catalytic and interaction domains can be clearly seen in cytoplasmic tyrosine kinases such as Src, Abl, Fes, and ZAP-70. Although the kinase and SH2 domains of these proteins possess similar intrinsic properties of phosphorylating tyrosine residues or binding phosphotyrosine sites, they also undergo intramolecular interactions when linked together, in a fashion that varies from protein to protein. These cooperative interactions can have diverse effects on substrate recognition and kinase activity, and provide a variety of mechanisms to link the stimulation of catalytic activity to substrate recognition. Taken together, these data have suggested how protein kinases, and the signaling pathways in which they are embedded, can evolve complex properties through the stepwise linkage of domains within single polypeptides or multi-protein assemblies.

Dispersion of speckle suppression efficiency for binary DOE structures: spectral domain and coherent matrix approaches.

PubMed

Lapchuk, Anatoliy; Prygun, Olexandr; Fu, Minglei; Le, Zichun; Xiong, Qiyuan; Kryuchyn, Andriy

2017-06-26

We present the first general theoretical description of speckle suppression efficiency based on an active diffractive optical element (DOE). The approach is based on spectral analysis of diffracted beams and a coherent matrix. Analytical formulae are obtained for the dispersion of speckle suppression efficiency using different DOE structures and different DOE activation methods. We show that a one-sided 2D DOE structure has smaller speckle suppression range than a two-sided 1D DOE structure. Both DOE structures have sufficient speckle suppression range to suppress low-order speckles in the entire visible range, but only the two-sided 1D DOE can suppress higher-order speckles. We also show that a linear shift 2D DOE in a laser projector with a large numerical aperture has higher effective speckle suppression efficiency than the method using switching or step-wise shift DOE structures. The generalized theoretical models elucidate the mechanism and practical realization of speckle suppression.

Be12O12 Nano-cage as a Promising Catalyst for CO2 Hydrogenation

PubMed Central

Zhu, Haiyan; Li, Yawei; Zhu, Guizhi; Su, Haibin; Chan, Siew Hwa; Sun, Qiang

2017-01-01

An efficient conversion of CO2 into valuable fuels and chemicals has been hotly pursued recently. Here, for the first time, we have explored a series of M12x12 nano-cages (M = B, Al, Be, Mg; X = N, P, O) for catalysis of CO2 to HCOOH. Two steps are identified in the hydrogenation process, namely, H2 activation to 2H*, and then 2H* transfer to CO2 forming HCOOH, where the barriers of two H* transfer are lower than that of the H2 activation reaction. Among the studied cages, Be12O12 is found to have the lowest barrier in the whole reaction process, showing two kinds of reaction mechanisms for 2H* (simultaneous transfer and a step-wise transfer with a quite low barrier). Moreover, the H2 activation energy barrier can be further reduced by introducing Al, Ga, Li, and Na to B12N12 cage. This study would provide some new ideas for the design of efficient cluster catalysts for CO2 reduction. PMID:28098191

Entanglement and co-tunneling of two equivalent protons in hydrogen bond pairs

NASA Astrophysics Data System (ADS)

Smedarchina, Zorka; Siebrand, Willem; Fernández-Ramos, Antonio

2018-03-01

A theoretical study is reported of a system of two identical symmetric hydrogen bonds, weakly coupled such that the two mobile protons can move either separately (stepwise) or together (concerted). It is modeled by two equivalent quartic potentials interacting through dipolar and quadrupolar coupling terms. The tunneling Hamiltonian has two imaginary modes (reaction coordinates) and a potential with a single maximum that may turn into a saddle-point of second order and two sets of (inequivalent) minima. Diagonalization is achieved via a modified Jacobi-Davidson algorithm. From this Hamiltonian the mechanism of proton transfer is derived. To find out whether the two protons move stepwise or concerted, a new tool is introduced, based on the distribution of the probability flux in the dividing plane of the transfer mode. While stepwise transfer dominates for very weak coupling, it is found that concerted transfer (co-tunneling) always occurs, even when the coupling vanishes since the symmetry of the Hamiltonian imposes permanent entanglement on the motions of the two protons. We quantify this entanglement and show that, for a wide range of parameters of interest, the lowest pair of states of the Hamiltonian represents a perfect example of highly entangled quantum states in continuous variables. The method is applied to the molecule porphycene for which the observed tunneling splitting is calculated in satisfactory agreement with experiment, and the mechanism of double-proton tunneling is found to be predominantly concerted. We show that, under normal conditions, when they are in the ground state, the two porphycene protons are highly entangled, which may have interesting applications. The treatment also identifies the conditions under which such a system can be handled by conventional one-instanton techniques.

Passive stiffness of rat skeletal muscle undernourished during fetal development

PubMed Central

Toscano, Ana Elisa; Ferraz, Karla Mônica; de Castro, Raul Manhães; Canon, Francis

2010-01-01

OBJECTIVES: The aim of the study was to investigate the effect of fetal undernutrition on the passive mechanical properties of skeletal muscle of weaned and young adult rats. INTRODUCTION: A poor nutrition supply during fetal development affects physiological functions of the fetus. From a mechanical point of view, skeletal muscle can be also characterized by its resistance to passive stretch. METHODS: Male Wistar rats were divided into two groups according to their mother's diet during pregnancy: a control group (mothers fed a 17% protein diet) and an isocaloric low‐protein group (mothers fed a 7.8% protein diet). At birth, all mothers received a standardized meal ad libitum. At the age of 25 and 90 days, the soleus muscle and extensor digitorum longus (EDL) muscles were removed in order to test the passive mechanical properties. A first mechanical test consisted of an incremental stepwise extension test using fast velocity stretching (500 mm/s) enabling us to measure, for each extension stepwise, the dynamic stress (σd) and the steady stress (σs). A second test consisted of a slow velocity stretch in order to calculate normalized stiffness and tangent modulus from the stress–strain relationship. RESULTS: The results for the mechanical properties showed an important increase in passive stiffness in both the soleus and EDL muscles in weaned rat. In contrast, no modification was observed in young adult rats. CONCLUSIONS: The increase in passive stiffness in skeletal muscle of weaned rat submitted to intrauterine undernutrition it is most likely due to changes in muscle passive stiffness. PMID:21340228

Structure and Dynamics of the tRNA-like Structure Domain of Brome Mosaic Virus

NASA Astrophysics Data System (ADS)

Vieweger, Mario; Nesbitt, David

2014-03-01

Conformational switching is widely accepted as regulatory mechanism in gene expression in bacterial systems. More recently, similar regulation mechanisms are emerging for viral systems. One of the most abundant and best studied systems is the tRNA-like structure domain that is found in a number of plant viruses across eight genera. In this work, the folding dynamics of the tRNA-like structure domain of Brome Mosaic Virus are investigated using single-molecule Fluorescence Resonance Energy Transfer techniques. In particular, Burst fluorescence is applied to observe metal-ion induced folding in freely diffusing RNA constructs resembling the 3'-terminal 169nt of BMV RNA3. Histograms of EFRET probabilities reveal a complex equilibrium of three distinct populations. A step-wise kinetic model for TLS folding is developed in accord with the evolution of conformational populations and structural information in the literature. In this mechanism, formation of functional TLS domains from unfolded RNAs requires two consecutive steps; 1) hybridization of a long-range stem interaction followed by 2) formation of a 3' pseudoknot. This three-state equilibrium is well described by step-wise dissociation constants K1(328(30) μM) and K2(1092(183) μM) for [Mg2+] and K1(74(6) mM) and K2(243(52) mM) for [Na+]-induced folding. The kinetic model is validated by oligo competition with the STEM interaction. Implications of this conformational folding mechanism are discussed in regards to regulation of virus replication.

Old Yellow Enzyme: Stepwise reduction of nitro-olefins and catalysis of aci-nitro tautomerization

PubMed Central

Meah, Younus; Massey, Vincent

2000-01-01

The Old Yellow Enzyme has been shown to catalyze efficiently the NADPH-linked reduction of nitro-olefins. The reduction of the nitro-olefin proceeds in a stepwise fashion, with formation of a nitronate intermediate that is freely dissociable from the enzyme. The first step involves hydride transfer from the enzyme-reduced flavin to carbon 2 of the nitro-olefin. The protonation of the nitronate at carbon 1 to form the final nitroalkane product also is catalyzed by the enzyme and involves Tyr-196 as an active site acid/base. This residue also is involved in aci-nitro tautomerization of nitroalkanes, the first example of a nonredox reaction catalyzed by the enzyme. PMID:10995477

Effects of Condensation on Peri-implant Bone Density and Remodeling

PubMed Central

Wang, L.; Wu, Y.; Perez, K.C.; Hyman, S.; Brunski, J.B.; Tulu, U.; Bao, C.; Salmon, B.; Helms, J.A.

2017-01-01

Bone condensation is thought to densify interfacial bone and thus improve implant primary stability, but scant data substantiate either claim. We developed a murine oral implant model to test these hypotheses. Osteotomies were created in healed maxillary extraction sites 1) by drilling or 2) by drilling followed by stepwise condensation with tapered osteotomes. Condensation increased interfacial bone density, as measured by a significant change in bone volume/total volume and trabecular spacing, but it simultaneously damaged the bone. On postimplant day 1, the condensed bone interface exhibited microfractures and osteoclast activity. Finite element modeling, mechanical testing, and immunohistochemical analyses at multiple time points throughout the osseointegration period demonstrated that condensation caused very high interfacial strains, marginal bone resorption, and no improvement in implant stability. Collectively, these multiscale analyses demonstrate that condensation does not positively contribute to implant stability. PMID:28048963

Effects of Condensation on Peri-implant Bone Density and Remodeling.

PubMed

Wang, L; Wu, Y; Perez, K C; Hyman, S; Brunski, J B; Tulu, U; Bao, C; Salmon, B; Helms, J A

2017-04-01

Bone condensation is thought to densify interfacial bone and thus improve implant primary stability, but scant data substantiate either claim. We developed a murine oral implant model to test these hypotheses. Osteotomies were created in healed maxillary extraction sites 1) by drilling or 2) by drilling followed by stepwise condensation with tapered osteotomes. Condensation increased interfacial bone density, as measured by a significant change in bone volume/total volume and trabecular spacing, but it simultaneously damaged the bone. On postimplant day 1, the condensed bone interface exhibited microfractures and osteoclast activity. Finite element modeling, mechanical testing, and immunohistochemical analyses at multiple time points throughout the osseointegration period demonstrated that condensation caused very high interfacial strains, marginal bone resorption, and no improvement in implant stability. Collectively, these multiscale analyses demonstrate that condensation does not positively contribute to implant stability.

Efficient synthesis of optically active 4-nitro-cyclohexanones via bifunctional thiourea-base catalyzed double-Michael addition of nitromethane to dienones.

PubMed

Wu, Bin; Liu, Guo-Gui; Li, Mei-Qiu; Zhang, Yong; Zhang, Shao-Yun; Qiu, Jun-Ru; Xu, Xiao-Ping; Ji, Shun-Jun; Wang, Xing-Wang

2011-04-07

Thiourea-modified cinchona alkaloids as bifunctional catalysts and a base could catalyze a stepwise [5+1] cyclization of divinyl ketones with nitromethane via double Michael additions, furnishing optically active 4-nitro-cyclohexanones with good yields, excellent diastereoselectivities (>20 : 1) and high enantiomeric ratios (up to 97 : 3).

Of Heart & Kidneys: Hands-On Activities for Demonstrating Organ Function & Repair

ERIC Educational Resources Information Center

Kao, Robert M.

2014-01-01

A major challenge in teaching organ development and disease is deconstructing a complex choreography of molecular and cellular changes over time into a linear stepwise process for students. As an entry toward learning developmental concepts, I propose two inexpensive hands-on activities to help facilitate learning of (1) how to identify defects in…

Towards lung EIT image segmentation: automatic classification of lung tissue state from analysis of EIT monitored recruitment manoeuvres.

PubMed

Grychtol, Bartłomiej; Wolf, Gerhard K; Adler, Andy; Arnold, John H

2010-08-01

There is emerging evidence that the ventilation strategy used in acute lung injury (ALI) makes a significant difference in outcome and that an inappropriate ventilation strategy may produce ventilator-associated lung injury. Most harmful during mechanical ventilation are lung overdistension and lung collapse or atelectasis. Electrical impedance tomography (EIT) as a non-invasive imaging technology may be helpful to identify lung areas at risk. Currently, no automated method is routinely available to identify lung areas that are overdistended, collapsed or ventilated appropriately. We propose a fuzzy logic-based algorithm to analyse EIT images obtained during stepwise changes of mean airway pressures during mechanical ventilation. The algorithm is tested on data from two published studies of stepwise inflation-deflation manoeuvres in an animal model of ALI using conventional and high-frequency oscillatory ventilation. The timing of lung opening and collapsing on segmented images obtained using the algorithm during an inflation-deflation manoeuvre is in agreement with well-known effects of surfactant administration and changes in shunt fraction. While the performance of the algorithm has not been verified against a gold standard, we feel that it presents an important first step in tackling this challenging and important problem.

Acquisition of thermotolerant yeast Saccharomyces cerevisiae by breeding via stepwise adaptation.

PubMed

Satomura, Atsushi; Katsuyama, Yoshiaki; Miura, Natsuko; Kuroda, Kouichi; Tomio, Ayako; Bamba, Takeshi; Fukusaki, Eiichiro; Ueda, Mitsuyoshi

2013-01-01

A thermotolerant Saccharomyces cerevisiae yeast strain, YK60-1, was bred from a parental strain, MT8-1, via stepwise adaptation. YK60-1 grew at 40°C, a temperature at which MT8-1 could not grow at all. YK60-1 exhibited faster growth than MT8-1 at 30°C. To investigate the mechanisms how MT8-1 acquired thermotolerance, DNA microarray analysis was performed. The analysis revealed the induction of stress-responsive genes such as those encoding heat shock proteins and trehalose biosynthetic enzymes in YK60-1. Furthermore, nontargeting metabolome analysis showed that YK60-1 accumulated more trehalose, a metabolite that contributes to stress tolerance in yeast, than MT8-1. In conclusion, S. cerevisiae MT8-1 acquired thermotolerance by induction of specific stress-responsive genes and enhanced intracellular trehalose levels. © 2013 American Institute of Chemical Engineers.

Cation Selectivity in Biological Cation Channels Using Experimental Structural Information and Statistical Mechanical Simulation.

PubMed

Finnerty, Justin John; Peyser, Alexander; Carloni, Paolo

2015-01-01

Cation selective channels constitute the gate for ion currents through the cell membrane. Here we present an improved statistical mechanical model based on atomistic structural information, cation hydration state and without tuned parameters that reproduces the selectivity of biological Na+ and Ca2+ ion channels. The importance of the inclusion of step-wise cation hydration in these results confirms the essential role partial dehydration plays in the bacterial Na+ channels. The model, proven reliable against experimental data, could be straightforwardly used for designing Na+ and Ca2+ selective nanopores.

Miscanthus x giganteus xylooligosaccharides: Purification andfermentation

USDA-ARS?s Scientific Manuscript database

A procedure was developed to recover xylooligosaccharides (XOS) from Miscanthus x giganteus (MxG) hydrolyzates. MxG hydrolyzates were prepared using autohydrolysis, and XOS rich fractions were acquired using activated carbon adsorption and stepwise ethanol elution. The combined XOS fractions were pu...

Development and implementation of the Caribbean Laboratory Quality Management Systems Stepwise Improvement Process (LQMS-SIP) Towards Accreditation

PubMed Central

Alemnji, George; Edghill, Lisa; Wallace-Sankarsingh, Sacha; Albalak, Rachel; Cognat, Sebastien; Nkengasong, John; Gabastou, Jean-Marc

2017-01-01

Background Implementing quality management systems and accrediting laboratories in the Caribbean has been a challenge. Objectives We report the development of a stepwise process for quality systems improvement in the Caribbean Region. Methods The Caribbean Laboratory Stakeholders met under a joint Pan American Health Organization/US Centers for Disease Control and Prevention initiative and developed a user-friendly framework called ‘Laboratory Quality Management System – Stepwise Improvement Process (LQMS-SIP) Towards Accreditation’ to support countries in strengthening laboratory services through a stepwise approach toward fulfilling the ISO 15189: 2012 requirements. Results This approach consists of a three-tiered framework. Tier 1 represents the minimum requirements corresponding to the mandatory criteria for obtaining a licence from the Ministry of Health of the participating country. The next two tiers are quality improvement milestones that are achieved through the implementation of specific quality management system requirements. Laboratories that meet the requirements of the three tiers will be encouraged to apply for accreditation. The Caribbean Regional Organisation for Standards and Quality hosts the LQMS-SIP Secretariat and will work with countries, including the Ministry of Health and stakeholders, including laboratory staff, to coordinate and implement LQMS-SIP activities. The Caribbean Public Health Agency will coordinate and advocate for the LQMS-SIP implementation. Conclusion This article presents the Caribbean LQMS-SIP framework and describes how it will be implemented among various countries in the region to achieve quality improvement. PMID:28879149

The MurC ligase essential for peptidoglycan biosynthesis is regulated by the serine/threonine protein kinase PknA in Corynebacterium glutamicum.

PubMed

Fiuza, Maria; Canova, Marc J; Patin, Delphine; Letek, Michal; Zanella-Cléon, Isabelle; Becchi, Michel; Mateos, Luís M; Mengin-Lecreulx, Dominique; Molle, Virginie; Gil, José A

2008-12-26

The Mur ligases play an essential role in the biosynthesis of bacterial cell-wall peptidoglycan and thus represent attractive targets for the design of novel antibacterials. These enzymes catalyze the stepwise formation of the peptide moiety of the peptidoglycan disaccharide peptide monomer unit. MurC is responsible of the addition of the first residue (L-alanine) onto the nucleotide precursor UDP-MurNAc. Phosphorylation of proteins by Ser/Thr protein kinases has recently emerged as a major physiological mechanism of regulation in prokaryotes. Herein, the hypothesis of a phosphorylation-dependent mechanism of regulation of the MurC activity was investigated in Corynebacterium glutamicum. We showed that MurC was phosphorylated in vitro by the PknA protein kinase. An analysis of the phosphoamino acid content indicated that phosphorylation exclusively occurred on threonine residues. Six phosphoacceptor residues were identified by mass spectrometry analysis, and we confirmed that mutagenesis to alanine residues totally abolished PknA-dependent phosphorylation of MurC. In vitro and in vivo ligase activity assays showed that the catalytic activity of MurC was impaired following mutation of these threonine residues. Further in vitro assays revealed that the activity of the MurC-phosphorylated isoform was severely decreased compared with the non-phosphorylated protein. To our knowledge, this is the first demonstration of a MurC ligase phosphorylation in vitro. The finding that phosphorylation is correlated with a decrease in MurC enzymatic activity could have significant consequences in the regulation of peptidoglycan biosynthesis.

The MurC Ligase Essential for Peptidoglycan Biosynthesis Is Regulated by the Serine/Threonine Protein Kinase PknA in Corynebacterium glutamicum*

PubMed Central

Fiuza, Maria; Canova, Marc J.; Patin, Delphine; Letek, Michal; Zanella-Cléon, Isabelle; Becchi, Michel; Mateos, Luís M.; Mengin-Lecreulx, Dominique; Molle, Virginie; Gil, José A.

2008-01-01

The Mur ligases play an essential role in the biosynthesis of bacterial cell-wall peptidoglycan and thus represent attractive targets for the design of novel antibacterials. These enzymes catalyze the stepwise formation of the peptide moiety of the peptidoglycan disaccharide peptide monomer unit. MurC is responsible of the addition of the first residue (l-alanine) onto the nucleotide precursor UDP-MurNAc. Phosphorylation of proteins by Ser/Thr protein kinases has recently emerged as a major physiological mechanism of regulation in prokaryotes. Herein, the hypothesis of a phosphorylation-dependent mechanism of regulation of the MurC activity was investigated in Corynebacterium glutamicum. We showed that MurC was phosphorylated in vitro by the PknA protein kinase. An analysis of the phosphoamino acid content indicated that phosphorylation exclusively occurred on threonine residues. Six phosphoacceptor residues were identified by mass spectrometry analysis, and we confirmed that mutagenesis to alanine residues totally abolished PknA-dependent phosphorylation of MurC. In vitro and in vivo ligase activity assays showed that the catalytic activity of MurC was impaired following mutation of these threonine residues. Further in vitro assays revealed that the activity of the MurC-phosphorylated isoform was severely decreased compared with the non-phosphorylated protein. To our knowledge, this is the first demonstration of a MurC ligase phosphorylation in vitro. The finding that phosphorylation is correlated with a decrease in MurC enzymatic activity could have significant consequences in the regulation of peptidoglycan biosynthesis. PMID:18974047

Prevalence and mechanism of rotor activation identified during atrial fibrillation by noncontact mapping: Lack of evidence for a role in the maintenance of atrial fibrillation.

PubMed

Yamabe, Hiroshige; Kanazawa, Hisanori; Ito, Miwa; Kaneko, Shozo; Ogawa, Hisao

2016-12-01

It remains unclear whether atrial fibrillation (AF) is maintained by the rotor. We evaluated the role of the rotor and examined its mechanism. Among 75 patients with AF (60 paroxysmal, 15 persistent AF) who underwent 3-dimensional noncontact left atrial mapping during AF, we examined the prevalence and location of rotor activation and elucidated its mechanism. Catheter ablation was performed in a stepwise fashion (linear roof lesion and complex fractionated atrial electrogram ablation after pulmonary vein [PV) isolation) until AF termination. Rotor activation was observed in 11 patients (14.7%; 10 paroxysmal and 1 persistent AF) (tachycardia cycle length 160.0 ± 19.8 ms). Rotors were observed transiently (duration 6128 ± 9094 ms) during AF at the roof (n = 5), septum (n = 3), and ostium of the left superior PV (n = 3). Five rotors circulated in clockwise and 6 in counterclockwise directions. The length of the block line at the center of the rotor was 15.2 ± 6.9 mm. The electrograms at the block line showed low-amplitude multiple deflections (n = 7) or double potentials (n = 4), and the amplitudes during rotor activation were significantly lower than those during sinus rhythm (0.27 ± 0.18 mV vs 1.22 ± 0.92 mV; P < .01). No conduction disturbances were found during sinus rhythm, suggesting that the central line of block was formed functionally. AF was terminated by PV isolation alone without additional lesions in patients with rotors. Functionally formed rotor activation was observed during AF in a limited number of patients. These rotor activations may not be related to AF maintenance, but rather may reflect a transient organization of random propagation. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

The control of the controller: molecular mechanisms for robust perfect adaptation and temperature compensation.

PubMed

Ni, Xiao Yu; Drengstig, Tormod; Ruoff, Peter

2009-09-02

Organisms have the property to adapt to a changing environment and keep certain components within a cell regulated at the same level (homeostasis). "Perfect adaptation" describes an organism's response to an external stepwise perturbation by regulating some of its variables/components precisely to their original preperturbation values. Numerous examples of perfect adaptation/homeostasis have been found, as for example, in bacterial chemotaxis, photoreceptor responses, MAP kinase activities, or in metal-ion homeostasis. Two concepts have evolved to explain how perfect adaptation may be understood: In one approach (robust perfect adaptation), the adaptation is a network property, which is mostly, but not entirely, independent of rate constant values; in the other approach (nonrobust perfect adaptation), a fine-tuning of rate constant values is needed. Here we identify two classes of robust molecular homeostatic mechanisms, which compensate for environmental variations in a controlled variable's inflow or outflow fluxes, and allow for the presence of robust temperature compensation. These two classes of homeostatic mechanisms arise due to the fact that concentrations must have positive values. We show that the concept of integral control (or integral feedback), which leads to robust homeostasis, is associated with a control species that has to work under zero-order flux conditions and does not necessarily require the presence of a physico-chemical feedback structure. There are interesting links between the two identified classes of homeostatic mechanisms and molecular mechanisms found in mammalian iron and calcium homeostasis, indicating that homeostatic mechanisms may underlie similar molecular control structures.

Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szebeni, Janos, E-mail: jszebeni2@gmail.com; Storm, Gert

Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequivalence evaluations of generic liposomal drug candidates. This review highlights the adverse consequences of C activation, the unique symptoms of CARPA triggered by essentially all i.v. administered liposomal drugs, and the various features of vesicles influencing this adverse immune effect. For the case of Doxil, we also address the mechanism of C activation and the opsonization vs.more » long circulation (stealth) paradox. In reviewing the methods of assessing C activation and CARPA, we delineate the most sensitive porcine model and an algorithm for stepwise evaluation of the CARPA risk of i.v. liposomes, which are proposed for standardization for preclinical toxicology evaluation of liposomal and other nanoparticulate drug candidates. - Highlights: • Outlining of difficulties in generic development of liposomal drugs. • New regulatory requirements to evaluate CARPA in preclinical studies. • Review of complement activation by liposomes and its adverse consequences (CARPA). • Assays of C activation in vitro and CARPA in vivo, with the porcine test in focus. • Decision tree how to handle the risk of CARPA assessed by a battery of tests.« less

Temperature stress, anti-oxidative enzyme activity and virus acquisition in Bemisia tabaci (Hemiptera: Aleyrodidae)

USDA-ARS?s Scientific Manuscript database

In most eukaryotic systems, antioxidants provide protection when cells are exposed to stressful environmental conditions. Antioxidants, such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase, function in a stepwise series with SOD initially preventing oxidative damage by conve...

Dynamics of ligand substitution in labile cobalt complexes resolved by ultrafast T-jump

PubMed Central

Ma, Hairong; Wan, Chaozhi; Zewail, Ahmed H.

2008-01-01

Ligand exchange of hydrated metal complexes is common in chemical and biological systems. Using the ultrafast T-jump, we examined this process, specifically the transformation of aqua cobalt (II) complexes to their fully halogenated species. The results reveal a stepwise mechanism with time scales varying from hundreds of picoseconds to nanoseconds. The dynamics are significantly faster when the structure is retained but becomes rate-limited when the octahedral-to-tetrahedral structural change bottlenecks the transformation. Evidence is presented, from bimolecular kinetics and energetics (enthalpic and entropic), for a reaction in which the ligand assists the displacement of water molecules, with the retention of the entering ligand in the activated state. The reaction time scale deviates by one to two orders of magnitude from that of ionic diffusion, suggesting the involvement of a collisional barrier between the ion and the much larger complex. PMID:18725628

Carbothermic reduction of uranium oxides into solvent metallic baths

NASA Astrophysics Data System (ADS)

Guisard Restivo, Thomaz A.; Capocchi, José D. T.

2004-09-01

The carbothermic reduction of UO 2 and U 3O 8 is studied employing tin and silicon solvent metallic baths in thermal analysis equipment, under Ar inert and N 2 reactive atmospheres. The metallic solvents are expected to lower the U activity by several orders of magnitude owing to strong interactions among the metals. The reduction products are composed of the solvent metal matrix and intermetallic U compounds. Silicon is more effective in driving the reduction since there is no residual UO 2 after the reaction. The gaseous product detected by mass spectrometer (MS) during the reduction is CO. A kinetic study for the Si case was accomplished by the stepwise isothermal analysis (SAI) method, leading to the identification of the controlling mechanisms as chemical reaction at the surface and nucleation, for UO 2 and U 3O 8 charges, respectively. One example for another system containing Al 2O 3 is also shown.

Foodstuffs for Preventing Cancer: The Preclinical and Clinical Development of Berries

PubMed Central

Stoner, Gary D.

2009-01-01

Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents, such as anthocyanins and ellagitannins, that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems; for determining these compounds’ mechanisms of action; and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts or individual constituents (anthocyanins) for cancer prevention are also discussed. PMID:19258544

Foodstuffs for preventing cancer: the preclinical and clinical development of berries.

PubMed

Stoner, Gary D

2009-03-01

Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents such as anthocyanins and ellagitannins that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems, for determining the mechanisms of action of these agents, and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus, and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts, or individual constituents (anthocyanins) for cancer prevention are also discussed.

Visible-light-driven chemoselective hydrogenation of nitroarenes to anilines in water via graphitic carbon nitride metal-free photocatalysis.

PubMed

Xiao, Gang; Li, Peifeng; Zhao, Yilin; Xu, Shengnan; Su, Haijia

2018-05-20

Green and efficient procedures are highly required for the chemoselective hydrogenation of functionalized nitroarenes to industrially important anilines. Here, we show that visible-light-driven, chemoselective hydrogenation of functionalized nitroarenes bearing the sensitive groups to anilines can be achieved in good to excellent yields (82-100%) in water under relatively mild conditions, catalyzed by low-cost and recyclable graphitic carbon nitride. It is also applicable in gram-scale reaction with 86% yield of aniline. Mechanism study reveals that visible light induced electrons are responsible for the hydrogenation reactions and thermal energy can also promote the photocatalytic activity. Kinetics study shows that this reaction possibly occurs via one-step hydrogenation or stepwise condensation route. Wide applications can be expected using this green, efficient, and highly selective photocatalysis system in reduction reactions for fine chemical synthesis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria

PubMed Central

Fooksman, David; Moore, Jamie M.; Saidi, Alex; Feintuch, Catherine M.; Reizis, Boris; Chorro, Laurent; Daily, Johanna; Lauvau, Grégoire

2016-01-01

Malaria remains a global health burden causing significant morbidity, yet the mechanisms underlying disease outcomes and protection are poorly understood. Herein, we analyzed the peripheral blood of a unique cohort of Malawian children with severe malaria, and performed a comprehensive overview of blood leukocytes and inflammatory mediators present in these patients. We reveal robust immune cell activation, notably of CD14+ inflammatory monocytes, NK cells and plasmacytoid dendritic cells (pDCs) that is associated with very high inflammation. Using the Plasmodium yoelii 17X YM surrogate mouse model of lethal malaria, we report a comparable pattern of immune cell activation and inflammation and found that type I IFN represents a key checkpoint for disease outcomes. Compared to wild type mice, mice lacking the type I interferon (IFN) receptor exhibited a significant decrease in immune cell activation and inflammatory response, ultimately surviving the infection. We demonstrate that pDCs were the major producers of systemic type I IFN in the bone marrow and the blood of infected mice, via TLR7/MyD88-mediated recognition of Plasmodium parasites. This robust type I IFN production required priming of pDCs by CD169+ macrophages undergoing activation upon STING-mediated sensing of parasites in the bone marrow. pDCs and macrophages displayed prolonged interactions in this compartment in infected mice as visualized by intravital microscopy. Altogether our findings describe a novel mechanism of pDC activation in vivo and precise stepwise cell/cell interactions taking place during severe malaria that contribute to immune cell activation and inflammation, and subsequent disease outcomes. PMID:27792766

Clinical Evaluation of Ozone on Dentinal Lesions in Young Permanent Molars using the Stepwise Excavation.

PubMed

Safwat, Osama; Elkateb, Mona; Dowidar, Karin; El Meligy, Omar

To evaluate the clinical changes in dentin of deep carious lesions in young permanent molars, following ozone application with and without the use of a remineralizing solution, using the stepwise excavation. The sample included 162 first permanent immature molars, showing deep occlusal carious cavities that were indicated for indirect pulp capping. Teeth were divided into 2 main groups according to the method of ozone treatment. Each group was further subdivided equally into test and control subgroups. Following caries excavation, color, consistency and DIAGNOdent assessments of dentin were evaluated after 6 and 12 months. Regarding dentin color and consistency, no significant differences were observed following ozone application, with and without a remineralizing solution. There were no significant differences between ozone treatment, and calcium hydroxide during the different evaluation periods, except in group I cases after 6 months, concerning the dentin color. The DIAGNOdent values were significantly reduced following ozone application, with or without a remineralizing solution, as well as between test and control cases in group I after 6 months. Ozone application through the stepwise excavation had no significant effect on dentin color and consistency in young permanent molars. DIAGNOdent was unreliable in monitoring caries activity.

Screening for increased cardiometabolic risk in primary care: a systematic review

PubMed Central

den Engelsen, Corine; Koekkoek, Paula S; Godefrooij, Merijn B; Spigt, Mark G; Rutten, Guy E

2014-01-01

Background Many programmes to detect and prevent cardiovascular disease (CVD) have been performed, but the optimal strategy is not yet clear. Aim To present a systematic review of cardiometabolic screening programmes performed among apparently healthy people (not yet known to have CVD, diabetes, or cardiometabolic risk factors) and mixed populations (apparently healthy people and people diagnosed with risk factor or disease) to define the optimal screening strategy. Design and setting Systematic review of studies performed in primary care in Western countries. Method MEDLINE, Embase, and CINAHL databases were searched for studies screening for increased cardiometabolic risk. Exclusion criteria were studies designed to assess prevalence of risk factors without follow-up or treatment; without involving a GP; when fewer than two risk factors were considered as the primary outcome; and studies constrained to ethnic minorities. Results The search strategy yielded 11 445 hits; 26 met the inclusion criteria. Five studies (1995–2012) were conducted in apparently healthy populations: three used a stepwise method. Response rates varied from 24% to 79%. Twenty-one studies (1967–2012) were performed in mixed populations; one used a stepwise method. Response rates varied from 50% to 75%. Prevalence rates could not be compared because of heterogeneity of used thresholds and eligible populations. Observed time trends were a shift from mixed to apparently healthy populations, increasing use of risk scores, and increasing use of stepwise screening methods. Conclusion The optimal screening strategy in primary care is likely stepwise, in apparently healthy people, with the use of risk scores. Increasing public awareness and actively involving GPs might facilitate screening efficiency and uptake. PMID:25267047

Auditory Proprioceptive Integration: Effects of Real-Time Kinematic Auditory Feedback on Knee Proprioception

PubMed Central

Ghai, Shashank; Schmitz, Gerd; Hwang, Tong-Hun; Effenberg, Alfred O.

2018-01-01

The purpose of the study was to assess the influence of real-time auditory feedback on knee proprioception. Thirty healthy participants were randomly allocated to control (n = 15), and experimental group I (15). The participants performed an active knee-repositioning task using their dominant leg, with/without additional real-time auditory feedback where the frequency was mapped in a convergent manner to two different target angles (40 and 75°). Statistical analysis revealed significant enhancement in knee re-positioning accuracy for the constant and absolute error with real-time auditory feedback, within and across the groups. Besides this convergent condition, we established a second divergent condition. Here, a step-wise transposition of frequency was performed to explore whether a systematic tuning between auditory-proprioceptive repositioning exists. No significant effects were identified in this divergent auditory feedback condition. An additional experimental group II (n = 20) was further included. Here, we investigated the influence of a larger magnitude and directional change of step-wise transposition of the frequency. In a first step, results confirm the findings of experiment I. Moreover, significant effects on knee auditory-proprioception repositioning were evident when divergent auditory feedback was applied. During the step-wise transposition participants showed systematic modulation of knee movements in the opposite direction of transposition. We confirm that knee re-positioning accuracy can be enhanced with concurrent application of real-time auditory feedback and that knee re-positioning can modulated in a goal-directed manner with step-wise transposition of frequency. Clinical implications are discussed with respect to joint position sense in rehabilitation settings. PMID:29568259

Cation Selectivity in Biological Cation Channels Using Experimental Structural Information and Statistical Mechanical Simulation

PubMed Central

Finnerty, Justin John

2015-01-01

Cation selective channels constitute the gate for ion currents through the cell membrane. Here we present an improved statistical mechanical model based on atomistic structural information, cation hydration state and without tuned parameters that reproduces the selectivity of biological Na+ and Ca2+ ion channels. The importance of the inclusion of step-wise cation hydration in these results confirms the essential role partial dehydration plays in the bacterial Na+ channels. The model, proven reliable against experimental data, could be straightforwardly used for designing Na+ and Ca2+ selective nanopores. PMID:26460827

Two-generation analysis of pollen flow across a landscape. V. A stepwise approach for extracting factors contributing to pollen structure.

Treesearch

R. J. Dyer; R. D. Westfall; V. L. Sork; P. E. Smouse

2004-01-01

Patterns of pollen dispersal are central to both the ecology and evolution of plant populations. However, the mechanisms controlling either the dispersal process itself or our estimation of that process may be influenced by site-specific factors such as local forest structure and nonuniform adult genetic structure. Here, we present an extension of the AMOVA model...

How Is Acetylcholinesterase Phosphonylated by Soman? An Ab Initio QM/MM Molecular Dynamics Study

PubMed Central

2015-01-01

Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. By employing Born–Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition–elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman’s phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman. PMID:24786171

Step-wise refolding of recombinant proteins.

PubMed

Tsumoto, Kouhei; Arakawa, Tsutomu; Chen, Linda

2010-04-01

Protein refolding is still on trial-and-error basis. Here we describe step-wise dialysis refolding, in which denaturant concentration is altered in step-wise fashion. This technology controls the folding pathway by adjusting the concentrations of the denaturant and other solvent additives to induce sequential folding or disulfide formation.

Project Physics Handbook 2, Motion in the Heavens.

ERIC Educational Resources Information Center

Harvard Univ., Cambridge, MA. Harvard Project Physics.

Nine experiments and 17 activities are presented in this handbook. The experiments are related to the earth's size and orbit, Piton height, telescope operations, Mars and Mercury orbits, stepwise approximation, and models of comet orbits. Further naked-eye observations in astronomy are designed in connection with the sun, moon, and planet…

Effects of temperature changes and stress loading on the mechanical and shape memory properties of thermoplastic materials with different glass transition behaviours and crystal structures.

PubMed

Iijima, Masahiro; Kohda, Naohisa; Kawaguchi, Kyotaro; Muguruma, Takeshi; Ohta, Mitsuru; Naganishi, Atsuko; Murakami, Takashi; Mizoguchi, Itaru

2015-12-01

To investigate the effects of temperature changes and stress loading on the mechanical and shape memory properties of thermoplastic materials with different glass transition behaviours and crystal structures. Five thermoplastic materials, polyethylene terephthalate glycol (Duran®, Scheu Dental), polypropylene (Hardcast®, Scheu Dental), and polyurethane (SMP MM®, SMP Technologies) with three different glass transition temperatures (T g) were selected. The T g and crystal structure were assessed using differential scanning calorimetry and X-ray diffraction. The deterioration of mechanical properties by thermal cycling and the orthodontic forces during stepwise temperature changes were investigated using nanoindentation testing and custom-made force-measuring system. The mechanical properties were also evaluated by three-point bending tests; shape recovery with heating was then investigated. The mechanical properties for each material were decreased significantly by 2500 cycles and great decrease was observed for Hardcast (crystal plastic) with higher T g (155.5°C) and PU 1 (crystalline or semi-crystalline plastic) with lower T g (29.6°C). The Duran, PU 2, and PU 3 with intermediate T g (75.3°C for Duran, 56.5°C for PU 2, and 80.7°C for PU 3) showed relatively stable mechanical properties with thermal cycling. The polyurethane polymers showed perfect shape memory effect within the range of intraoral temperature changes. The orthodontic force produced by thermoplastic appliances decreased with the stepwise temperature change for all materials. Orthodontic forces delivered by thermoplastic appliances may influence by the T g of the materials, but not the crystal structure. Polyurethane is attractive thermoplastic materials due to their unique shape memory phenomenon, but stress relaxation with temperature changes is expected. © The Author 2015. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Quantal concept of T-cell activation: adhesion domains as immunological synapses

NASA Astrophysics Data System (ADS)

Sackmann, Erich

2011-06-01

Adhesion micro-domains (ADs) formed during encounters of lymphocytes with antigen-presenting cells (APC) mediate the genetic expression of quanta of cytokines interleukin-2 (IL-2). The IL-2-induced activation of IL-2 receptors promotes the stepwise progression of the T-cells through the cell cycle, hence their name, immunological synapses. The ADs form short-lived reaction centres controlling the recruitment of activators of the biochemical pathway (the kinases Lck and ZAP) while preventing the access of inhibitors (phosphatase CD45) through steric repulsion forces. CD45 acts as the generator of adhesion domains and, through its role as a spacer protein, also as the promoter of the reaction. In a second phase of T-cell-APC encounters, long-lived global reaction spaces (called supramolecular activation complexes (SMAC)) form by talin-mediated binding of the T-cell integrin (LFA-1) to the counter-receptor ICAM-1, resulting in the formation of ring-like tight adhesion zones (peripheral SMAC). The ADs move to the centre of the intercellular adhesion zone forming the central SMAC, which serve in the recycling of the AD. We propose that cell stimulation is triggered by integrating the effect evoked by the short-lived adhesion domains. Similar global reaction platforms are formed by killer cells to destruct APC. We present a testable mechanical model showing that global reaction spaces (SMAC or dome-like contacts between cytotoxic cells and APC) form by self-organization through delayed activation of the integrin-binding affinity and stabilization of the adhesion zones by F-actin recruitment. The mechanical stability and the polarization of the adhering T-cells are mediated by microtubule-actin cross-talk.

Are the argon metastables important in high power impulse magnetron sputtering discharges?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gudmundsson, J. T., E-mail: tumi@hi.is; Science Institute, University of Iceland, Dunhaga 3, IS-107 Reykjavik; Lundin, D.

2015-11-15

We use an ionization region model to explore the ionization processes in the high power impulse magnetron sputtering (HiPIMS) discharge in argon with a titanium target. In conventional dc magnetron sputtering (dcMS), stepwise ionization can be an important route for ionization of the argon gas. However, in the HiPIMS discharge stepwise ionization is found to be negligible during the breakdown phase of the HiPIMS pulse and becomes significant (but never dominating) only later in the pulse. For the sputtered species, Penning ionization can be a significant ionization mechanism in the dcMS discharges, while in the HiPIMS discharge Penning ionization ismore » always negligible as compared to electron impact ionization. The main reasons for these differences are a higher plasma density in the HiPIMS discharge, and a higher electron temperature. Furthermore, we explore the ionization fraction and the ionized flux fraction of the sputtered vapor and compare with recent experimental work.« less

Specificity in endoplasmic reticulum-stress signaling in yeast entails a step-wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1.

PubMed

van Anken, Eelco; Pincus, David; Coyle, Scott; Aragón, Tomás; Osman, Christof; Lari, Federica; Gómez Puerta, Silvia; Korennykh, Alexei V; Walter, Peter

2014-12-30

Insufficient protein-folding capacity in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR). In the ER lumen, accumulation of unfolded proteins activates the transmembrane ER-stress sensor Ire1 and drives its oligomerization. In the cytosol, Ire1 recruits HAC1 mRNA, mediating its non-conventional splicing. The spliced mRNA is translated into Hac1, the key transcription activator of UPR target genes that mitigate ER-stress. In this study, we report that oligomeric assembly of the ER-lumenal domain is sufficient to drive Ire1 clustering. Clustering facilitates Ire1's cytosolic oligomeric assembly and HAC1 mRNA docking onto a positively charged motif in Ire1's cytosolic linker domain that tethers the kinase/RNase to the transmembrane domain. By the use of a synthetic bypass, we demonstrate that mRNA docking per se is a pre-requisite for initiating Ire1's RNase activity and, hence, splicing. We posit that such step-wise engagement between Ire1 and its mRNA substrate contributes to selectivity and efficiency in UPR signaling.

Stepwise vs concerted excited state tautomerization of 2-hydroxypyridine: Ammonia dimer wire mediated hydrogen/proton transfer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Esboui, Mounir, E-mail: mounir.esboui@fst.rnu.tn; Technical and Vocational Training Corporation, Hail College of Technology, P.O. Box 1960, Hail 81441

The stepwise and concerted excited state intermolecular proton transfer (PT) and hydrogen transfer (HT) reactions in 2-hydroxypyridine-(NH{sub 3}){sub 2} complex in the gas phase under Cs symmetry constraint and without any symmetry constraints were performed using quantum chemical calculations. It shows that upon excitation, the hydrogen bonded in 2HP-(NH{sub 3}){sub 2} cluster facilitates the releasing of both hydrogen and proton transfer reactions along ammonia wire leading to the formation of the 2-pyridone tautomer. For the stepwise mechanism, it has been found that the proton and the hydrogen may transfer consecutively. These processes are distinguished from each other through charge translocationmore » analysis and the coupling between the motion of the proton and the electron density distribution along ammonia wire. For the complex under Cs symmetry, the excited state HT occurs on the A″({sup 1}πσ{sup ∗}) and A′({sup 1}nσ{sup ∗}) states over two accessible energy barriers along reaction coordinates, and excited state PT proceeds mainly through the A′({sup 1}ππ{sup ∗}) and A″({sup 1}nπ{sup ∗}) potential energy surfaces. For the unconstrained complex, potential energy profiles show two {sup 1}ππ{sup ∗}-{sup 1}πσ{sup ∗} conical intersections along enol → keto reaction path indicating that proton and H atom are localized, respectively, on the first and second ammonia of the wire. Moreover, the concerted excited state PT is competitive to take place with the stepwise process, because it proceeds over low barriers of 0.14 eV and 0.11 eV with respect to the Franck-Condon excitation of enol tautomer, respectively, under Cs symmetry and without any symmetry constraints. These barriers can be probably overcome through tunneling effect.« less

Structural Insights into E. coli Porphobilinogen Deaminase during Synthesis and Exit of 1-Hydroxymethylbilane

PubMed Central

Bulusu, Gopalakrishnan

2014-01-01

Porphobilinogen deaminase (PBGD) catalyzes the formation of 1-hydroxymethylbilane (HMB), a crucial intermediate in tetrapyrrole biosynthesis, through a step-wise polymerization of four molecules of porphobilinogen (PBG), using a unique dipyrromethane (DPM) cofactor. Structural and biochemical studies have suggested residues with catalytic importance, but their specific role in the mechanism and the dynamic behavior of the protein with respect to the growing pyrrole chain remains unknown. Molecular dynamics simulations of the protein through the different stages of pyrrole chain elongation suggested that the compactness of the overall protein decreases progressively with addition of each pyrrole ring. Essential dynamics showed that domains move apart while the cofactor turn region moves towards the second domain, thus creating space for the pyrrole rings added at each stage. Residues of the flexible active site loop play a significant role in its modulation. Steered molecular dynamics was performed to predict the exit mechanism of HMB from PBGD at the end of the catalytic cycle. Based on the force profile and minimal structural changes the proposed path for the exit of HMB is through the space between the domains flanking the active site loop. Residues reported as catalytically important, also play an important role in the exit of HMB. Further, upon removal of HMB, the structure of PBGD gradually relaxes to resemble its initial stage structure, indicating its readiness to resume a new catalytic cycle. PMID:24603363

Clinical utility of the AlphaFIM® instrument in stroke rehabilitation.

PubMed

Lo, Alexander; Tahair, Nicola; Sharp, Shelley; Bayley, Mark T

2012-02-01

The AlphaFIM instrument is an assessment tool designed to facilitate discharge planning of stroke patients from acute care, by extrapolating overall functional status from performance in six key Functional Independence Measure (FIM) instrument items. To determine whether acute care AlphaFIM rating is correlated to stroke rehabilitation outcomes. In this prospective observational study, data were analyzed from 891 patients referred for inpatient stroke rehabilitation through an Internet-based referral system. Simple linear and stepwise regression models determined correlations between rehabilitation-ready AlphaFIM rating and rehabilitation outcomes (admission and discharge FIM ratings, FIM gain, FIM efficiency, and length of stay). Covariates including demographic data, stroke characteristics, medical history, cognitive deficits, and activity tolerance were included in the stepwise regressions. The AlphaFIM instrument was significant in predicting admission and discharge FIM ratings at rehabilitation (adjusted R² 0.40 and 0.28, respectively; P < 0.0001) and was weakly correlated with FIM gain and length of stay (adjusted R² 0.04 and 0.09, respectively; P < 0.0001), but not FIM efficiency. AlphaFIM rating was inversely related to FIM gain. Age, bowel incontinence, left hemiparesis, and previous infarcts were negative predictors of discharge FIM rating on stepwise regression. Intact executive function and physical activity tolerance of 30 to 60 mins were predictors of FIM gain. The AlphaFIM instrument is a valuable tool for triaging stroke patients from acute care to rehabilitation and predicts functional status at discharge from rehabilitation. Patients with low AlphaFIM ratings have the potential to make significant functional gains and should not be denied admission to inpatient rehabilitation programs.

A novel simple QSAR model for the prediction of anti-HIV activity using multiple linear regression analysis.

PubMed

Afantitis, Antreas; Melagraki, Georgia; Sarimveis, Haralambos; Koutentis, Panayiotis A; Markopoulos, John; Igglessi-Markopoulou, Olga

2006-08-01

A quantitative-structure activity relationship was obtained by applying Multiple Linear Regression Analysis to a series of 80 1-[2-hydroxyethoxy-methyl]-6-(phenylthio) thymine (HEPT) derivatives with significant anti-HIV activity. For the selection of the best among 37 different descriptors, the Elimination Selection Stepwise Regression Method (ES-SWR) was utilized. The resulting QSAR model (R (2) (CV) = 0.8160; S (PRESS) = 0.5680) proved to be very accurate both in training and predictive stages.

Stepwise drying of medicinal plants as alternative to reduce time and energy processing

NASA Astrophysics Data System (ADS)

Cuervo-Andrade, S. P.; Hensel, O.

2016-07-01

The objective of drying medicinal plants is to extend the shelf life and conserving the fresh characteristics. This is achieved by reducing the water activity (aw) of the product to a value which will inhibit the growth and development of pathogenic and spoilage microorganisms, significantly reducing enzyme activity and the rate at which undesirable chemical reactions occur. The technical drying process requires an enormous amount of thermal and electrical energy. An improvement in the quality of the product to be dried and at the same time a decrease in the drying cost and time are achieved through the utilization of a controlled conventional drying method, which is based on a good utilization of the renewable energy or looking for other alternatives which achieve lower processing times without sacrificing the final product quality. In this work the method of stepwise drying of medicinal plants is presented as an alternative to the conventional drying that uses a constant temperature during the whole process. The objective of stepwise drying is the decrease of drying time and reduction in energy consumption. In this process, apart from observing the effects on decreases the effective drying process time and energy, the influence of the different combinations of drying phases on several characteristics of the product are considered. The tests were carried out with Melissa officinalis L. variety citronella, sowed in greenhouse. For the stepwise drying process different combinations of initial and final temperature, 40/50°C, are evaluated, with different transition points associated to different moisture contents (20, 30, 40% and 50%) of the product during the process. Final quality of dried foods is another important issue in food drying. Drying process has effect in quality attributes drying products. This study was determining the color changes and essential oil loses by reference the measurement of the color and essential oil content of the fresh product was used. Drying curves were obtained to observe the dynamics of the process for different combinations of temperature and points of change, corresponding to different conditions of moisture content of the product.

Stepwise Analysis of Differential Item Functioning Based on Multiple-Group Partial Credit Model.

ERIC Educational Resources Information Center

Muraki, Eiji

1999-01-01

Extended an Item Response Theory (IRT) method for detection of differential item functioning to the partial credit model and applied the method to simulated data using a stepwise procedure. Then applied the stepwise DIF analysis based on the multiple-group partial credit model to writing trend data from the National Assessment of Educational…

Changing paradigms in thrombolysis in acute myocardial infarction.

PubMed

Gotsman, M S; Rozenman, Y; Admon, D; Mosseri, M; Lotan, C; Zahger, D; Weiss, A T

1997-05-23

Acute myocardial infarction occurs when a ruptured coronary artery plaque causes sudden thrombotic occlusion of a coronary artery and cessation of coronary artery blood flow. This paper reviews the underlying coronary pathology in progressive coronary atherosclerosis, mechanisms of plaque rupture and arterial occlusion and the time relationship between coronary occlusion and myocardial necrosis. Reperfusion can be achieved by chemical thrombolysis with different thrombolytic agents. Early lysis is achieved best by prehospital administration, a transtelephonic monitor, a mobile intensive care unit, active general practitioner treatment or by warning the emergency room of impending arrival of a patient. Thrombolytic therapy may be unsuccessful and not achieve Grade III TIMI flow in less than 4 h (or even 2 h) due to inadequate or intermittent perfusion or reocclusion. Adjuvant therapy includes aspirin and platelet receptor antagonists. Bleeding is a constant danger. Direct percutaneous transluminal coronary angioplasty (PTCA) may be as effective or better than chemical thrombolysis. Reperfusion protects the myocardium and salvages viable tissue. It also improves mechanical remodelling of the ventricle. Long-term follow-up has shown that quantum leaps of fresh coronary occlusion causes step-wise progression in patient disability and that further early, prompt reperfusion can salvage myocardium and prevent this inexorable progress of the disease.

Step-wise extinctions at the Cretaceous-Tertiary boundary and their climatic implications

NASA Technical Reports Server (NTRS)

Maurrasse, Florentin J-M. R.

1988-01-01

A comparative study of planktonic foraminifera and radiolarian assemblages from the Cretaceous-Tertiary (K-T) boundary section of the Beloc Formation in the southern Peninsula of Haiti, and the lowermost Danian sequence of the Micara Formation in southern Cuba reveals a remarkable pattern of step-wise extinctions. This pattern is consistent in both places despite the widely different lithologies of the two formations. Because of a step-wise extinction and the delayed disappearance of taxa known to be more representative of cooler water realms, it is inferred that a cooling trend which characterized the close of the Maastrichtian and the onset of the Tertiary had the major adverse effect on the existing biota. Although repetitive lithologic and faunal fluctuations throughout the Maastrichtian sediments found at Deep Sea Drilling Project (DSDP) site 146/149 in the Caribbean Sea indicate variations reminiscent of known climatically induced cycles in the Cenozoic, rapid biotic succession appears to have taken place during a crisis period of a duration greater than 2 mission years. Widespread and abundant volcanic activities recorded in the Caribbean area during the crisis period gives further credence to earlier contention that intense volcanism may have played a major role in exhacerbating pre-existing climatic conditions during that time.

Neurotrophin receptor structure and interactions.

PubMed

Yano, H; Chao, M V

2000-03-01

Although ligand-induced dimerization or oligomerization of receptors is a well established mechanism of growth factor signaling, increasing evidence indicates that biological responses are often mediated by receptor trans-signaling mechanisms involving two or more receptor systems. These include G protein-coupled receptors, cytokine, growth factor and trophic factor receptors. Greater flexibility is provided when different signaling pathways are merged through multiple receptor signaling systems. Trophic factors exemplified by NGF and its family members, ciliary neurotrophic factor (CNTF) and glial derived neurotrophic factor (GDNF) all utilize increased tyrosine phosphorylation of cellular substrates to mediate neuronal cell survival. Actions of the NGF family of neurotrophins are not only dictated by ras activation through the Trk family of receptor tyrosine kinases, but also a survival pathway defined by phosphatidylinositol-3-kinase activity (Yao and Cooper, 1995), which gives rise to phosphoinositide intermediates that activate the serine/threonine kinase Akt/PKB (Dudek et al., 1997). Induction of the serine-threonine kinase activity is critical for cell survival, as well as cell proliferation. Hence, for many trophic factors, multiple proteins constitute a functional multisubunit receptor complex that activates ras-dependent and ras-independent intracellular signaling. The NGF receptors provide an example of bidirectional crosstalk. In the presence of TrkA receptors, p75 can participate in the formation of high affinity binding sites and enhanced neurotrophin responsiveness leading to a survival or differentiation signal. In the absence of TrkA receptors, p75 can generate, in only specific cell populations, a death signal. These activities include the induction of NF kappa B (Carter et al., 1996); the hydrolysis of sphingomyelin to ceramide (Dobrowsky et al., 1995); and the pro-apoptotic functions attributed to p75. Receptors are generally drawn and viewed as isolated integral membrane proteins which span the lipid bilayer, with signal transduction proceeding in a linear step-wise fashion. There are now numerous examples which indicate that each receptor acts not only in a linear, independent manner, but can also influence the activity of other cell surface receptors, either directly or through signaling intermediates. Which step and which intermediates are utilized for crosstalk between the receptors is a critical question. For neurotrophins, their primary function in sustaining the viability of neurons is counterbalanced by a receptor mechanism to eliminate cells by an apoptotic mechanism. It is conceivable that this bidirectional system may be utilized selectively during development and in neurodegenerative diseases.

The inverse problem of argon diffusion from minerals: Determination of kinetic parameters from stepwise-heating experiments

USGS Publications Warehouse

Brandt, Stephen B.; Rasskazov, S.V.; Brandt, I.S.; Ivanov, A.V.; Kunk, Michael J.

1997-01-01

Results of two routine 40Ar/39Ar stepwise heating experiments on a biotite and a basanite are interpreted in terms of Fick's and Arrhenius' laws. Both patterns represent a saddle-shaped 39Ar release. Argon isotope spectra are suggested to be controlled by the activation energy of diffusion E and the frequency factor D(o). The activation energy of 39Ar is lower than the one of 40Ar. This results in a preferable release of 40Ar relatively to 39Ar at high-temperature steps and an increasing high-temperature wing in the saddle-shaped age spectrum. At low temperatures, considerable losses and irregularities in release of mainly 39Ar are observed, which cause the decreasing low-temperature wing in the 'saddle'. The suggestion of argon losses (mainly of 39Ar) from a loose, 'unstable' zone of the mineral structures becomes justified. The n-irradiation of the samples and the shift of E of 39Ar towards lower values seems to explain the saddle-shaped age-spectra often encountered in 40Ar/39Ar-geochronometry.

Is there a step-wise migration in Nigeria? A case study of the migrational histories of migrants in Lagos.

PubMed

Afolayan, A A

1985-09-01

"The paper sets out to test whether or not the movement pattern of people in Nigeria is step-wise. It examines the spatial order in the country and the movement pattern of people. It then analyzes the survey data and tests for the validity of step-wise migration in the country. The findings show that step-wise migration cannot adequately describe all the patterns observed." The presence of large-scale circulatory migration between rural and urban areas is noted. Ways to decrease the pressure on Lagos by developing intermediate urban areas are considered. excerpt

Stepwise morphological changes and cytoskeletal reorganization of human mesenchymal stem cells treated by short-time cyclic uniaxial stretch.

PubMed

Parandakh, Azim; Tafazzoli-Shadpour, Mohammad; Khani, Mohammad-Mehdi

2017-06-01

This study aimed to investigate stepwise remodeling of human mesenchymal stem cells (hMSCs) in response to cyclic stretch through rearrangement and alignment of cells and cytoskeleton regulation toward smooth muscle cell (SMC) fate in different time spans. Image analysis techniques were utilized to calculate morphological parameters. Cytoskeletal reorganization was observed by investigating F-actin filaments using immunofluorescence staining, and expression level of contractile SMC markers was followed by a quantitative polymerase chain reaction method. Applying cyclic uniaxial stretch on cultured hMSCs, utilizing a costume-made device, led to alteration in fractal dimension (FD) and cytoskeleton structure toward continuous alignment and elongation of cells by elevation of strain duration. Actin filaments became more aligned perpendicular to the axis of mechanical stretch by increasing uniaxial loading duration. At first, FD met a significant decrease in 4 h loading duration then increased significantly by further loading up to 16 h, followed by another decrease up to 1 d of uniaxial stretching. HMSCs subjected to 24 h cyclic uniaxial stretching significantly expressed early and intermediate contractile SM markers. It was hypothesized that the increase in FD after 4 h while cells continuously became more aligned and elongated was due to initiation of change in phenotype that influenced arrangement of cells. At this point, change in cell phenotype started leading to change in morphology while mechanical loading still caused cell alignment and rearrangement. Results can be helpful when optimized engineered cells are needed based on mechanical condition for functional engineered tissue and cell therapy.

Time-elapsed screw insertion with microCT imaging.

PubMed

Ryan, M K; Mohtar, A A; Cleek, T M; Reynolds, K J

2016-01-25

Time-elapsed analysis of bone is an innovative technique that uses sequential image data to analyze bone mechanics under a given loading regime. This paper presents the development of a novel device capable of performing step-wise screw insertion into excised bone specimens, within the microCT environment, whilst simultaneously recording insertion torque, compression under the screw head and rotation angle. The system is computer controlled and screw insertion is performed in incremental steps of insertion torque. A series of screw insertion tests to failure were performed (n=21) to establish a relationship between the torque at head contact and stripping torque (R(2)=0.89). The test-device was then used to perform step-wise screw insertion, stopping at intervals of 20%, 40%, 60% and 80% between screw head contact and screw stripping. Image data-sets were acquired at each of these time-points as well as at head contact and post-failure. Examination of the image data revealed the trabecular deformation as a result of increased insertion torque was restricted to within 1mm of the outer diameter of the screw thread. Minimal deformation occurred prior to the step between the 80% time-point and post-failure. The device presented has allowed, for the first time, visualization of the micro-mechanical response in the peri-implant bone with increased tightening torque. Further testing on more samples is expected to increase our understanding of the effects of increased tightening torque at the micro-structural level, and the failure mechanisms of trabeculae. Copyright © 2015 Elsevier Ltd. All rights reserved.

The role of multicollinearity in landslide susceptibility assessment by means of Binary Logistic Regression: comparison between VIF and AIC stepwise selection

NASA Astrophysics Data System (ADS)

Cama, Mariaelena; Cristi Nicu, Ionut; Conoscenti, Christian; Quénéhervé, Geraldine; Maerker, Michael

2016-04-01

Landslide susceptibility can be defined as the likelihood of a landslide occurring in a given area on the basis of local terrain conditions. In the last decades many research focused on its evaluation by means of stochastic approaches under the assumption that 'the past is the key to the future' which means that if a model is able to reproduce a known landslide spatial distribution, it will be able to predict the future locations of new (i.e. unknown) slope failures. Among the various stochastic approaches, Binary Logistic Regression (BLR) is one of the most used because it calculates the susceptibility in probabilistic terms and its results are easily interpretable from a geomorphological point of view. However, very often not much importance is given to multicollinearity assessment whose effect is that the coefficient estimates are unstable, with opposite sign and therefore difficult to interpret. Therefore, it should be evaluated every time in order to make a model whose results are geomorphologically correct. In this study the effects of multicollinearity in the predictive performance and robustness of landslide susceptibility models are analyzed. In particular, the multicollinearity is estimated by means of Variation Inflation Index (VIF) which is also used as selection criterion for the independent variables (VIF Stepwise Selection) and compared to the more commonly used AIC Stepwise Selection. The robustness of the results is evaluated through 100 replicates of the dataset. The study area selected to perform this analysis is the Moldavian Plateau where landslides are among the most frequent geomorphological processes. This area has an increasing trend of urbanization and a very high potential regarding the cultural heritage, being the place of discovery of the largest settlement belonging to the Cucuteni Culture from Eastern Europe (that led to the development of the great complex Cucuteni-Tripyllia). Therefore, identifying the areas susceptible to landslides may lead to a better understanding and mitigation for government, local authorities and stakeholders to plan the economic activities, minimize the damages costs, environmental and cultural heritage protection. The results show that although the VIF Stepwise selection allows a more stable selection of the controlling factors, the AIC Stepwise selection produces better predictive performance. Moreover, when working with replicates the effect of multicollinearity are statistically reduced by the application of the AIC stepwise selection and the results are easily interpretable in geomorphologic terms.

Enhanced cognitive activity – over and above social or physical activity – is required to protect Alzheimer’s mice against cognitive impairment, reduce Aβ deposition, and increase synaptic immunoreactivity

PubMed Central

Cracchiolo, Jennifer R.; Mori, Takashi; Nazian, Stanley J.; Tan, Jun; Potter, Huntington; Arendash, Gary W.

2007-01-01

Although social, physical, and cognitive activities have each been suggested to reduce the risk of Alzheimer’s Disease (AD), epidemiologic studies cannot determine which activity or combination of activities is most important. To address this question, mutant APP transgenic AD mice were reared long-term in one of four housing conditions (impoverished, social, social+physical, or complete enrichment) from 1½ through 9 months of age. Thus, a stepwise layering of social, physical, and enhanced cognitive activity was created. Behavioral evaluation in a full battery of sensorimotor, anxiety, and cognitive tasks was carried out during the final 5 weeks of housing. Only AD mice raised in complete enrichment (i.e., enhanced cognitive activity) showed: 1) protection against cognitive impairment, 2) decreased brain β-amyloid deposition, and 3) increased hippocampal synaptic immunoreactivity. The protection provided by enhanced cognitive activity spanned multiple cognitive domains (working memory, reference learning, and recognition/identification). Cognitive and neurohistologic benefits of complete enrichment occurred without any changes in blood cytokine or corticosterone levels, suggesting that enrichment-dependent mechanisms do not involve changes in the inflammatory response or stress levels, respectively. These results indicate that the enhanced cognitive activity of complete enrichment is required for cognitive and neurologic benefit to AD mice – physical and/or social activity are insufficient. Thus, our data suggest that humans who emphasize a high lifelong level of cognitive activity (over and above social and physical activities) will attain the maximal environmental protection against AD. PMID:17714960

Outpost in Jovian system - a stepwise long-term undertaking

NASA Astrophysics Data System (ADS)

Yasaka, Tetsuo

2003-11-01

Space has been attracting human attention since the dawn of our history, and clues thus given have triggered scientific and cultural evolutions. Now the space is in our hands. Near earth space has been developed, providing benefits to daily life. Moon and Mars will become the stage of human activity in a few decades. What will be the next logical step? The next step should be an undertaking that promises substantial influence to human history, both in knowledge and productive activities. Looking into the future directions of technology development combined with their outcome, Kyushu University selected a stepwise long-term undertaking toward establishment of an outpost in the Jovian system. Jupiter is our closest gas planet, which is a replica of the Sun. Its true understanding is essential to our knowledge of the universe. Its satellites abounds versatility providing not only the crucial knowledge of science but energy and materials vital to space activities. Jovian outpost consists of the central station on or around Callisto, controlling several laboratories on other Galilean satellites and dispatching probes to the main planet including Jovian-Crafts to cruise within its atmosphere and Deep Probes to explore the depth of the hydrogen ocean. Utilization of materials especially water on Europa will enable energy management of the stations and probes, and will further provide sound base toward exploration of the outskirts of the solar system and beyond. This understanding needs a long term endeavor that should be handed over many generations. This is a technology development program but education is an essential part of the process. The task is based on a series of short (5 year) targets. Each target provides stepwise solution to the objective, yet provides substantial outputs to the society and industries in a timely manner. The paper describes the overall program and details of the first 5 year targets.

Outpost in Jovian system—a stepwise long-term undertaking

NASA Astrophysics Data System (ADS)

Yasaka, Tetsuo

2006-10-01

Space has been attracting human attention since the dawn of our history, and clues thus given have triggered scientific and cultural evolutions. Now the space is in our hands. Near earth space has been developed, providing benefits to daily life. Moon and Mars will become the stage of human activity in a few decades. What will be the next logical step? The next step should be an undertaking that promises substantial influence to human history, both in knowledge and productive activities. Looking into the future directions of technology development combined with their outcome, Kyushu University selected a stepwise long-term undertaking toward establishment of an outpost in the Jovian system. Jupiter is our closest gas planet, which is a replica of the Sun. Its true understanding is essential to our knowledge of the universe. Its satellites abounds versatility providing not only the crucial knowledge of science but energy and materials vital to space activities. Jovian outpost consists of the central station on or around Callisto, controlling several laboratories on other Galilean satellites and dispatching probes to the main planet including Jovian-Crafts to cruise within its atmosphere and Deep Probes to explore the depth of the hydrogen ocean. Utilization of materials especially water on Europa will enable energy management of the stations and probes, and will further provide sound base toward exploration of the outskirts of the solar system and beyond. This understanding needs a long-term endeavor that should be handed over many generations. This is a technology development program but education is an essential part of the process. The task is based on a series of short (5 year) targets. Each target provides stepwise solution to the objective, yet provides substantial outputs to the society and industries in a timely manner. The paper describes the overall program and details of the first 5 year targets.

Aluminum Agglomeration and Trajectory in Solid Rocket Motors

DTIC Science & Technology

2007-08-30

34the stepwise oxidation of aluminum (that) is caused by the sequence of polymorphic phase transitions occurring in the growing oxide film",2 5 . 25...C. and Yang, V., "Analysis of RDX Monopropellant Combustion with Two-Phase Subsurface Reactions", Journal of Propulsion and Power, Vol. 11, No. 4...temperature. Generalized mechanisms have been developed and applied to many ingredients such as HMX , GAP, NG, BTTN, ADN and AP.10 The burning rates of

Mapping the Shh long-range regulatory domain

PubMed Central

Anderson, Eve; Devenney, Paul S.; Hill, Robert E.; Lettice, Laura A.

2014-01-01

Coordinated gene expression controlled by long-distance enhancers is orchestrated by DNA regulatory sequences involving transcription factors and layers of control mechanisms. The Shh gene and well-established regulators are an example of genomic composition in which enhancers reside in a large desert extending into neighbouring genes to control the spatiotemporal pattern of expression. Exploiting the local hopping activity of the Sleeping Beauty transposon, the lacZ reporter gene was dispersed throughout the Shh region to systematically map the genomic features responsible for expression activity. We found that enhancer activities are retained inside a genomic region that corresponds to the topological associated domain (TAD) defined by Hi-C. This domain of approximately 900 kb is in an open conformation over its length and is generally susceptible to all Shh enhancers. Similar to the distal enhancers, an enhancer residing within the Shh second intron activates the reporter gene located at distances of hundreds of kilobases away, suggesting that both proximal and distal enhancers have the capacity to survey the Shh topological domain to recognise potential promoters. The widely expressed Rnf32 gene lying within the Shh domain evades enhancer activities by a process that may be common among other housekeeping genes that reside in large regulatory domains. Finally, the boundaries of the Shh TAD do not represent the absolute expression limits of enhancer activity, as expression activity is lost stepwise at a number of genomic positions at the verges of these domains. PMID:25252942

Mps1 kinase-dependent Sgo2 centromere localisation mediates cohesin protection in mouse oocyte meiosis I.

PubMed

El Yakoubi, Warif; Buffin, Eulalie; Cladière, Damien; Gryaznova, Yulia; Berenguer, Inés; Touati, Sandra A; Gómez, Rocío; Suja, José A; van Deursen, Jan M; Wassmann, Katja

2017-09-25

A key feature of meiosis is the step-wise removal of cohesin, the protein complex holding sister chromatids together, first from arms in meiosis I and then from the centromere region in meiosis II. Centromeric cohesin is protected by Sgo2 from Separase-mediated cleavage, in order to maintain sister chromatids together until their separation in meiosis II. Failures in step-wise cohesin removal result in aneuploid gametes, preventing the generation of healthy embryos. Here, we report that kinase activities of Bub1 and Mps1 are required for Sgo2 localisation to the centromere region. Mps1 inhibitor-treated oocytes are defective in centromeric cohesin protection, whereas oocytes devoid of Bub1 kinase activity, which cannot phosphorylate H2A at T121, are not perturbed in cohesin protection as long as Mps1 is functional. Mps1 and Bub1 kinase activities localise Sgo2 in meiosis I preferentially to the centromere and pericentromere respectively, indicating that Sgo2 at the centromere is required for protection.In meiosis I centromeric cohesin is protected by Sgo2 from Separase-mediated cleavage ensuring that sister chromatids are kept together until their separation in meiosis II. Here the authors demonstrate that Bub1 and Mps1 kinase activities are required for Sgo2 localisation to the centromere region.

Improving meat quality of organic pork through post mortem handling of carcasses: an innovative approach.

PubMed

Therkildsen, Margrethe; Kristensen, Lars; Kyed, Sybille; Oksbjerg, Niels

2012-06-01

This study was conducted to examine the best combination of post mortem chilling, suspension and ageing in order to optimize tenderness of organic pork at slaughter, which may be tougher than conventionally produced pork, because of lower daily gain. Combinations of stepwise chilling with a holding period of 6h at 10°C or traditional blast tunnel chilling, suspension in the pelvic bone or Achilles Tendon and ageing 2 or 4 days post mortem were tested. Stepwise chilling and ageing improved tenderness of the loin, and the effects were additive, whereas pelvic suspension was less effective in texture improvements, and non-additive to stepwise chilling. Stepwise chilling improved tenderness to a similar degree as can be obtained within 2-4 days of extended ageing, however, the minimum temperature during the holding period seems to be crucial in order to obtain a positive effect of stepwise chilling, and it should be above 7.5°C. Copyright © 2011 Elsevier Ltd. All rights reserved.

The [C{sub 6}H{sub 10}]{sup {sm{underscore}bullet}+} hypersurface: The parent radical cation Diels-Alder reaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoffmann, M.; Schaefer, H.F. III

1999-07-21

Various possible reaction pathways between ethene and butadiene radical cation (cis- and trans-), have been investigated at different levels of theory up to UCCSD(T)/DZP/UMP2(fc)/DZP and with density functional theory at B3LYP/DZP. A stepwise addition involving open chain intermediates and leading to the Diels-Alder product, the cyclohexene radical cation, was found to have a total activation barrier {Delta}G{sup 298{ne}} = 6.3 kcal mol{sup {minus}1} and a change in free Gibbs energy, {Delta}G{sup 298}, of {minus}33.5 kcal mol{sup {minus}1}. On the E{degree} potential energy surface, all transition states are lower in energy than separated ethene and butadiene, the exothermicity {Delta}E = -45.6more » kcal mol{sup {minus}1}. A more direct path could be characterized as stepwise with one intermediate only at the SCF level but not at electron-correlated levels and hence might actually be a concerted strongly asynchronous addition with a very small or no activation barrier (UCCSD(T)/DZP/UHF/6-31G* gives a {Delta}G{sup 298{ne}} of 0.8 kcal mol{sup {minus}1}). The critical step for another alternative, the cyclobutanation-vinylcyclobutane/cyclohexene rearrangement, is a 1,3-alkyl shift which involves a barrier ({Delta}G{sup 298{ne}}) only 1.7 kcal mol{sup {minus}1} higher than that of stop use addition for both cis-, and trans-butadiene radical cation. However, from the (ethene and trans-butadiene) reactions, ring expansion of the vinylcyclobutane radical cation intermediate, to a methylene cyclopentane radical cation, requires an activation only 1.3 kcal mol{sup {minus}1} larger than for (trans-butadiene radical). While cis/trans isomerization of free butadiene radical cation requires a high activation (24.9 kcal mol{sup {minus}1}), a reaction sequence involving addition of ethene (to stepwise give an open chain intermediate and vinyl cyclobutane radical cation) has a barrier of only 3.5 kcal mol{sup {minus}1} ({Delta}G{sup 298{ne}}). This sequence also makes ethene and butadiene radical cations to exchange terminal methylene groups.« less

Thrombomodulin, von Willebrand factor and E-selectin as plasma markers of endothelial damage/dysfunction and activation in pregnancy induced hypertension.

PubMed

Nadar, Sunil K; Al Yemeni, Eman; Blann, Andrew D; Lip, Gregory Y H

2004-01-01

Endothelial disturbance (whether activation, dysfunction or damage) is a likely pathogenic mechanism in pre-eclampsia and pregnancy-induced hypertension (PIH). We set out to determine which of three plasma markers of endothelial disturbance, indicating endothelial activation (E-selectin) or damage/dysfunction (von Willebrand factor (vWf), soluble thrombomodulin), would provide the best discriminator of PIH compared to normotensive pregnancy. Cross-sectional study of 36 consecutive women with PIH (age 31+/-6 years) and 36 consecutive women with normotensive pregnancies (age 29+/-5 years) of similar parity. Plasma levels of vWf, E-selectin and thrombomodulin were measured using ELISA. As expected, women with PIH had significantly higher levels of plasma vWf (by 19%, p=0.003), E-selectin (by 40%, p<0.001) and thrombomodulin (by 61%, p=0.01) than normotensive women. However, on stepwise multiple regression analysis, only thrombomodulin was an independent significant predictor of the presence of PIH (p=0.023). We conclude that although vWf, E-selectin and thrombomodulin are all raised in PIH, only thrombomodulin was independently associated with PIH. This molecule could potentially be useful in monitoring and in providing clues in aetiology and pathophysiology, and may have implications for the clinical complications associated with PIH.

Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

PubMed Central

Kovtonyuk, Larisa V.; Fritsch, Kristin; Feng, Xiaomin; Manz, Markus G.; Takizawa, Hitoshi

2016-01-01

All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of “Inflamm-Aging,” or inflammation-associated aging of hematopoiesis. PMID:27895645

Prescribing physical activity for older patients.

PubMed

Kligman, E W; Pepin, E

1992-08-01

Regular exercise is an effective nonpharmacologic therapy for stress, sleep disorders, depression, and anxiety, as well as such chronic conditions of aging as hypertension, obesity, diabetes mellitus, coronary artery disease, hyperlipidemia, and constipation. Pre-exercise office assessment of cardiac risk, possible limitations, and contraindications is advised. A balanced fitness training program includes activities to increase flexibility, strength, and cardiovascular endurance. The most effective exercise prescription begins with a type of aerobic activity the patient enjoys. A prescribed schedule of stepwise increments in frequency, duration, and intensity gradually leads to a maintenance level of fitness.

Stepwise introduction of laparoscopic liver surgery: validation of guideline recommendations.

PubMed

van der Poel, Marcel J; Huisman, Floor; Busch, Olivier R; Abu Hilal, Mohammad; van Gulik, Thomas M; Tanis, Pieter J; Besselink, Marc G

2017-10-01

Uncontrolled introduction of laparoscopic liver surgery (LLS) could compromise postoperative outcomes. A stepwise introduction of LLS combined with structured training is advised. This study aimed to evaluate the impact of such a stepwise introduction. A retrospective, single-center case series assessing short term outcomes of all consecutive LLS in the period November 2006-January 2017. The technique was implemented in a stepwise fashion. To evaluate the impact of this stepwise approach combined with structured training, outcomes of LLS before and after a laparoscopic HPB fellowship were compared. A total of 135 laparoscopic resections were performed. Overall conversion rate was 4% (n = 5), clinically relevant complication rate 13% (n = 18) and mortality 0.7% (n = 1). A significant increase in patients with major LLS, multiple liver resections, previous abdominal surgery, malignancies and lesions located in posterior segments was observed after the fellowship as well as a decrease in the use of hand-assistance. Increasing complexity in the post fellowship period was reflected by an increase in operating times, but without comprising other surgical outcomes. A stepwise introduction of LLS combined with structured training reduced the clinical impact of the learning curve, thereby confirming guideline recommendations. Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Stepwise high-throughput virtual screening of Rho kinase inhibitors from natural product library and potential therapeutics for pulmonary hypertension.

PubMed

Su, Hao; Yan, Ji; Xu, Jian; Fan, Xi-Zhen; Sun, Xian-Lin; Chen, Kang-Yu

2015-08-01

Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling. The activation of RhoA/Rho-kinase (ROCK) pathway plays a central role in the pathologic progression of PH and thus the Rho kinase, an essential effector of the ROCK pathway, is considered as a potential therapeutic target to attenuate PH. In the current study, a synthetic pipeline is used to discover new potent Rho inhibitors from various natural products. In the pipeline, the stepwise high-throughput virtual screening, quantitative structure-activity relationship (QSAR)-based rescoring, and kinase assay were integrated. The screening was performed against a structurally diverse, drug-like natural product library, from which six identified compounds were tested to determine their inhibitory potencies agonist Rho by using a standard kinase assay protocol. With this scheme, we successfully identified two potent Rho inhibitors, namely phloretin and baicalein, with activity values of IC50 = 0.22 and 0.95 μM, respectively. Structural examination suggested that complicated networks of non-bonded interactions such as hydrogen bonding, hydrophobic forces, and van der Waals contacts across the complex interfaces of Rho kinase are formed with the screened compounds.

Catalytic oxidation of toluene and tetralin in supercritical carbon dioxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, L.; Erkey, C.; Akgerman, A.

1995-09-01

The catalytic total oxidation of toluene and tetrahydronaphthalene (tetralin) in supercritical carbon dioxide over a 0.5% platinum {gamma}-alumina catalyst was studied in a fixed-bed reactor. Toluene oxidation experiments were performed at 618, 633, 648 and 663 K, and at 7.93, 9.31 and 10.7 MPa. Tetralin oxidation experiments were performed at 573, 598, 623 and 648 K and at 8.96 and 10.0 MPa. Inlet concentrations of toluene and tetralin were varied in the ranges 569 to 2,858 ppm (mass/mass) and 1,420 to 3,648 ppm, respectively. Reactions were run at excess oxygen with a 25:1 molar ratio of oxygen to toluene andmore » a 15:1 molar ratio of oxygen to tetralin. A stepwise mechanism was postulated for the oxidation reaction to describe the kinetics of toluene and tetralin oxidation in supercritical carbon dioxide, and the reaction orders and activation energies were determined.« less

Development of a chitosan based double layer-coated tablet as a platform for colon-specific drug delivery

PubMed Central

Kim, Min Soo; Yeom, Dong Woo; Kim, Sung Rae; Yoon, Ho Yub; Kim, Chang Hyun; Son, Ho Yong; Kim, Jin Han; Lee, Sangkil; Choi, Young Wook

2017-01-01

A double layer-coated colon-specific drug delivery system (DL-CDDS) was developed, which consisted of chitosan (CTN) based polymeric subcoating of the core tablet containing citric acid for microclimate acidification, followed by an enteric coating. The polymeric composition ratio of Eudragit E100 and ethyl cellulose and amount of subcoating were optimized using a two-level factorial design method. Drug-release characteristics in terms of dissolution efficiency and controlled-release duration were evaluated in various dissolution media, such as simulated colonic fluid in the presence or absence of CTNase. Microflora activation and a stepwise mechanism for drug release were postulated. Consequently, the optimized DL-CDDS showed drug release in a controlled manner by inhibiting drug release in the stomach and intestine, but releasing the drug gradually in the colon (approximately 40% at 10 hours and 92% at 24 hours in CTNase-supplemented simulated colonic fluid), indicating its feasibility as a novel platform for CDD. PMID:28053506

Emergence of context-dependent variability across a basal ganglia network.

PubMed

Woolley, Sarah C; Rajan, Raghav; Joshua, Mati; Doupe, Allison J

2014-04-02

Context dependence is a key feature of cortical-basal ganglia circuit activity, and in songbirds the cortical outflow of a basal ganglia circuit specialized for song, LMAN, shows striking increases in trial-by-trial variability and bursting when birds sing alone rather than to females. To reveal where this variability and its social regulation emerge, we recorded stepwise from corticostriatal (HVC) neurons and their target spiny and pallidal neurons in Area X. We find that corticostriatal and spiny neurons both show precise singing-related firing across both social settings. Pallidal neurons, in contrast, exhibit markedly increased trial-by-trial variation when birds sing alone, created by highly variable pauses in firing. This variability persists even when recurrent inputs from LMAN are ablated. These data indicate that variability and its context sensitivity emerge within the basal ganglia network, suggest a network mechanism for this emergence, and highlight variability generation and regulation as basal ganglia functions. Copyright © 2014 Elsevier Inc. All rights reserved.

Emergence of context-dependent variability across a basal ganglia network

PubMed Central

Woolley, Sarah C.; Rajan, Raghav; Joshua, Mati; Doupe, Allison J.

2014-01-01

Summary Context-dependence is a key feature of cortical-basal ganglia circuit activity, and in songbirds, the cortical outflow of a basal ganglia circuit specialized for song, LMAN, shows striking increases in trial-by-trial variability and bursting when birds sing alone rather than to females. To reveal where this variability and its social regulation emerge, we recorded stepwise from cortico-striatal (HVC) neurons and their target spiny and pallidal neurons in Area X. We find that cortico-striatal and spiny neurons both show precise singing-related firing across both social settings. Pallidal neurons, in contrast, exhibit markedly increased trial-by-trial variation when birds sing alone, created by highly variable pauses in firing. This variability persists even when recurrent inputs from LMAN are ablated. These data indicate that variability and its context-sensitivity emerge within the basal ganglia network, suggest a network mechanism for this emergence, and highlight variability generation and regulation as basal ganglia functions. PMID:24698276

Role of pendant proton relays and proton-coupled electron transfer on the hydrogen evolution reaction by nickel hangman porphyrins

DOE PAGES

Bediako, D. Kwabena; Solis, Brian H.; Dogutan, Dilek K.; ...

2014-10-08

Here, the hangman motif provides mechanistic insights into the role of pendant proton relays in governing proton-coupled electron transfer (PCET) involved in the hydrogen evolution reaction (HER). We now show improved HER activity of Ni compared with Co hangman porphyrins. Cyclic voltammogram data and simulations, together with computational studies using density functional theory, implicate a shift in electrokinetic zone between Co and Ni hangman porphyrins due to a change in the PCET mechanism. Unlike the Co hangman porphyrin, the Ni hangman porphyrin does not require reduction to the formally metal(0) species before protonation by weak acids in acetonitrile. We concludemore » that protonation likely occurs at the Ni(I) state followed by reduction, in a stepwise proton transfer–electron transfer pathway. Spectroelectrochemical and computational studies reveal that upon reduction of the Ni(II) compound, the first electron is transferred to a metal-based orbital, whereas the second electron is transferred to a molecular orbital on the porphyrin ring.« less

Role of pendant proton relays and proton-coupled electron transfer on the hydrogen evolution reaction by nickel hangman porphyrins

PubMed Central

Bediako, D. Kwabena; Solis, Brian H.; Dogutan, Dilek K.; Roubelakis, Manolis M.; Maher, Andrew G.; Lee, Chang Hoon; Chambers, Matthew B.; Hammes-Schiffer, Sharon; Nocera, Daniel G.

2014-01-01

The hangman motif provides mechanistic insights into the role of pendant proton relays in governing proton-coupled electron transfer (PCET) involved in the hydrogen evolution reaction (HER). We now show improved HER activity of Ni compared with Co hangman porphyrins. Cyclic voltammogram data and simulations, together with computational studies using density functional theory, implicate a shift in electrokinetic zone between Co and Ni hangman porphyrins due to a change in the PCET mechanism. Unlike the Co hangman porphyrin, the Ni hangman porphyrin does not require reduction to the formally metal(0) species before protonation by weak acids in acetonitrile. We conclude that protonation likely occurs at the Ni(I) state followed by reduction, in a stepwise proton transfer–electron transfer pathway. Spectroelectrochemical and computational studies reveal that upon reduction of the Ni(II) compound, the first electron is transferred to a metal-based orbital, whereas the second electron is transferred to a molecular orbital on the porphyrin ring. PMID:25298534

A PEG/copper(i) halide cluster as an eco-friendly catalytic system for C-N bond formation.

PubMed

Li, Cheng-An; Ji, Wei; Qu, Jian; Jing, Su; Gao, Fei; Zhu, Dun-Ru

2018-05-22

The catalytic activities of eight copper(i) halide clusters assembled from copper(i) halide and ferrocenyltelluroethers, 1-8, were investigated in C-N formation under various conditions. A catalytic procedure using poly(ethylene glycol) (PEG-400) as a greener alternative organic solvent has been developed. The PEG-400/5 system can achieve 99% targeted yield with a mild reaction temperature and short reaction time. After the isolation of the products by extraction with diethyl ether, this PEG-400/cluster system could be easily recycled. Spectroscopic studies elucidate a stepwise mechanism: firstly, proton-coupled electron transfer (PCET) involving the transfer of an electron from Cu+ and a proton from imidazole results in the formation of a labile penta-coordinated Cu2+ and aryl radical; the following effective electron transfer from the ferrocene unit reduces Cu2+ and forms the target product; finally, the ferrocenium unit is reduced by the I- anion. The merits of this eco-friendly synthesis are the efficient utilization of reagents and easy recyclability.

Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building.

PubMed

Sherer, Eric A; Sale, Mark E; Pollock, Bruce G; Belani, Chandra P; Egorin, Merrill J; Ivy, Percy S; Lieberman, Jeffrey A; Manuck, Stephen B; Marder, Stephen R; Muldoon, Matthew F; Scher, Howard I; Solit, David B; Bies, Robert R

2012-08-01

A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three compounds. The root mean squared error and absolute mean prediction error of the best single-objective hybrid genetic algorithm candidates were a median of 0.2 points higher (range of 38.9 point decrease to 27.3 point increase) and 0.02 points lower (range of 0.98 point decrease to 0.74 point increase), respectively, than that of the final stepwise models. In addition, the best single-objective, hybrid genetic algorithm candidate models had successful convergence and covariance steps for each compound, used the same compartment structure as the manual stepwise approach for 6 of 7 (86 %) compounds, and identified 54 % (7 of 13) of covariates included by the manual stepwise approach and 16 covariate relationships not included by manual stepwise models. The model parameter values between the final manual stepwise and best single-objective, hybrid genetic algorithm models differed by a median of 26.7 % (q₁ = 4.9 % and q₃ = 57.1 %). Finally, the single-objective, hybrid genetic algorithm approach was able to identify models capable of estimating absorption rate parameters for four compounds that the manual stepwise approach did not identify. The single-objective, hybrid genetic algorithm represents a general pharmacokinetic model building methodology whose ability to rapidly search the feasible solution space leads to nearly equivalent or superior model fits to pharmacokinetic data.

Structure and function of NADPH-cytochrome P450 reductase and nitric oxide synthase reductase domain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iyanagi, Takashi

2005-12-09

NADPH-cytochrome P450 reductase (CPR) and the nitric oxide synthase (NOS) reductase domains are members of the FAD-FMN family of proteins. The FAD accepts two reducing equivalents from NADPH (dehydrogenase flavin) and FMN acts as a one-electron carrier (flavodoxin-type flavin) for the transfer from NADPH to the heme protein, in which the FMNH {sup {center_dot}}/FMNH{sub 2} couple donates electrons to cytochrome P450 at constant oxidation-reduction potential. Although the interflavin electron transfer between FAD and FMN is not strictly regulated in CPR, electron transfer is activated in neuronal NOS reductase domain upon binding calmodulin (CaM), in which the CaM-bound activated form canmore » function by a similar mechanism to that of CPR. The oxygenated form and spin state of substrate-bound cytochrome P450 in perfused rat liver are also discussed in terms of stepwise one-electron transfer from CPR. This review provides a historical perspective of the microsomal mixed-function oxidases including CPR and P450. In addition, a new model for the redox-linked conformational changes during the catalytic cycle for both CPR and NOS reductase domain is also discussed.« less

Variable selection with stepwise and best subset approaches

PubMed Central

2016-01-01

While purposeful selection is performed partly by software and partly by hand, the stepwise and best subset approaches are automatically performed by software. Two R functions stepAIC() and bestglm() are well designed for stepwise and best subset regression, respectively. The stepAIC() function begins with a full or null model, and methods for stepwise regression can be specified in the direction argument with character values “forward”, “backward” and “both”. The bestglm() function begins with a data frame containing explanatory variables and response variables. The response variable should be in the last column. Varieties of goodness-of-fit criteria can be specified in the IC argument. The Bayesian information criterion (BIC) usually results in more parsimonious model than the Akaike information criterion. PMID:27162786

Melanin fluorescence spectra by step-wise three photon excitation

NASA Astrophysics Data System (ADS)

Lai, Zhenhua; Kerimo, Josef; DiMarzio, Charles A.

2012-03-01

Melanin is the characteristic chromophore of human skin with various potential biological functions. Kerimo discovered enhanced melanin fluorescence by stepwise three-photon excitation in 2011. In this article, step-wise three-photon excited fluorescence (STPEF) spectrum between 450 nm -700 nm of melanin is reported. The melanin STPEF spectrum exhibited an exponential increase with wavelength. However, there was a probability of about 33% that another kind of step-wise multi-photon excited fluorescence (SMPEF) that peaks at 525 nm, shown by previous research, could also be generated using the same process. Using an excitation source at 920 nm as opposed to 830 nm increased the potential for generating SMPEF peaks at 525 nm. The SMPEF spectrum peaks at 525 nm photo-bleached faster than STPEF spectrum.

Stepwise assembly of a semiconducting coordination polymer [Cd8S(SPh)14(DMF)(bpy)]n and its photodegradation of organic dyes.

PubMed

Xu, Chao; Hedin, Niklas; Shi, Hua-Tian; Xin, ZhiFeng; Zhang, Qian-Feng

2015-04-14

Chalcogenolate clusters can be interlinked with organic linkers into semiconducting coordination polymers with photocatalytic properties. Here, discrete clusters of Cd8S(SPh)14(DMF)3 were interlinked with 4,4'-bipyridine into a one dimensional coordination polymer of [Cd8S(SPh)14(DMF)(bpy)]n with helical chains. A stepwise mechanism for the assembly of the coordination polymer in DMF was revealed by an ex situ dynamic light scattering study. The cluster was electrostatically neutral and showed a penta-supertetrahedral structure. During the assembly each cluster was interlinked with two 4,4'-bipyridine molecules, which replaced the two terminal DMF molecules of the clusters. In their solid-state forms, the cluster and the coordination polymer were semiconductors with wide band gaps of 3.08 and 2.80 ev. They photocatalytically degraded rhodamine B and methylene blue in aqueous solutions. The moderate conditions used for the synthesis could allow for further in situ studies of the reaction-assembly of related clusters and coordination polymers.

Triple Nucleophilic Attack of Nitromethane on (2-Iminoaryl)divinyl Ketones: A Domino Synthetic Strategy for Hexahydrophenanthridinones.

PubMed

Feng, Chengjie; Li, Yifei; Xu, Qi; Pan, Ling; Liu, Qun; Xu, Xianxiu

2018-02-02

A novel domino reaction of (2-iminoaryl)divinyl ketones with nitromethane was developed for the efficient synthesis of hexahydrophenanthridin-9(5H)-ones. The reaction proceeded smoothly from readily available starting materials under mild reaction conditions to construct three new bonds and two rings with high diastereoselectivities in good to excellent yields in a single step. A mechanism is proposed, involving a stepwise double Michael addition/aza-Henry reaction cascade, and in this transformation, nitromethane acts as a trinucleophile.

Single molecule detection, thermal fluctuation and life

PubMed Central

YANAGIDA, Toshio; ISHII, Yoshiharu

2017-01-01

Single molecule detection has contributed to our understanding of the unique mechanisms of life. Unlike artificial man-made machines, biological molecular machines integrate thermal noises rather than avoid them. For example, single molecule detection has demonstrated that myosin motors undergo biased Brownian motion for stepwise movement and that single protein molecules spontaneously change their conformation, for switching to interactions with other proteins, in response to thermal fluctuation. Thus, molecular machines have flexibility and efficiency not seen in artificial machines. PMID:28190869

Mechanisms of excitatory synapse maturation by trans-synaptic organizing complexes

PubMed Central

McMahon, Samuel A.; Díaz, Elva

2011-01-01

Synapses are specialized cell-cell adhesion contacts that mediate communication within neural networks. During development, excitatory synapses are generated by step-wise recruitment of pre- and postsynaptic proteins to sites of contact. Several classes of synaptic organizing complexes have been identified that function during the initial stages of synapse formation. However, mechanisms underlying the later stages of synapse development are less well understood. In recent years, molecules have been discovered that appear to play a role in synapse maturation. In this review, we highlight recent findings that have provided key insights for understanding postsynaptic maturation of developing excitatory synapses with a focus on recruitment of AMPA receptors to developing synapses. PMID:21242087

Voltage-Clamp Studies on Uterine Smooth Muscle

PubMed Central

Anderson, Nels C.

1969-01-01

These studies have developed and tested an experimental approach to the study of membrane ionic conductance mechanisms in strips of uterine smooth muscle. The experimental and theoretical basis for applying the double sucrose-gap technique is described along with the limitations of this system. Nonpropagating membrane action potentials were produced in response to depolarizing current pulses under current-clamp conditions. The stepwise change of membrane potential under voltage-clamp conditions resulted in a family of ionic currents with voltage- and time-dependent characteristics. In sodium-free solution the peak transient current decreased and its equilibrium potential shifted along the voltage axis toward a more negative internal potential. These studies indicate a sodium-dependent, regenerative excitation mechanism. PMID:5796366

A stepwise-cluster microbial biomass inference model in food waste composting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun Wei; Huang, Guo H., E-mail: huangg@iseis.or; Chinese Research Academy of Environmental Science, North China Electric Power University, Beijing 100012-102206

2009-12-15

A stepwise-cluster microbial biomass inference (SMI) model was developed through introducing stepwise-cluster analysis (SCA) into composting process modeling to tackle the nonlinear relationships among state variables and microbial activities. The essence of SCA is to form a classification tree based on a series of cutting or mergence processes according to given statistical criteria. Eight runs of designed experiments in bench-scale reactors in a laboratory were constructed to demonstrate the feasibility of the proposed method. The results indicated that SMI could help establish a statistical relationship between state variables and composting microbial characteristics, where discrete and nonlinear complexities exist. Significance levelsmore » of cutting/merging were provided such that the accuracies of the developed forecasting trees were controllable. Through an attempted definition of input effects on the output in SMI, the effects of the state variables on thermophilic bacteria were ranged in a descending order as: Time (day) > moisture content (%) > ash content (%, dry) > Lower Temperature (deg. C) > pH > NH{sub 4}{sup +}-N (mg/Kg, dry) > Total N (%, dry) > Total C (%, dry); the effects on mesophilic bacteria were ordered as: Time > Upper Temperature (deg. C) > Total N > moisture content > NH{sub 4}{sup +}-N > Total C > pH. This study made the first attempt in applying SCA to mapping the nonlinear and discrete relationships in composting processes.« less

Computational Insight into the Mechanism of Alkane Hydroxylation by Non-heme Fe(PyTACN) Iron Complexes. Effects of the Substrate and Solvent.

PubMed

Postils, Verònica; Company, Anna; Solà, Miquel; Costas, Miquel; Luis, Josep M

2015-09-08

The reaction mechanisms for alkane hydroxylation catalyzed by non-heme Fe(V)O complexes presented in the literature vary from rebound stepwise to concerted highly asynchronous processes. The origin of these important differences is still not completely understood. Herein, in order to clarify this apparent inconsistency, the hydroxylation of a series of alkanes (methane and substrates bearing primary, secondary, and tertiary C-H bonds) through a Fe(V)O species, [Fe(V)(O)(OH)(PyTACN)](2+) (PyTACN = 1-(2'-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclononane), has been computationally examined at the gas phase and in acetonitrile solution. The initial breaking of the C-H bond can occur via hydrogen atom transfer (HAT), leading to an intermediate where there is an interaction between the radical substrate and [Fe(IV)(OH)2(PyTACN)](2+), or through hydride transfer to form a cationic substrate interacting with the [Fe(III)(OH)2(PyTACN)](+) species. Our calculations show the following: (i) except for methane in the rest of the alkanes studied, the intermediate formed by R(+) and [Fe(III)(OH)2(PyTACN)](+) is more stable than that involving the alkyl radical and the [Fe(IV)(OH)2(PyTACN)](2+) complex; (ii) in spite of (i), the first step of the reaction mechanism for all substrates is a HAT instead of hydride abstraction; (iii) the HAT is the rate-determining step for all analyzed cases; and (iv) the barrier for the HAT decreases along methane → primary → secondary → tertiary carbon. The second part of the reaction mechanism corresponds to the rebound process. Therefore, the stereospecific hydroxylation of alkane C-H bonds by non-heme Fe(V)(O) species occurs through a rebound stepwise mechanism that resembles that taking place at heme analogues. Finally, our study also shows that, to properly describe alkane hydroxylation processes mediated by Fe(V)O species, it is essential to consider the solvent effects during geometry optimizations. The use of gas-phase geometries explains the variety of mechanisms for the hydroxylation of alkanes reported in the literature.

Inverse Thio Effects in the Hepatitis Delta Virus Ribozyme Reveal that the Reaction Pathway Is Controlled by Metal Ion Charge Density

PubMed Central

2015-01-01

The hepatitis delta virus (HDV) ribozyme self-cleaves in the presence of a wide range of monovalent and divalent ions. Prior theoretical studies provided evidence that self-cleavage proceeds via a concerted or stepwise pathway, with the outcome dictated by the valency of the metal ion. In the present study, we measure stereospecific thio effects at the nonbridging oxygens of the scissile phosphate under a wide range of experimental conditions, including varying concentrations of diverse monovalent and divalent ions, and combine these with quantum mechanical/molecular mechanical (QM/MM) free energy simulations on the stereospecific thio substrates. The RP substrate gives large normal thio effects in the presence of all monovalent ions. The SP substrate also gives normal or no thio effects, but only for smaller monovalent and divalent cations, such as Li+, Mg2+, Ca2+, and Sr2+; in contrast, sizable inverse thio effects are found for larger monovalent and divalent cations, including Na+, K+, NH4+, and Ba2+. Proton inventories are found to be unity in the presence of the larger monovalent and divalent ions, but two in the presence of Mg2+. Additionally, rate–pH profiles are inverted for the low charge density ions, and only imidazole plus ammonium ions rescue an inactive C75Δ variant in the absence of Mg2+. Results from the thio effect experiments, rate–pH profiles, proton inventories, and ammonium/imidazole rescue experiments, combined with QM/MM free energy simulations, support a change in the mechanism of HDV ribozyme self-cleavage from concerted and metal ion-stabilized to stepwise and proton transfer-stabilized as the charge density of the metal ion decreases. PMID:25799319

Effects of inhibition of nitric oxide synthase on basal anterior segment ocular blood flows and on potential autoregulatory mechanisms.

PubMed

Koss, M C

2001-08-01

Experiments were undertaken to determine the role played by nitric oxide (NO) in basal ocular blood flow in the anterior aspect of the eye. Subsequent studies focused on existence of autoregulatory mechanisms and on the potential involvement of NO. Cats were anesthetized with pentobarbital (36 mg/kg, i.p.). A femoral artery and vein were cannulated for measuring blood pressure and for drug administration, respectively. Anterior segment blood flow was measured in a continuous fashion from the long posterior ciliary artery (LPCA) using ultrasonic flowmetry and from the anterior choroid using laser-Doppler flowmetry. A needle was placed into the anterior chamber, and autoregulatory mechanisms were studied by decreasing ocular perfusion pressure via stepwise elevations of IOP. Non-selective inhibition of NO synthase with L-NAME (20 mg/kg, i.v.) significantly decreased basal blood flow from both sites. L-NAME (5 mg/kg, i.v.) was without effect as was D-NAME (25 mg/kg, i.v.). Increasing IOP produced a linear decrease on LPCA blood flow indicating absence of autoregulation. In contrast, stepwise elevation of IOP produced a delayed, non-linear response in the anterior choroid suggestive of a strong autoregulatory response. Neither response to elevated ocular perfusion pressure was further altered by inhibition of NO synthase with L-NAME (20 mg/kg, i.v.). The results confirm previous reports that nitric oxide plays a pivotal role in maintenance of basal ocular blood flow. Autoregulation was not seen in the LPCA. In contrast, there was a clear autoregulatory response in the anterior choroid, although neither response was altered by inhibition of NO synthase.

Discrimination of Geographical Origin of Asian Garlic Using Isotopic and Chemical Datasets under Stepwise Principal Component Analysis.

PubMed

Liu, Tsang-Sen; Lin, Jhen-Nan; Peng, Tsung-Ren

2018-01-16

Isotopic compositions of δ 2 H, δ 18 O, δ 13 C, and δ 15 N and concentrations of 22 trace elements from garlic samples were analyzed and processed with stepwise principal component analysis (PCA) to discriminate garlic's country of origin among Asian regions including South Korea, Vietnam, Taiwan, and China. Results indicate that there is no single trace-element concentration or isotopic composition that can accomplish the study's purpose and the stepwise PCA approach proposed does allow for discrimination between countries on a regional basis. Sequentially, Step-1 PCA distinguishes garlic's country of origin among Taiwanese, South Korean, and Vietnamese samples; Step-2 PCA discriminates Chinese garlic from South Korean garlic; and Step-3 and Step-4 PCA, Chinese garlic from Vietnamese garlic. In model tests, countries of origin of all audit samples were correctly discriminated by stepwise PCA. Consequently, this study demonstrates that stepwise PCA as applied is a simple and effective approach to discriminating country of origin among Asian garlics. © 2018 American Academy of Forensic Sciences.

Supramolecular self-assembly of heterobimetallic complexes: a new N,P-based, selective heteroditopic ligand.

PubMed

Hutchinson, Daniel John; Clauss, Reike; Sárosi, Menyhárt-Botond; Hey-Hawkins, Evamarie

2018-01-23

Pyrimidine-hydrazone and phosphole architectures have been combined to create a new heteroditopic ligand capable of forming heterobimetallic Zn II /Pd II , Pb II /Pd II and Cu II /Pd II complexes in high yielding stepwise or one pot reactions. The catalytic activity of these complexes in Heck coupling and Miyaura borylation reactions was investigated.

Breaking Benzene Aromaticity-Computational Insights into the Mechanism of the Tungsten-Containing Benzoyl-CoA Reductase.

PubMed

Culka, Martin; Huwiler, Simona G; Boll, Matthias; Ullmann, G Matthias

2017-10-18

Aromatic compounds are environmental pollutants with toxic and carcinogenic properties. Despite the stability of aromatic rings, bacteria are able to degrade the aromatic compounds into simple metabolites and use them as growth substrates under oxic or even under anoxic conditions. In anaerobic microorganisms, most monocyclic aromatic growth substrates are converted to the central intermediate benzoyl-coenzyme A, which is enzymatically reduced to cyclohexa-1,5-dienoyl-CoA. The strictly anaerobic bacterium Geobacter metallireducens uses the class II benzoyl-CoA reductase complex for this reaction. The catalytic BamB subunit of this complex harbors an active site tungsten-bis-pyranopterin cofactor with the metal being coordinated by five protein/cofactor-derived sulfur atoms and a sixth, so far unknown, ligand. Although BamB has been biochemically and structurally characterized, its mechanism still remains elusive. Here we use continuum electrostatic and QM/MM calculations to model benzoyl-CoA reduction by BamB. We aim to elucidate the identity of the sixth ligand of the active-site tungsten ion together with the interplay of the electron and proton transfer events during the aromatic ring reduction. On the basis of our calculations, we propose that benzoyl-CoA reduction is initiated by a hydrogen atom transfer from a W(IV) species with an aqua ligand, yielding W(V)-[OH - ] and a substrate radical intermediate. In the next step, a proton-assisted second electron transfer takes place with a conserved active-site histidine serving as the second proton donor. Interestingly, our calculations suggest that the electron for the second reduction step is taken from the pyranopterin cofactors rather than from the tungsten ion. The resulting cationic radical, which is distributed over both pyranopterins, is stabilized by conserved anionic amino acid residues. The stepwise mechanism of the reduction shows similarities to the Birch reduction known from organic chemistry. However, the strict coupling of protons and electrons allows the reaction to proceed under milder conditions.

The genetic basis of a plant–insect coevolutionary key innovation

PubMed Central

Wheat, Christopher W.; Vogel, Heiko; Wittstock, Ute; Braby, Michael F.; Underwood, Dessie; Mitchell-Olds, Thomas

2007-01-01

Ehrlich and Raven formally introduced the concept of stepwise coevolution using butterfly and angiosperm interactions in an attempt to account for the impressive biological diversity of these groups. However, many biologists currently envision butterflies evolving 50 to 30 million years (Myr) after the major angiosperm radiation and thus reject coevolutionary origins of butterfly biodiversity. The unresolved central tenet of Ehrlich and Raven's theory is that evolution of plant chemical defenses is followed closely by biochemical adaptation in insect herbivores, and that newly evolved detoxification mechanisms result in adaptive radiation of herbivore lineages. Using one of their original butterfly-host plant systems, the Pieridae, we identify a pierid glucosinolate detoxification mechanism, nitrile-specifier protein (NSP), as a key innovation. Larval NSP activity matches the distribution of glucosinolate in their host plants. Moreover, by using five different temporal estimates, NSP seems to have evolved shortly after the evolution of the host plant group (Brassicales) (≈10 Myr). An adaptive radiation of these glucosinolate-feeding Pierinae followed, resulting in significantly elevated species numbers compared with related clades. Mechanistic understanding in its proper historical context documents more ancient and dynamic plant–insect interactions than previously envisioned. Moreover, these mechanistic insights provide the tools for detailed molecular studies of coevolution from both the plant and insect perspectives. PMID:18077380

Insulin degludec/insulin aspart once daily in Type 2 diabetes: a comparison of simple or stepwise titration algorithms (BOOST® : SIMPLE USE).

PubMed

Park, S W; Bebakar, W M W; Hernandez, P G; Macura, S; Hersløv, M L; de la Rosa, R

2017-02-01

To compare the efficacy and safety of two titration algorithms for insulin degludec/insulin aspart (IDegAsp) administered once daily with metformin in participants with insulin-naïve Type 2 diabetes mellitus. This open-label, parallel-group, 26-week, multicentre, treat-to-target trial, randomly allocated participants (1:1) to two titration arms. The Simple algorithm titrated IDegAsp twice weekly based on a single pre-breakfast self-monitored plasma glucose (SMPG) measurement. The Stepwise algorithm titrated IDegAsp once weekly based on the lowest of three consecutive pre-breakfast SMPG measurements. In both groups, IDegAsp once daily was titrated to pre-breakfast plasma glucose values of 4.0-5.0 mmol/l. Primary endpoint was change from baseline in HbA 1c (%) after 26 weeks. Change in HbA 1c at Week 26 was IDegAsp Simple -14.6 mmol/mol (-1.3%) (to 52.4 mmol/mol; 6.9%) and IDegAsp Stepwise -11.9 mmol/mol (-1.1%) (to 54.7 mmol/mol; 7.2%). The estimated between-group treatment difference was -1.97 mmol/mol [95% confidence interval (CI) -4.1, 0.2] (-0.2%, 95% CI -0.4, 0.02), confirming the non-inferiority of IDegAsp Simple to IDegAsp Stepwise (non-inferiority limit of ≤ 0.4%). Mean reduction in fasting plasma glucose and 8-point SMPG profiles were similar between groups. Rates of confirmed hypoglycaemia were lower for IDegAsp Stepwise [2.1 per patient years of exposure (PYE)] vs. IDegAsp Simple (3.3 PYE) (estimated rate ratio IDegAsp Simple /IDegAsp Stepwise 1.8; 95% CI 1.1, 2.9). Nocturnal hypoglycaemia rates were similar between groups. No severe hypoglycaemic events were reported. In participants with insulin-naïve Type 2 diabetes mellitus, the IDegAsp Simple titration algorithm improved HbA 1c levels as effectively as a Stepwise titration algorithm. Hypoglycaemia rates were lower in the Stepwise arm. © 2016 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Step-wise pulling protocols for non-equilibrium dynamics

NASA Astrophysics Data System (ADS)

Ngo, Van Anh

The fundamental laws of thermodynamics and statistical mechanics, and the deeper understandings of quantum mechanics have been rebuilt in recent years. It is partly because of the increasing power of computing resources nowadays, that allow shedding direct insights into the connections among the thermodynamics laws, statistical nature of our world, and the concepts of quantum mechanics, which have not yet been understood. But mostly, the most important reason, also the ultimate goal, is to understand the mechanisms, statistics and dynamics of biological systems, whose prevailing non-equilibrium processes violate the fundamental laws of thermodynamics, deviate from statistical mechanics, and finally complicate quantum effects. I believe that investigations of the fundamental laws of non-equilibrium dynamics will be a frontier research for at least several more decades. One of the fundamental laws was first discovered in 1997 by Jarzynski, so-called Jarzynski's Equality. Since then, different proofs, alternative descriptions of Jarzynski's Equality, and its further developments and applications have been quickly accumulated. My understandings, developments and applications of an alternative theory on Jarzynski's Equality form the bulk of this dissertation. The core of my theory is based on stepwise pulling protocols, which provide deeper insight into how fluctuations of reaction coordinates contribute to free-energy changes along a reaction pathway. We find that the most optimal pathways, having the largest contribution to free-energy changes, follow the principle of detailed balance. This is a glimpse of why the principle of detailed balance appears so powerful for sampling the most probable statistics of events. In a further development on Jarzynski's Equality, I have been trying to use it in the formalism of diagonal entropy to propose a way to extract useful thermodynamic quantities such temperature, work and free-energy profiles from far-from-equilibrium ensembles, which can be used to characterize non-equilibrium dynamics. Furthermore, we have applied the stepwise pulling protocols and Jarzynski's Equality to investigate the ion selectivity of potassium channels via molecular dynamics simulations. The mechanism of the potassium ion selectivity has remained poorly understood for over fifty years, although a Nobel Prize was awarded to the discovery of the molecular structure of a potassium-selective channel in 2003. In one year of performing simulations, we were able to reproduce the major results of ion selectivity accumulated in fifty years. We have been even boldly going further to propose a new model for ion selectivity based on the structural rearrangement of the selectivity filter of potassium-selective KcsA channels. This structural rearrangement has never been shown to play such a pivotal role in selecting and conducting potassium ions, but effectively rejecting sodium ions. Using the stepwise pulling protocols, we are also able to estimate conductance for ion channels, which remains elusive by using other methods. In the light of ion channels, we have also investigated how a synthetic channel of telemeric G-quadruplex conducts different types of ions. These two studies on ion selectivity not only constitute an interesting part of this dissertation, but also will enable us to further explore a new set of ion-selectivity principles. Beside the focus of my dissertation, I used million-atom molecular dynamics simulations to investigate the mechanical properties of body-centered-cubic (BCCS) and face-centered-cubic (FCCS) supercrystals of DNA-functionalized gold nanoparticles. These properties are valuable for examining whether these supercrystals can be used in gene delivery and gene therapy. The formation of such ordered supercrystals is useful to protect DNAs or RNAs from being attacked and destroyed by enzymes in cells. I also performed all-atom molecular dynamics simulations to study a pure oleic acid (OA) membrane in water that results into a triple-layer structure. The simulations show that the trans-membrane movement of water and OAs is cooperative and correlated, and agrees with experimentally measured absorption rates. The simulation results support the idea that OA flip-flop is more favorable than transport by means of functional proteins. This study might provide further insight into how primitive cell membranes work, and how the interplay and correlation between water and fatty acids may occur.

Studies on the Himbert Intramolecular Arene/ Allene Diels – Alder Cycloaddition. Mechanistic Studies and Expansion of Scope to All-Carbon Tethers

PubMed Central

Schmidt, Yvonne; Lam, Jonathan K.; Pham, Hung V.; Houk, K. N.; Vanderwal, Christopher D.

2013-01-01

The unusual intramolecular arene/allene cycloaddition described thirty years ago by Himbert permits rapid access to strained polycyclic compounds that offer great potential for the synthesis of complex scaffolds. To more fully understand the mechanism of this cycloaddition reaction, and to guide efforts to extend its scope to new substrates, quantum mechanical computational methods were employed in concert with laboratory experiments. These studies indicated that the cycloadditions likely proceed via concerted processes; a stepwise biradical mechanism was shown to be higher in energy in the cases studied. The original Himbert cycloaddition chemistry is also extended from heterocyclic to carbocyclic systems, with computational guidance used to predict thermodynamically favorable cases. Complex polycyclic scaffolds result from the combination of the cycloaddition and subsequent ring-rearrangement metathesis reactions. PMID:23634642

Thermal properties of alkali-activated aluminosilicates

NASA Astrophysics Data System (ADS)

Florian, Pavel; Valentova, Katerina; Fiala, Lukas; Zmeskal, Oldrich

2017-07-01

The paper is focused on measurements and evaluation of thermal properties of alkali-activated aluminosilicates (AAA) with various carbon admixtures. Such composites consisting of blast-furnace slag, quartz sand, water glass as alkali activator and small amount of electrically conductive carbon admixture exhibit better electric and thermal properties than the reference material. Such enhancement opens up new practical applications, such as designing of snow-melting, de-icing or self-sensing systems that do not need any external sensors to detect current condition of building material. Thermal properties of the studied materials were measured by the step-wise transient method and mutually compared.

Tandem phosphorylation of Ser-911 and Thr-912 at the C terminus of yeast plasma membrane H+-ATPase leads to glucose-dependent activation.

PubMed

Lecchi, Silvia; Nelson, Clark J; Allen, Kenneth E; Swaney, Danielle L; Thompson, Katie L; Coon, Joshua J; Sussman, Michael R; Slayman, Carolyn W

2007-12-07

In recent years there has been growing interest in the post-translational regulation of P-type ATPases by protein kinase-mediated phosphorylation. Pma1 H(+)-ATPase, which is responsible for H(+)-dependent nutrient uptake in yeast (Saccharomyces cerevisiae), is one such example, displaying a rapid 5-10-fold increase in activity when carbon-starved cells are exposed to glucose. Activation has been linked to Ser/Thr phosphorylation in the C-terminal tail of the ATPase, but the specific phosphorylation sites have not previously been mapped. The present study has used nanoflow high pressure liquid chromatography coupled with electrospray electron transfer dissociation tandem mass spectrometry to identify Ser-911 and Thr-912 as two major phosphorylation sites that are clearly related to glucose activation. In carbon-starved cells with low Pma1 activity, peptide 896-918, which was derived from the C terminus upon Lys-C proteolysis, was found to be singly phosphorylated at Thr-912, whereas in glucose-metabolizing cells with high ATPase activity, the same peptide was doubly phosphorylated at Ser-911 and Thr-912. Reciprocal (14)N/(15)N metabolic labeling of cells was used to measure the relative phosphorylation levels at the two sites. The addition of glucose to carbon-starved cells led to a 3-fold reduction in the singly phosphorylated form and an 11-fold increase in the doubly phosphorylated form. These results point to a mechanism in which the stepwise phosphorylation of two tandemly positioned residues near the C terminus mediates glucose-dependent activation of the H(+)-ATPase.

Behavioral activation: Is it the expectation or achievement, of mastery or pleasure that contributes to improvement in depression?

PubMed

Furukawa, Toshi A; Imai, Hissei; Horikoshi, Masaru; Shimodera, Shinji; Hiroe, Takahiro; Funayama, Tadashi; Akechi, Tatsuo

2018-06-06

Behavioral activation (BA) is receiving renewed interest as a stand-alone or as a component of cognitive-behavior therapy (CBT) for depression. However, few studies have examined which aspects of BA are most contributory to its efficacy. This is a secondary analysis of a 9-week randomized controlled trial of smartphone CBT for patients with major depression. Depression severity was measured at baseline and at end of treatment by the Patient Health Questionnaire-9. All aspects of behavioral activation tasks that the participants had engaged in, including their expected mastery and pleasure and obtained mastery and pleasure, were recorded in the web server. We examined their contribution to improvement in depression as simple correlations and in stepwise multivariable linear regression. Among the 78 patients who completed at least one behavioral experiment, all aspects of expected or achieved mastery or pleasure correlated with change in depression severity. Discrepancy between the expectation and achievement, representing unexpected gain in mastery or pleasure, was not correlated. In stepwise regression, expected mastery and pleasure, especially the maximum level of the latter, emerged as the strongest contributing factors. The study is observational and cannot deduce cause-effect relationships. It may be the expected and continued sense of pleasure in planning activities that are most meaningful and rewarding to individuals, and not the simple level or amount of obtained pleasure, that contributes to the efficacy of BA. Copyright © 2018. Published by Elsevier B.V.

Loss of EGFR confers acquired resistance to AZD9291 in an EGFR-mutant non-small cell lung cancer cell line with an epithelial-mesenchymal transition phenotype.

PubMed

Xu, Jing; Zhao, Xiaoting; He, Dengfeng; Wang, Jinghui; Li, Weiying; Liu, Yinghui; Ma, Li; Jiang, Mei; Teng, Yu; Wang, Ziyu; Gu, Meng; Wu, Jianbin; Wang, Yue; Yue, Wentao; Zhang, Shucai

2018-05-24

AZD9291 is an irreversible, small-molecule inhibitor which has potency against mutant EGFR- and T790M-resistant mutation. Despite the encouraging efficacy in clinical, the acquired resistance will finally occur. Further study will need to be done to identify the acquired resistance mechanisms and determine the next treatment. We established an AZD9291-resistant cell line (HCC827/AZDR) from parental HCC827 cell line through stepwise pulsed selection of AZD9291. The expression of EGFR and its downstream pathways were determined by western blot analysis or immunofluorescence assay. The sensitivity to indicated agents were evaluated by MTS. Compared with parental HCC827 cells, the HCC827/AZDR cells showed high resistance to AZD9291 and other EGFR-TKIs, and exhibited a mesenchymal-like phenotype. Almost complete loss of EGFR expression was observed in HCC827/AZDR cells. But the activation of downstream pathway, MAPK signaling, was found in HCC827/AZDR cells even in the presence of AZD9291. Inhibition of MAPK signaling had no effect on cell viability of HCC827/AZDR and could not reverse AZD9291 resistance because of the subsequent activation of AKT signaling. When treated with the combination of AKT and MAPK inhibitor, HCC827/AZDR showed remarkable growth inhibition. Loss of EGFR could be proposed as a potential acquired resistance mechanism of AZD9291 in EGFR-mutant NSCLC cells with an EMT phenotype. Despite the loss of EGFR, the activation of MAPK pathway which had crosstalk with AKT pathway could maintain the proliferation and survival of resistant cells. Blocking MAPK and AKT signaling may be a potential therapeutic strategy following AZD9291 resistance.

Transition State Analysis of Thymidine Hydrolysis by Human Thymidine Phosphorylase*

PubMed Central

Schwartz, Phillip A.; Vetticatt, Mathew; Schramm, Vern L.

2010-01-01

Human thymidine phosphorylase (hTP) is responsible for thymidine (dT) homeostasis and its action promotes angiogenesis. In the absence of phosphate, hTP catalyzes a slow hydrolytic depyrimidination of dT yielding thymine and 2-deoxyribose (dRib). Its transition state was characterized using multiple kinetic isotope effect (KIE) measurements. Isotopically enriched thymidines were synthesized enzymatically from glucose or (deoxy)ribose and intrinsic KIEs were used to interpret the transition state structure. KIEs from [1′-14C]-, [1-15N]-, [1′-3H]-, [2′R-3H]-, [2′S-3H]-, [4′-3H]-, [5′-3H]dTs provided values of 1.033 ± 0.002, 1.004 ± 0.002, 1.325 ± 0.003, 1.101 ± 0.004, 1.087 ± 0.005, 1.040 ± 0.003, and 1.033 ± 0.003, respectively. Transition state analysis revealed a stepwise mechanism with a 2-deoxyribocation formed early and a higher energetic barrier for nucleophilic attack of a water molecule on the high energy intermediate. An equilibrium exists between the deoxyribocation and reactants prior to the irreversible nucleophilic attack by water. The results establish activation of the thymine leaving group without requirement for phosphate. A transition state constrained to match the intrinsic KIEs was found using density functional theory. An active site histidine (His116) is implicated as the catalytic base for activation of the water nucleophile at the rate-limiting transition state. The distance between the water nucleophile and the anomeric carbon (rC-O) is predicted to be 2.3 Å at the transition state. The transition state model predicts that deoxyribose adopts a mild 3′-endo confirmation during nucleophilic capture. These results differ from the concerted bimolecular mechanism reported for the arsenolytic reaction PMID:20804144

Role of platinum DNA damage-induced transcriptional inhibition in chemotherapy-induced neuronal atrophy and peripheral neurotoxicity.

PubMed

Yan, Fang; Liu, Johnson J; Ip, Virginia; Jamieson, Stephen M F; McKeage, Mark J

2015-12-01

Platinum-based anticancer drugs cause peripheral neurotoxicity by damaging sensory neurons within the dorsal root ganglia (DRG), but the mechanisms are incompletely understood. The roles of platinum DNA binding, transcription inhibition and altered cell size were investigated in primary cultures of rat DRG cells. Click chemistry quantitative fluorescence imaging of RNA-incorporated 5-ethynyluridine showed high, but wide ranging, global levels of transcription in individual neurons that correlated with their cell body size. Treatment with platinum drugs reduced neuronal transcription and cell body size to an extent that corresponded to the amount of preceding platinum DNA binding, but without any loss of neuronal cells. The effects of platinum drugs on neuronal transcription and cell body size were inhibited by blocking platinum DNA binding with sodium thiosulfate, and mimicked by treatment with a model transcriptional inhibitor, actinomycin D. In vivo oxaliplatin treatment depleted the total RNA content of DRG tissue concurrently with altering DRG neuronal size. These findings point to a mechanism of chemotherapy-induced peripheral neurotoxicity, whereby platinum DNA damage induces global transcriptional arrest leading in turn to neuronal atrophy. DRG neurons may be particularly vulnerable to this mechanism of toxicity because of their requirements for high basal levels of global transcriptional activity. Findings point to a new stepwise mechanism of chemotherapy-induced peripheral neurotoxicity, whereby platinum DNA damage induces global transcriptional arrest leading in turn to neuronal atrophy. Dorsal root ganglion neurons may be particularly vulnerable to this neurotoxicity because of their high global transcriptional outputs, demonstrated in this study by click chemistry quantitative fluorescence imaging. © 2015 International Society for Neurochemistry.

Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015.

PubMed

Bousquet, J; Anto, J M; Akdis, M; Auffray, C; Keil, T; Momas, I; Postma, D S; Valenta, R; Wickman, M; Cambon-Thomsen, A; Haahtela, T; Lambrecht, B N; Lodrup Carlsen, K C; Koppelman, G H; Sunyer, J; Zuberbier, T; Annesi-Maesano, I; Arno, A; Bindslev-Jensen, C; De Carlo, G; Forastiere, F; Heinrich, J; Kowalski, M L; Maier, D; Melén, E; Palkonen, S; Smit, H A; Standl, M; Wright, J; Asarnoj, A; Benet, M; Ballardini, N; Garcia-Aymerich, J; Gehring, U; Guerra, S; Hohman, C; Kull, I; Lupinek, C; Pinart, M; Skrindo, I; Westman, M; Smagghe, D; Akdis, C; Albang, R; Anastasova, V; Anderson, N; Bachert, C; Ballereau, S; Ballester, F; Basagana, X; Bedbrook, A; Bergstrom, A; von Berg, A; Brunekreef, B; Burte, E; Carlsen, K H; Chatzi, L; Coquet, J M; Curin, M; Demoly, P; Eller, E; Fantini, M P; Gerhard, B; Hammad, H; von Hertzen, L; Hovland, V; Jacquemin, B; Just, J; Keller, T; Kerkhof, M; Kiss, R; Kogevinas, M; Koletzko, S; Lau, S; Lehmann, I; Lemonnier, N; McEachan, R; Mäkelä, M; Mestres, J; Minina, E; Mowinckel, P; Nadif, R; Nawijn, M; Oddie, S; Pellet, J; Pin, I; Porta, D; Rancière, F; Rial-Sebbag, A; Saeys, Y; Schuijs, M J; Siroux, V; Tischer, C G; Torrent, M; Varraso, R; De Vocht, J; Wenger, K; Wieser, S; Xu, C

2016-11-01

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda. © 2016 The Authors. Allergy Published by John Wiley & Sons Ltd.

Dietary Manganese Modulates PCB126 Toxicity, Metal Status, and MnSOD in the Rat

PubMed Central

Wang, Bingxuan; Klaren, William D.; Wels, Brian R.; Simmons, Donald L.; Olivier, Alicia K.; Wang, Kai; Robertson, Larry W.; Ludewig, Gabriele

2016-01-01

PCB126 (3,3′,4,4′,5-pentachlorobiphenyl) is a potent aryl hydrocarbon receptor agonist and induces oxidative stress. Because liver manganese (Mn) levels decrease in response to PCB126, a Mn dietary study was designed to investigate the role of Mn in PCB126 toxicity. Male Sprague Dawley rats received diets containing 0, 10, or 150 ppm added Mn for 3 weeks, followed by a single ip injection of corn oil or PCB126 (5 µmol/kg body weight). After 2 weeks, Mn, Cu, Zn, and Fe levels in the heart, liver, and liver mitochondria, and Mn-containing superoxide dismutase (MnSOD) and metallothionein mRNA, MnSOD protein, and MnSOD activity were determined. Mn levels in liver, heart, and liver mitochondria were strongly decreased by the Mn-deficient diet. Small effects on Fe levels and a stepwise increase in MnSOD activity with dietary Mn were also visible. PCB126 caused profound changes in Cu (up), Zn, Fe, and Mn (down) in liver, but not in heart, and differing effects (Cu, Zn, and Fe up, Mn down) in liver mitochondria. Liver MnSOD and metallothionein mRNA levels and MnSOD protein were increased but MnSOD activity was decreased by PCB126. PCB126-induced liver enlargement was dose-dependently reduced with increasing dietary Mn. These changes in metals homeostasis and MnSOD activity in liver but not heart may be a/the mechanism of PCB126 liver-specific toxicity. Specifically, transport of Fenton metals (Cu, Fe) into and Mn out of the mitochondria, a probable mechanism for lower MnSOD activity, may be a/the cause of PCB126-induced oxidative stress. The role of metallothioneins needs further evaluation. Dietary Mn slightly alleviated PCB126-induced toxicities. PMID:26660635

Cerebral Activations Related to Ballistic, Stepwise Interrupted and Gradually Modulated Movements in Parkinson Patients

PubMed Central

Toxopeus, Carolien M.; Maurits, Natasha M.; Valsan, Gopal; Conway, Bernard A.; Leenders, Klaus L.; de Jong, Bauke M.

2012-01-01

Patients with Parkinson’s disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular. PMID:22911738

Effects of stepwise dry/wet-aging and freezing on meat quality of beef loins.

PubMed

Kim, Yuan H Brad; Meyers, Brandon; Kim, Hyun-Wook; Liceaga, Andrea M; Lemenager, Ronald P

2017-01-01

The objective of this study was to evaluate the effects of stepwise dry/wet-aging and freezing method on quality attributes of beef loins. Paired loins (M. Longissimus lumborum) from eight carcasses were assigned to either stepwise dry/wet-aging (carcass dry-aging for 10days then further wet-aging for 7days in vacuum bags) or carcass dry-aging only for 17days. Then, each loin was divided into three sections for freezing (never-frozen, blast or cryogenic freezing). Stepwise dry/wet-aged loin had lower purge/drip loss and shear force than conventionally dry-aged loin (P<0.05), but similar color and sensory characteristics (P>0.05). The cryogenic freezing resulted in a significant decrease in shear force values and a significant improvement in water-holding capacity (WHC). These findings indicate that the stepwise dry/wet-aging coupled with cryogenic freezing could provide beneficial impacts to the local meat industry by providing equivalent quality attributes as conventional dry-aging and improving WHC of frozen/thawed meat, while reducing the time needed for dry-aging. Copyright © 2016 Elsevier Ltd. All rights reserved.

Revisit of the Saito-Dresselhaus-Dresselhaus C2 ingestion model: on the mechanism of atomic-carbon-participated fullerene growth.

PubMed

Wang, Wei-Wei; Dang, Jing-Shuang; Zhao, Xiang; Nagase, Shigeru

2017-11-09

We introduce a mechanistic study based on a controversial fullerene bottom-up growth model proposed by R. Saito, G. Dresselhaus, and M. S. Dresselhaus. The so-called SDD C 2 addition model has been dismissed as chemically inadmissible but here we prove that it is feasible via successive atomic-carbon-participated addition and migration reactions. Kinetic calculations on the formation of isolated pentagon rule (IPR)-obeying C 70 and Y 3 N@C 80 are carried out by employing the SDD model for the first time. A stepwise mechanism is proposed with a considerably low barrier of ca. 2 eV which is about 3 eV lower than a conventional isomerization-containing fullerene growth pathway.

Theoretical study on the ring-opening hydrolysis reactions of N-alkylmaleimide dimers

NASA Astrophysics Data System (ADS)

Tan, Xue-Jie; Wang, Chao; Guo, Xian-Kun

2018-01-01

On the basis of our previous experimental results, the ring-opening hydrolysis reaction mechanisms of two kinds of N-alkylmaleimide dimers without or with the assistance of one and two water molecules have been theoretically investigated in detail. All possible geometries were optimized using the B3LYP/6-311+G(d,p)//B3LYP/6-31+G(d) method in the gas phase and ethanol solution. Calculated results show that every pathway is a four-step hydrolytic degradation process and every step could occur in a concerted way, instead of previously suggested asynchronous stepwise mechanism. Extra H2O or ethanol could act as carriers of proton. The results are consistent with experimental observations.

β-Thalassemia intermedia: a comprehensive overview and novel approaches.

PubMed

Asadov, Chingiz; Alimirzoeva, Zohra; Mammadova, Tahira; Aliyeva, Gunay; Gafarova, Shahla; Mammadov, Jeyhun

2018-01-29

β-Thalassemia intermedia is a clinical condition of intermediate gravity between β-thalassemia minor, the asymptomatic carrier, and β-thalassemia major, the transfusion-dependent severe anemia. It is characterized by a significant clinical polymorphism, which is attributable to its genetic heterogeneity. Ineffective erythropoiesis, chronic anemia, and iron overload contribute to the clinical complications of thalassemia intermedia through stepwise pathophysiological mechanisms. These complications, including splenomegaly, extramedullary erythropoiesis, iron accumulation, leg ulcers, thrombophilia, and bone abnormalities can be managed via fetal hemoglobin induction, occasional transfusions, chelation, and in some cases, stem cell transplantation. Given its clinical diversity, thalassemia intermedia patients require tailored approaches to therapy. Here we present an overview and novel approaches to the genetic basis, pathophysiological mechanisms, clinical complications, and optimal management of thalassemia intermedia.

2D-QSAR study of fullerene nanostructure derivatives as potent HIV-1 protease inhibitors

NASA Astrophysics Data System (ADS)

Barzegar, Abolfazl; Jafari Mousavi, Somaye; Hamidi, Hossein; Sadeghi, Mehdi

2017-09-01

The protease of human immunodeficiency virus1 (HIV-PR) is an essential enzyme for antiviral treatments. Carbon nanostructures of fullerene derivatives, have nanoscale dimension with a diameter comparable to the diameter of the active site of HIV-PR which would in turn inhibit HIV. In this research, two dimensional quantitative structure-activity relationships (2D-QSAR) of fullerene derivatives against HIV-PR activity were employed as a powerful tool for elucidation the relationships between structure and experimental observations. QSAR study of 49 fullerene derivatives was performed by employing stepwise-MLR, GAPLS-MLR, and PCA-MLR models for variable (descriptor) selection and model construction. QSAR models were obtained with higher ability to predict the activity of the fullerene derivatives against HIV-PR by a correlation coefficient (R2training) of 0.942, 0.89, and 0.87 as well as R2test values of 0.791, 0.67and 0.674 for stepwise-MLR, GAPLS-MLR, and PCA -MLR models, respectively. Leave-one-out cross-validated correlation coefficient (R2CV) and Y-randomization methods confirmed the models robustness. The descriptors indicated that the HIV-PR inhibition depends on the van der Waals volumes, polarizability, bond order between two atoms and electronegativities of fullerenes derivatives. 2D-QSAR simulation without needing receptor's active site geometry, resulted in useful descriptors mainly denoting ;C60 backbone-functional groups; and ;C60 functional groups; properties. Both properties in fullerene refer to the ligand fitness and improvement van der Waals interactions with HIV-PR active site. Therefore, the QSAR models can be used in the search for novel HIV-PR inhibitors based on fullerene derivatives.

Factors affecting match performance in professional Australian football.

PubMed

Sullivan, Courtney; Bilsborough, Johann C; Cianciosi, Michael; Hocking, Joel; Cordy, Justin T; Coutts, Aaron J

2014-05-01

To determine the physical activity measures and skill-performance characteristics that contribute to coaches' perception of performance and player performance rank in professional Australian Football (AF). Prospective, longitudinal. Physical activity profiles were assessed via microtechnology (GPS and accelerometer) from 40 professional AF players from the same team during 15 Australian Football League games. Skill-performance measure and player-rank scores (Champion Data Rank) were provided by a commercial statistical provider. The physical-performance variables, skill involvements, and individual player performance scores were expressed relative to playing time for each quarter. A stepwise multiple regression was used to examine the contribution of physical activity and skill involvements to coaches' perception of performance and player rank in AF. Stepwise multiple-regression analysis revealed that 42.2% of the variance in coaches' perception of a player's performance could be explained by the skill-performance characteristics (player rank/min, effective kicks/min, pressure points/min, handballs/min, and running bounces/ min), with a small contribution from physical activity measures (accelerations/min) (adjusted R2 = .422, F6,282 = 36.054, P < .001). Multiple regression also revealed that 66.4% of the adjusted variance in player rank could be explained by total disposals/min, effective kicks/min, pressure points/min, kick clangers/min, marks/min, speed (m/min), and peak speed (adjusted R2 = .664, F7,281 = 82.289, P < .001). Increased physical activity throughout a match (speed [m/min] β - 0.097 and peak speed β - 0.116) negatively affects player rank in AF. Skill performance rather than increased physical activity is more important to coaches' perception of performance and player rank in professional AF.

A mechanistic study and computational prediction of iron, cobalt and manganese cyclopentadienone complexes for hydrogenation of carbon dioxide.

PubMed

Ge, Hongyu; Chen, Xiangyang; Yang, Xinzheng

2016-10-13

A series of cobalt and manganese cyclopentadienone complexes are proposed and examined computationally as promising catalysts for hydrogenation of CO 2 to formic acid with total free energies as low as 20.0 kcal mol -1 in aqueous solution. Density functional theory study of the newly designed cobalt and manganese complexes and experimentally reported iron cyclopentadienone complexes reveals a stepwise hydride transfer mechanism with a water or a methanol molecule assisted proton transfer for the cleavage of H 2 as the rate-determining step.

Serum levels of fatty acid binding protein 4 and fat metabolic markers in relation to catecholamines following exercise.

PubMed

Iso, Tatsuya; Sunaga, Hiroaki; Matsui, Hiroki; Kasama, Shu; Oshima, Naomi; Haruyama, Hikari; Furukawa, Nozomi; Nakajima, Kiyomi; Machida, Tetsuo; Murakami, Masami; Yokoyama, Tomoyuki; Kurabayashi, Masahiko

2017-11-01

Lipolysis is stimulated by activation of adrenergic inputs to adipose tissues. Our recent study showed that serum concentrations of fatty acid binding protein 4 (FABP4) are robustly elevated in patients with acute myocardial infarction and ventricular tachyarrhythmia, that display a marked activation of the sympathetic nervous system (SNS). However, it remains unknown whether circulating FABP4 concentrations are associated with exercise-induced SNS activation. Thirty one healthy volunteers underwent cardiopulmonary exercise testing on a cycle ergometer up to the workload levels below and above anaerobic threshold, low- and high-intensity exercise, respectively. Serial blood samplings were performed before and after exercise. High-intensity exercise significantly increased serum concentrations of FABP4 and catecholamines, and their concentrations declined fast thereafter in a similar fashion. These changes were accompanied by little, if any, changes in other metabolic markers. Regardless of adiposity, percent change from baseline to peak FABP4 levels (%FABP4) was comparable in all subjects. Stepwise regression analysis revealed that %FABP4 was highly correlated with that in norepinephrine. Our study reveals the significant correlation between circulating FABP4 and norepinephrine levels during exercise testing. Together with the fact that FABP4 is secreted from adipocytes via β-adrenergic-mediated lipolytic mechanisms, this study suggests FABP4 as a potential biomarker for adrenergic overdrive. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Evolution of insecticide resistance in non-target black flies (Diptera: Simuliidae) from Argentina.

PubMed

Montagna, Cristina Mónica; Gauna, Lidia Ester; D'Angelo, Ana Pechen de; Anguiano, Olga Liliana

2012-06-01

Black flies, a non-target species of the insecticides used in fruit production, represent a severe medical and veterinary problem. Large increases in the level of resistance to the pyrethroids fenvalerate (more than 355-fold) and deltamethrin (162-fold) and a small increase in resistance to the organophosphate azinphos methyl (2-fold) were observed between 1996-2008 in black fly larvae under insecticide pressure. Eventually, no change or a slight variation in insecticide resistance was followed by a subsequent increase in resistance. The evolution of pesticide resistance in a field population is a complex and stepwise process that is influenced by several factors, the most significant of which is the insecticide selection pressure, such as the dose and frequency of application. The variation in insecticide susceptibility within a black fly population in the productive area may be related to changes in fruit-pest control. The frequency of individuals with esterase activities higher than the maximum value determined in the susceptible population increased consistently over the sampling period. However, the insecticide resistance was not attributed to glutathione S-transferase activity. In conclusion, esterase activity in black flies from the productive area is one mechanism underlying the high levels of resistance to pyrethroids, which have been recently used infrequently. These enzymes may be reselected by currently used pesticides and enhance the resistance to these insecticides.

Multiobjective Model of Time-of-Use and Stepwise Power Tariff for Residential Consumers in Regulated Power Markets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Bin; Yang, Rui; Li, Canbing

Here, time-of-use (TOU) rates and stepwise power tariff (SPT) are important economic levers to motivate residents to shift their electricity usage in response to electricity price. In this paper, a new multiobjective optimal tariff-making model of time-of-use and stepwise power tariff (TOUSPT) is proposed, which combines the complementary characteristics of two power tariffs, for residential energy conservation and peak load shaving. In the proposed approach, the residential demand response with price elasticity in regulated power market is considered to determine the optimum peak-valley TOU tariffs for each stepwise electricity partition. Furthermore, a practical case study is implemented to test themore » effectiveness of the proposed TOUSPT, and the results demonstrate that TOUSPT can achieve efficient end-use energy saving and also shift load from peak to off-peak periods.« less

Multiobjective Model of Time-of-Use and Stepwise Power Tariff for Residential Consumers in Regulated Power Markets

DOE PAGES

Zhou, Bin; Yang, Rui; Li, Canbing; ...

2017-07-04

Here, time-of-use (TOU) rates and stepwise power tariff (SPT) are important economic levers to motivate residents to shift their electricity usage in response to electricity price. In this paper, a new multiobjective optimal tariff-making model of time-of-use and stepwise power tariff (TOUSPT) is proposed, which combines the complementary characteristics of two power tariffs, for residential energy conservation and peak load shaving. In the proposed approach, the residential demand response with price elasticity in regulated power market is considered to determine the optimum peak-valley TOU tariffs for each stepwise electricity partition. Furthermore, a practical case study is implemented to test themore » effectiveness of the proposed TOUSPT, and the results demonstrate that TOUSPT can achieve efficient end-use energy saving and also shift load from peak to off-peak periods.« less

Impact of chemical oxidation on indigenous bacteria and mobilization of nutrients and subsequent bioremediation of crude oil-contaminated soil.

PubMed

Xu, Jinlan; Deng, Xin; Cui, Yiwei; Kong, Fanxing

2016-12-15

Fenton pre-oxidation provides nutrients to promote bioremediation. However, the effects of the indigenous bacteria that remain following Fenton oxidation on nutrient mobilization and subsequent bioremediation remain unclear. Experiments were performed with inoculation with native bacteria and foreign bacteria or without inoculation after four regimens of stepwise pre-oxidations. The effects of the indigenous bacteria remaining after stepwise oxidation on nutrient mobilization and subsequent bioremediation over 80 days were investigated. After stepwise Fenton pre-oxidation at a low H 2 O 2 concentration (225×4), the remaining indigenous bacterial populations reached their peak (4.8±0.17×10 6 CFU/g), the nutrients were mobilized rapidly, and the subsequent bioremediation of crude oil was improved (biodegradation efficiency of 35%). However, after stepwise Fenton pre-oxidation at a high H 2 O 2 concentration (450×4), only 3.6±0.16×10 3 CFU/g of indigenous bacteria remained, and the indigenous bacteria that degrade C 15 -C 30 alkanes were inhibited. The nutrient mobilization was then highly limited, and only 19% of total petroleum hydrocarbon was degraded. Furthermore, the recovery period after the low H 2 O 2 concentration stepwise Fenton pre-oxidation (225×4) was less than 20 days, which was 20-30 days shorter than with the other pre-oxidation treatments. Therefore, stepwise Fenton pre-oxidation at a low H 2 O 2 concentration protects indigenous bacterial populations and improves the nutrient mobilization and subsequent bioremediation. Copyright © 2016 Elsevier B.V. All rights reserved.

Quantitative and Mechanistic Assessment of Model Lipophilic Drugs in Micellar Solutions in the Transport Kinetics Across MDR1-MDCK Cell Monolayers.

PubMed

Ho, Norman F H; Nielsen, James; Peterson, Michelle; Burton, Philip S

2016-02-01

An approach to characterizing P-glycoprotein (Pgp) interaction potential for sparingly water-soluble compounds was developed using bidirectional transport kinetics in MDR1-MDCK cell monolayers. Paclitaxel, solubilized in a dilute polysorbate 80 (PS80) micellar solution, was used as a practical example. Although the passage of paclitaxel across the cell monolayer was initially governed by the thermodynamic activity of the micelle-solubilized drug solution, Pgp inhibition was sustained by the thermodynamic activity (i.e., critical micelle concentration) of the PS80 micellar solution bathing the apical (ap) membrane. The mechanistic understanding of the experimental strategies and treatment of data was supported by a biophysical model expressed in the form of transport events occurring at the ap and basolateral (bl) membranes in series whereas the vectorial directions of the transcellular kinetics were accommodated. The derived equations permitted the stepwise quantitative delineation of the Pgp efflux activity (inhibited and uninhibited by PS80) and the passive permeability coefficient of the ap membrane, the passive permeability at the bl membrane and, finally, the distinct coupling of these with efflux pump activity to identify the rate-determining steps and mechanisms. The Jmax/KM(∗) for paclitaxel was in the order of 10(-4) cm/s and the ap- and bl-membrane passive permeability coefficients were asymmetric, with bl-membrane permeability significantly greater than ap. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Neighborhood Stress and Autonomic Nervous System Activity during Sleep.

PubMed

Mellman, Thomas Alan; Bell, Kimberly Ann; Abu-Bader, Soleman Hassan; Kobayashi, Ihori

2018-04-04

Stressful neighborhood environments are known to adversely impact health and contribute to health disparities but underlying mechanisms are not well understood. Healthy sleep can provide a respite from sustained sympathetic nervous system (SNS) activity. Our objective was to evaluate relationships between neighborhood stress and nocturnal and daytime SNS and parasympathetic nervous system (PNS) activity. Eighty five urban-residing African Americans (56.5% female; mean age of 23.0) participated. Evaluation included surveys of neighborhood stress and sleep-related vigilance; and continuous ECG and actigraphic recording in participants' homes from which heart rate variability (HRV) analysis for low frequency/high frequency (LF/HF) ratio and normalized high frequency (nHF), as indicators of SNS and PNS activity, respectively, and total sleep time (TST), and wake after sleep onset were derived. All significant relationships with HRV measures were from the sleep period. Neighborhood disorder correlated negatively with nHF (r = -.24, p = .035). There were also significant correlations of HRV indices with sleep duration and sleep fears. Among females, LF/HF correlated with exposure to violence, r = .39, p = .008 and nHF with census tract rates for violent crime (r = -.35, p = .035). In a stepwise regression, TST accounted for the variance contributed by violent crime to nHF in the female participants. Further investigation of relationships between neighborhood environments and SNS/PNS balance during sleep and their consequences, and strategies for mitigating such effects would have implications for health disparities.

Gene Rearrangement Attenuates Expression and Lethality of a Nonsegmented Negative Strand RNA Virus

NASA Astrophysics Data System (ADS)

Williams Wertz, Gail; Perepelitsa, Victoria P.; Ball, L. Andrew

1998-03-01

The nonsegmented negative strand RNA viruses comprise hundreds of human, animal, insect, and plant pathogens. Gene expression of these viruses is controlled by the highly conserved order of genes relative to the single transcriptional promoter. We utilized this regulatory mechanism to alter gene expression levels of vesicular stomatitis virus by rearranging the gene order. This report documents that gene expression levels and the viral phenotype can be manipulated in a predictable manner. Translocation of the promoter-proximal nucleocapsid protein gene N, whose product is required stoichiometrically for genome replication, to successive positions down the genome reduced N mRNA and protein expression in a stepwise manner. The reduction in N gene expression resulted in a stepwise decrease in genomic RNA replication. Translocation of the N gene also attenuated the viruses to increasing extents for replication in cultured cells and for lethality in mice, without compromising their ability to elicit protective immunity. Because monopartite negative strand RNA viruses have not been reported to undergo homologous recombination, gene rearrangement should be irreversible and may provide a rational strategy for developing stably attenuated live vaccines against this type of virus.

Quantitative structure-activity relationship of the curcumin-related compounds using various regression methods

NASA Astrophysics Data System (ADS)

Khazaei, Ardeshir; Sarmasti, Negin; Seyf, Jaber Yousefi

2016-03-01

Quantitative structure activity relationship were used to study a series of curcumin-related compounds with inhibitory effect on prostate cancer PC-3 cells, pancreas cancer Panc-1 cells, and colon cancer HT-29 cells. Sphere exclusion method was used to split data set in two categories of train and test set. Multiple linear regression, principal component regression and partial least squares were used as the regression methods. In other hand, to investigate the effect of feature selection methods, stepwise, Genetic algorithm, and simulated annealing were used. In two cases (PC-3 cells and Panc-1 cells), the best models were generated by a combination of multiple linear regression and stepwise (PC-3 cells: r2 = 0.86, q2 = 0.82, pred_r2 = 0.93, and r2m (test) = 0.43, Panc-1 cells: r2 = 0.85, q2 = 0.80, pred_r2 = 0.71, and r2m (test) = 0.68). For the HT-29 cells, principal component regression with stepwise (r2 = 0.69, q2 = 0.62, pred_r2 = 0.54, and r2m (test) = 0.41) is the best method. The QSAR study reveals descriptors which have crucial role in the inhibitory property of curcumin-like compounds. 6ChainCount, T_C_C_1, and T_O_O_7 are the most important descriptors that have the greatest effect. With a specific end goal to design and optimization of novel efficient curcumin-related compounds it is useful to introduce heteroatoms such as nitrogen, oxygen, and sulfur atoms in the chemical structure (reduce the contribution of T_C_C_1 descriptor) and increase the contribution of 6ChainCount and T_O_O_7 descriptors. Models can be useful in the better design of some novel curcumin-related compounds that can be used in the treatment of prostate, pancreas, and colon cancers.

Differentiation of depression and anxiety groups using defense mechanisms.

PubMed

Olson, Trevor R; Presniak, Michelle D; MacGregor, Michael Wm

2009-11-01

We examined whether participants in depressed and anxious groups could be classified correctly using observer and self-report measures of defense mechanisms. A sample of 1182 university students completed the Personality Assessment Inventory and those scoring in the clinical range on either depression or anxiety indices were selected for participation. In total, 25 participants met criteria for the depressed group and 94 met criteria for the anxious group. Individual defense scores from the Defense-Q and the Defense Style Questionnaire were separately entered into 2 stepwise discriminant analyses. After cross-validation, the Defense-Q and Defense Style Questionnaire analyses classified participants with 75.0% and 71.3% accuracy, respectively. The results indicated that depression and anxiety groups can be significantly differentiated by defense use alone. Important differences in defensive functioning between these groups were confirmed and differences between observer and self-report measures of defenses mechanisms and current challenges in defense research were highlighted.

The role of proton shuttling mechanisms in solvent-free and catalyst-free acetalization reactions of imines.

PubMed

Lillo, Victor J; Mansilla, Javier; Saá, José M

2018-06-06

Proton transfer is central to the understanding of chemical processes. More so in addition reactions of the type NuH + E → Nu-EH taking place under solvent-free and catalyst-free conditions. Herein we show that the addition of alcohols or amines (the NuH component) to imine derivatives (the E component), in 1 : 1 ratio, under solvent-free and catalyst-free conditions, are efficient methods to access N,O and N,N-acetal derivatives. In addition, computational studies reveal that they are catalyzed reactions involving two or even three NuH molecules operating in a cooperative manner as H-bonded NuH(NuH)nNuH associates (many body effects) in the transition state through a concerted proton shuttling mechanism (addition of alcohols) or stepwise proton shuttling mechanism (addition of amines), thereby facilitating the key proton transfer step.

beta-endorphin: synthesis of analogs with extension at the carboxyl terminus with high radioreceptor binding activity.

PubMed

Yamashiro, D; Ferrara, P; Li, C H

1980-07-01

Four analogs of human beta-endorphin (beta h-EP) have been synthesized: [Gly31]-Beta h-EP-Gly-NH2, [CH3(CH2)4NH231]-beta h-EP, [Gly31]-beta h-EP-Gly-Gly-NH2, and [Gln8, Gly31]-betah-EP-Gly-Gly-NH2. All are more active than beta h-EP in an opiate receptor binding assay. Stepwise extension at the COOH-terminus shows a progressive increase in binding activity. The last analog, which combines extension at the COOH-terminus with elimination of the remaining anionic charge in beta h-EP, is nine times more active than the parent molecule.

Assessment of factors that predict physical activity among Oklahoma clergy: a theory of planned behavior approach.

PubMed

Gwin, Shannon; Taylor, E Laurette; Branscum, Paul; Hofford, Craig

2013-01-01

The purpose of this study was to examine predictors of physical activity among clergy members in Oklahoma, using the theory of planned behavior. A 51-item valid and reliable instrument, measuring theory of planned behavior constructs and physical activity, was developed and administered to 141 clergy members. Results indicated that the majority of those surveyed were white (93%), college educated (97%), and overweight or obese (84%). Stepwise multiple regression analysis found that intentions accounted for 13.8% of the variance of physical activity whereas attitudes, subjective norms, and perceived behavioral control accounted for 54.8% of the variance of intention. Implications for intervention development are discussed.

ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat.

PubMed

Meidhof, Simone; Brabletz, Simone; Lehmann, Waltraut; Preca, Bogdan-Tiberius; Mock, Kerstin; Ruh, Manuel; Schüler, Julia; Berthold, Maria; Weber, Anika; Burk, Ulrike; Lübbert, Michael; Puhr, Martin; Culig, Zoran; Wellner, Ulrich; Keck, Tobias; Bronsert, Peter; Küsters, Simon; Hopt, Ulrich T; Stemmler, Marc P; Brabletz, Thomas

2015-06-01

Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial-mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT-activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR-203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR-203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism-based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

Cushing's syndrome: Stepwise approach to diagnosis

PubMed Central

Lila, Anurag R.; Sarathi, Vijaya; Jagtap, Varsha S.; Bandgar, Tushar; Menon, Padmavathy; Shah, Nalini S.

2011-01-01

The projected prevalence of Cushing's syndrome (CS) inclusive of subclinical cases in the adult population ranges from 0.2–2% and it may no longer be considered as an orphan disease (2–3 cases/million/year). The recognition of CS by physicians is important for early diagnosis and treatment. Late-night salivary cortisol, dexamethasone suppressiontesti, or 24-h urine free cortisol are good screening tests. Positively screened cases need stepwise evaluation by an endocrinologist. This paper discusses the importance of screening for CS and suggests a stepwise diagnostic approach to a case of suspected hypercortisolism. PMID:22145134

Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin.

PubMed

Chen, Wei-Liang; Li, Fang; Tang, Yan; Yang, Shu-di; Li, Ji-Zhao; Yuan, Zhi-Qiang; Liu, Yang; Zhou, Xiao-Feng; Liu, Chun; Zhang, Xue-Nong

2017-01-01

Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on-demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents.

Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin

PubMed Central

Chen, Wei-liang; Li, Fang; Tang, Yan; Yang, Shu-di; Li, Ji-zhao; Yuan, Zhi-qiang; Liu, Yang; Zhou, Xiao-feng; Liu, Chun; Zhang, Xue-nong

2017-01-01

Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on-demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents. PMID:28652730

Free Energy Landscape and Multiple Folding Pathways of an H-Type RNA Pseudoknot

PubMed Central

Bian, Yunqiang; Zhang, Jian; Wang, Jun; Wang, Jihua; Wang, Wei

2015-01-01

How RNA sequences fold to specific tertiary structures is one of the key problems for understanding their dynamics and functions. Here, we study the folding process of an H-type RNA pseudoknot by performing a large-scale all-atom MD simulation and bias-exchange metadynamics. The folding free energy landscapes are obtained and several folding intermediates are identified. It is suggested that the folding occurs via multiple mechanisms, including a step-wise mechanism starting either from the first helix or the second, and a cooperative mechanism with both helices forming simultaneously. Despite of the multiple mechanism nature, the ensemble folding kinetics estimated from a Markov state model is single-exponential. It is also found that the correlation between folding and binding of metal ions is significant, and the bound ions mediate long-range interactions in the intermediate structures. Non-native interactions are found to be dominant in the unfolded state and also present in some intermediates, possibly hinder the folding process of the RNA. PMID:26030098

Modeling and optimization of Look-Locker spin labeling for measuring perfusion and transit time changes in activation studies taking into account arterial blood volume.

PubMed

Francis, S T; Bowtell, R; Gowland, P A

2008-02-01

This work describes a new compartmental model with step-wise temporal analysis for a Look-Locker (LL)-flow-sensitive alternating inversion-recovery (FAIR) sequence, which combines the FAIR arterial spin labeling (ASL) scheme with a LL echo planar imaging (EPI) measurement, using a multireadout EPI sequence for simultaneous perfusion and T*(2) measurements. The new model highlights the importance of accounting for the transit time of blood through the arteriolar compartment, delta, in the quantification of perfusion. The signal expected is calculated in a step-wise manner to avoid discontinuities between different compartments. The optimal LL-FAIR pulse sequence timings for the measurement of perfusion with high signal-to-noise ratio (SNR), and high temporal resolution at 1.5, 3, and 7T are presented. LL-FAIR is shown to provide better SNR per unit time compared to standard FAIR. The sequence has been used experimentally for simultaneous monitoring of perfusion, transit time, and T*(2) changes in response to a visual stimulus in four subjects. It was found that perfusion increased by 83 +/- 4% on brain activation from a resting state value of 94 +/- 13 ml/100 g/min, while T*(2) increased by 3.5 +/- 0.5%. (c) 2008 Wiley-Liss, Inc.

The rise and fall of periodic 'drumbeat' seismicity at Tungurahua volcano, Ecuador

NASA Astrophysics Data System (ADS)

Bell, Andrew F.; Hernandez, Stephen; Gaunt, H. Elizabeth; Mothes, Patricia; Ruiz, Mario; Sierra, Daniel; Aguaiza, Santiago

2017-10-01

Highly periodic 'drumbeat' long period (LP) earthquakes have been described from several andesitic and dacitic volcanoes, commonly accompanying incremental ascent and effusion of viscous magma. However, the processes controlling the occurrence and characteristics of drumbeat, and LP earthquakes more generally, remain contested. Here we use new quantitative tools to describe the emergence, evolution, and degradation of drumbeat LP seismicity at the andesitic Tungurahua volcano, Ecuador, in April 2015. The signals were recorded during an episode of minor explosive activity and ash emission, without lava effusion, and are the first to be reported at Tungurahua during the ongoing 17 yrs of eruption. Following four days of high levels of continuous and 'pulsed' tremor, highly-periodic LP earthquakes first appear on 10 April. Over the next four days, inter-event times and event amplitudes evolve through a series of step-wise transitions between stable behaviors, each involving a decrease in the degree of periodicity. Families of similar waveforms persist before, during, and after drumbeat activity, but the activity levels of different families change coincidentally with transitions in event rate, amplitude, and periodicity. A complex micro-seismicity 'initiation' sequence shows pulse-like and stepwise changes in inter-event times and amplitudes in the hours preceding the onset of drumbeat activity that indicate a partial de-coupling between event size and rate. The observations increase the phenomenology of drumbeat LP earthquakes, and suggest that at Tungurahua they result from gas flux and rapid depressurization controlled by shear failure of the margins of the ascending magma column.

Ex vivo generation of a functional and regenerative wound epithelium from axolotl (Ambystoma mexicanum) skin.

PubMed

Ferris, Donald R; Satoh, Akira; Mandefro, Berhan; Cummings, Gillian M; Gardiner, David M; Rugg, Elizabeth L

2010-10-01

Urodele amphibians (salamanders) are unique among adult vertebrates in their ability to regenerate structurally complete and fully functional limbs. Regeneration is a stepwise process that requires interactions between keratinocytes, nerves and fibroblasts. The formation of a wound epithelium covering the amputation site is an early and necessary event in the process but the molecular mechanisms that underlie the role of the wound epithelium in regeneration remain unclear. We have developed an ex vivo model that recapitulates many features of in vivo wound healing. The model comprises a circular explant of axolotl (Ambystoma mexicanum) limb skin with a central circular, full thickness wound. Re-epithelialization of the wound area is rapid (typically <11 h) and is dependent on metalloproteinase activity. The ex vivo wound epithelium is viable, responds to neuronal signals and is able to participate in ectopic blastema formation and limb regeneration. This ex vivo model provides a reproducible and tractable system in which to study the cellular and molecular events that underlie wound healing and regeneration. © 2010 The Authors. Journal compilation © 2010 Japanese Society of Developmental Biologists.

Pressure relaxation and diffusion of vacancies in rapidly grown helium crystals

NASA Astrophysics Data System (ADS)

Birchenko, A. P.; Mikhin, N. P.; Rudavskii, E. Ya.; Smirnov, S. N.; Fysun, Ya. Yu.

2018-04-01

An experimental study of the features of pressure relaxation in rapidly grown crystals of a diluted solid solution 3He-4He, at temperatures above 1.3 K, was performed. A cylindrical cell with capacitive pressure sensors at the ends was used for measurements. It was found that, when the helium crystals were grown at cooling rates ≳4 mK/s, the difference in pressure ΔP registered by the sensors at 1.3 K reached 2.4 bars. The ΔP value decreased with subsequent stepwise increase in temperature, but reached zero only after thorough annealing at the premelting temperatures. The kinetics of pressure changes at the sample ends at different temperatures was recorded. The results obtained were interpreted within the framework of the structural relaxation model based on the monovacancy diffusion mechanism. The proposed model made it possible to explain the dependence of ΔP on the time and temperature recorded in the experiment, as well as to determine the activation energy of the structural relaxation process and the diffusion coefficient of vacancies. The details of the vacancy model are described in the Appendix.

Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy.

PubMed

Cabezas-Wallscheid, Nina; Buettner, Florian; Sommerkamp, Pia; Klimmeck, Daniel; Ladel, Luisa; Thalheimer, Frederic B; Pastor-Flores, Daniel; Roma, Leticia P; Renders, Simon; Zeisberger, Petra; Przybylla, Adriana; Schönberger, Katharina; Scognamiglio, Roberta; Altamura, Sandro; Florian, Carolina M; Fawaz, Malak; Vonficht, Dominik; Tesio, Melania; Collier, Paul; Pavlinic, Dinko; Geiger, Hartmut; Schroeder, Timm; Benes, Vladimir; Dick, Tobias P; Rieger, Michael A; Stegle, Oliver; Trumpp, Andreas

2017-05-18

Dormant hematopoietic stem cells (dHSCs) are atop the hematopoietic hierarchy. The molecular identity of dHSCs and the mechanisms regulating their maintenance or exit from dormancy remain uncertain. Here, we use single-cell RNA sequencing (RNA-seq) analysis to show that the transition from dormancy toward cell-cycle entry is a continuous developmental path associated with upregulation of biosynthetic processes rather than a stepwise progression. In addition, low Myc levels and high expression of a retinoic acid program are characteristic for dHSCs. To follow the behavior of dHSCs in situ, a Gprc5c-controlled reporter mouse was established. Treatment with all-trans retinoic acid antagonizes stress-induced activation of dHSCs by restricting protein translation and levels of reactive oxygen species (ROS) and Myc. Mice maintained on a vitamin A-free diet lose HSCs and show a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. Our results highlight the impact of dietary vitamin A on the regulation of cell-cycle-mediated stem cell plasticity. VIDEO ABSTRACT. Copyright © 2017. Published by Elsevier Inc.

A perspective of stepwise utilisation of Bayer red mud: Step two--Extracting and recovering Ti from Ti-enriched tailing with acid leaching and precipitate flotation.

PubMed

Huang, Yanfang; Chai, Wencui; Han, Guihong; Wang, Wenjuan; Yang, Shuzhen; Liu, Jiongtian

2016-04-15

The extraction and recovery of Ti from Ti-enriched tailing with acid leaching and precipitate flotation, as one of the critical steps, was proposed for the stepwise utilization of red mud. The factors influencing acid leaching and precipitate flotation were examined by factorial design. The leaching thermodynamics, kinetics of Ti(4+), Al(3+) and Fe(3+), and the mechanism of selectively Fe(3+) removal using [Hbet][Tf2N] as precipitating reagent were discussed. The extracting of Ti(4+), Al(3+) and Fe(3+) in concentrated H2SO4 is controlled by diffusion reactions, depending mainly upon leaching time and temperature. The maximum extracting efficiency of Ti(4+) is approximately 92.3%, whereas Al(3+) and Fe(3+) leaching are respectively 75.8% and 84.2%. [Hbet][Tf2N], as a precipitating reagent, operates through a coordination mechanism in flotation. The pH value is the key factor influencing the flotation recovery of Ti(4+), whereas the dosage of precipitating reagent is that for Al(3+) recovery. The maximum flotation recovery of Ti(4+) is 92.7%, whereas the maximum Al(3+) recovery is 93.5%. The total recovery rate for extracting and recovering titanium is 85.5%. The liquor with Ti(4+) of 15.5g/L, Al(3+) of 30.4g/L and Fe(3+) of 0.48g/L was obtained for the following hydrolysis step in the integrated process for red mud utilisation. Copyright © 2016 Elsevier B.V. All rights reserved.

Validation of a Statistical Methodology for Extracting Vegetation Feedbacks: Focus on North African Ecosystems in the Community Earth System Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Yan; Notaro, Michael; Wang, Fuyao

Generalized equilibrium feedback assessment (GEFA) is a potentially valuable multivariate statistical tool for extracting vegetation feedbacks to the atmosphere in either observations or coupled Earth system models. The reliability of GEFA at capturing the terrestrial impacts on regional climate is demonstrated in this paper using the National Center for Atmospheric Research Community Earth System Model (CESM), with focus on North Africa. The feedback is assessed statistically by applying GEFA to output from a fully coupled control run. To reduce the sampling error caused by short data records, the traditional or full GEFA is refined through stepwise GEFA by dropping unimportantmore » forcings. Two ensembles of dynamical experiments are developed for the Sahel or West African monsoon region against which GEFA-based vegetation feedbacks are evaluated. In these dynamical experiments, regional leaf area index (LAI) is modified either alone or in conjunction with soil moisture, with the latter runs motivated by strong regional soil moisture–LAI coupling. Stepwise GEFA boasts higher consistency between statistically and dynamically assessed atmospheric responses to land surface anomalies than full GEFA, especially with short data records. GEFA-based atmospheric responses are more consistent with the coupled soil moisture–LAI experiments, indicating that GEFA is assessing the combined impacts of coupled vegetation and soil moisture. Finally, both the statistical and dynamical assessments reveal a negative vegetation–rainfall feedback in the Sahel associated with an atmospheric stability mechanism in CESM versus a weaker positive feedback in the West African monsoon region associated with a moisture recycling mechanism in CESM.« less

Stepwise Mechanism of Temperature-Dependent Coacervation of the Elastin-like Peptide Analogue Dimer, (C(WPGVG)3)2.

PubMed

Tatsubo, Daiki; Suyama, Keitaro; Miyazaki, Masaya; Maeda, Iori; Nose, Takeru

2018-03-13

Elastin-like peptides (ELPs) are distinct, repetitive, hydrophobic sequences, such as (VPGVG) n , that exhibit coacervation, the property of reversible, temperature-dependent self-association and dissociation. ELPs can be found in elastin and have been developed as new scaffold biomaterials. However, the detailed relationship between their amino acid sequences and coacervation properties remains obscure because of the structural flexibility of ELPs. In this study, we synthesized a novel, dimeric ELP analogue (H-C(WPGVG) 3 -NH 2 ) 2 , henceforth abbreviated (CW3)2, and analyzed its self-assembly properties and structural factors as indicators of coacervation. Turbidity measurements showed that (CW3)2 demonstrated coacervation at a concentration much lower than that of its monomeric form and another ELP. In addition, the coacervate held water-soluble dye molecules. Thus, potent and distinct coacervation was obtained with a remarkably short sequence of (CW3)2. Furthermore, fluorescence microscopy, dynamic light scattering, and optical microscopy revealed that the coacervation of (CW3)2 was a stepwise process. The structural factors of (CW3)2 were analyzed by molecular dynamics simulations and circular dichroism spectroscopy. These measurements indicated that helical structures primarily consisting of proline and glycine became more disordered at high temperatures with concurrent, significant exposure of their hydrophobic surfaces. This extreme change in the hydrophobic surface contributes to the potent coacervation observed for (CW3)2. These results provide important insights into more efficient applications of ELPs and their analogues, as well as the coacervation mechanisms of ELP and elastin.

Validation of a Statistical Methodology for Extracting Vegetation Feedbacks: Focus on North African Ecosystems in the Community Earth System Model

DOE PAGES

Yu, Yan; Notaro, Michael; Wang, Fuyao; ...

2018-02-05

Generalized equilibrium feedback assessment (GEFA) is a potentially valuable multivariate statistical tool for extracting vegetation feedbacks to the atmosphere in either observations or coupled Earth system models. The reliability of GEFA at capturing the terrestrial impacts on regional climate is demonstrated in this paper using the National Center for Atmospheric Research Community Earth System Model (CESM), with focus on North Africa. The feedback is assessed statistically by applying GEFA to output from a fully coupled control run. To reduce the sampling error caused by short data records, the traditional or full GEFA is refined through stepwise GEFA by dropping unimportantmore » forcings. Two ensembles of dynamical experiments are developed for the Sahel or West African monsoon region against which GEFA-based vegetation feedbacks are evaluated. In these dynamical experiments, regional leaf area index (LAI) is modified either alone or in conjunction with soil moisture, with the latter runs motivated by strong regional soil moisture–LAI coupling. Stepwise GEFA boasts higher consistency between statistically and dynamically assessed atmospheric responses to land surface anomalies than full GEFA, especially with short data records. GEFA-based atmospheric responses are more consistent with the coupled soil moisture–LAI experiments, indicating that GEFA is assessing the combined impacts of coupled vegetation and soil moisture. Finally, both the statistical and dynamical assessments reveal a negative vegetation–rainfall feedback in the Sahel associated with an atmospheric stability mechanism in CESM versus a weaker positive feedback in the West African monsoon region associated with a moisture recycling mechanism in CESM.« less

Stepwise-activable multifunctional peptide-guided prodrug micelles for cancerous cells intracellular drug release

NASA Astrophysics Data System (ADS)

Zhang, Jing; Li, Mengfei; Yuan, Zhefan; Wu, Dan; Chen, Jia-da; Feng, Jie

2016-10-01

A novel type of stepwise-activable multifunctional peptide-guided prodrug micelles (MPPM) was fabricated for cancerous cells intracellular drug release. Deca-lysine sequence (K10), a type of cell-penetrating peptide, was synthesized and terminated with azido-glycine. Then a new kind of molecule, alkyne modified doxorubicin (DOX) connecting through disulfide bond (DOX-SS-alkyne), was synthesized. After coupling via Cu-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry reaction, reduction-sensitive peptide-guided prodrug was obtained. Due to the amphiphilic property of the prodrug, it can assemble to form micelles. To prevent the nanocarriers from unspecific cellular uptake, the prodrug micelles were subsequently modified with 2,3-dimethyl maleic anhydride to obtain MPPM with a negatively charged outer shell. In vitro studies showed that MPPM could be shielded from cells under psychological environment. However, when arriving at mild acidic tumor site, the cell-penetrating capacity of MPPM would be activated by charge reversal of the micelles via hydrolysis of acid-labile β-carboxylic amides and regeneration of K10, which enabled efficient internalization of MPPM by tumor cells as well as following glutathione- and protease-induced drug release inside the cancerous cells. Furthermore, since the guide peptide sequences can be accurately designed and synthesized, it can be easily changed for various functions, such as targeting peptide, apoptotic peptide, even aptamers, only need to be terminated with azido-glycine. This method can be used as a template for reduction-sensitive peptide-guided prodrug for cancer therapy.

Theoretical investigation on the chemoselective N-heterocyclic carbene-catalyzed cross-benzoin reactions.

PubMed

Liu, Tao; Han, Shu-Min; Han, Ling-Li; Wang, Lu; Cui, Xiang-Yang; Du, Chong-Yang; Bi, Siwei

2015-03-28

A density functional theory study was performed to understand the detailed mechanisms of the cross-benzoin reactions catalyzed by N-heterocyclic carbene (NHC) species. Our theoretical study predicted that the first H-transfer operates with water in solution as a mediator, and the second H-transfer undergoes a concerted mechanism rather than a stepwise one. In addition, the chemoselectivity of the reactions studied in this work has been explored. P1 was obtained as a major product mainly due to the more stable intermediate formed by reaction of NHC with reactant R1. Different steric effects resulting from the fused six-membered ring in transition state TS7 and the fused five-membered ring in transition state TS13 are the origin leading to the chemoselectivity.

Complex formation equilibria of binary and ternary complexes involving 3,3-bis(1-methylimidazol-2yl)propionic acid and bio-relevant ligands as 1-aminocyclopropane carboxylic acid with reference to plant hormone

NASA Astrophysics Data System (ADS)

Shoukry, Mohamed M.; Hassan, Safaa S.

2014-01-01

The formation equilibria for the binary complexes of Cu(II) with 1-aminocyclopropane carboxylic acid (ACC) and 3,3-bis(1-methylimidazol-2-yl)propionic acid (BIMP) were investigated. ACC and BIMP form the complexes 1 1 0, 1 2 0 and 1 1 -1. The ternary complexes of Cu(II) with BIMP and biorelevant ligands as some selected amino acids, peptides and DNA constituents are formed in a stepwise mechanism. The stability constants of the complexes formed were determined and their distribution diagrams were evaluated. The kinetics of hydrolysis of glycine methyl ester in presence of [Cu(BIMP)]+ was investigated by pH-stat technique and the mechanism was discussed.

Impact of statistical learning methods on the predictive power of multivariate normal tissue complication probability models.

PubMed

Xu, Cheng-Jian; van der Schaaf, Arjen; Schilstra, Cornelis; Langendijk, Johannes A; van't Veld, Aart A

2012-03-15

To study the impact of different statistical learning methods on the prediction performance of multivariate normal tissue complication probability (NTCP) models. In this study, three learning methods, stepwise selection, least absolute shrinkage and selection operator (LASSO), and Bayesian model averaging (BMA), were used to build NTCP models of xerostomia following radiotherapy treatment for head and neck cancer. Performance of each learning method was evaluated by a repeated cross-validation scheme in order to obtain a fair comparison among methods. It was found that the LASSO and BMA methods produced models with significantly better predictive power than that of the stepwise selection method. Furthermore, the LASSO method yields an easily interpretable model as the stepwise method does, in contrast to the less intuitive BMA method. The commonly used stepwise selection method, which is simple to execute, may be insufficient for NTCP modeling. The LASSO method is recommended. Copyright © 2012 Elsevier Inc. All rights reserved.

Hormone activation induces nucleosome positioning in vivo

PubMed Central

Belikov, Sergey; Gelius, Birgitta; Almouzni, Geneviève; Wrange, Örjan

2000-01-01

The mouse mammary tumor virus (MMTV) promoter is induced by glucocorticoid hormone. A robust hormone- and receptor-dependent activation could be reproduced in Xenopus laevis oocytes. The homogeneous response in this system allowed a detailed analysis of the transition in chromatin structure following hormone activation. This revealed two novel findings: hormone activation led to the establishment of specific translational positioning of nucleosomes despite the lack of significant positioning in the inactive state; and, in the active promoter, a subnucleosomal particle encompassing the glucocorticoid receptor (GR)-binding region was detected. The presence of only a single GR-binding site was sufficient for the structural transition to occur. Both basal promoter elements and ongoing transcription were dispensable. These data reveal a stepwise process in the transcriptional activation by glucocorticoid hormone. PMID:10698943

Fishing for drifts: detecting buoyancy changes of a top marine predator using a step-wise filtering method

PubMed Central

Gordine, Samantha Alex; Fedak, Michael; Boehme, Lars

2015-01-01

ABSTRACT In southern elephant seals (Mirounga leonina), fasting- and foraging-related fluctuations in body composition are reflected by buoyancy changes. Such buoyancy changes can be monitored by measuring changes in the rate at which a seal drifts passively through the water column, i.e. when all active swimming motion ceases. Here, we present an improved knowledge-based method for detecting buoyancy changes from compressed and abstracted dive profiles received through telemetry. By step-wise filtering of the dive data, the developed algorithm identifies fragments of dives that correspond to times when animals drift. In the dive records of 11 southern elephant seals from South Georgia, this filtering method identified 0.8–2.2% of all dives as drift dives, indicating large individual variation in drift diving behaviour. The obtained drift rate time series exhibit that, at the beginning of each migration, all individuals were strongly negatively buoyant. Over the following 75–150 days, the buoyancy of all individuals peaked close to or at neutral buoyancy, indicative of a seal's foraging success. Independent verification with visually inspected detailed high-resolution dive data confirmed that this method is capable of reliably detecting buoyancy changes in the dive records of drift diving species using abstracted data. This also affirms that abstracted dive profiles convey the geometric shape of drift dives in sufficient detail for them to be identified. Further, it suggests that, using this step-wise filtering method, buoyancy changes could be detected even in old datasets with compressed dive information, for which conventional drift dive classification previously failed. PMID:26486362

A stepwise approach to stroke surveillance in Brazil: the EMMA (Estudo de Mortalidade e Morbidade do Acidente Vascular Cerebral) study.

PubMed

Goulart, Alessandra C; Bustos, Iara R; Abe, Ivana M; Pereira, Alexandre C; Fedeli, Ligia M; Benseñor, Isabela M; Lotufo, Paulo A

2010-08-01

Stroke mortality rates in Brazil are the highest in the Americas. Deaths from cerebrovascular disease surpass coronary heart disease. To verify stroke mortality rates and morbidity in an area of São Paulo, Brazil, using the World Health Organization Stepwise Approach to Stroke Surveillance. We used the World Health Organization Stepwise Approach to Stroke Surveillance structure of stroke surveillance. The hospital-based data comprised fatal and nonfatal stroke (Step 1). We gathered stroke-related mortality data in the community using World Health Organization questionnaires (Step 2). The questionnaire determining stroke prevalence was activated door to door in a family-health-programme neighbourhood (Step 3). A total of 682 patients 18 years and above, including 472 incident cases, presented with cerebrovascular disease and were enrolled in Step 1 during April-May 2009. Cerebral infarction (84.3%) and first-ever stroke (85.2%) were the most frequent. In Step 2, 256 deaths from stroke were identified during 2006-2007. Forty-four per cent of deaths were classified as unspecified stroke, 1/3 as ischaemic stroke, and 1/4 due to haemorrhagic subtype. In Step 3, 577 subjects over 35 years old were evaluated at home, and 244 cases of stroke survival were diagnosed via a questionnaire, validated by a board-certified neurologist. The population demographic characteristics were similar in the three steps, except in terms of age and gender. By including data from all settings, World Health Organization stroke surveillance can provide data to help plan future resources that meet the needs of the public-health system.

MULGRES: a computer program for stepwise multiple regression analysis

Treesearch

A. Jeff Martin

1971-01-01

MULGRES is a computer program source deck that is designed for multiple regression analysis employing the technique of stepwise deletion in the search for most significant variables. The features of the program, along with inputs and outputs, are briefly described, with a note on machine compatibility.

Gynecomastia: pathophysiology, evaluation, and management.

PubMed

Johnson, Ruth E; Murad, M Hassan

2009-11-01

Gynecomastia, defined as benign proliferation of male breast glandular tissue, is usually caused by increased estrogen activity, decreased testosterone activity, or the use of numerous medications. Although a fairly common presentation in the primary care setting and mostly of benign etiology, it can cause patients considerable anxiety. The initial step is to rule out pseudogynecomastia by careful history taking and physical examination. A stepwise approach that includes imaging and laboratory testing to exclude neoplasms and endocrinopathies may facilitate cost-effective diagnosis. If results of all studies are normal, idiopathic gynecomastia is diagnosed. The evidence in this area is mainly of observational nature and lower quality.

Finite cohesion due to chain entanglement in polymer melts.

PubMed

Cheng, Shiwang; Lu, Yuyuan; Liu, Gengxin; Wang, Shi-Qing

2016-04-14

Three different types of experiments, quiescent stress relaxation, delayed rate-switching during stress relaxation, and elastic recovery after step strain, are carried out in this work to elucidate the existence of a finite cohesion barrier against free chain retraction in entangled polymers. Our experiments show that there is little hastened stress relaxation from step-wise shear up to γ = 0.7 and step-wise extension up to the stretching ratio λ = 1.5 at any time before or after the Rouse time. In contrast, a noticeable stress drop stemming from the built-in barrier-free chain retraction is predicted using the GLaMM model. In other words, the experiment reveals a threshold magnitude of step-wise deformation below which the stress relaxation follows identical dynamics whereas the GLaMM or Doi-Edwards model indicates a monotonic acceleration of the stress relaxation dynamics as a function of the magnitude of the step-wise deformation. Furthermore, a sudden application of startup extension during different stages of stress relaxation after a step-wise extension, i.e. the delayed rate-switching experiment, shows that the geometric condensation of entanglement strands in the cross-sectional area survives beyond the reptation time τd that is over 100 times the Rouse time τR. Our results point to the existence of a cohesion barrier that can prevent free chain retraction upon moderate deformation in well-entangled polymer melts.

Identification method of laser gyro error model under changing physical field

NASA Astrophysics Data System (ADS)

Wang, Qingqing; Niu, Zhenzhong

2018-04-01

In this paper, the influence mechanism of temperature, temperature changing rate and temperature gradient on the inertial devices is studied. The two-order model of zero bias and the three-order model of the calibration factor of lster gyro under temperature variation are deduced. The calibration scheme of temperature error is designed, and the experiment is carried out. Two methods of stepwise regression analysis and BP neural network are used to identify the parameters of the temperature error model, and the effectiveness of the two methods is proved by the temperature error compensation.

Reactive collisions of electrons with H2+ , HD+, BeH+, BeD+ and SH+

NASA Astrophysics Data System (ADS)

Pop, Nicolina; Iacob, Felix; Mezei, János Zsolt; Motapon, Ousmanou; Niyonzima, Sebastien; Kashinski, David O.; Talbi, Dahbia; Hickman, Albert Peet; Schneider, Ioan F.

2017-12-01

In numerous cold ionized gases the dissociative recombination (DR), the elastic collisions (EC), the vibrational excitation (VE) (inelastic collisions) and the vibrational de-excitation (VdE) (super-elastic collisions) of molecular cations with electrons are major elementary processes. Using a stepwise method based on the Multichannel Quantum Defect Theory (MQDT), cross sections and rate coefficients have been obtained for reactions induced on HD+, H2+, BeH+, BeD+ and SH+. Moreover, the relative importance of the different reaction mechanisms, direct vs. indirect and rotational vs. non-rotational, have been studied for these molecular systems.

Kinetic Studies on the Reaction of Chlorosulfonyl Isocyanate with Monofluoralkenes: Experimental Evidence for Both Stepwise and Concerted Mechanisms, and a Pre-equilibrium Complex on the Reaction Pathway

DTIC Science & Technology

2012-12-14

lactams that are readily reduced to β-lactams. Substitution of a vinyl hydrogen for a vinyl fluorine changes the dynamics for reaction with CSI so...hydrogen for a vinyl fluorine changes the dynamics for reaction with CSI so that a concerted pathway is favored. Rate constants were measured for...step pathway has not been demonstrated experimentally.3c In a recent paper, we found that substituting a hydrogen for a fluorine on the π-bond of an

Ultrafast electron crystallography of the cooperative reaction path in vanadium dioxide

PubMed Central

Yang, Ding-Shyue; Baum, Peter; Zewail, Ahmed H.

2016-01-01

Time-resolved electron diffraction with atomic-scale spatial and temporal resolution was used to unravel the transformation pathway in the photoinduced structural phase transition of vanadium dioxide. Results from bulk crystals and single-crystalline thin-films reveal a common, stepwise mechanism: First, there is a femtosecond V−V bond dilation within 300 fs, second, an intracell adjustment in picoseconds and, third, a nanoscale shear motion within tens of picoseconds. Experiments at different ambient temperatures and pump laser fluences reveal a temperature-dependent excitation threshold required to trigger the transitional reaction path of the atomic motions. PMID:27376103

Stepwise morphological evolution of the active Yellow River (Huanghe) delta lobe (1976-2013): Dominant roles of riverine discharge and sediment grain size

NASA Astrophysics Data System (ADS)

Wu, Xiao; Bi, Naishuang; Xu, Jingping; Nittrouer, Jeffrey A.; Yang, Zuosheng; Saito, Yoshiki; Wang, Houjie

2017-09-01

The presently active Yellow River (Huanghe) delta lobe has been formed since 1976 when the river was artificially diverted. The process and driving forces of morphological evolution of the present delta lobe still remain unclear. Here we examined the stepwise morphological evolution of the active Yellow River delta lobe including both the subaerial and the subaqueous components, and illustrated the critical roles of riverine discharge and sediment grain size in dominating the deltaic evolution. The critical sediment loads for maintaining the delta stability were also calculated from water discharge and sediment load measured at station Lijin, the last gauging station approximately 100 km upstream from the river mouth. The results indicated that the development of active delta lobe including both subaerial and subaqueous components has experienced four sequential stages. During the first stage (1976-1981) after the channel migration, the unchannelized river flow enhanced deposition within the channel and floodplain between Lijin station and the river mouth. Therefore, the critical sediment supply calculated by the river inputs obtained from station Lijin was the highest. However, the actual sediment load at this stage (0.84 Gt/yr) was more than twice of the critical sediment load ( 0.35 Gt/yr) for sustaining the active subaerial area, which favored a rapid seaward progradation of the Yellow River subaerial delta. During the second stage (1981-1996), the engineering-facilitated channelized river flow and the increase in median grain size of suspended sediment delivered to the sea resulted in the critical sediment load for keeping the delta stability deceasing to 0.29 Gt/yr. The active delta lobe still gradually prograded seaward at an accretion rate of 11.9 km2/yr at this stage as the annual sediment load at Lijin station was 0.55 Gt/yr. From 1996 to 2002, the critical sediment load further decreased to 0.15 Gt/yr with the sediment grain size increased to 22.5 μm; however, the delta suffered net erosion because of the insufficient sediment supply (0.11 Gt/yr). In the most recent stage (2002 - 2013), the intensive scouring of the lower river channel induced by the dam regulation provided relatively coarser sediment, which effectively reduced the critical sediment load to 0.06 Gt/yr, much lower than the corresponding sediment load at Lijin station ( 0.16 Gt/yr). Consequently, the subaerial Yellow River delta transitioned to a slight accretion phase. Overall, the evolution of the active Yellow River delta is highly correlated to riverine water and sediment discharge. The sediment supply for keeping the subaerial delta stability is inconstant and varying with the river channel morphology and sediment grain size. We conclude that the human-impacted riverine sediment discharge and grain-size composition play dominant roles in the stepwise morphological evolution of the active delta lobe.

Experience, Reflect, Critique: The End of the "Learning Cycles" Era

ERIC Educational Resources Information Center

Seaman, Jayson

2008-01-01

According to prevailing models, experiential learning is by definition a stepwise process beginning with direct experience, followed by reflection, followed by learning. It has been argued, however, that stepwise models inadequately explain the holistic learning processes that are central to learning from experience, and that they lack scientific…

A Latent-Variable Causal Model of Faculty Reputational Ratings.

ERIC Educational Resources Information Center

King, Suzanne; Wolfle, Lee M.

A reanalysis was conducted of Saunier's research (1985) on sources of variation in the National Research Council (NRC) reputational ratings of university faculty. Saunier conducted a stepwise regression analysis using 12 predictor variables. Due to problems with multicollinearity and because of the atheoretical nature of stepwise regression,…

Testing Different Model Building Procedures Using Multiple Regression.

ERIC Educational Resources Information Center

Thayer, Jerome D.

The stepwise regression method of selecting predictors for computer assisted multiple regression analysis was compared with forward, backward, and best subsets regression, using 16 data sets. The results indicated the stepwise method was preferred because of its practical nature, when the models chosen by different selection methods were similar…

Explanation of the variance in quality of life and activity capacity of patients with heart failure by laboratory data.

PubMed

Athanasopoulos, Leonidas V; Dritsas, Athanasios; Doll, Helen A; Cokkinos, Dennis V

2010-08-01

This study was conducted to explain the variance in quality of life (QoL) and activity capacity of patients with congestive heart failure from pathophysiological changes as estimated by laboratory data. Peak oxygen consumption (peak VO2) and ventilation (VE)/carbon dioxide output (VCO2) slope derived from cardiopulmonary exercise testing, plasma N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and echocardiographic markers [left atrium (LA), left ventricular ejection fraction (LVEF)] were measured in 62 patients with congestive heart failure, who also completed the Minnesota Living with Heart Failure Questionnaire and the Specific Activity Questionnaire. All regression models were adjusted for age and sex. On linear regression analysis, peak VO2 with P value less than 0.001, VE/VCO2 slope with P value less than 0.01, LVEF with P value less than 0.001, LA with P=0.001, and logNT-proBNP with P value less than 0.01 were found to be associated with QoL. On stepwise multiple linear regression, peak VO2 and LVEF continued to be predictive, accounting for 40% of the variability in Minnesota Living with Heart Failure Questionnaire score. On linear regression analysis, peak VO2 with P value less than 0.001, VE/VCO2 slope with P value less than 0.001, LVEF with P value less than 0.05, LA with P value less than 0.001, and logNT-proBNP with P value less than 0.001 were found to be associated with activity capacity. On stepwise multiple linear regression, peak VO2 and LA continued to be predictive, accounting for 53% of the variability in Specific Activity Questionnaire score. Peak VO2 is independently associated both with QoL and activity capacity. In addition to peak VO2, LVEF is independently associated with QoL, and LA with activity capacity.

Left atrial dysfunction in patients with patent foramen ovale and atrial septal aneurysm: an alternative concurrent mechanism for arterial embolism?

PubMed

Rigatelli, Gianluca; Aggio, Silvio; Cardaioli, Paolo; Braggion, Gabriele; Giordan, Massimo; Dell'avvocata, Fabio; Chinaglia, Mauro; Rigatelli, Giorgio; Roncon, Loris; Chen, Jack P

2009-07-01

We postulate that, in patients with large patent foramen ovales (PFO) and atrial septal aneurysms (ASA), left atrial (LA) dysfunction simulating "atrial fibrillation (AF)-like" pathophysiology might represent an alternate mechanism in the promotion of arterial embolism. Despite prior reports concerning paradoxical embolism through a PFO, the magnitude of this phenomenon as a risk factor for stroke remains undefined, because deep venous thrombosis is infrequently detected in such patients. To test our hypothesis, we prospectively enrolled 98 consecutive patients with previous stroke (mean age 37 +/- 12.5 years, 58 women) referred to our center for catheter-based PFO closure. Baseline values of LA passive and active emptying, LA conduit function, LA ejection fraction, and spontaneous echocontrast (SEC) in the LA and LA appendage were compared with those of 50 AF patients as well as a sex/age/cardiac risk-matched population of 70 healthy control subjects. Pre-closure PFO subjects demonstrated significantly greater reservoir function as well as passive and active emptying, with significantly reduced conduit function and LA ejection fraction, when compared with AF and control patients. Furthermore, in PFO patients, 66.3% (65 of 98) had moderate-to-severe ASA and basal shunt; SEC was observed in 52% of PFO plus ASA patients before closure. Multivariate stepwise logistic regression revealed moderate-to-severe ASA (odds ratio: 9.4, 95% confidence interval: 7.0 to 23.2, p < 0.001) as the most powerful predictor of LA dysfunction. After closure, all LA parameters normalized to the levels of control subjects: no SEC, device-related thrombosis, or aortic erosion were observed on follow-up echocardiography. This study suggests that moderate-to-severe ASA might be associated with LA dysfunction in patients with PFO. The resultant similarities to the pathophysiology of AF might represent an additional contributing mechanism for arterial embolism in such patients.

Speech and motor disturbances in Rett syndrome.

PubMed

Bashina, V M; Simashkova, N V; Grachev, V V; Gorbachevskaya, N L

2002-01-01

Rett syndrome is a severe, genetically determined disease of early childhood which produces a defined clinical phenotype in girls. The main clinical manifestations include lesions affecting speech functions, involving both expressive and receptive speech, as well as motor functions, producing apraxia of the arms and profound abnormalities of gait in the form of ataxia-apraxia. Most investigators note that patients have variability in the severity of derangement to large motor acts and in the damage to fine hand movements and speech functions. The aims of the present work were to study disturbances of speech and motor functions over 2-5 years in 50 girls aged 12 months to 14 years with Rett syndrome and to analyze the correlations between these disturbances. The results of comparing clinical data and EEG traces supported the stepwise involvement of frontal and parietal-temporal cortical structures in the pathological process. The ability to organize speech and motor activity is affected first, with subsequent development of lesions to gnostic functions, which are in turn followed by derangement of subcortical structures and the cerebellum and later by damage to structures in the spinal cord. A clear correlation was found between the severity of lesions to motor and speech functions and neurophysiological data: the higher the level of preservation of elements of speech and motor functions, the smaller were the contributions of theta activity and the greater the contributions of alpha and beta activities to the EEG. The possible pathogenetic mechanisms underlying the motor and speech disturbances in Rett syndrome are discussed.

Two protein kinase C isoforms, δ and ε, regulate energy homeostasis in mitochondria by transmitting opposing signals to the pyruvate dehydrogenase complex.

PubMed

Gong, Jianli; Hoyos, Beatrice; Acin-Perez, Rebeca; Vinogradov, Valerie; Shabrova, Elena; Zhao, Feng; Leitges, Michael; Fischman, Donald; Manfredi, Giovanni; Hammerling, Ulrich

2012-08-01

Energy production in mitochondria is a multistep process that requires coordination of several subsystems. While reversible phosphorylation is emerging as the principal tool, it is still unclear how this signal network senses the workloads of processes as different as fuel procurement, catabolism in the Krebs cycle, and stepwise oxidation of reducing equivalents in the electron transfer chain. We previously proposed that mitochondria use oxidized cytochrome c in concert with retinol to activate protein kinase Cδ, thereby linking a prominent kinase network to the redox balance of the ETC. Here, we show that activation of PKCε in mitochondria also requires retinol as a cofactor, implying a redox-mechanism. Whereas activated PKCδ transmits a stimulatory signal to the pyruvate dehdyrogenase complex (PDHC), PKCε opposes this signal and inhibits the PDHC. Our results suggest that the balance between PKCδ and ε is of paramount importance not only for flux of fuel entering the Krebs cycle but for overall energy homeostasis. We observed that the synthetic retinoid fenretinide substituted for the retinol cofactor function but, on chronic use, distorted this signal balance, leading to predominance of PKCε over PKCδ. The suppression of the PDHC might explain the proapoptotic effect of fenretinide on tumor cells, as well as the diminished adiposity observed in experimental animals and humans. Furthermore, a disturbed balance between PKCδ and PKCε might underlie the injury inflicted on the ischemic myocardium during reperfusion. dehydrogenase complex.

CI-KNOW: Cyberinfrastructure Knowledge Networks on the Web. A Social Network Enabled Recommender System for Locating Resources in Cyberinfrastructures

NASA Astrophysics Data System (ADS)

Green, H. D.; Contractor, N. S.; Yao, Y.

2006-12-01

A knowledge network is a multi-dimensional network created from the interactions and interconnections among the scientists, documents, data, analytic tools, and interactive collaboration spaces (like forums and wikis) associated with a collaborative environment. CI-KNOW is a suite of software tools that leverages automated data collection, social network theories, analysis techniques and algorithms to infer an individual's interests and expertise based on their interactions and activities within a knowledge network. The CI-KNOW recommender system mines the knowledge network associated with a scientific community's use of cyberinfrastructure tools and uses relational metadata to record connections among entities in the knowledge network. Recent developments in social network theories and methods provide the backbone for a modular system that creates recommendations from relational metadata. A network navigation portlet allows users to locate colleagues, documents, data or analytic tools in the knowledge network and to explore their networks through a visual, step-wise process. An internal auditing portlet offers administrators diagnostics to assess the growth and health of the entire knowledge network. The first instantiation of the prototype CI-KNOW system is part of the Environmental Cyberinfrastructure Demonstration project at the National Center for Supercomputing Applications, which supports the activities of hydrologic and environmental science communities (CLEANER and CUAHSI) under the umbrella of the WATERS network environmental observatory planning activities (http://cleaner.ncsa.uiuc.edu). This poster summarizes the key aspects of the CI-KNOW system, highlighting the key inputs, calculation mechanisms, and output modalities.

Infrared laser driven double proton transfer. An optimal control theory study

NASA Astrophysics Data System (ADS)

Abdel-Latif, Mahmoud K.; Kühn, Oliver

2010-02-01

Laser control of ultrafast double proton transfer is investigated for a two-dimensional model system describing stepwise and concerted transfer pathways. The pulse design has been done by employing optimal control theory in combination with the multiconfiguration time-dependent Hartree wave packet propagation. The obtained laser fields correspond to multiple pump-dump pulse sequences. Special emphasis is paid to the relative importance of stepwise and concerted transfer pathways for the driven wave packet and its dependence on the parameters of the model Hamiltonian as well as on the propagation time. While stepwise transfer is dominating in all cases considered, for high barrier systems concerted transfer proceeding via tunneling can make a contribution.

Response time of mitochondrial oxygen consumption following stepwise changes in cardiac energy demand.

PubMed

van Beek, J H; Westerhof, N

1990-01-01

We determined the speed with which mitochondrial oxygen consumption and therefore the mitochondrial ATP-synthesis adapted to changes in metabolic demand in the rabbit heart. This was done by measuring the oxygen uptake of the whole heart during a stepwise change in heart rate and correcting for the time taken by diffusion and by convective transport in the blood vessels. Data for the correction for transport time were obtained from the response of venous oxygen concentration to a stepwise change of arterial oxygen concentration. The time constant of the response of mitochondrial oxygen consumption to a step change in heart rate was found to be 4-8 s.

Application of stepwise multiple regression techniques to inversion of Nimbus 'IRIS' observations.

NASA Technical Reports Server (NTRS)

Ohring, G.

1972-01-01

Exploratory studies with Nimbus-3 infrared interferometer-spectrometer (IRIS) data indicate that, in addition to temperature, such meteorological parameters as geopotential heights of pressure surfaces, tropopause pressure, and tropopause temperature can be inferred from the observed spectra with the use of simple regression equations. The technique of screening the IRIS spectral data by means of stepwise regression to obtain the best radiation predictors of meteorological parameters is validated. The simplicity of application of the technique and the simplicity of the derived linear regression equations - which contain only a few terms - suggest usefulness for this approach. Based upon the results obtained, suggestions are made for further development and exploitation of the stepwise regression analysis technique.

Confined compression and torsion experiments on a pHEMA gel in various bath concentrations.

PubMed

Roos, Reinder W; Petterson, Rob; Huyghe, Jacques M

2013-06-01

The constitutive behaviour of cartilaginous tissue is the result of complex interaction between electrical, chemical and mechanical forces. Electrostatic interactions between fixed charges and mobile ions are usually accounted for by means of Donnan osmotic pressure. Recent experimental data show, however, that the shear modulus of articular cartilage depends on ionic concentration even if the strain is kept constant. Poisson-Boltzmann simulations suggest that this dependence is intrinsic to the double-layer around the proteoglycan chains. In order to verify this premise, this study measures whether--at a given strain--this ionic concentration-dependent shear modulus is present in a polymerized hydroxy-ethyl-methacrylate gel or not. A combined 1D confined compression and torque experiment is performed on a thin cylindrical hydrogel sample, which is brought in equilibrium with, respectively, 1, 0.1 and 0.03 M NaCl. The sample was placed in a chamber that consists of a stainless steel ring placed on a sintered glass filter, and on top a sintered glass piston. Stepwise ionic loading was cascaded by stepwise 1D compression, measuring the total stress after equilibration of the sample. In addition, a torque experiment was interweaved by applying a harmonic angular displacement and measuring the torque, revealing the relation between aggregate shear modulus and salt concentration at a given strain.

Stepwise mechanism and H2O-assisted hydrolysis in atomic layer deposition of SiO2 without a catalyst.

PubMed

Fang, Guo-Yong; Xu, Li-Na; Wang, Lai-Guo; Cao, Yan-Qiang; Wu, Di; Li, Ai-Dong

2015-01-01

Atomic layer deposition (ALD) is a powerful deposition technique for constructing uniform, conformal, and ultrathin films in microelectronics, photovoltaics, catalysis, energy storage, and conversion. The possible pathways for silicon dioxide (SiO2) ALD using silicon tetrachloride (SiCl4) and water (H2O) without a catalyst have been investigated by means of density functional theory calculations. The results show that the SiCl4 half-reaction is a rate-determining step of SiO2 ALD. It may proceed through a stepwise pathway, first forming a Si-O bond and then breaking Si-Cl/O-H bonds and forming a H-Cl bond. The H2O half-reaction may undergo hydrolysis and condensation processes, which are similar to conventional SiO2 chemical vapor deposition (CVD). In the H2O half-reaction, there are massive H2O molecules adsorbed on the surface, which can result in H2O-assisted hydrolysis of the Cl-terminated surface and accelerate the H2O half-reaction. These findings may be used to improve methods for the preparation of SiO2 ALD and H2O-based ALD of other oxides, such as Al2O3, TiO2, ZrO2, and HfO2.

Stepwise mechanism and H2O-assisted hydrolysis in atomic layer deposition of SiO2 without a catalyst

NASA Astrophysics Data System (ADS)

Fang, Guo-Yong; Xu, Li-Na; Wang, Lai-Guo; Cao, Yan-Qiang; Wu, Di; Li, Ai-Dong

2015-02-01

Atomic layer deposition (ALD) is a powerful deposition technique for constructing uniform, conformal, and ultrathin films in microelectronics, photovoltaics, catalysis, energy storage, and conversion. The possible pathways for silicon dioxide (SiO2) ALD using silicon tetrachloride (SiCl4) and water (H2O) without a catalyst have been investigated by means of density functional theory calculations. The results show that the SiCl4 half-reaction is a rate-determining step of SiO2 ALD. It may proceed through a stepwise pathway, first forming a Si-O bond and then breaking Si-Cl/O-H bonds and forming a H-Cl bond. The H2O half-reaction may undergo hydrolysis and condensation processes, which are similar to conventional SiO2 chemical vapor deposition (CVD). In the H2O half-reaction, there are massive H2O molecules adsorbed on the surface, which can result in H2O-assisted hydrolysis of the Cl-terminated surface and accelerate the H2O half-reaction. These findings may be used to improve methods for the preparation of SiO2 ALD and H2O-based ALD of other oxides, such as Al2O3, TiO2, ZrO2, and HfO2.

High Resolution Structures of the Human ABO(H) Blood Group Enzymes in Complex with Donor Analogs Reveal That the Enzymes Utilize Multiple Donor Conformations to Bind Substrates in a Stepwise Manner*

PubMed Central

Gagnon, Susannah M. L.; Meloncelli, Peter J.; Zheng, Ruixiang B.; Haji-Ghassemi, Omid; Johal, Asha R.; Borisova, Svetlana N.; Lowary, Todd L.; Evans, Stephen V.

2015-01-01

Homologous glycosyltransferases α-(1→3)-N-acetylgalactosaminyltransferase (GTA) and α-(1→3)-galactosyltransferase (GTB) catalyze the final step in ABO(H) blood group A and B antigen synthesis through sugar transfer from activated donor to the H antigen acceptor. These enzymes have a GT-A fold type with characteristic mobile polypeptide loops that cover the active site upon substrate binding and, despite intense investigation, many aspects of substrate specificity and catalysis remain unclear. The structures of GTA, GTB, and their chimeras have been determined to between 1.55 and 1.39 Å resolution in complex with natural donors UDP-Gal, UDP-Glc and, in an attempt to overcome one of the common problems associated with three-dimensional studies, the non-hydrolyzable donor analog UDP-phosphono-galactose (UDP-C-Gal). Whereas the uracil moieties of the donors are observed to maintain a constant location, the sugar moieties lie in four distinct conformations, varying from extended to the “tucked under” conformation associated with catalysis, each stabilized by different hydrogen bonding partners with the enzyme. Further, several structures show clear evidence that the donor sugar is disordered over two of the observed conformations and so provide evidence for stepwise insertion into the active site. Although the natural donors can both assume the tucked under conformation in complex with enzyme, UDP-C-Gal cannot. Whereas UDP-C-Gal was designed to be “isosteric” with natural donor, the small differences in structure imposed by changing the epimeric oxygen atom to carbon appear to render the enzyme incapable of binding the analog in the active conformation and so preclude its use as a substrate mimic in GTA and GTB. PMID:26374898

Structural Characterization of Early Michaelis Complexes in the Reaction Catalyzed by (+)-Limonene Synthase from Citrus sinensis Using Fluorinated Substrate Analogues.

PubMed

Kumar, Ramasamy P; Morehouse, Benjamin R; Matos, Jason O; Malik, Karan; Lin, Hongkun; Krauss, Isaac J; Oprian, Daniel D

2017-03-28

The stereochemical course of monoterpene synthase reactions is thought to be determined early in the reaction sequence by selective binding of distinct conformations of the geranyl diphosphate (GPP) substrate. We explore here formation of early Michaelis complexes of the (+)-limonene synthase [(+)-LS] from Citrus sinensis using monofluorinated substrate analogues 2-fluoro-GPP (FGPP) and 2-fluoroneryl diphosphate (FNPP). Both are competitive inhibitors for (+)-LS with K I values of 2.4 ± 0.5 and 39.5 ± 5.2 μM, respectively. The K I values are similar to the K M for the respective nonfluorinated substrates, indicating that fluorine does not significantly perturb binding of the ligand to the enzyme. FGPP and FNPP are also substrates, but with dramatically reduced rates (k cat values of 0.00054 ± 0.00005 and 0.00024 ± 0.00002 s -1 , respectively). These data are consistent with a stepwise mechanism for (+)-LS involving ionization of the allylic GPP substrate to generate a resonance-stabilized carbenium ion in the rate-limiting step. Crystals of apo-(+)-LS were soaked with FGPP and FNPP to obtain X-ray structures at 2.4 and 2.2 Å resolution, respectively. The fluorinated analogues are found anchored in the active site through extensive interactions involving the diphosphate, three metal ions, and three active-site Asp residues. Electron density for the carbon chains extends deep into a hydrophobic pocket, while the enzyme remains mostly in the open conformation observed for the apoprotein. While FNPP was found in multiple conformations, FGPP, importantly, was in a single, relatively well-defined, left-handed screw conformation, consistent with predictions for the mechanism of stereoselectivity in the monoterpene synthases.

Characterization of pressure-mediated vascular tone in resistance arteries from bile duct-ligated rats

PubMed Central

Jadeja, Ravirajsinh N.; Thounaojam, Menaka C.; Khurana, Sandeep

2017-01-01

In cirrhosis, changes in pressure-mediated vascular tone, a key determinant of systemic vascular resistance (SVR), are unknown. To address this gap in knowledge, we assessed ex vivo dynamics of pressurized mesenteric resistance arteries (diameter ~ 260 μm) from bile duct-ligated (BDL) and sham-operated (SHAM) rats and determined the underlying mechanisms. At isobaric intraluminal pressure (70 mmHg) as well as with step-wise increase in pressure (10-110 mmHg), arteries from SHAM-rats constricted more than BDL-rats, and had reduced luminal area. In both groups, incubation with LNAME (a NOS inhibitor) had no effect on pressure-mediated tone, and expression of NOS isoforms were similar. TEA, which enhances Ca2+ influx, augmented arterial tone only in SHAM-rats, with minimal effect in those from BDL-rats that was associated with reduced expression of Ca2+ channel TRPC6. In permeabilized arteries, high-dose Ca2+ and γGTP enhanced the vascular tone, which remained lower in BDL-rats that was associated with reduced ROCK2 and pMLC expression. Further, compared to SHAM-rats, in BDL-rats, arteries had reduced collagen expression which was associated with increased expression and activity of MMP-9. BDL-rats also had increased plasma reactive oxygen species (ROS). In vascular smooth muscle cells in vitro, peroxynitrite enhanced MMP-9 activity and reduced ROCK2 expression. These data provide evidence that in cirrhosis, pressure-mediated tone is reduced in resistance arteries, and suggest that circulating ROS play a role in reducing Ca2+ sensitivity and enhancing elasticity to induce arterial adaptations. These findings provide insights into mechanisms underlying attenuated SVR in cirrhosis. PMID:28430609

Reactivity of Household Oxygen Bleaches: A Stepwise Laboratory Exercise in High School Chemistry Course

ERIC Educational Resources Information Center

Nakano, Masayoshi; Ogasawara, Haruka; Wada, Takeshi; Koga, Nobuyoshi

2016-01-01

This paper reports on a learning program designed for high school chemistry classes that involves laboratory exercises using household oxygen bleaches. In this program, students are taught the chemistry of oxygen bleaches through a stepwise inquiry using laboratory exercises organized with different pedagogical intents. Through comparative…

Prayer at Midlife is Associated with Reduced Risk of Cognitive Decline in Arabic Women

PubMed Central

Inzelberg, Rivka; Afgin, Anne E; Massarwa, Magda; Schechtman, Edna; Israeli-Korn, Simon D.; Strugatsky, Rosa; Abuful, Amin; Kravitz, Efrat; Farrer, Lindsay A.; Friedland, Robert P.

2013-01-01

Midlife habits may be important for the later development of Alzheimer's disease (AD). We estimated the contribution of midlife prayer to the development of cognitive decline. In a door-to-door survey, residents aged ≥65 years were systematically evaluated in Arabic including medical history, neurological, cognitive examination, and a midlife leisure-activities questionnaire. Praying was assessed by the number of monthly praying hours at midlife. Stepwise logistic regression models were used to evaluate the effect of prayer on the odds of mild cognitive impairment (MCI) and AD versus cognitively normal individuals. Of 935 individuals that were approached, 778 [normal controls (n=448), AD (n=92) and MCI (n=238)] were evaluated. A higher proportion of cognitively normal individuals engaged in prayer at midlife [(87%) versus MCI (71%) or AD (69%) (p<0.0001)]. Since 94% of males engaged in prayer, the effect on cognitive decline could not be assessed in men. Among women, stepwise logistic regression adjusted for age and education, showed that prayer was significantly associated with reduced risk of MCI (p=0.027, OR=0.55, 95% CI 0.33-0.94), but not AD. Among individuals endorsing prayer activity, the amount of prayer was not associated with MCI or AD in either gender. Praying at midlife is associated with lower risk of mild cognitive impairment in women. PMID:23116476

Prayer at midlife is associated with reduced risk of cognitive decline in Arabic women.

PubMed

Inzelberg, Rivka; Afgin, Anne E; Massarwa, Magda; Schechtman, Edna; Israeli-Korn, Simon D; Strugatsky, Rosa; Abuful, Amin; Kravitz, Efrat; Farrer, Lindsay A; Friedland, Robert P

2013-03-01

Midlife habits may be important for the later development of Alzheimer's disease (AD). We estimated the contribution of midlife prayer to the development of cognitive decline. In a door-to-door survey, residents aged ≥65 years were systematically evaluated in Arabic including medical history, neurological, cognitive examination, and a midlife leisure-activities questionnaire. Praying was assessed by the number of monthly praying hours at midlife. Stepwise logistic regression models were used to evaluate the effect of prayer on the odds of mild cognitive impairment (MCI) and AD versus cognitively normal individuals. Of 935 individuals that were approached, 778 [normal controls (n=448), AD (n=92) and MCI (n=238)] were evaluated. A higher proportion of cognitively normal individuals engaged in prayer at midlife [(87%) versus MCI (71%) or AD (69%) (p<0.0001)]. Since 94% of males engaged in prayer, the effect on cognitive decline could not be assessed in men. Among women, stepwise logistic regression adjusted for age and education, showed that prayer was significantly associated with reduced risk of MCI (p=0.027, OR=0.55, 95% CI 0.33-0.94), but not AD. Among individuals endorsing prayer activity, the amount of prayer was not associated with MCI or AD in either gender. Praying at midlife is associated with lower risk of mild cognitive impairment in women.

Controlled breathing protocols probe human autonomic cardiovascular rhythms

NASA Technical Reports Server (NTRS)

Cooke, W. H.; Cox, J. F.; Diedrich, A. M.; Taylor, J. A.; Beightol, L. A.; Ames, J. E. 4th; Hoag, J. B.; Seidel, H.; Eckberg, D. L.

1998-01-01

The purpose of this study was to determine how breathing protocols requiring varying degrees of control affect cardiovascular dynamics. We measured inspiratory volume, end-tidal CO2, R-R interval, and arterial pressure spectral power in 10 volunteers who followed the following 5 breathing protocols: 1) uncontrolled breathing for 5 min; 2) stepwise frequency breathing (at 0.3, 0.25, 0.2, 0.15, 0.1, and 0.05 Hz for 2 min each); 3) stepwise frequency breathing as above, but with prescribed tidal volumes; 4) random-frequency breathing (approximately 0.5-0.05 Hz) for 6 min; and 5) fixed-frequency breathing (0.25 Hz) for 5 min. During stepwise breathing, R-R interval and arterial pressure spectral power increased as breathing frequency decreased. Control of inspired volume reduced R-R interval spectral power during 0.1 Hz breathing (P < 0.05). Stepwise and random-breathing protocols yielded comparable coherence and transfer functions between respiration and R-R intervals and systolic pressure and R-R intervals. Random- and fixed-frequency breathing reduced end-tidal CO2 modestly (P < 0.05). Our data suggest that stringent tidal volume control attenuates low-frequency R-R interval oscillations and that fixed- and random-rate breathing may decrease CO2 chemoreceptor stimulation. We conclude that autonomic rhythms measured during different breathing protocols have much in common but that a stepwise protocol without stringent control of inspired volume may allow for the most efficient assessment of short-term respiratory-mediated autonomic oscillations.

Characterization of the L4-L5-S1 motion segment using the stepwise reduction method.

PubMed

Jaramillo, Héctor Enrique; Puttlitz, Christian M; McGilvray, Kirk; García, José J

2016-05-03

The two aims of this study were to generate data for a more accurate calibration of finite element models including the L5-S1 segment, and to find mechanical differences between the L4-L5 and L5-S1 segments. Then, the range of motion (ROM) and facet forces for the L4-S1 segment were measured using the stepwise reduction method. This consists of sequentially testing and reducing each segment in nine stages by cutting the ligaments, facet capsules, and removing the nucleus. Five L4-S1 human segments (median: 65 years, range: 53-84 years, SD=11.0 years) were loaded under a maximum pure moment of 8Nm. The ROM was measured using stereo-photogrammetry via tracking of three markers and the facet contact forces (CF) were measured using a Tekscan system. The ROM for the L4-L5 segment and all stages showed good agreement with published data. The major differences in ROM between the L4-L5 and L5-S1 segments were found for lateral bending and all stages, for which the L4-L5 ROM was about 1.5-3 times higher than that of the L5-S1 segment, consistent with L5-S1 facet CF about 1.3 to 4 times higher than those measured for the L4-L5 segment. For the other movements and few stages, the L4-L5 ROM was significantly lower that of the L5-S1 segment. ROM and CF provide important baseline data for more accurate calibration of FE models and to understand the role that their structures play in lower lumbar spine mechanics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Phyllotactic transformations as plastic deformations of tubular crystals with defects

NASA Astrophysics Data System (ADS)

Beller, Daniel; Nelson, David

Tubular crystals are 2D lattices in cylindrical topologies, which could be realized as assemblies of colloidal particles, and occur naturally in biological microtubules and in single-walled carbon nanotubes. Their geometry can be understood in the language of phyllotaxis borrowed from botany. We study the mechanics of plastic deformations in tubular crystals in response to tensile stress, as mediated by the formation and separation of dislocation pairs in a triangular lattice. Dislocation motion allows the growth of one phyllotactic arrangement at the expense of another, offering a low-energy, stepwise mode of plastic deformation in response to external stresses. Through theory and simulation, we examine how the tube's radius and helicity affects, and is in turn altered by, dislocation glide. The crystal's bending modulus is found to produce simple but important corrections to the tube's deformation mechanics.

Insight into Chemistry on Cloud/Aerosol Water Surfaces.

PubMed

Zhong, Jie; Kumar, Manoj; Francisco, Joseph S; Zeng, Xiao Cheng

2018-05-15

Cloud/aerosol water surfaces exert significant influence over atmospheric chemical processes. Atmospheric processes at the water surface are observed to follow mechanisms that are quite different from those in the gas phase. This Account summarizes our recent findings of new reaction pathways on the water surface. We have studied these surface reactions using Born-Oppenheimer molecular dynamics simulations. These studies provide useful information on the reaction time scale, the underlying mechanism of surface reactions, and the dynamic behavior of the product formed on the aqueous surface. According to these studies, the aerosol water surfaces confine the atmospheric species into a specific orientation depending on the hydrophilicity of atmospheric species or the hydrogen-bonding interactions between atmospheric species and interfacial water. As a result, atmospheric species are activated toward a particular reaction on the aerosol water surface. For example, the simplest Criegee intermediate (CH 2 OO) exhibits high reactivity toward the interfacial water and hydrogen sulfide, with the reaction times being a few picoseconds, 2-3 orders of magnitude faster than that in the gas phase. The presence of interfacial water molecules induces proton-transfer-based stepwise pathways for these reactions, which are not possible in the gas phase. The strong hydrophobicity of methyl substituents in larger Criegee intermediates (>C1), such as CH 3 CHOO and (CH 3 ) 2 COO, blocks the formation of the necessary prereaction complexes for the Criegee-water reaction to occur at the water droplet surface, which lowers their proton-transfer ability and hampers the reaction. The aerosol water surface provides a solvent medium for acids (e.g., HNO 3 and HCOOH) to participate in reactions via mechanisms that are different from those in the gas and bulk aqueous phases. For example, the anti-CH 3 CHOO-HNO 3 reaction in the gas phase follows a direct reaction between anti-CH 3 CHOO and HNO 3 , whereas on a water surface, the HNO 3 -mediated stepwise hydration of anti-CH 3 CHOO is dominantly observed. The high surface/volume ratio of interfacial water molecules at the aerosol water surface can significantly lower the energy barriers for the proton transfer reactions in the atmosphere. Such catalysis by the aerosol water surface is shown to cause the barrier-less formation of ammonium bisulfate from hydrated NH 3 and SO 3 molecules rather than from the reaction of H 2 SO 4 with NH 3 . Finally, an aerosol water droplet is a polar solvent, which would favorably interact with high polarity substrates. This can accelerate interconversion of different conformers (e.g., anti and syn) of atmospheric species, such as glyoxal, depending on their polarity. The results discussed here enable an improved understanding of atmospheric processes on the aerosol water surface.

A stepwise protocol for the treatment of refractory gastroesophageal reflux-induced chronic cough

PubMed Central

Xu, Xianghuai; Lv, Hanjing; Yu, Li; Chen, Qiang; Liang, Siwei

2016-01-01

Background Refractory gastroesophageal reflux-induced chronic cough (GERC) is difficult to manage. The purpose of the study is to evaluate the efficacy of a novel stepwise protocol for treating this condition. Methods A total of 103 consecutive patients with suspected refractory reflux-induced chronic cough failing to a standard anti-reflux therapy were treated with a stepwise therapy. Treatment commences with high-dose omeprazole and, if necessary, is escalated to subsequent sequential treatment with ranitidine and finally baclofen. The primary end-point was overall cough resolution, and the secondary end-point was cough resolution after each treatment step. Results High-dose omeprazole eliminated or improved cough in 28.1% of patients (n=29). Further stepwise of treatment with the addition of ranitide yielded a favorable response in an additional 12.6% (n=13) of patients, and subsequent escalation to baclofen provoked response in another 36.9% (n=38) of patients. Overall, this stepwise protocol was successful in 77.6% (n=80) of patients. The diurnal cough symptom score fell from 3 [1] to 1 [0] (Z=6.316, P=0.000), and the nocturnal cough symptom score decreased from 1 [1] to 0 [1] (Z=–4.511, P=0.000), with a corresponding reduction in the Gastroesophageal Reflux Diagnostic Questionnaire score from 8.6±1.7 to 6.8±0.7 (t=3.612, P=0.000). Conversely, the cough threshold C2 to capsaicin was increased from 0.49 (0.49) µmol/L to 1.95 (2.92) µmol/L (Z=–5.892, P=0.000), and the cough threshold C5 was increased from 1.95 (2.92) µmol/L to 7.8 (5.85) µmol/L (Z=–5.171, P=0.000). Conclusions Sequential stepwise anti-reflux therapy is a useful therapeutic strategy for refractory reflux-induced chronic cough. PMID:26904227

Adhesive Dimerization of Human P-Cadherin Catalyzed by a Chaperone-like Mechanism.

PubMed

Kudo, Shota; Caaveiro, Jose M M; Tsumoto, Kouhei

2016-09-06

Orderly assembly of classical cadherins governs cell adhesion and tissue maintenance. A key event is the strand-swap dimerization of the extracellular ectodomains of two cadherin molecules from apposing cells. Here we have determined crystal structures of P-cadherin in six different conformational states to elaborate a motion picture of its adhesive dimerization at the atomic level. The snapshots revealed that cell-adhesive dimerization is facilitated by several intermediate states collectively termed X-dimer in analogy to other classical cadherins. Based on previous studies and on the combined structural, kinetic, thermodynamic, biochemical, and cellular data reported herein, we propose that the adhesive dimerization of human P-cadherin is achieved by a stepwise mechanism analogous to that of assembly chaperones. This mechanism, applicable to type I classical cadherins, confers high specificity and fast association rates. We expect these findings to guide innovative therapeutic approaches targeting P-cadherin in cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

A non-canonical mechanism for Crm1-export cargo complex assembly.

PubMed

Fischer, Ute; Schäuble, Nico; Schütz, Sabina; Altvater, Martin; Chang, Yiming; Faza, Marius Boulos; Panse, Vikram Govind

2015-04-21

The transport receptor Crm1 mediates the export of diverse cargos containing leucine-rich nuclear export signals (NESs) through complex formation with RanGTP. To ensure efficient cargo release in the cytoplasm, NESs have evolved to display low affinity for Crm1. However, mechanisms that overcome low affinity to assemble Crm1-export complexes in the nucleus remain poorly understood. In this study, we reveal a new type of RanGTP-binding protein, Slx9, which facilitates Crm1 recruitment to the 40S pre-ribosome-associated NES-containing adaptor Rio2. In vitro, Slx9 binds Rio2 and RanGTP, forming a complex. This complex directly loads Crm1, unveiling a non-canonical stepwise mechanism to assemble a Crm1-export complex. A mutation in Slx9 that impairs Crm1-export complex assembly inhibits 40S pre-ribosome export. Thus, Slx9 functions as a scaffold to optimally present RanGTP and the NES to Crm1, therefore, triggering 40S pre-ribosome export. This mechanism could represent one solution to the paradox of weak binding events underlying rapid Crm1-mediated export.

Mechanistic investigations of the hydrolysis of amides, oxoesters and thioesters via kinetic isotope effects and positional isotope exchange.

PubMed

Robins, Lori I; Fogle, Emily J; Marlier, John F

2015-11-01

The hydrolysis of amides, oxoesters and thioesters is an important reaction in both organic chemistry and biochemistry. Kinetic isotope effects (KIEs) are one of the most important physical organic methods for determining the most likely transition state structure and rate-determining step of these reaction mechanisms. This method induces a very small change in reaction rates, which, in turn, results in a minimum disturbance of the natural mechanism. KIE studies were carried out on both the non-enzymatic and the enzyme-catalyzed reactions in an effort to compare both types of mechanisms. In these studies the amides and esters of formic acid were chosen because this molecular structure allowed development of methodology to determine heavy-atom solvent (nucleophile) KIEs. This type of isotope effect is difficult to measure, but is rich in mechanistic information. Results of these investigations point to transition states with varying degrees of tetrahedral character that fit a classical stepwise mechanism. This article is part of a special issue entitled: Enzyme Transition States from Theory and Experiment. Copyright © 2014 Elsevier B.V. All rights reserved.

Dynamic in vivo binding of transcription factors to cis-regulatory modules of cer and gsc in the stepwise formation of the Spemann–Mangold organizer

PubMed Central

Sudou, Norihiro; Yamamoto, Shinji; Ogino, Hajime; Taira, Masanori

2012-01-01

How multiple developmental cues are integrated on cis-regulatory modules (CRMs) for cell fate decisions remains uncertain. The Spemann–Mangold organizer in Xenopus embryos expresses the transcription factors Lim1/Lhx1, Otx2, Mix1, Siamois (Sia) and VegT. Reporter analyses using sperm nuclear transplantation and DNA injection showed that cerberus (cer) and goosecoid (gsc) are activated by the aforementioned transcription factors through CRMs conserved between X. laevis and X. tropicalis. ChIP-qPCR analysis for the five transcription factors revealed that cer and gsc CRMs are initially bound by both Sia and VegT at the late blastula stage, and subsequently bound by all five factors at the gastrula stage. At the neurula stage, only binding of Lim1 and Otx2 to the gsc CRM, among others, persists, which corresponds to their co-expression in the prechordal plate. Based on these data, together with detailed expression pattern analysis, we propose a new model of stepwise formation of the organizer, in which (1) maternal VegT and Wnt-induced Sia first bind to CRMs at the blastula stage; then (2) Nodal-inducible Lim1, Otx2, Mix1 and zygotic VegT are bound to CRMs in the dorsal endodermal and mesodermal regions where all these genes are co-expressed; and (3) these two regions are combined at the gastrula stage to form the organizer. Thus, the in vivo dynamics of multiple transcription factors highlight their roles in the initiation and maintenance of gene expression, and also reveal the stepwise integration of maternal, Nodal and Wnt signaling on CRMs of organizer genes to generate the organizer. PMID:22492356

Dynamic in vivo binding of transcription factors to cis-regulatory modules of cer and gsc in the stepwise formation of the Spemann-Mangold organizer.

PubMed

Sudou, Norihiro; Yamamoto, Shinji; Ogino, Hajime; Taira, Masanori

2012-05-01

How multiple developmental cues are integrated on cis-regulatory modules (CRMs) for cell fate decisions remains uncertain. The Spemann-Mangold organizer in Xenopus embryos expresses the transcription factors Lim1/Lhx1, Otx2, Mix1, Siamois (Sia) and VegT. Reporter analyses using sperm nuclear transplantation and DNA injection showed that cerberus (cer) and goosecoid (gsc) are activated by the aforementioned transcription factors through CRMs conserved between X. laevis and X. tropicalis. ChIP-qPCR analysis for the five transcription factors revealed that cer and gsc CRMs are initially bound by both Sia and VegT at the late blastula stage, and subsequently bound by all five factors at the gastrula stage. At the neurula stage, only binding of Lim1 and Otx2 to the gsc CRM, among others, persists, which corresponds to their co-expression in the prechordal plate. Based on these data, together with detailed expression pattern analysis, we propose a new model of stepwise formation of the organizer, in which (1) maternal VegT and Wnt-induced Sia first bind to CRMs at the blastula stage; then (2) Nodal-inducible Lim1, Otx2, Mix1 and zygotic VegT are bound to CRMs in the dorsal endodermal and mesodermal regions where all these genes are co-expressed; and (3) these two regions are combined at the gastrula stage to form the organizer. Thus, the in vivo dynamics of multiple transcription factors highlight their roles in the initiation and maintenance of gene expression, and also reveal the stepwise integration of maternal, Nodal and Wnt signaling on CRMs of organizer genes to generate the organizer.

Some Considerations on the Partial Credit Model

ERIC Educational Resources Information Center

Verhelst, N. D.; Verstralen, H. H. F. M.

2008-01-01

The Partial Credit Model (PCM) is sometimes interpreted as a model for stepwise solution of polytomously scored items, where the item parameters are interpreted as difficulties of the steps. It is argued that this interpretation is not justified. A model for stepwise solution is discussed. It is shown that the PCM is suited to model sums of binary…

Stepwise Inquiry into Hard Water in a High School Chemistry Laboratory

ERIC Educational Resources Information Center

Kakisako, Mami; Nishikawa, Kazuyuki; Nakano, Masayoshi; Harada, Kana S.; Tatsuoka, Tomoyuki; Koga, Nobuyoshi

2016-01-01

This study focuses on the design of a learning program to introduce complexometric titration as a method for determining water hardness in a high school chemistry laboratory. Students are introduced to the different properties and reactions of hard water in a stepwise manner so that they gain the necessary chemical knowledge and conceptual…

Evolution of Rubisco activase gene in plants.

PubMed

Nagarajan, Ragupathi; Gill, Kulvinder S

2018-01-01

Rubisco activase of plants evolved in a stepwise manner without losing its function to adapt to the major evolutionary events including endosymbiosis and land colonization. Rubisco activase is an essential enzyme for photosynthesis, which removes inhibitory sugar phosphates from the active sites of Rubisco, a process necessary for Rubisco activation and carbon fixation. The gene probably evolved in cyanobacteria as different species differ for its presence. However, the gene is present in all other plant species. At least a single gene copy was maintained throughout plant evolution; but various genome and gene duplication events, which occurred during plant evolution, increased its copy number in some species. The exons and exon-intron junctions of present day higher plant's Rca, which is conserved in most species seem to have evolved in charophytes. A unique tandem duplication of Rca gene occurred in a common grass ancestor, and the two genes evolved differently for gene structure, sequence, and expression pattern. At the protein level, starting with a primitive form in cyanobacteria, RCA of chlorophytes evolved by integrating chloroplast transit peptide (cTP), and N-terminal domains to the ATPase, Rubisco recognition and C-terminal domains. The redox regulated C-terminal extension (CTE) and the associated alternate splicing mechanism, which splices the RCA-α and RCA-β isoforms were probably gained from another gene in charophytes, conserved in most species except the members of Solanaceae family.

The DEAD-box Protein Dbp2 Functions with the RNA-binding Protein Yra1 to Promote mRNP Assembly

PubMed Central

Ma, Wai Kit; Cloutier, Sara C.; Tran, Elizabeth J.

2013-01-01

Eukaryotic gene expression involves numerous biochemical steps that are dependent on RNA structure and ribonucleoprotein (RNP) complex formation. The DEAD-box class of RNA helicases plays fundamental roles in formation of RNA and RNP structure in every aspect of RNA metabolism. In an effort to explore the diversity of biological roles for DEAD-box proteins, our laboratory recently demonstrated that the DEAD-box protein Dbp2 associates with actively transcribing genes and is required for normal gene expression in Saccharomyces cerevisiae. We now provide evidence that Dbp2 interacts genetically and physically with the mRNA export factor Yra1. In addition, we find that Dbp2 is required for in vivo assembly of mRNA-binding proteins Yra1, Nab2 and Mex67 onto poly(A)+ RNA. Strikingly, we also show that Dbp2 is an efficient RNA helicase in vitro and that Yra1 decreases the efficiency of ATP-dependent duplex unwinding. We provide a model whereby mRNP assembly requires Dbp2 unwinding activity and once the mRNP is properly assembled, inhibition by Yra1 prevents further rearrangements. Both Yra1 and Dbp2 are conserved in multicellular eukaryotes suggesting that this constitutes a broadly conserved mechanism for stepwise assembly of mature mRNPs in the nucleus. PMID:23721653

Caloric restriction delays yeast chronological aging by remodeling carbohydrate and lipid metabolism, altering peroxisomal and mitochondrial functionalities, and postponing the onsets of apoptotic and liponecrotic modes of regulated cell death

PubMed Central

Arlia-Ciommo, Anthony; Leonov, Anna; Beach, Adam; Richard, Vincent R.; Bourque, Simon D.; Burstein, Michelle T.; Kyryakov, Pavlo; Gomez-Perez, Alejandra; Koupaki, Olivia; Feldman, Rachel; Titorenko, Vladimir I.

2018-01-01

A dietary regimen of caloric restriction delays aging in evolutionarily distant eukaryotes, including the budding yeast Saccharomyces cerevisiae. Here, we assessed how caloric restriction influences morphological, biochemical and cell biological properties of chronologically aging yeast advancing through different stages of the aging process. Our findings revealed that this low-calorie diet slows yeast chronological aging by mechanisms that coordinate the spatiotemporal dynamics of various cellular processes before entry into a non-proliferative state and after such entry. Caloric restriction causes a stepwise establishment of an aging-delaying cellular pattern by tuning a network that assimilates the following: 1) pathways of carbohydrate and lipid metabolism; 2) communications between the endoplasmic reticulum, lipid droplets, peroxisomes, mitochondria and the cytosol; and 3) a balance between the processes of mitochondrial fusion and fission. Through different phases of the aging process, the caloric restriction-dependent remodeling of this intricate network 1) postpones the age-related onsets of apoptotic and liponecrotic modes of regulated cell death; and 2) actively increases the chance of cell survival by supporting the maintenance of cellular proteostasis. Because caloric restriction decreases the risk of cell death and actively increases the chance of cell survival throughout chronological lifespan, this dietary intervention extends longevity of chronologically aging yeast. PMID:29662634

Gynecomastia: Pathophysiology, Evaluation, and Management

PubMed Central

Johnson, Ruth E.; Murad, M. Hassan

2009-01-01

Gynecomastia, defined as benign proliferation of male breast glandular tissue, is usually caused by increased estrogen activity, decreased testosterone activity, or the use of numerous medications. Although a fairly common presentation in the primary care setting and mostly of benign etiology, it can cause patients considerable anxiety. The initial step is to rule out pseudogynecomastia by careful history taking and physical examination. A stepwise approach that includes imaging and laboratory testing to exclude neoplasms and endocrinopathies may facilitate cost-effective diagnosis. If results of all studies are normal, idiopathic gynecomastia is diagnosed. The evidence in this area is mainly of observational nature and lower quality. PMID:19880691

Controlling self-assembly of microtubule spools via kinesin motor density

PubMed Central

Lam, A.T.; Curschellas, C.; Krovvidi, D.; Hess, H.

2014-01-01

Active self-assembly, in which non-thermal energy is consumed by the system to put together building blocks, allows the creation of non-equilibrium structures and active materials. Microtubule spools assembled in gliding assays are one example of such non-equilibrium structures, capable of storing bending energies on the order of 105 kT. Although these structures arise spontaneously in experiments, the origin of microtubule spooling has long been debated. Here, using a stepwise kinesin gradient, we demonstrate that spool assembly can be controlled by the surface density of kinesin motors, showing that pinning of microtubules due to dead motors plays a dominant role in spool initiation. PMID:25269076

Controlling self-assembly of microtubule spools via kinesin motor density.

PubMed

Lam, A T; Curschellas, C; Krovvidi, D; Hess, H

2014-11-21

Active self-assembly, in which non-thermal energy is consumed by the system to put together building blocks, allows the creation of non-equilibrium structures and active materials. Microtubule spools assembled in gliding assays are one example of such non-equilibrium structures, capable of storing bending energies on the order of 10(5) kT. Although these structures arise spontaneously in experiments, the origin of microtubule spooling has long been debated. Here, using a stepwise kinesin gradient, we demonstrate that spool assembly can be controlled by the surface density of kinesin motors, showing that pinning of microtubules due to dead motors plays a dominant role in spool initiation.

Synthesis and biological evaluation of Raddeanin A, a triterpene saponin isolated from Anemone raddeana.

PubMed

Qian, Shan; Chen, Quan Long; Guan, Jin Long; Wu, Yong; Wang, Zhou Yu

2014-01-01

First, Raddeanin A, a cytotoxic oleanane-type triterpenoid saponin isolated from Anemone raddeana REGEL, was synthesized. Stepwise glycosylation was adopted in the synthesis from oleanolic acid, employing arabinosyl, glucosyl and rhamnosyl trichloroacetimidate as donors. The chemical structure of Raddeanin A was confirmed by means of (1)H-NMR, (13)C-NMR, IR, MS and elemental analysis, which elucidated the structure to be 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→2)-α-L-arabinopyranoside oleanolic acid. Biological activity tests showed that in the range of low concentrations, Raddeanin A displayed moderate inhibitory activity against histone deacetylases (HDACs), indicating that the HDACs' inhibitory activity of Raddeanin A may contribute to its cytotoxicity.

Non-enzymatic oxidation of NADH by quinones

NASA Astrophysics Data System (ADS)

Scherbak, Nikolai; Strid, Åke; Eriksson, Leif A.

2005-10-01

Non-enzymatic oxidation of NADH by a large number of different quinones has been explored both theoretically and experimentally. It is concluded that the smaller benzo- and naphtho-quinones are capable of oxidising NADH in aqueous solution, whereas the larger anthraquinone is not. The mechanisms of stepwise electron and proton transfers are explored, and ruled out in favour of direct hydride transfer. For menadione (2-methyl-1,4-naphthoquinone), no reaction is observed experimentally; theoretically we find that there is a very close balance between the energetic cost of hydride removal from NADH and the energy gain of formation of the menadione semiquinone radical anion.

Prebiotic NH3 Formation: Insights from Simulations.

PubMed

Stirling, András; Rozgonyi, Tamás; Krack, Matthias; Bernasconi, Marco

2016-02-15

Simulations of prebiotic NH₃ synthesis from NO₃⁻ and NO₂⁻ on pyrite surfaces under hydrothermal conditions are reported. Ab initio metadynamics calculations have successfully explored the full reaction path which explains earlier experimental observations. We have found that the reaction mechanism can be constructed from stepwise single atom transfers which are compatible with the expected reaction time scales. The roles of the hot-pressurized water and of the pyrite surfaces have been addressed. The mechanistic picture that emerged from the simulations strengthens the theory of chemoautotrophic origin of life by providing plausible reaction pathways for the formation of ammonia within the iron-sulfur-world scenario.

Targeted drug delivery to the brain using magnetic nanoparticles.

PubMed

Thomsen, Louiza Bohn; Thomsen, Maj Schneider; Moos, Torben

2015-01-01

Brain capillary endothelial cells denote the blood-brain barrier (BBB), and conjugation of nanoparticles with antibodies that target molecules expressed by these endothelial cells may facilitate their uptake and transport into the brain. Magnetic nanoparticles can be encapsulated in liposomes and carry large molecules with therapeutic potential, for example, siRNA, cDNA and polypeptides. An additional approach to enhance the transport of magnetic nanoparticles across the BBB is the application of extracranially applied magnetic force. Stepwise targeting of magnetic nanoparticles to brain capillary endothelial cells followed by transport through the BBB using magnetic force may prove a novel mechanism for targeted therapy of macromolecules to the brain.

Highly efficient spin polarizer based on individual heterometallic cubane single-molecule magnets

NASA Astrophysics Data System (ADS)

Dong, Damin

2015-09-01

The spin-polarized transport across a single-molecule magnet [Mn3Zn(hmp)3O(N3)3(C3H5O2)3].2CHCl3 has been investigated using a density functional theory combined with Keldysh non-equilibrium Green's function formalism. It is shown that this single-molecule magnet has perfect spin filter behaviour. By adsorbing Ni3 cluster onto non-magnetic Au electrode, a large magnetoresistance exceeding 172% is found displaying molecular spin valve feature. Due to the tunneling via discrete quantum-mechanical states, the I-V curve has a stepwise character and negative differential resistance behaviour.

Mission requirements for a manned earth observatory. Volume 1, task 1: Experiment selection, definition, and documentation

NASA Technical Reports Server (NTRS)

1973-01-01

Information related to proposed earth observation experiments for shuttle sortie missions (SSM) in the 1980's is presented. The step-wise progression of study activities and the development of the rationale that led to the identification, selection, and description of earth observation experiments for SSM are listed. The selected experiments are described, defined, and documented by individual disciplines. These disciplines include: oceanography; meteorology; agriculture, forestry, and rangeland; geology; hydrology; and environmental impact.

The effects of pure potassium channel blocker nifekalant and sodium channel blocker mexiletine on malignant ventricular tachyarrhythmias.

PubMed

Otuki, Sou; Hasegawa, Kanae; Watanabe, Hiroshi; Katsuumi, Goro; Yagihara, Nobue; Iijima, Kenichi; Sato, Akinori; Izumi, Daisuke; Furushima, Hiroshi; Chinushi, Masaomi; Aizawa, Yoshifusa; Minamino, Tohru

Patients with repetitive ventricular tachyarrhythmias - so-called electrical storm - frequently require antiarrhythmic drugs. Amiodarone is widely used for the treatment of electrical storm but is ineffective in some patients. Therefore, we investigated the efficacy of stepwise administration of nifekalant, a pure potassium channel blocker, and mexiletine for electrical storm. This study included 44 patients with repetitive ventricular tachyarrhythmias who received stepwise therapy with nifekalant and mexiletine for electrical storm. Nifekalant was initially administered, and mexiletine was subsequently added if nifekalant failed to control ventricular tachyarrhythmias. Nifekalant completely suppressed recurrences of ventricular arrhythmias in 28 patients (64%), including 6 patients in whom oral amiodarone failed to control arrhythmias. In 9 of 16 patients in whom nifekalant was partially effective but failed to suppress ventricular arrhythmias, mexiletine was added. The addition of mexiletine prevented recurrences of ventricular tachyarrhythmias in 5 of these 9 patients (56%). There was no death associated with electrical storm. In total, the stepwise treatment with nifekalant and mexiletine was effective in preventing ventricular tachyarrhythmias in 33 of 44 patients (75%). There was no difference in cycle length of the ventricular tachycardia, QRS interval, QT interval, or left ventricular ejection fraction between patients who responded to antiarrhythmic drugs and those who did not. During follow-up, 8 patients had repetitive ventricular tachyarrhythmia recurrences, and the stepwise treatment was effective in 6 of these 8 patients (75%). The stepwise treatment with nifekalant and mexiletine was highly effective in the suppression of electrical storm. Copyright © 2016. Published by Elsevier Inc.

A stepwise model to predict monthly streamflow

NASA Astrophysics Data System (ADS)

Mahmood Al-Juboori, Anas; Guven, Aytac

2016-12-01

In this study, a stepwise model empowered with genetic programming is developed to predict the monthly flows of Hurman River in Turkey and Diyalah and Lesser Zab Rivers in Iraq. The model divides the monthly flow data to twelve intervals representing the number of months in a year. The flow of a month, t is considered as a function of the antecedent month's flow (t - 1) and it is predicted by multiplying the antecedent monthly flow by a constant value called K. The optimum value of K is obtained by a stepwise procedure which employs Gene Expression Programming (GEP) and Nonlinear Generalized Reduced Gradient Optimization (NGRGO) as alternative to traditional nonlinear regression technique. The degree of determination and root mean squared error are used to evaluate the performance of the proposed models. The results of the proposed model are compared with the conventional Markovian and Auto Regressive Integrated Moving Average (ARIMA) models based on observed monthly flow data. The comparison results based on five different statistic measures show that the proposed stepwise model performed better than Markovian model and ARIMA model. The R2 values of the proposed model range between 0.81 and 0.92 for the three rivers in this study.

Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1

DOE PAGES

Eustermann, Sebastian; Wu, Wing -Fung; Langelier, Marie -France; ...

2015-11-25

Poly(ADP-ribose)polymerase 1 (PARP-1) is a key eukaryotic stress sensor that responds in seconds to DNA single-strand breaks (SSBs), the most frequent genomic damage. A burst of poly(ADP-ribose) synthesis initiates DNA damage response, whereas PARP-1 inhibition kills BRCA-deficient tumor cells selectively, providing the first anti-cancer therapy based on synthetic lethality. However, the mechanism underlying PARP-1’s function remained obscure; inherent dynamics of SSBs and PARP-1’s multi-domain architecture hindered structural studies. Here we reveal the structural basis of SSB detection and how multi-domain folding underlies the allosteric switch that determines PARP-1’s signaling response. Two flexibly linked N-terminal zinc fingers recognize the extreme deformabilitymore » of SSBs and drive co-operative, stepwise self-assembly of remaining PARP-1 domains to control the activity of the C-terminal catalytic domain. Automodifcation in cis explains the subsequent release of monomeric PARP-1 from DNA, allowing repair and replication to proceed. Finally, our results provide a molecular framework for understanding PARP inhibitor action and, more generally, allosteric control of dynamic, multi-domain proteins.« less

The Unfolded Protein Response in Retinal Vascular Diseases: Implications and Therapeutic Potential Beyond Protein Folding

PubMed Central

Zhang, Sarah X.; Ma, Jacey H.; Bhatta, Maulasri; Fliesler, Steven J.; Wang, Joshua J.

2015-01-01

Angiogenesis is a complex, step-wise process of new vessel formation that is involved in both normal embryonic development as well as postnatal pathological processes, such as cancer, cardiovascular disease, and diabetes. Aberrant blood vessel growth, also known as neovascularization, in the retina and the choroid is a major cause of vision loss in severe eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Yet, retinal neovascularization is causally and dynamically associated with vasodegeneration, ischemia, and vascular remodeling in retinal tissues. Understanding the mechanisms of retinal neovascularization is an urgent unmet need for developing new treatments for these devastating diseases. Accumulating evidence suggests a vital role for the unfolded protein response (UPR) in regulation of angiogenesis, in part through coordinating the secretion of pro-angiogenic growth factors, such as VEGF, and modulating endothelial cell survival and activity. Herein, we summarize current research in the context of endoplasmic reticulum (ER) stress and UPR signaling in retinal angiogenesis and vascular remodeling, highlighting potential implications of targeting these stress response pathways in the prevention and treatment of retinal vascular diseases that result in visual deficits and blindness. PMID:25529848

Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective

PubMed Central

Tan, Hor-Yue; San-Marina, Serban; Wang, Ning; Hong, Ming; Li, Sha; Li, Lei; Cheung, Fan; Wen, Xiao-Yan; Feng, Yibin

2016-01-01

Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field. PMID:26941826

DEVELOPMENT OF MICROORGANISMS WITH IMPROVED TRANSPORT AND BIOSURFACTANT ACTIVITY FOR ENHANCED OIL RECOVERY

DOE Office of Scientific and Technical Information (OSTI.GOV)

M.J. McInerney; N. Youssef; T. Fincher

2004-05-31

Diverse microorganisms were screened for biosurfactant production and anaerobic growth at elevated salt concentrations to obtain candidates most suitable for microbial oil recovery. Seventy percent of the 205 strains tested, mostly strains of Bacillus mojavensis, Bacillus subtilis, Bacillus licheniformis, and Bacillus sonorensis, produced biosurfactants aerobically and 41% of the strains had biosurfactant activity greater than Bacillus mojavensis JF-2, the current candidate for oil recovery. Biosurfactant activity varied with the percentage of the 3-hydroxy-tetradecanoate isomers in the fatty acid portion of the biosurfactant. Changing the medium composition by incorporation of different precursors of 3-hydroxy tetradecanoate increased the activity of biosurfactant. Themore » surface tension and critical micelle concentration of 15 different, biosurfactant-producing Bacillus strains was determined individually and in combination with other biosurfactants. Some biosurfactant mixtures were found to have synergistic effect on surface tension (e.g. surface tension was lowered from 41 to 31 mN/m in some cases) while others had a synergistic effect on CMD-1 values. We compared the transport abilities of spores from three Bacillus strains using a model porous system to study spore recovery and transport. Sand-packed columns were used to select for spores or cells with the best transport abilities through brine-saturated sand. Spores of Bacillus mojavensis strains JF-2 and ROB-2 and a natural recombinant, strain C-9, transported through sand at very high efficiencies. The earliest cells/spores that emerged from the column were re-grown, allowed to sporulate, and applied to a second column. This procedure greatly enhanced the transport of strain C-9. Spores with enhanced transport abilities can be easily obtained and that the preparation of inocula for use in MEOR is feasible. Tertiary oil recovery experiments showed that 10 to 40 mg/l of JF-2 biosurfactant in the presence of 0.1 mM 2,3-butanediol and 1 g/l of partially hydrolyzed polyacrylamide (PHPA) recovered 10-40% of residual oil from Berea sandstone cores. When PHPA was used alone, about 10% of the residual oil was recovered. Interfacial tension (IFT) decreased in a stepwise manner as biosurfactant concentration increased with marked reductions in IFT occurring at biosurfactant concentrations of 10 and 40 mg/l. When the biosurfactant concentration was greater than 10 mg/l, residual oil recovery linearly increased with biosurfactant concentration. A mathematical model that relates oil recovery to biosurfactant concentration was modified to include the stepwise changes in IFT as biosurfactant concentrations changes. This model adequately predicted the experimentally observed changes in IFT as a function of biosurfactant concentration. Our work shows that (1) diverse microorganisms produce biosurfactants, (2) nutrient manipulation may provide a mechanism to increase biosurfactant activity, (3) biosurfactant concentrations in excess of the critical micelle concentration recover substantial amounts of residual oil, and (4) equations that describe the effect of the biosurfactant on IFT adequately predict residual oil recovery in sandstone cores.« less

The role of sense of coherence and physical activity in positive and negative affect of Turkish adolescents.

PubMed

Oztekin, Ceyda; Tezer, Esin

2009-01-01

This study investigated the role of sense of coherence and total physical activity in positive and negative affect. Participants were 376 (169 female, 206 male, and 1 missing value) student volunteers from different faculties of Middle East Technical University. Three questionnaires: Sense of Coherence Scale (SOC), Physical Activity Assessment Questionnaire (PAAQ), and Positive and Negative Affect Schedule (PANAS) were administered to the students together with the demographic information sheet. Two separate stepwise multiple linear regression analyses were conducted to examine the predictive power of sense of coherence and total physical activity on positive and negative affect scores. Results revealed that both sense of coherence and total physical activity predicted the positive affect whereas only the sense of coherence predicted the negative affect on university students. Findings are discussed in light of sense of coherence, physical activity, and positive and negative affect literature.

Mechanics of the canine diaphragm in pleural effusion.

PubMed

De Troyer, André; Leduc, Dimitri; Cappello, Matteo; Gevenois, Pierre Alain

2012-09-01

Pleural effusion is a complicating feature of many diseases of the lung and pleura, but its effects on the mechanics of the diaphragm have not been assessed. In the present study, radiopaque markers were attached along muscle bundles in the midcostal region of the diaphragm in anesthetized dogs, and the three-dimensional location of the markers during relaxation before and after the stepwise introduction of liquid into the left or right pleural space and during phrenic nerve stimulation in the same conditions was determined using computed tomography. From these data, accurate measurements of diaphragm muscle length and displacement were obtained, and the changes in pleural and abdominal pressure were analyzed as functions of these parameters. The effect of liquid instillation on the axial position of rib 5 was also measured. The data showed that 1) liquid leaked through the dorsal mediastinal sheet behind the pericardium so that effusion was bilateral; 2) effusion caused a caudal displacement of the relaxed diaphragm; 3) this displacement was, compared with passive lung inflation, much larger than the cranial displacement of the ribs; and 4) the capacity of the diaphragm to generate pressure, in particular pleural pressure, decreased markedly as effusion increased, and this decrease was well explained by the decrease in active muscle length. It is concluded that pleural effusion has a major adverse effect on the pressure-generating capacity of the diaphragm and that this is the result of the action of hydrostatic forces on the muscle.

Water-tunnel studies of heat balance in swimming mako sharks.

PubMed

Bernal, D; Sepulveda, C; Graham, J B

2001-12-01

The mako shark (Isurus oxyrinchus) has specialized vascular networks (retia mirabilia) forming counter-current heat exchangers that allow metabolic heat retention in certain regions of the body, including the aerobic, locomotor red muscle and the viscera. Red muscle, white muscle and stomach temperatures were measured in juvenile (5-13.6 kg) makos swimming steadily in a water tunnel and exposed to stepwise square-wave changes in ambient temperature (T(a)) to estimate the rates of heat transfer and to determine their capacity for the activity-independent control of heat balance. The rates of heat gain of red muscle during warming were significantly higher than the rates of heat loss during cooling, and neither the magnitude of the change in T(a) nor the direction of change in T(a) had a significant effect on red muscle latency time. Our findings for mako red muscle are similar to those recorded for tunas and suggest modulation of retial heat-exchange efficiency as the underlying mechanism controlling heat balance. However, the red muscle temperatures measured in swimming makos (0.3-3 degrees C above T(a)) are cooler than those measured previously in larger decked makos. Also, the finding of non-stable stomach temperatures contrasts with the predicted independence from T(a) recorded in telemetry studies of mako and white sharks. Our studies on live makos provide new evidence that, in addition to the unique convergent morphological properties between makos and tunas, there is a strong functional similarity in the mechanisms used to regulate heat transfer.

A stepwise regression tree for nonlinear approximation: applications to estimating subpixel land cover

USGS Publications Warehouse

Huang, C.; Townshend, J.R.G.

2003-01-01

A stepwise regression tree (SRT) algorithm was developed for approximating complex nonlinear relationships. Based on the regression tree of Breiman et al . (BRT) and a stepwise linear regression (SLR) method, this algorithm represents an improvement over SLR in that it can approximate nonlinear relationships and over BRT in that it gives more realistic predictions. The applicability of this method to estimating subpixel forest was demonstrated using three test data sets, on all of which it gave more accurate predictions than SLR and BRT. SRT also generated more compact trees and performed better than or at least as well as BRT at all 10 equal forest proportion interval ranging from 0 to 100%. This method is appealing to estimating subpixel land cover over large areas.

A method for the selection of a functional form for a thermodynamic equation of state using weighted linear least squares stepwise regression

NASA Technical Reports Server (NTRS)

Jacobsen, R. T.; Stewart, R. B.; Crain, R. W., Jr.; Rose, G. L.; Myers, A. F.

1976-01-01

A method was developed for establishing a rational choice of the terms to be included in an equation of state with a large number of adjustable coefficients. The methods presented were developed for use in the determination of an equation of state for oxygen and nitrogen. However, a general application of the methods is possible in studies involving the determination of an optimum polynomial equation for fitting a large number of data points. The data considered in the least squares problem are experimental thermodynamic pressure-density-temperature data. Attention is given to a description of stepwise multiple regression and the use of stepwise regression in the determination of an equation of state for oxygen and nitrogen.

Caregiver Input to Optimize the Design of a Pediatric Care Planning Guide for Rehabilitation: Descriptive Study

PubMed Central

Lim, Heather K; Corden, Marya E

2017-01-01

Background Caregiver input has informed the design of a valid electronic patient-reported outcome (PRO) measure for use in pediatric rehabilitation. This proxy assessment may be further developed to expedite and enhance patient-centered care planning processes, but user input is first needed to finalize the core requirements that will guide its design. Objective The objective of this study was to examine the feasibility of a stepwise process for building on a baseline assessment of young children's participation in activities to develop a care plan relevant to pediatric rehabilitation. Methods A cross-sectional descriptive study design was employed using qualitative methods. Data were collected via Web-based technology and by telephone. Twenty-five caregivers of young children (9 with developmental delays, 16 without delays) and between 1 and 7 years were recruited from a subsample of parents who had previously enrolled in a Web-based validation of a PRO on children’s participation and provided consent for future contact. Each caregiver completed a demographic questionnaire and Young Children’s Participation and Environment Measure (YC-PEM) online, followed by a 20- to 60-min semistructured and audiotaped phone interview to review and build upon PRO results as summarized in an electronic report. Interview data were content coded to the interview guide and reviewed by multiple research staff to estimate feasibility according to stepwise completion rates, perceptions of difficulty in step completion, and perceptions of overall utility. Results Half of the participants in the final study sample (N=25) fully completed a stepwise process of building on their baseline PRO assessment to develop an initial care plan for their child. In most cases, similar stepwise completion rates and trends in the approaches taken for step completion were found regardless of the child’s disability status. However, more parents of children with disabilities reported difficulties in rank ordering their priorities for change and identified child-focused strategies for goal attainment. Nearly 77% (19/25) of users were willing to use the process to develop and communicate intervention priorities and strategies with professionals, family, and friends. Conclusions Results informed revisions to the care planning guide before usability and feasibility testing of an initial Web-based prototype that is now underway. PMID:29066421

Microbial arms race: Ballistic "nematocysts" in dinoflagellates represent a new extreme in organelle complexity.

PubMed

Gavelis, Gregory S; Wakeman, Kevin C; Tillmann, Urban; Ripken, Christina; Mitarai, Satoshi; Herranz, Maria; Özbek, Suat; Holstein, Thomas; Keeling, Patrick J; Leander, Brian S

2017-03-01

We examine the origin of harpoon-like secretory organelles (nematocysts) in dinoflagellate protists. These ballistic organelles have been hypothesized to be homologous to similarly complex structures in animals (cnidarians); but we show, using structural, functional, and phylogenomic data, that nematocysts evolved independently in both lineages. We also recorded the first high-resolution videos of nematocyst discharge in dinoflagellates. Unexpectedly, our data suggest that different types of dinoflagellate nematocysts use two fundamentally different types of ballistic mechanisms: one type relies on a single pressurized capsule for propulsion, whereas the other type launches 11 to 15 projectiles from an arrangement similar to a Gatling gun. Despite their radical structural differences, these nematocysts share a single origin within dinoflagellates and both potentially use a contraction-based mechanism to generate ballistic force. The diversity of traits in dinoflagellate nematocysts demonstrates a stepwise route by which simple secretory structures diversified to yield elaborate subcellular weaponry.

25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end.

PubMed

Heim, Markus H

2013-07-01

Chronic hepatitis caused by infection with hepatitis C virus C (HCV) (therefore known as chronic hepatitis C (CHC)) is a leading cause of liver disease worldwide. For the past 25 years, recombinant interferon-α (IFNα) has been the main component of treatments for HCV infection. Treatment efficacy has shown a stepwise improvement following the pegylation of IFNα and its use in combination with other antiviral drugs. However, viral escape mechanisms, refractory IFNα signalling in the liver and substantial drug toxicity still limit the efficacy of this treatment. A new generation of HCV-specific antiviral drugs will probably improve response rates and might replace IFNs in CHC treatment in the next few years. This Timeline article summarizes the history of CHC treatment using recombinant IFNα with an emphasis on the mechanisms of action and the causes of non-response.

Branchy alumina nanotubes

NASA Astrophysics Data System (ADS)

Zou, Jianping; Pu, Lin; Bao, Ximao; Feng, Duan

2002-02-01

Branchy alumina nanotubes (bANTs) have been shown to exist in aluminum oxide. Electron-beam evaporated 400 nm Al film on Si substrate is stepwise anodized in dilute sulfuric acid under the constant dc voltage 40 V at 10.0 °C. This electrochemical-anodizing route resulted in the formation of individual bANTs. Transmission electron microscopy showed that the length of the bANTs was around 450 nm, and the inner diameter was around 10-20 nm. We deduced that the bANTs, the completely detached multibranchy cells of anodic porous alumina (APA) film, should be evolved from the stagnant cells of the APA mother film. The bANTs may be used as templates in fabrication of individual branchy nanoscale cables, jacks, and heterojunctions. The proposed formation mechanisms of the bANTs and the stagnant cells should give some insights into the long-standing problem of APA film, i.e., the self-ordering mechanism of the cells arrangement in porous anodization of aluminum.

Visualizing Cochlear Mechanics Using Confocal Microscopy

NASA Astrophysics Data System (ADS)

Ulfendahl, M.; Boutet de Monvel, J.; Fridberger, A.

2003-02-01

The sound-evoked vibration pattern of the hearing organ is based on complex mechanical interactions between different cellular structures. To explore the structural changes occurring within the organ of Corti during basilar-membrane motion, stepwise alterations of the scala tympani pressure were applied in an in vitro preparation of the guinea-pig temporal bone. Confocal images were acquired at each pressure level. In this way, the motion of several structures could be simultaneously observed with high resolution in a nearly intact system. Images were analyzed using a novel wavelet-based optical-flow estimation algorithm. Under the present experimental conditions, the reticular lamina moved as a stiff plate with a center of rotation in the region of the inner hair cells. The outer hair cells appeared non-rigid and the basal, synaptic regions of these cells displayed significant radial motion indicative of cellular bending and internal shearing.

Non-fluent speech following stroke is caused by impaired efference copy.

PubMed

Feenaughty, Lynda; Basilakos, Alexandra; Bonilha, Leonardo; den Ouden, Dirk-Bart; Rorden, Chris; Stark, Brielle; Fridriksson, Julius

2017-09-01

Efference copy is a cognitive mechanism argued to be critical for initiating and monitoring speech: however, the extent to which breakdown of efference copy mechanisms impact speech production is unclear. This study examined the best mechanistic predictors of non-fluent speech among 88 stroke survivors. Objective speech fluency measures were subjected to a principal component analysis (PCA). The primary PCA factor was then entered into a multiple stepwise linear regression analysis as the dependent variable, with a set of independent mechanistic variables. Participants' ability to mimic audio-visual speech ("speech entrainment response") was the best independent predictor of non-fluent speech. We suggest that this "speech entrainment" factor reflects integrity of internal monitoring (i.e., efference copy) of speech production, which affects speech initiation and maintenance. Results support models of normal speech production and suggest that therapy focused on speech initiation and maintenance may improve speech fluency for individuals with chronic non-fluent aphasia post stroke.

Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation.

PubMed

Belcik, J Todd; Mott, Brian H; Xie, Aris; Zhao, Yan; Kim, Sajeevani; Lindner, Nathan J; Ammi, Azzdine; Linden, Joel M; Lindner, Jonathan R

2015-04-01

Ultrasound can increase tissue blood flow, in part, through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation and sought to characterize the biological mediators. Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in nonischemic mice after unilateral 10-minute exposure to intermittent ultrasound alone (mechanical index, 0.6 or 1.3) or ultrasound with lipid microbubbles (2×10(8) IV). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (P<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3- and 10-fold higher than control for mechanical index 0.6 and 1.3, respectively; P<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase attenuated flow augmentation produced by ultrasound and microbubbles by 70% (P<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide production and muscle phospho-endothelial nitric oxide synthase increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40%-50% reduction in flow), ultrasound (mechanical index, 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control nonischemic limb. Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of endothelial nitric oxide synthase. © 2015 American Heart Association, Inc.

Divergent assembly mechanisms of the manganese/iron cofactors in R2lox and R2c proteins.

PubMed

Kutin, Yuri; Srinivas, Vivek; Fritz, Matthieu; Kositzki, Ramona; Shafaat, Hannah S; Birrell, James; Bill, Eckhard; Haumann, Michael; Lubitz, Wolfgang; Högbom, Martin; Griese, Julia J; Cox, Nicholas

2016-09-01

A manganese/iron cofactor which performs multi-electron oxidative chemistry is found in two classes of ferritin-like proteins, the small subunit (R2) of class Ic ribonucleotide reductase (R2c) and the R2-like ligand-binding oxidase (R2lox). It is unclear how a heterodimeric Mn/Fe metallocofactor is assembled in these two related proteins as opposed to a homodimeric Fe/Fe cofactor, especially considering the structural similarity and proximity of the two metal-binding sites in both protein scaffolds and the similar first coordination sphere ligand preferences of Mn II and Fe II . Using EPR and Mössbauer spectroscopies as well as X-ray anomalous dispersion, we examined metal loading and cofactor activation of both proteins in vitro (in solution). We find divergent cofactor assembly mechanisms for the two systems. In both cases, excess Mn II promotes heterobimetallic cofactor assembly. In the absence of Fe II , R2c cooperatively binds Mn II at both metal sites, whereas R2lox does not readily bind Mn II at either site. Heterometallic cofactor assembly is favored at substoichiometric Fe II concentrations in R2lox. Fe II and Mn II likely bind to the protein in a stepwise fashion, with Fe II binding to site 2 initiating cofactor assembly. In R2c, however, heterometallic assembly is presumably achieved by the displacement of Mn II by Fe II at site 2. The divergent metal loading mechanisms are correlated with the putative in vivo functions of R2c and R2lox, and most likely with the intracellular Mn II /Fe II concentrations in the host organisms from which they were isolated. Copyright © 2016 Elsevier Inc. All rights reserved.

Theoretical study on the mechanism of the gas-phase elimination kinetics of alkyl chloroformates

NASA Astrophysics Data System (ADS)

Alcázar, Jackson J.; Marquez, Edgar; Mora, José R.; Cordova-Sintjago, Tania; Chuchani, Gabriel

2016-03-01

The theoretical calculations on the mechanism of the homogeneous and unimolecular gas-phase elimination kinetics of alkyl chloroformates- ethyl chloroformate (ECF), isopropyl chloroformate (ICF), and sec-butyl chloroformate (SCF) - have been carried out by using CBS-QB3 level of theory and density functional theory (DFT) functionals CAM-B3LYP, M06, MPW1PW91, and PBE1PBE with the basis sets 6-311++G(d,p) and 6-311++G(2d,2p). The chlorofomate compounds with alkyl ester Cβ-H bond undergo thermal decomposition producing the corresponding olefin, HCl and CO2. These homogeneous eliminations are proposed to undergo two different types of mechanisms: a concerted process, or via the formation of an unstable intermediate chloroformic acid (ClCOOH), which rapidly decomposes to HCl and CO2 gas. Since both elimination mechanisms may occur through a six-membered cyclic transition state structure, it is difficult to elucidate experimentally which is the most reasonable reaction mechanism. Theoretical calculations show that the stepwise mechanism with the formation of the unstable intermediate chloroformic acid from ECF, ICF, and SCF is favoured over one-step elimination. Reasonable agreements were found between theoretical and experimental values at the CAM-B3LYP/6-311++G(d,p) level.

Analyzing urban ecosystem variation in the City of Dongguan: A stepwise cluster modeling approach.

PubMed

Sun, J; Li, Y P; Gao, P P; Suo, C; Xia, B C

2018-06-13

In this study, a stepwise cluster modeling approach (SCMA) is developed for analyzing urban ecosystem variation via Normalized Difference Vegetation Index (NDVI). NDVI is an indicator of vegetation growth and coverage and useful in reflecting urban ecosystem. SCMA is established on a cluster tree that can characterize the complex relationship between independent and dependent variables. SCMA is applied to the City of Dongguan for simulating the urban NDVI and identifying associated drivers of human activity, topography and meteorology without specific functions. Results show that SCMA performances better than conventional statistical methods, illustrating the ability of SCMA in capturing the complex and nonlinear features of urban ecosystem. Results disclose that human activities play negative effects on NDVI due to the destruction of green space for pursuing more space for buildings. NDVI reduces gradually from the south part to the north part of Dongguan due to increased gross domestic product and population density, indicating that the ecosystem in Dongguan is better in the south part. NDVI in the northeast part (dominated by agriculture) is sensitive to the growth of economy and population. More attention should be paid to this part for sustainable development, such as increasing afforestation, planting grass and constructing parks. Precipitation has a positive effect on NDVI due to the promotion of soil moisture that is beneficial to plants' growth. Awareness of these complexities is helpful for sustainable development of urban ecosystem. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of experimentally induced low back pain on the sit-to-stand movement and electroencephalographic contingent negative variation

PubMed Central

Jacobs, Jesse V.; Yaguchi, Chie; Kaida, Chizuru; Irei, Mariko; Naka, Masami; Henry, Sharon M.; Fujiwara, Katsuo

2011-01-01

It is becoming increasingly evident that people with chronic, recurrent low back pain (LBP) exhibit changes in cerebrocortical activity that associate with altered postural coordination, suggesting a need for a better understanding of how the experience of LBP alters postural coordination and cerebrocortical activity. To characterize changes in postural coordination and pre-movement cerebrocortical activity related to the experience of acutely induced LBP, 14 healthy participants with no history of LBP performed sit-to-stand movements in 3 sequential conditions: (1) without experimentally induced LBP; NoPain1, (2) with movement-associated LBP induced by electrocutaneous stimulation; Pain, and (3) again without induced LBP; NoPain2. The Pain condition elicited altered muscle activation and redistributed forces under the seat and feet prior to movement, decreased peak vertical force exerted under the feet during weight transfer, longer movement times, as well as decreased and earlier peak hip extension. Stepwise regression models demonstrated that electroencephalographic amplitudes of contingent negative variation during the Pain condition significantly correlated with the participants’ change in sit-to-stand measures between the NoPain1 and Pain conditions, as well as with the subsequent difference in sit-to-stand measures between the NoPain1 and NoPain2 conditions. The results, therefore, identify the contingent negative variation as a correlate for the extent of an individual’s LBP-related movement modifications and to the subsequent change in movement patterns from before to after the experience of acutely induced LBP, thereby providing a direction for future studies aimed to understand the neural mechanisms underlying the development of altered movement patterns with LBP. PMID:21952791

Physiological responses to salt stress of salt-adapted and directly salt (NaCl and NaCl+Na2SO4 mixture)-stressed cyanobacterium Anabaena fertilissima.

PubMed

Swapnil, Prashant; Rai, Ashwani K

2018-05-01

Soil salinity in nature is generally mixed type; however, most of the studies on salt toxicity are performed with NaCl and little is known about sulfur type of salinity (Na 2 SO 4 ). Present study discerns the physiologic mechanisms responsible for salt tolerance in salt-adapted Anabaena fertilissima, and responses of directly stressed parent cells to NaCl and NaCl+Na 2 SO 4 mixture. NaCl at 500 mM was lethal to the cyanobacterium, whereas salt-adapted cells grew luxuriantly. Salinity impaired gross photosynthesis, electron transport activities, and respiration in parent cells, but not in the salt-adapted cells, except a marginal increase in PSI activity. Despite higher Na + concentration in the salt mixture, equimolar NaCl appeared more inhibitive to growth. Sucrose and trehalose content and antioxidant activities were maximal in 250 mM NaCl-treated cells, followed by salt mixture and was almost identical in salt-adapted (exposed to 500 mm NaCl) and control cells, except a marginal increase in ascorbate peroxidase activity and an additional fourth superoxide dismutase isoform. Catalase isoform of 63 kDa was induced only in salt-stressed cells. Salinity increased the uptake of intracellular Na + and Ca 2+ and leakage of K + in parent cells, while cation level in salt-adapted cells was comparable to control. Though there was differential increase in intracellular Ca 2+ under different salt treatments, ratio of Ca 2+ /Na + remained the same. It is inferred that stepwise increment in the salt concentration enabled the cyanobacterium to undergo priming effect and acquire robust and efficient defense system involving the least energy.

Preparative isolation and purification of lignans from Justicia procumbens using high-speed counter-current chromatography in stepwise elution mode.

PubMed

Zhou, Peijuan; Luo, Qijun; Ding, Lijian; Fang, Fang; Yuan, Ye; Chen, Juanjuan; Zhang, Jinrong; Jin, Haixiao; He, Shan

2015-04-20

Lignans, which are recognized as main constituents in Justicia procumbens, have attracted considerable attention due to their pharmacological activities, including antitumor, anti-hepatitic, cytotoxic, anti-microbial, and anti-virus properties. Preparative high-speed counter-current chromatography (HSCCC) was successfully applied to the isolation and purification of four lignans (justicidin B (1), justicidin A (2), 6'-hydroxyjusticidin C (3) and lignan J1 (4)) from J. procumbens using stepwise elution with a pair of two-phase solvent systems composed of n-hexane-ethyl acetate-methanol-water at (1.3:1:1.3:1, v/v) and (2.5:1:2.5:1, v/v). The preparative HSCCC separation was performed on 300 mg of crude sample yielding compounds 1 (19.7 mg), 2 (9.86 mg), 3 (11.26 mg), and 4 (2.54 mg) in a one-step separation, with purities over 95% as determined by HPLC. The structures of these compounds were identified by MS, 1H-NMR and 13C-NMR. This is the first report on the application of HSCCC to the efficient separation of lignans from J. procumbens.

The relation between high-density and very-high-density amorphous ice.

PubMed

Loerting, Thomas; Salzmann, Christoph G; Winkel, Katrin; Mayer, Erwin

2006-06-28

The exact nature of the relationship between high-density (HDA) and very-high-density (VHDA) amorphous ice is unknown at present. Here we review the relation between HDA and VHDA, concentrating on experimental aspects and discuss these with respect to the relation between low-density amorphous ice (LDA) and HDA. On compressing LDA at 125 K up to 1.5 GPa, two distinct density steps are observable in the pressure-density curves which correspond to the LDA --> HDA and HDA --> VHDA conversion. This stepwise formation process LDA --> HDA --> VHDA at 125 K is the first unambiguous observation of a stepwise amorphous-amorphous-amorphous transformation sequence. Density values of amorphous ice obtained in situ between 0.3 and 1.9 GPa on isobaric heating up to the temperatures of crystallization show a pronounced change of slope at ca. 0.8 GPa which could indicate formation of a distinct phase. We infer that the relation between HDA and VHDA is very similar to that between LDA and HDA except for a higher activation barrier between the former. We further discuss the two options of thermodynamic phase transition versus kinetic densification for the HDA --> VHDA conversion.

Binding mechanisms for histamine and agmatine ligands in plasmid deoxyribonucleic acid purifications.

PubMed

Sousa, Ângela; Pereira, Patrícia; Sousa, Fani; Queiroz, João A

2014-10-31

Histamine and agmatine amino acid derivatives were immobilized into monolithic disks, in order to combine the specificity and selectivity of the ligand with the high mass transfer and binding capacity offered by monolithic supports, to purify potential plasmid DNA biopharmaceuticals. Different elution strategies were explored by changing the type and salt concentration, as well as the pH, in order to understand the retention pattern of different plasmids isoforms The pVAX1-LacZ supercoiled isoform was isolated from a mixture of pDNA isoforms by using NaCl increasing stepwise gradient and also by ammonium sulfate decreasing stepwise gradient, in both histamine and agmatine monoliths. Acidic pH in the binding buffer mainly strengthened ionic interactions with both ligands in the presence of sodium chloride. Otherwise, for histamine ligand, pH values higher than 7 intensified hydrophobic interactions in the presence of ammonium sulfate. In addition, circular dichroism spectroscopy studies revealed that the binding and elution chromatographic conditions, such as the combination of high ionic strength with extreme pH values can reversibly influence the structural stability of the target nucleic acid. Therefore, ascending sodium chloride gradients with pH manipulation can be preferable chromatographic conditions to be explored in the purification of plasmid DNA biopharmaceuticals, in order to avoid the environmental impact of ammonium sulfate. Copyright © 2014. Published by Elsevier B.V.

Shear Adhesion of Tapered Nanopillar Arrays.

PubMed

Cho, Younghyun; Minsky, Helen K; Jiang, Yijie; Yin, Kaiyang; Turner, Kevin T; Yang, Shu

2018-04-04

Tapered nanopillars with various cross sections, including cone-shaped, stepwise, and pencil-like structures (300 nm in diameter at the base of the pillars and 1.1 μm in height), are prepared from epoxy resin templated by nanoporous anodic aluminum oxide (AAO) membranes. The effect of pillar geometry on the shear adhesion behavior of these nanopillar arrays is investigated via sliding experiments in a nanoindentation system. In a previous study of arrays with the same geometry, it was shown that cone-shaped nanopillars exhibit the highest adhesion under normal loading while stepwise and pencil-like nanopillars exhibit lower normal adhesion strength due to significant deformation of the pillars that occurs with increasing indentation depth. Contrary to the previous studies, here, we show that pencil-like nanopillars exhibit the highest shear adhesion strength at all indentation depths among three types of nanopillar arrays and that the shear adhesion increases with greater indentation depth due to the higher bending stiffness and closer packing of the pencil-like nanopillar array. Finite element simulations are used to elucidate the deformation of the pillars during the sliding experiments and agree with the nanoindentation-based sliding measurements. The experiments and finite element simulations together demonstrate that the shape of the nanopillars plays a key role in shear adhesion and that the mechanism is quite different from that of adhesion under normal loading.

Selecting predictors for discriminant analysis of species performance: an example from an amphibious softwater plant.

PubMed

Vanderhaeghe, F; Smolders, A J P; Roelofs, J G M; Hoffmann, M

2012-03-01

Selecting an appropriate variable subset in linear multivariate methods is an important methodological issue for ecologists. Interest often exists in obtaining general predictive capacity or in finding causal inferences from predictor variables. Because of a lack of solid knowledge on a studied phenomenon, scientists explore predictor variables in order to find the most meaningful (i.e. discriminating) ones. As an example, we modelled the response of the amphibious softwater plant Eleocharis multicaulis using canonical discriminant function analysis. We asked how variables can be selected through comparison of several methods: univariate Pearson chi-square screening, principal components analysis (PCA) and step-wise analysis, as well as combinations of some methods. We expected PCA to perform best. The selected methods were evaluated through fit and stability of the resulting discriminant functions and through correlations between these functions and the predictor variables. The chi-square subset, at P < 0.05, followed by a step-wise sub-selection, gave the best results. In contrast to expectations, PCA performed poorly, as so did step-wise analysis. The different chi-square subset methods all yielded ecologically meaningful variables, while probable noise variables were also selected by PCA and step-wise analysis. We advise against the simple use of PCA or step-wise discriminant analysis to obtain an ecologically meaningful variable subset; the former because it does not take into account the response variable, the latter because noise variables are likely to be selected. We suggest that univariate screening techniques are a worthwhile alternative for variable selection in ecology. © 2011 German Botanical Society and The Royal Botanical Society of the Netherlands.

Functional assessment of the diaphragm by speckle tracking ultrasound during inspiratory loading.

PubMed

Oppersma, Eline; Hatam, Nima; Doorduin, Jonne; van der Hoeven, Johannes G; Marx, Gernot; Goetzenich, Andreas; Fritsch, Sebastian; Heunks, Leo M A; Bruells, Christian S

2017-11-01

Assessment of diaphragmatic effort is challenging, especially in critically ill patients in the phase of weaning. Fractional thickening during inspiration assessed by ultrasound has been used to estimate diaphragm effort. It is unknown whether more sophisticated ultrasound techniques such as speckle tracking are superior in the quantification of inspiratory effort. This study evaluates the validity of speckle tracking ultrasound to quantify diaphragm contractility. Thirteen healthy volunteers underwent a randomized stepwise threshold loading protocol of 0-50% of the maximal inspiratory pressure. Electric activity of the diaphragm and transdiaphragmatic pressures were recorded. Speckle tracking ultrasound was used to assess strain and strain rate as measures of diaphragm tissue deformation and deformation velocity, respectively. Fractional thickening was assessed by measurement of diaphragm thickness at end-inspiration and end-expiration. Strain and strain rate increased with progressive loading of the diaphragm. Both strain and strain rate were highly correlated to transdiaphragmatic pressure (strain r 2  = 0.72; strain rate r 2  = 0.80) and diaphragm electric activity (strain r 2  = 0.60; strain rate r 2  = 0.66). We conclude that speckle tracking ultrasound is superior to conventional ultrasound techniques to estimate diaphragm contractility under inspiratory threshold loading. NEW & NOTEWORTHY Transdiaphragmatic pressure using esophageal and gastric balloons is the gold standard to assess diaphragm effort. However, this technique is invasive and requires expertise, and the interpretation may be complex. We report that speckle tracking ultrasound can be used to detect stepwise increases in diaphragmatic effort. Strain and strain rate were highly correlated with transdiaphragmatic pressure, and therefore, diaphragm electric activity and speckle tracking might serve as reliable tools to quantify diaphragm effort in the future. Copyright © 2017 the American Physiological Society.

Stratification of pediatric heart failure on the basis of neurohormonal and cardiac autonomic nervous activities in patients with congenital heart disease.

PubMed

Ohuchi, Hideo; Takasugi, Hisashi; Ohashi, Hiroyuki; Okada, Yoko; Yamada, Osamu; Ono, Yasuo; Yagihara, Toshikatsu; Echigo, Shigeyuki

2003-11-11

Stratification of pediatric patients with congenital heart disease (CHD) has been based on their hemodynamics and/or functional capacity. Our purpose was to compare cardiac autonomic nervous activity (CANA) and neurohormonal activities (NHA) with postoperative status in stable CHD patients with biventricular physiology. We divided 379 subjects (297 CHD patients, 28 dilated cardiomyopathy patient, and 54 control subjects) into 4 subgroups according to New York Heart Association (NYHA) class (1.3+/-0.7) and measured various CANA and NHA indices. Stepwise decreases in baroreflex sensitivity (BRS), heart rate variability (HRV), adrenergic imaging, and vital capacity (VC) were observed in proportion to functional capacity in normal to NYHA II patients (P<0.001). However, there were no differences in these indices between NYHA II and III+IV groups, whereas a stepwise proportional increase in NHA indices was observed in these groups (P<0.001). Natriuretic peptides differentiated all NYHA classes. BRS, HRV, and VC were greater in the adult patients than in the child patients (P<0.05 to 0.01), although the functional class in adult patients was lower. Cardiac surgeries resulted in low BRS and VC, and the VC reduction independently determined a small HRV. Even if functional class and ejection fraction were comparable, CANA and brain natriuretic peptide were lower in CHD patients than in dilated cardiomyopathy patients (P<0.05 to 0.001). CANA and NHA indices are useful to stratify mild and severe heart failure in stable postoperative CHD patients, respectively. However, careful attention should be paid to age- and surgery-related influences on these indices.

Three-step method for menstrual and oral contraceptive cycle verification.

PubMed

Schaumberg, Mia A; Jenkins, David G; Janse de Jonge, Xanne A K; Emmerton, Lynne M; Skinner, Tina L

2017-11-01

Fluctuating endogenous and exogenous ovarian hormones may influence exercise parameters; yet control and verification of ovarian hormone status is rarely reported and limits current exercise science and sports medicine research. The purpose of this study was to determine the effectiveness of an individualised three-step method in identifying the mid-luteal or high hormone phase in endogenous and exogenous hormone cycles in recreationally-active women and determine hormone and demographic characteristics associated with unsuccessful classification. Cross-sectional study design. Fifty-four recreationally-active women who were either long-term oral contraceptive users (n=28) or experiencing regular natural menstrual cycles (n=26) completed step-wise menstrual mapping, urinary ovulation prediction testing and venous blood sampling for serum/plasma hormone analysis on two days, 6-12days after positive ovulation prediction to verify ovarian hormone concentrations. Mid-luteal phase was successfully verified in 100% of oral contraceptive users, and 70% of naturally-menstruating women. Thirty percent of participants were classified as luteal phase deficient; when excluded, the success of the method was 89%. Lower age, body fat and longer menstrual cycles were significantly associated with luteal phase deficiency. A step-wise method including menstrual cycle mapping, urinary ovulation prediction and serum/plasma hormone measurement was effective at verifying ovarian hormone status. Additional consideration of age, body fat and cycle length enhanced identification of luteal phase deficiency in physically-active women. These findings enable the development of stricter exclusion criteria for female participants in research studies and minimise the influence of ovarian hormone variations within sports and exercise science and medicine research. Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Time-resolved observation of thermally activated rupture of a capillary-condensed water nanobridge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bak, Wan; Sung, Baekman; Kim, Jongwoo

2015-01-05

The capillary-condensed liquid bridge is one of the most ubiquitous forms of liquid in nature and contributes significantly to adhesion and friction of biological molecules as well as microscopic objects. Despite its important role in nanoscience and technology, the rupture process of the bridge is not well understood and needs more experimental works. Here, we report real-time observation of rupture of a capillary-condensed water nanobridge in ambient condition. During slow and stepwise stretch of the nanobridge, we measured the activation time for rupture, or the latency time required for the bridge breakup. By statistical analysis of the time-resolved distribution ofmore » activation time, we show that rupture is a thermally activated stochastic process and follows the Poisson statistics. In particular, from the Arrhenius law that the rupture rate satisfies, we estimate the position-dependent activation energies for the capillary-bridge rupture.« less

Active microwave responses - An aid in improved crop classification

NASA Technical Reports Server (NTRS)

Rosenthal, W. D.; Blanchard, B. J.

1984-01-01

A study determined the feasibility of using visible, infrared, and active microwave data to classify agricultural crops such as corn, sorghum, alfalfa, wheat stubble, millet, shortgrass pasture and bare soil. Visible through microwave data were collected by instruments on board the NASA C-130 aircraft over 40 agricultural fields near Guymon, OK in 1978 and Dalhart, TX in 1980. Results from stepwise and discriminant analysis techniques indicated 4.75 GHz, 1.6 GHz, and 0.4 GHz cross-polarized microwave frequencies were the microwave frequencies most sensitive to crop type differences. Inclusion of microwave data in visible and infrared classification models improved classification accuracy from 73 percent to 92 percent. Despite the results, further studies are needed during different growth stages to validate the visible, infrared, and active microwave responses to vegetation.

Mood and Balance are Associated with Free-Living Physical Activity of People after Stroke Residing in the community

PubMed Central

Alzahrani, Matar A.; Dean, Catherine M.; Ada, Louise; Dorsch, Simone; Canning, Colleen G.

2012-01-01

Purpose. To determine which characteristics are most associated with free-living physical activity in community-dwelling ambulatory people after stroke. Method. Factors (age, gender, side of stroke, time since stroke, BMI, and spouse), sensory-motor impairments (weakness, contracture, spasticity, coordination, proprioception, and balance), and non-sensory-motor impairments (cognition, language, perception, mood, and confidence) were collected on 42 people with chronic stroke. Free-living physical activity was measured using an activity monitor and reported as time on feet and activity counts. Results. Univariate analysis showed that balance and mood were correlated with time on feet (r = 0.42, 0.43, P < 0.01) and also with activity counts (r = 0.52, 0.54, P < 0.01). Stepwise multiple regression showed that mood and balance accounted for 25% of the variance in time on feet and 40% of the variance in activity counts. Conclusions. Mood and balance are associated with free-living physical activity in ambulatory people after stroke residing in the community. PMID:22013550

Renewable platform chemicals from directional microwave-assisted liquefaction coupling stepwise extraction of waste biomass

Treesearch

Junfeng Feng; Chungyun Hse; Zhongzhi Yang; Kui Wang; Jianchun Jiang; Junming Xu

2017-01-01

Directional microwave-assisted liquefaction and stepwise extraction are introduced for producing platform chemicals: aromatics and monosaccharides. When sulfuric acid was used as a catalyst, a 45% monosaccharides yield and a 29% aromatics yield were obtained from bamboo with 0.3 g catalyst per 18 g methanol and 2 g bamboo at 160 °C with 10 min. Approximately 78–86 wt%...

Application of the stepwise focusing method to optimize the cost-effectiveness of genome-wide association studies with limited research budgets for genotyping and phenotyping.

PubMed

Ohashi, J; Clark, A G

2005-05-01

The recent cataloguing of a large number of SNPs enables us to perform genome-wide association studies for detecting common genetic variants associated with disease. Such studies, however, generally have limited research budgets for genotyping and phenotyping. It is therefore necessary to optimize the study design by determining the most cost-effective numbers of SNPs and individuals to analyze. In this report we applied the stepwise focusing method, with two-stage design, developed by Satagopan et al. (2002) and Saito & Kamatani (2002), to optimize the cost-effectiveness of a genome-wide direct association study using a transmission/disequilibrium test (TDT). The stepwise focusing method consists of two steps: a large number of SNPs are examined in the first focusing step, and then all the SNPs showing a significant P-value are tested again using a larger set of individuals in the second focusing step. In the framework of optimization, the numbers of SNPs and families and the significance levels in the first and second steps were regarded as variables to be considered. Our results showed that the stepwise focusing method achieves a distinct gain of power compared to a conventional method with the same research budget.

Multi-layered nanoparticles for penetrating the endosome and nuclear membrane via a step-wise membrane fusion process.

PubMed

Akita, Hidetaka; Kudo, Asako; Minoura, Arisa; Yamaguti, Masaya; Khalil, Ikramy A; Moriguchi, Rumiko; Masuda, Tomoya; Danev, Radostin; Nagayama, Kuniaki; Kogure, Kentaro; Harashima, Hideyoshi

2009-05-01

Efficient targeting of DNA to the nucleus is a prerequisite for effective gene therapy. The gene-delivery vehicle must penetrate through the plasma membrane, and the DNA-impermeable double-membraned nuclear envelope, and deposit its DNA cargo in a form ready for transcription. Here we introduce a concept for overcoming intracellular membrane barriers that involves step-wise membrane fusion. To achieve this, a nanotechnology was developed that creates a multi-layered nanoparticle, which we refer to as a Tetra-lamellar Multi-functional Envelope-type Nano Device (T-MEND). The critical structural elements of the T-MEND are a DNA-polycation condensed core coated with two nuclear membrane-fusogenic inner envelopes and two endosome-fusogenic outer envelopes, which are shed in stepwise fashion. A double-lamellar membrane structure is required for nuclear delivery via the stepwise fusion of double layered nuclear membrane structure. Intracellular membrane fusions to endosomes and nuclear membranes were verified by spectral imaging of fluorescence resonance energy transfer (FRET) between donor and acceptor fluorophores that had been dually labeled on the liposome surface. Coating the core with the minimum number of nucleus-fusogenic lipid envelopes (i.e., 2) is essential to facilitate transcription. As a result, the T-MEND achieves dramatic levels of transgene expression in non-dividing cells.

COPD: A stepwise or a hit hard approach?

PubMed

Ferreira, A J; Reis, A; Marçal, N; Pinto, P; Bárbara, C

2016-01-01

Current guidelines differ slightly on the recommendations for treatment of Chronic Obstructive Pulmonary Disease (COPD) patients, and although there are some undisputed recommendations, there is still debate regarding the management of COPD. One of the hindrances to deciding which therapeutic approach to choose is late diagnosis or misdiagnosis of COPD. After a proper diagnosis is achieved and severity assessed, the choice between a stepwise or "hit hard" approach has to be made. For GOLD A patients the stepwise approach is recommended, whilst for B, C and D patients this remains debatable. Moreover, in patients for whom inhaled corticosteroids (ICS) are recommended, a step-up or "hit hard" approach with triple therapy will depend on the patient's characteristics and, for patients who are being over-treated with ICS, ICS withdrawal should be performed, in order to optimize therapy and reduce excessive medications. This paper discusses and proposes stepwise, "hit hard", step-up and ICS withdrawal therapeutic approaches for COPD patients based on their GOLD group. We conclude that all approaches have benefits, and only a careful patient selection will determine which approach is better, and which patients will benefit the most from each approach. Copyright © 2016 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.

Models to predict emissions of health-damaging pollutants and global warming contributions of residential fuel/stove combinations in China.

PubMed

Edwards, Rufus D; Smith, Kirk R; Zhang, Junfeng; Ma, Yuqing

2003-01-01

Residential energy use in developing countries has traditionally been associated with combustion devices of poor energy efficiency, which have been shown to produce substantial health-damaging pollution, contributing significantly to the global burden of disease, and greenhouse gas (GHG) emissions. Precision of these estimates in China has been hampered by limited data on stove use and fuel consumption in residences. In addition limited information is available on variability of emissions of pollutants from different stove/fuel combinations in typical use, as measurement of emission factors requires measurement of multiple chemical species in complex burn cycle tests. Such measurements are too costly and time consuming for application in conjunction with national surveys. Emissions of most of the major health-damaging pollutants (HDP) and many of the gases that contribute to GHG emissions from cooking stoves are the result of the significant portion of fuel carbon that is diverted to products of incomplete combustion (PIC) as a result of poor combustion efficiencies. The approximately linear increase in emissions of PIC with decreasing combustion efficiencies allows development of linear models to predict emissions of GHG and HDP intrinsically linked to CO2 and PIC production, and ultimately allows the prediction of global warming contributions from residential stove emissions. A comprehensive emissions database of three burn cycles of 23 typical fuel/stove combinations tested in a simulated village house in China has been used to develop models to predict emissions of HDP and global warming commitment (GWC) from cooking stoves in China, that rely on simple survey information on stove and fuel use that may be incorporated into national surveys. Stepwise regression models predicted 66% of the variance in global warming commitment (CO2, CO, CH4, NOx, TNMHC) per 1 MJ delivered energy due to emissions from these stoves if survey information on fuel type was available. Subsequently if stove type is known, stepwise regression models predicted 73% of the variance. Integrated assessment of policies to change stove or fuel type requires that implications for environmental impacts, energy efficiency, global warming and human exposures to HDP emissions can be evaluated. Frequently, this involves measurement of TSP or CO as the major HDPs. Incorporation of this information into models to predict GWC predicted 79% and 78% of the variance respectively. Clearly, however, the complexity of making multiple measurements in conjunction with a national survey would be both expensive and time consuming. Thus, models to predict HDP using simple survey information, and with measurement of either CO/CO2 or TSP/CO2 to predict emission factors for the other HDP have been derived. Stepwise regression models predicted 65% of the variance in emissions of total suspended particulate as grams of carbon (TSPC) per 1 MJ delivered if survey information on fuel and stove type was available and 74% if the CO/CO2 ratio was measured. Similarly stepwise regression models predicted 76% of the variance in COC emissions per MJ delivered with survey information on stove and fuel type and 85% if the TSPC/CO2 ratio was measured. Ultimately, with international agreements on emissions trading frameworks, similar models based on extensive databases of the fate of fuel carbon during combustion from representative household stoves would provide a mechanism for computing greenhouse credits in the residential sector as part of clean development mechanism frameworks and monitoring compliance to control regimes.

A non-canonical mechanism for Crm1-export cargo complex assembly

PubMed Central

Fischer, Ute; Schäuble, Nico; Schütz, Sabina; Altvater, Martin; Chang, Yiming; Boulos Faza, Marius; Panse, Vikram Govind

2015-01-01

The transport receptor Crm1 mediates the export of diverse cargos containing leucine-rich nuclear export signals (NESs) through complex formation with RanGTP. To ensure efficient cargo release in the cytoplasm, NESs have evolved to display low affinity for Crm1. However, mechanisms that overcome low affinity to assemble Crm1-export complexes in the nucleus remain poorly understood. In this study, we reveal a new type of RanGTP-binding protein, Slx9, which facilitates Crm1 recruitment to the 40S pre-ribosome-associated NES-containing adaptor Rio2. In vitro, Slx9 binds Rio2 and RanGTP, forming a complex. This complex directly loads Crm1, unveiling a non-canonical stepwise mechanism to assemble a Crm1-export complex. A mutation in Slx9 that impairs Crm1-export complex assembly inhibits 40S pre-ribosome export. Thus, Slx9 functions as a scaffold to optimally present RanGTP and the NES to Crm1, therefore, triggering 40S pre-ribosome export. This mechanism could represent one solution to the paradox of weak binding events underlying rapid Crm1-mediated export. DOI: http://dx.doi.org/10.7554/eLife.05745.001 PMID:25895666

Proteolytic processing and activation of Clostridium perfringens epsilon toxin by caprine small intestinal contents.

PubMed

Freedman, John C; Li, Jihong; Uzal, Francisco A; McClane, Bruce A

2014-10-21

Epsilon toxin (ETX), a pore-forming toxin produced by type B and D strains of Clostridium perfringens, mediates severe enterotoxemia in livestock and possibly plays a role in human disease. During enterotoxemia, the nearly inactive ETX prototoxin is produced in the intestines but then must be activated by proteolytic processing. The current study sought to examine ETX prototoxin processing and activation ex vivo using the intestinal contents of a goat, a natural host species for ETX-mediated disease. First, this study showed that the prototoxin has a KEIS N-terminal sequence with a molecular mass of 33,054 Da. When the activation of ETX prototoxin ex vivo by goat small intestinal contents was assessed by SDS-PAGE, the prototoxin was processed in a stepwise fashion into an ~27-kDa band or higher-molecular-mass material that could be toxin oligomers. Purified ETX corresponding to the ~27-kDa band was cytotoxic. When it was biochemically characterized by mass spectrometry, the copresence of three ETX species, each with different C-terminal residues, was identified in the purified ~27-kDa ETX preparation. Cytotoxicity of each of the three ETX species was then demonstrated using recombinant DNA approaches. Serine protease inhibitors blocked the initial proteotoxin processing, while carboxypeptidase inhibitors blocked further processing events. Taken together, this study provides important new insights indicating that, in the intestinal lumen, serine protease (including trypsin and possibly chymotrypsin) initiates the processing of the prototoxin but other proteases, including carboxypeptidases, then process the prototoxin into multiple active and stable species. Importance: Processing and activation by intestinal proteases is a prerequisite for ETX-induced toxicity. Previous studies had characterized the activation of ETX using only arbitrarily chosen amounts of purified trypsin and/or chymotrypsin. Therefore, the current study examined ETX activation ex vivo by natural host intestinal contents. These analyses demonstrated that (i) ETX processing in host intestinal contents occurs in an ordered, stepwise fashion, (ii) processing of prototoxin by host intestinal contents results in higher-molecular-mass material and 3 distinct ~27-kDa ETX species, and (iii) serine proteases, such as trypsin, chymotrypsin, and other proteases, including carboxypeptidases, play a role in the activation of ETX by intestinal contents. These studies provide new insights into the activation and processing of ETX and demonstrate that this process is more complicated than previously appreciated. Copyright © 2014 Freedman et al.

The histone shuffle: histone chaperones in an energetic dance

PubMed Central

Das, Chandrima; Tyler, Jessica K.; Churchill, Mair E.A.

2014-01-01

Our genetic information is tightly packaged into a rather ingenious nucleoprotein complex called chromatin in a manner that enables it to be rapidly accessed during genomic processes. Formation of the nucleosome, which is the fundamental unit of chromatin, occurs via a stepwise process that is reversed to enable the disassembly of nucleosomes. Histone chaperone proteins have prominent roles in facilitating these processes as well as in replacing old histones with new canonical histones or histone variants during the process of histone exchange. Recent structural, biophysical and biochemical studies have begun to shed light on the molecular mechanisms whereby histone chaperones promote chromatin assembly, disassembly and histone exchange to facilitate DNA replication, repair and transcription. PMID:20444609

Ovulation induction in women with polycystic ovary syndrome.

PubMed

Perales-Puchalt, Alfredo; Legro, Richard S

2013-08-01

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. There are multiple ways to induce ovulation in PCOS patients, which will eventually provide a successful live birth. Each of these treatments varies in aggressiveness and effectiveness. Ranging from lifestyle modifications, through insulin-sensitizing agents, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, to laparoscopic ovarian drilling and assisted reproductive techniques, each method achieves ovulation induction through different mechanisms of action. This review provides a description and specific characteristics of the different methods used for ovulation induction which can help to design a personalized approach to each PCOS patient, and a general stepwise approach to ovulation induction in these patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Positive emotions in early life and longevity: findings from the nun study.

PubMed

Danner, D D; Snowdon, D A; Friesen, W V

2001-05-01

Handwritten autobiographies from 180 Catholic nuns, composed when participants were a mean age of 22 years, were scored for emotional content and related to survival during ages 75 to 95. A strong inverse association was found between positive emotional content in these writings and risk of mortality in late life (p < .001). As the quartile ranking of positive emotion in early life increased, there was a stepwise decrease in risk of mortality resulting in a 2.5-fold difference between the lowest and highest quartiles. Positive emotional content in early-life autobiographies was strongly associated with longevity 6 decades later. Underlying mechanisms of balanced emotional states are discussed.

Formation of MoS2 inorganic fullerenes (IFs) by the reaction of MoO3 nanobelts and S.

PubMed

Li, Xiao Lin; Li, Ya Dong

2003-06-16

The reaction of MoO3 and S at temperatures higher than 300 degrees C in an argon atmosphere provides a convenient and effective method for the synthesis of MoS2 nanocrystalline substances. MoS2 nanotubes and fullerene-like nanoparticles have been obtained by the reaction at 850 degrees C under well-controlled conditions. The influences of reaction temperature and duration were carefully investigated in this paper. All of the nanostructures were characterized by Xray powder diffraction (XRD), transmission electron microscopy (TEM), and high-resolution transmission electron microscopy (HRTEM). A stepwise reaction model and rolling mechanism were proposed based on the experimental results.

Evolution of the Pseudomonas aeruginosa Aminoglycoside Mutational Resistome In Vitro and in the Cystic Fibrosis Setting.

PubMed

López-Causapé, Carla; Rubio, Rosa; Cabot, Gabriel; Oliver, Antonio

2018-04-01

Inhaled administration of high doses of aminoglycosides is a key maintenance treatment of Pseudomonas aeruginosa chronic respiratory infections in cystic fibrosis (CF). We analyzed the dynamics and mechanisms of stepwise high-level tobramycin resistance development in vitro and compared the results with those of isogenic pairs of susceptible and resistant clinical isolates. Resistance development correlated with fusA1 mutations in vitro and in vivo. pmrB mutations, conferring polymyxin resistance, were also frequently selected in vitro In contrast, mutational overexpression of MexXY, a hallmark of aminoglycoside resistance in CF, was not observed in in vitro evolution experiments. Copyright © 2018 American Society for Microbiology.

Influence of the mechanical properties of resilient denture liners on the retention of overdenture attachments.

PubMed

Kubo, Keitaro; Koike, Takashi; Ueda, Takayuki; Sakurai, Kaoru

2018-03-15

Information is lacking about the selection criteria for silicone resilient denture liners applied as a matrix material for attachments on overdentures. The purpose of this in vitro study was to investigate the mechanical properties of silicone resilient denture liners and their influence on the initial retention force of overdenture attachments and the reduction in retention force over time. Nine types of silicone resilient denture liner were injected and fixed to the matrix section of an experimental denture base. They were then fitted to an epoxy resin model that simulated the residual ridge with a patrix ball attachment (n=10). The retention force of the denture was measured with a digital force gauge, and the maximum force of traction (N) was regarded as the initial retention force. The retention force reduction (N) after repeated insertion and removal (n=5) was calculated by subtracting the retention force after 3348 cycles (3-year simulated insertion and removal) from the initial retention force. The intaglio of the matrix was observed with a scanning electron microscope (SEM) before and after the 3348 cycles. Four mechanical properties (hardness, strain-in-compression, tensile strength, and arithmetic mean roughness) of the resilient denture liners were measured. One-way ANOVA of the initial retention force of each lining material was performed, followed by the Scheffe test (α=.05). Pearson correlation analysis was used (α=.05) to analyze correlations of the initial retention force with the retention force reduction after insertion and removal and the mechanical properties of each material. Multiple regression analysis with the stepwise method extracted the initial retention force and the retention force reduction as dependent variables, and the resilient denture liner mechanical properties as explanatory variables (α=.05). The initial retention force of the resilient denture liners was 1.3 to 5.4 N. Multiple comparisons showed significant differences in some groups (P<.05). The retention force reduction of the resilient denture liners was 0.2 to 1.9 N. Multiple regression analysis with the stepwise method extracted hardness and strain-in-compression as explanatory variables for the initial retention force and the retention force reduction. Within the limitations of this in vitro study, we found that hardness influenced the initial retention force of the overdenture, and that strain-in-compression influenced the retention force reduction in the 3-year simulation. Copyright © 2017 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Solvent effect on the intermolecular proton transfer of the Watson and Crick guanine-cytosine and adenine-thymine base pairs: a polarizable continuum model study.

PubMed

Romero, Eduardo E; Hernandez, Florencio E

2018-01-03

Herein we present our results on the study of the double proton transfer (DPT) mechanism in the adenine-thymine (AT) and guanine-cytosine (GC) base pairs, both in gas phase and in solution. The latter was modeled using the polarizable continuum method (PCM) in different solvents. According to our DFT calculations, the DPT may occur for both complexes in a stepwise mechanism in condensate phase. In gas phase only the GC base pair exhibits a concerted DPT mechanism. Using the Wigner's tunneling corrections to the transition state theory we demonstrate that such corrections are important for the prediction of the rate constants of both systems in gas and in condensate phase. We also show that (i) as the polarity of the medium decreases the equilibrium constant of the DPT reaction increases in both complexes, and (ii) that the equilibrium constant in the GC complex is four orders of magnitude larger than in AT. This observation suggests that the spontaneous mutations in DNA base pairs are more probable in GC than in AT.

Building a model of the blue cone pigment based on the wild type rhodopsin structure with QM/MM methods.

PubMed

Frähmcke, Jan S; Wanko, Marius; Elstner, Marcus

2012-03-15

Understanding the mechanism of color tuning of the retinal chromophore by its host protein became one of the key issues in the research on rhodopsins. While early mutation studies addressed its genetic origin, recent studies advanced to investigate its structural origin, based on X-ray crystallographic structures. For the human cone pigments, no crystal structures have been produced, and homology models were employed to elucidate the origin of its blue-shifted absorption. In this theoretical study, we take a different route to establish a structural model for human blue. Starting from the well-resolved structure of bovine rhodopsin, we derive multiple mutant models by stepwise mutation and equilibration using molecular dynamics simulations in a hybrid quantum mechanics/molecular mechanics framework. Our 30fold mutant reproduces the experimental UV-vis absorption shift of 0.45 eV and provides new insights about both structural and genetic factors that affect the excitation energy. Electrostatic effects of individual amino acids and collaborative structural effects are analyzed using semiempirical (OM2/MRCI) and ab initio (SORCI) multireference approaches. © 2012 American Chemical Society

Requirements for the formal representation of pathophysiology mechanisms by clinicians

PubMed Central

Helvensteijn, M.; Kokash, N.; Martorelli, I.; Sarwar, D.; Islam, S.; Grenon, P.; Hunter, P.

2016-01-01

Knowledge of multiscale mechanisms in pathophysiology is the bedrock of clinical practice. If quantitative methods, predicting patient-specific behaviour of these pathophysiology mechanisms, are to be brought to bear on clinical decision-making, the Human Physiome community and Clinical community must share a common computational blueprint for pathophysiology mechanisms. A number of obstacles stand in the way of this sharing—not least the technical and operational challenges that must be overcome to ensure that (i) the explicit biological meanings of the Physiome's quantitative methods to represent mechanisms are open to articulation, verification and study by clinicians, and that (ii) clinicians are given the tools and training to explicitly express disease manifestations in direct contribution to modelling. To this end, the Physiome and Clinical communities must co-develop a common computational toolkit, based on this blueprint, to bridge the representation of knowledge of pathophysiology mechanisms (a) that is implicitly depicted in electronic health records and the literature, with (b) that found in mathematical models explicitly describing mechanisms. In particular, this paper makes use of a step-wise description of a specific disease mechanism as a means to elicit the requirements of representing pathophysiological meaning explicitly. The computational blueprint developed from these requirements addresses the Clinical community goals to (i) organize and manage healthcare resources in terms of relevant disease-related knowledge of mechanisms and (ii) train the next generation of physicians in the application of quantitative methods relevant to their research and practice. PMID:27051514

Method of selective reduction of polyhalosilanes with alkyltin hydrides

DOEpatents

Sharp, Kenneth G.; D'Errico, John J.

1989-01-01

The invention relates to the selective and stepwise reduction of polyhalosilanes by reacting at room temperature or below with alkyltin hydrides without the use of free radical intermediates. Alkyltin hydrides selectively and stepwise reduce the Si--Br, Si--Cl, or Si--I bonds while leaving intact any Si--F bonds. When two or more different halogens are present on the polyhalosilane, the halogen with the highest atomic weight is preferentially reduced.

Efficient red organic electroluminescent devices by doping platinum(II) Schiff base emitter into two host materials with stepwise energy levels.

PubMed

Zhou, Liang; Kwok, Chi-Chung; Cheng, Gang; Zhang, Hongjie; Che, Chi-Ming

2013-07-15

In this work, organic electroluminescent (EL) devices with double light-emitting layers (EMLs) having stepwise energy levels were designed to improve the EL performance of a red-light-emitting platinum(II) Schiff base complex. A series of devices with single or double EML(s) were fabricated and characterized. Compared with single-EML devices, double-EML devices showed improved EL efficiency and brightness, attributed to better balance in carriers. In addition, the stepwise distribution in energy levels of host materials is instrumental in broadening the recombination zone, thus delaying the roll-off of EL efficiency. The highest EL current efficiency and power efficiency of 17.36 cd/A and 14.73 lm/W, respectively, were achieved with the optimized double-EML devices. At high brightness of 1000 cd/m², EL efficiency as high as 8.89 cd/A was retained.

Stepwise photochromism of bisnaphthopyrans exhibiting an excitation intensity-dependent color change.

PubMed

Inagaki, Yuki; Mutoh, Katsuya; Abe, Jiro

2018-06-07

Non-linear photoresponses against excitation light intensity are important for the development of attractive photofunctional materials exhibiting high spatial selective photoswitching that is not affected by weak background light. Biphotochromic systems composed of two fast photochromic units have the potential to show a stepwise two-photon absorption process in which the optical properties can be non-linearly controlled by changing the excitation light conditions. Herein, we designed and synthesized novel bisnaphthopyran derivatives containing fast photoswitchable naphthopyran units. The bisnaphthopyran derivatives show a stepwise two-photon-induced photochromic reaction upon UV light irradiation accompanied by a drastic color change due to a large change in the molecular structure between the one-photon product and the two-photon product. Consequently, the color of the bisnaphthopyran derivatives can be non-linearly controlled by changing the excitation intensity. This characteristic photochromic property of the biphotochromic system provides important insight into advanced photoresponsive materials.

CORRELATION PURSUIT: FORWARD STEPWISE VARIABLE SELECTION FOR INDEX MODELS

PubMed Central

Zhong, Wenxuan; Zhang, Tingting; Zhu, Yu; Liu, Jun S.

2012-01-01

In this article, a stepwise procedure, correlation pursuit (COP), is developed for variable selection under the sufficient dimension reduction framework, in which the response variable Y is influenced by the predictors X1, X2, …, Xp through an unknown function of a few linear combinations of them. Unlike linear stepwise regression, COP does not impose a special form of relationship (such as linear) between the response variable and the predictor variables. The COP procedure selects variables that attain the maximum correlation between the transformed response and the linear combination of the variables. Various asymptotic properties of the COP procedure are established, and in particular, its variable selection performance under diverging number of predictors and sample size has been investigated. The excellent empirical performance of the COP procedure in comparison with existing methods are demonstrated by both extensive simulation studies and a real example in functional genomics. PMID:23243388

Stability, folding dynamics, and long-range conformational transition of the synaptic t-SNARE complex

PubMed Central

Zhang, Xinming; Rebane, Aleksander A.; Ma, Lu; Li, Feng; Jiao, Junyi; Qu, Hong; Pincet, Frederic; Rothman, James E.

2016-01-01

Synaptic soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs) couple their stepwise folding to fusion of synaptic vesicles with plasma membranes. In this process, three SNAREs assemble into a stable four-helix bundle. Arguably, the first and rate-limiting step of SNARE assembly is the formation of an activated binary target (t)-SNARE complex on the target plasma membrane, which then zippers with the vesicle (v)-SNARE on the vesicle to drive membrane fusion. However, the t-SNARE complex readily misfolds, and its structure, stability, and dynamics are elusive. Using single-molecule force spectroscopy, we modeled the synaptic t-SNARE complex as a parallel three-helix bundle with a small frayed C terminus. The helical bundle sequentially folded in an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a central ionic layer, with total unfolding energy of ∼17 kBT, where kB is the Boltzmann constant and T is 300 K. Peptide binding to the CTD activated the t-SNARE complex to initiate NTD zippering with the v-SNARE, a mechanism likely shared by the mammalian uncoordinated-18-1 protein (Munc18-1). The NTD zippering then dramatically stabilized the CTD, facilitating further SNARE zippering. The subtle bidirectional t-SNARE conformational switch was mediated by the ionic layer. Thus, the t-SNARE complex acted as a switch to enable fast and controlled SNARE zippering required for synaptic vesicle fusion and neurotransmission. PMID:27911771

Binding Specificity Determines the Cytochrome P450 3A4 Mediated Enantioselective Metabolism of Metconazole.

PubMed

Zhuang, Shulin; Zhang, Leili; Zhan, Tingjie; Lu, Liping; Zhao, Lu; Wang, Haifei; Morrone, Joseph A; Liu, Weiping; Zhou, Ruhong

2018-01-25

Cytochrome P450 3A4 (CYP3A4) is a promiscuous enzyme, mediating the biotransformations of ∼50% of clinically used drugs, many of which are chiral molecules. Probing the interactions between CYP3A4 and chiral chemicals is thus essential for the elucidation of molecular mechanisms of enantioselective metabolism. We developed a stepwise-restrained-molecular-dynamics (MD) method to model human CYP3A4 in a complex with cis-metconazole (MEZ) isomers and performed conventional MD simulations with a total simulation time of 2.2 μs to probe the molecular interactions. Our current study, which employs a combined experimental and theoretical approach, reports for the first time on the distinct conformational changes of CYP3A4 that are induced by the enantioselective binding of cis-MEZ enantiomers. CYP3A4 preferably metabolizes cis-RS MEZ over the cis-SR isomer, with the resultant enantiomer fraction for cis-MEZ increasing rapidly from 0.5 to 0.82. cis-RS MEZ adopts a more extended structure in the active pocket with its Cl atom exposed to the solvent, whereas cis-SR MEZ sits within the hydrophobic core of the active pocket. Free-energy-perturbation calculations indicate that unfavorable van der Waals interactions between the cis-MEZ isomers and the CYP3A4 binding pocket predominantly contribute to their binding-affinity differences. These results demonstrate that binding specificity determines the cytochrome P450 3A4 mediated enantioselective metabolism of cis-MEZ.

Characterization of the endogenous enzymatic hydrolyses of Petroselinum crispum glycosides: determined by chromatography upon their sugar and flavonoid products.

PubMed

Boldizsár, Imre; Füzfai, Zsófia; Molnár-Perl, Ibolya

2013-06-07

The behavior of the flavonoid diglycosides, relevant constituents of parsley (Petroselinum crispum) fruit (PFr) and leaf (PLe) samples was characterized upon their enzymatic hydrolyses applying complementary liquid chromatography-ultraviolet (LC-UV) and gas chromatography mass selective (GC-MS) detections. Analyses were performed in quantitative manner, from the same extracts as a function of hydrolysis times. Both in fruit and leaf tissue extracts, in intact and in enzyme hydrolyzed ones, apigenin, chrysoeriol, their glycosides, sugars, sugar alcohols, carboxylic acids and phytosterols, in total 17 constituents were identified and quantified. Based primarily on the selective mass fragmentation properties of the trimethylsilyl (oxime) ether/ester derivatives of constituents, we confirmed several novelties to the field. (i) It was shown for the first time that in parsley tissues different types of glycosidase enzyme are active. In PFr samples, both the stepwise and disaccharide specific endogenous mechanisms were certified, quantifying simultaneously the continuous release of apigenin, chrysoeriol, 2-O-apiosyl-apiose, apiose and glucose. (ii) 2-O-Apiosyl-glucose was demonstrated as disaccharide due to its formation under derivatization conditions from parsley glycosides. (iii) Both in PFr and in PLe samples even the invertase enzyme activity was attainable: sucrose decomposition in both tissues was going on with the same intensity. Three different types of enzymatic glycosidase processes were followed with their specific hydrolysis products by means of HPLC-UV and GC-MS, simultaneously. Copyright © 2013 Elsevier B.V. All rights reserved.

Stepwise group sparse regression (SGSR): gene-set-based pharmacogenomic predictive models with stepwise selection of functional priors.

PubMed

Jang, In Sock; Dienstmann, Rodrigo; Margolin, Adam A; Guinney, Justin

2015-01-01

Complex mechanisms involving genomic aberrations in numerous proteins and pathways are believed to be a key cause of many diseases such as cancer. With recent advances in genomics, elucidating the molecular basis of cancer at a patient level is now feasible, and has led to personalized treatment strategies whereby a patient is treated according to his or her genomic profile. However, there is growing recognition that existing treatment modalities are overly simplistic, and do not fully account for the deep genomic complexity associated with sensitivity or resistance to cancer therapies. To overcome these limitations, large-scale pharmacogenomic screens of cancer cell lines--in conjunction with modern statistical learning approaches--have been used to explore the genetic underpinnings of drug response. While these analyses have demonstrated the ability to infer genetic predictors of compound sensitivity, to date most modeling approaches have been data-driven, i.e. they do not explicitly incorporate domain-specific knowledge (priors) in the process of learning a model. While a purely data-driven approach offers an unbiased perspective of the data--and may yield unexpected or novel insights--this strategy introduces challenges for both model interpretability and accuracy. In this study, we propose a novel prior-incorporated sparse regression model in which the choice of informative predictor sets is carried out by knowledge-driven priors (gene sets) in a stepwise fashion. Under regularization in a linear regression model, our algorithm is able to incorporate prior biological knowledge across the predictive variables thereby improving the interpretability of the final model with no loss--and often an improvement--in predictive performance. We evaluate the performance of our algorithm compared to well-known regularization methods such as LASSO, Ridge and Elastic net regression in the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (Sanger) pharmacogenomics datasets, demonstrating that incorporation of the biological priors selected by our model confers improved predictability and interpretability, despite much fewer predictors, over existing state-of-the-art methods.

Spontaneous membrane formation and self-encapsulation of active rods in an inhomogeneous motility field

NASA Astrophysics Data System (ADS)

Grauer, Jens; Löwen, Hartmut; Janssen, Liesbeth M. C.

2018-02-01

We study the collective dynamics of self-propelled rods in an inhomogeneous motility field. At the interface between two regions of constant but different motility, a smectic rod layer is spontaneously created through aligning interactions between the active rods, reminiscent of an artificial, semipermeable membrane. This "active membrane" engulfes rods which are locally trapped in low-motility regions and thereby further enhances the trapping efficiency by self-organization, an effect which we call "self-encapsulation." Our results are gained by computer simulations of self-propelled rod models confined on a two-dimensional planar or spherical surface with a stepwise constant motility field, but the phenomenon should be observable in any geometry with sufficiently large spatial inhomogeneity. We also discuss possibilities to verify our predictions of active-membrane formation in experiments of self-propelled colloidal rods and vibrated granular matter.

Temporal Activity Modulation of Deep Very Low Frequency Earthquakes in Shikoku, Southwest Japan

NASA Astrophysics Data System (ADS)

Baba, Satoru; Takeo, Akiko; Obara, Kazushige; Kato, Aitaro; Maeda, Takuto; Matsuzawa, Takanori

2018-01-01

We investigated long-term changes in the activity of deep very low frequency earthquakes (VLFEs) in western Shikoku, southwest part of the Nankai subduction zone in Japan for 13 years by the matched-filter technique. VLFE activity is expected to be a proxy of interplate slips. In the Bungo channel, where long-term slow slip events (SSEs) occurred frequently, the cumulative number of detected VLFEs increased rapidly in 2010 and 2014, which were modulated by long-term SSEs. In the neighboring inland region near the Bungo channel, the cumulative number increased steeply every 6 months. This stepwise change was accompanied by episodic tremors and slips. Deep VLFE activity in western Shikoku has been low since the latter half of 2014. This decade-scale quiescence may be attributed to the change in interplate coupling strength in the Nankai subduction zone.

Adaptive evolution of Escherichia coli to Ciprofloxacin in controlled stress environments: emergence of resistance in continuous and step-wise gradients

NASA Astrophysics Data System (ADS)

Deng, J.; Zhou, L.; Dong, Y.; Sanford, R. A.; Shechtman, L. A.; Alcalde, R.; Werth, C. J.; Fouke, B. W.

2017-12-01

Microorganisms in nature have evolved in response to a variety of environmental stresses, including gradients in pH, flow and chemistry. While environmental stresses are generally considered to be the driving force of adaptive evolution, the impact and extent of any specific stress needed to drive such changes has not been well characterized. In this study, a microfluidic diffusion chamber (MDC) and a batch culturing system were used to systematically study the effects of continuous versus step-wise stress increments on adaptation of E. coli to the antibiotic ciprofloxacin. In the MDC, a diffusion gradient of ciprofloxacin was established across a microfluidic well array to microscopically observe changes in Escherichia coli strain 307 replication and migration patterns that would indicate emergence of resistance due to genetic mutations. Cells recovered from the MDC only had resistance of 50-times the original minimum inhibition concentration (MICoriginal) of ciprofloxacin, although minimum exposure concentrations were over 80 × MICoriginal by the end of the experiment. In complementary batch experiments, E. coli 307 were exposed to step-wise daily increases of ciprofloxacin at rates equivalent to 0.1×, 0.2×, 0.4× or 0.8× times MICoriginal/day. Over a period of 18 days, E. coli cells were able to acquire resistance of up to 225 × MICoriginal, with exposure to ciprofloxacin concentration up to only 14.9 × MIC­original. The different levels of acquired resistance in the continuous MDC versus step-wise batch increment experiments suggests that the intrinsic rate of E. coli adaptation was exceeded in the MDC, while the step-wise experiments favor adaptation to the highest ciprofloxacin experiments. Genomic analyses of E. coli DNA extracted from the microfluidic cell and batch cultures indicated four single nucleotide polymorphism (SNP) mutations of amino acid 82, 83 and 87 in the gyrA gene. The progression of adaptation in the step-wise increments of ciprofloxacin indicate that the Ser83-Leu mutation gradually becomes dominant over other gyrA mutations with increased antibiotic resistance. Co-existence of the Ser83-Leu and Asp87—Gly mutations appear to provide the greatest level of resistance (i.e., 85 × to 225 × MICoriginal), and only emerged after the whole community acquired the Ser83—Leu mutation.

QSAR and docking based semi-synthesis and in vitro evaluation of 18 β-glycyrrhetinic acid derivatives against human lung cancer cell line A-549.

PubMed

Yadav, Dharmendra Kumar; Kalani, Komal; Khan, Feroz; Srivastava, Santosh Kumar

2013-12-01

For the prediction of anticancer activity of glycyrrhetinic acid (GA-1) analogs against the human lung cancer cell line (A-549), a QSAR model was developed by forward stepwise multiple linear regression methodology. The regression coefficient (r(2)) and prediction accuracy (rCV(2)) of the QSAR model were taken 0.94 and 0.82, respectively in terms of correlation. The QSAR study indicates that the dipole moments, size of smallest ring, amine counts, hydroxyl and nitro functional groups are correlated well with cytotoxic activity. The docking studies showed high binding affinity of the predicted active compounds against the lung cancer target EGFR. These active glycyrrhetinic acid derivatives were then semi-synthesized, characterized and in-vitro tested for anticancer activity. The experimental results were in agreement with the predicted values and the ethyl oxalyl derivative of GA-1 (GA-3) showed equal cytotoxic activity to that of standard anticancer drug paclitaxel.

Stepwise synthesis and characterization of germa[4], [5], [8], and [10]pericyclynes.

PubMed

Tanimoto, Hiroki; Nagao, Tomohiko; Fujiwara, Taro; Nishiyama, Yasuhiro; Morimoto, Tsumoru; Suzuka, Toshimasa; Tsutsumi, Ken; Kakiuchi, Kiyomi

2015-07-14

The stepwise syntheses of germa[N]pericyclynes, including [5]pericyclynes, and their characterization are described. The yields of germa[4] and [8]pericyclynes were improved significantly compared to those obtained in previous studies. The routes reported herein afforded the novel germa[5] and [10]pericyclynes, which were characterized by X-ray crystallography, UV-Vis spectroscopy, and fluorescence emission spectroscopy. A unique fluorescence emission was observed for the large germa[10]pericyclyne ring.

Evaluation of alternative model selection criteria in the analysis of unimodal response curves using CART

USGS Publications Warehouse

Ribic, C.A.; Miller, T.W.

1998-01-01

We investigated CART performance with a unimodal response curve for one continuous response and four continuous explanatory variables, where two variables were important (ie directly related to the response) and the other two were not. We explored performance under three relationship strengths and two explanatory variable conditions: equal importance and one variable four times as important as the other. We compared CART variable selection performance using three tree-selection rules ('minimum risk', 'minimum risk complexity', 'one standard error') to stepwise polynomial ordinary least squares (OLS) under four sample size conditions. The one-standard-error and minimum-risk-complexity methods performed about as well as stepwise OLS with large sample sizes when the relationship was strong. With weaker relationships, equally important explanatory variables and larger sample sizes, the one-standard-error and minimum-risk-complexity rules performed better than stepwise OLS. With weaker relationships and explanatory variables of unequal importance, tree-structured methods did not perform as well as stepwise OLS. Comparing performance within tree-structured methods, with a strong relationship and equally important explanatory variables, the one-standard-error-rule was more likely to choose the correct model than were the other tree-selection rules 1) with weaker relationships and equally important explanatory variables; and 2) under all relationship strengths when explanatory variables were of unequal importance and sample sizes were lower.

Improved model of the retardance in citric acid coated ferrofluids using stepwise regression

NASA Astrophysics Data System (ADS)

Lin, J. F.; Qiu, X. R.

2017-06-01

Citric acid (CA) coated Fe3O4 ferrofluids (FFs) have been conducted for biomedical application. The magneto-optical retardance of CA coated FFs was measured by a Stokes polarimeter. Optimization and multiple regression of retardance in FFs were executed by Taguchi method and Microsoft Excel previously, and the F value of regression model was large enough. However, the model executed by Excel was not systematic. Instead we adopted the stepwise regression to model the retardance of CA coated FFs. From the results of stepwise regression by MATLAB, the developed model had highly predictable ability owing to F of 2.55897e+7 and correlation coefficient of one. The average absolute error of predicted retardances to measured retardances was just 0.0044%. Using the genetic algorithm (GA) in MATLAB, the optimized parametric combination was determined as [4.709 0.12 39.998 70.006] corresponding to the pH of suspension, molar ratio of CA to Fe3O4, CA volume, and coating temperature. The maximum retardance was found as 31.712°, close to that obtained by evolutionary solver in Excel and a relative error of -0.013%. Above all, the stepwise regression method was successfully used to model the retardance of CA coated FFs, and the maximum global retardance was determined by the use of GA.

A stepwise composite echocardiographic score predicts severe pulmonary hypertension in patients with interstitial lung disease.

PubMed

Bax, Simon; Bredy, Charlene; Kempny, Aleksander; Dimopoulos, Konstantinos; Devaraj, Anand; Walsh, Simon; Jacob, Joseph; Nair, Arjun; Kokosi, Maria; Keir, Gregory; Kouranos, Vasileios; George, Peter M; McCabe, Colm; Wilde, Michael; Wells, Athol; Li, Wei; Wort, Stephen John; Price, Laura C

2018-04-01

European Respiratory Society (ERS) guidelines recommend the assessment of patients with interstitial lung disease (ILD) and severe pulmonary hypertension (PH), as defined by a mean pulmonary artery pressure (mPAP) ≥35 mmHg at right heart catheterisation (RHC). We developed and validated a stepwise echocardiographic score to detect severe PH using the tricuspid regurgitant velocity and right atrial pressure (right ventricular systolic pressure (RVSP)) and additional echocardiographic signs. Consecutive ILD patients with suspected PH underwent RHC between 2005 and 2015. Receiver operating curve analysis tested the ability of components of the score to predict mPAP ≥35 mmHg, and a score devised using a stepwise approach. The score was tested in a contemporaneous validation cohort. The score used "additional PH signs" where RVSP was unavailable, using a bootstrapping technique. Within the derivation cohort (n=210), a score ≥7 predicted severe PH with 89% sensitivity, 71% specificity, positive predictive value 68% and negative predictive value 90%, with similar performance in the validation cohort (n=61) (area under the curve (AUC) 84.8% versus 83.1%, p=0.8). Although RVSP could be estimated in 92% of studies, reducing this to 60% maintained a fair accuracy (AUC 74.4%). This simple stepwise echocardiographic PH score can predict severe PH in patients with ILD.

A stepwise composite echocardiographic score predicts severe pulmonary hypertension in patients with interstitial lung disease

PubMed Central

Bax, Simon; Bredy, Charlene; Kempny, Aleksander; Dimopoulos, Konstantinos; Devaraj, Anand; Walsh, Simon; Jacob, Joseph; Nair, Arjun; Kokosi, Maria; Keir, Gregory; Kouranos, Vasileios; George, Peter M.; McCabe, Colm; Wilde, Michael; Wells, Athol; Li, Wei; Wort, Stephen John; Price, Laura C.

2018-01-01

European Respiratory Society (ERS) guidelines recommend the assessment of patients with interstitial lung disease (ILD) and severe pulmonary hypertension (PH), as defined by a mean pulmonary artery pressure (mPAP) ≥35 mmHg at right heart catheterisation (RHC). We developed and validated a stepwise echocardiographic score to detect severe PH using the tricuspid regurgitant velocity and right atrial pressure (right ventricular systolic pressure (RVSP)) and additional echocardiographic signs. Consecutive ILD patients with suspected PH underwent RHC between 2005 and 2015. Receiver operating curve analysis tested the ability of components of the score to predict mPAP ≥35 mmHg, and a score devised using a stepwise approach. The score was tested in a contemporaneous validation cohort. The score used “additional PH signs” where RVSP was unavailable, using a bootstrapping technique. Within the derivation cohort (n=210), a score ≥7 predicted severe PH with 89% sensitivity, 71% specificity, positive predictive value 68% and negative predictive value 90%, with similar performance in the validation cohort (n=61) (area under the curve (AUC) 84.8% versus 83.1%, p=0.8). Although RVSP could be estimated in 92% of studies, reducing this to 60% maintained a fair accuracy (AUC 74.4%). This simple stepwise echocardiographic PH score can predict severe PH in patients with ILD. PMID:29750141

Joint effect of unlinked genotypes: application to type 2 diabetes in the EPIC-Potsdam case-cohort study.

PubMed

Knüppel, Sven; Meidtner, Karina; Arregui, Maria; Holzhütter, Hermann-Georg; Boeing, Heiner

2015-07-01

Analyzing multiple single nucleotide polymorphisms (SNPs) is a promising approach to finding genetic effects beyond single-locus associations. We proposed the use of multilocus stepwise regression (MSR) to screen for allele combinations as a method to model joint effects, and compared the results with the often used genetic risk score (GRS), conventional stepwise selection, and the shrinkage method LASSO. In contrast to MSR, the GRS, conventional stepwise selection, and LASSO model each genotype by the risk allele doses. We reanalyzed 20 unlinked SNPs related to type 2 diabetes (T2D) in the EPIC-Potsdam case-cohort study (760 cases, 2193 noncases). No SNP-SNP interactions and no nonlinear effects were found. Two SNP combinations selected by MSR (Nagelkerke's R² = 0.050 and 0.048) included eight SNPs with mean allele combination frequency of 2%. GRS and stepwise selection selected nearly the same SNP combinations consisting of 12 and 13 SNPs (Nagelkerke's R² ranged from 0.020 to 0.029). LASSO showed similar results. The MSR method showed the best model fit measured by Nagelkerke's R² suggesting that further improvement may render this method a useful tool in genetic research. However, our comparison suggests that the GRS is a simple way to model genetic effects since it does not consider linkage, SNP-SNP interactions, and no non-linear effects. © 2015 John Wiley & Sons Ltd/University College London.

Impacts of different climate change regimes and extreme climatic events on an alpine meadow community

PubMed Central

Alatalo, Juha M.; Jägerbrand, Annika K.; Molau, Ulf

2016-01-01

Climate variability is expected to increase in future but there exist very few experimental studies that apply different warming regimes on plant communities over several years. We studied an alpine meadow community under three warming regimes over three years. Treatments consisted of (a) a constant level of warming with open-top chambers (ca. 1.9 °C above ambient), (b) yearly stepwise increases in warming (increases of ca. 1.0, 1.9 and 3.5 °C), and (c) pulse warming, a single first-year pulse event of warming (increase of ca. 3.5 °C). Pulse warming and stepwise warming was hypothesised to cause distinct first-year and third-year effects, respectively. We found support for both hypotheses; however, the responses varied among measurement levels (whole community, canopy, bottom layer, and plant functional groups), treatments, and time. Our study revealed complex responses of the alpine plant community to the different experimentally imposed climate warming regimes. Plant cover, height and biomass frequently responded distinctly to the constant level of warming, the stepwise increase in warming and the extreme pulse-warming event. Notably, we found that stepwise warming had an accumulating effect on biomass, the responses to the different warming regimes varied among functional groups, and the short-term perturbations had negative effect on species richness and diversity PMID:26888225

Effect of Isomorphous Substitution on the Thermal Decomposition Mechanism of Hydrotalcites

PubMed Central

Crosby, Sergio; Tran, Doanh; Cocke, David; Duraia, El-Shazly M.; Beall, Gary W.

2014-01-01

Hydrotalcites have many important applications in catalysis, wastewater treatment, gene delivery and polymer stabilization, all depending on preparation history and treatment scenarios. In catalysis and polymer stabilization, thermal decomposition is of great importance. Hydrotalcites form easily with atmospheric carbon dioxide and often interfere with the study of other anion containing systems, particularly if formed at room temperature. The dehydroxylation and decomposition of carbonate occurs simultaneously, making it difficult to distinguish the dehydroxylation mechanisms directly. To date, the majority of work on understanding the decomposition mechanism has utilized hydrotalcite precipitated at room temperature. In this study, evolved gas analysis combined with thermal analysis has been used to show that CO2 contamination is problematic in materials being formed at RT that are poorly crystalline. This has led to some dispute as to the nature of the dehydroxylation mechanism. In this paper, data for the thermal decomposition of the chloride form of hydrotalcite are reported. In addition, carbonate-free hydrotalcites have been synthesized with different charge densities and at different growth temperatures. This combination of parameters has allowed a better understanding of the mechanism of dehydroxylation and the role that isomorphous substitution plays in these mechanisms to be delineated. In addition, the effect of anion type on thermal stability is also reported. A stepwise dehydroxylation model is proposed that is mediated by the level of aluminum substitution. PMID:28788231

Forming trifluoromethylmetallates: competition between decarboxylation and C-F bond activation of group 11 trifluoroacetate complexes, [CF3CO2ML]-.

PubMed

Rijs, Nicole J; O'Hair, Richard A J

2012-03-28

A combination of gas-phase 3D quadrupole ion trap mass spectrometry experiments and density functional theory (DFT) calculations have been used to examine the mechanism of thermal decomposition of fluorinated coinage metal carboxylates. The precursor anions, [CF(3)CO(2)MO(2)CCF(3)](-) (M = Cu, Ag and Au), were introduced into the gas-phase via electrospray ionization. Multistage mass spectrometry (MS(n)) experiments were conducted utilizing collision-induced dissociation, yielding a series of trifluoromethylated organometallic species and fluorides via the loss of CO(2), CF(2) or "CF(2)CO(2)". Carboxylate ligand loss was insignificant or absent in all cases. DFT calculations were carried out on a range of potentially competing fragmentation pathways for [CF(3)CO(2)MO(2)CCF(3)](-), [CF(3)CO(2)MCF(3)](-) and [CF(3)CO(2)MF](-). These shed light on possible products and mechanisms for loss of "CF(2)CO(2)", namely, concerted or step-wise loss of CO(2) and CF(2) and a CF(2)CO(2) lactone pathway. The lactone pathway was found to be higher in energy in all cases. In addition, the possibility of forming [CF(3)MCF(3)](-) and [CF(3)MF](-), via decarboxylation is discussed. For the first time the novel fluoride complexes [FMF](-), M = Cu, Ag and Au have been experimentally observed. Finally, the decomposition reactions of [CF(3)CO(2)ML](-) (where L = CF(3) and CF(3)CO(2)) and [CH(3)CO(2)ML](-) (where L = CH(3) and CH(3)CO(2)) are compared.

Multifaceted catalytic hydrogenation of amides via diverse activation of a sterically confined bipyridine-ruthenium framework.

PubMed

Miura, Takashi; Naruto, Masayuki; Toda, Katsuaki; Shimomura, Taiki; Saito, Susumu

2017-05-16

Amides are ubiquitous and abundant in nature and our society, but are very stable and reluctant to salt-free, catalytic chemical transformations. Through the activation of a "sterically confined bipyridine-ruthenium (Ru) framework (molecularly well-designed site to confine adsorbed H 2 in)" of a precatalyst, catalytic hydrogenation of formamides through polyamide is achieved under a wide range of reaction conditions. Both C=O bond and C-N bond cleavage of a lactam became also possible using a single precatalyst. That is, catalyst diversity is induced by activation and stepwise multiple hydrogenation of a single precatalyst when the conditions are varied. The versatile catalysts have different structures and different resting states for multifaceted amide hydrogenation, but the common structure produced upon reaction with H 2 , which catalyzes hydrogenation, seems to be "H-Ru-N-H."

Using a Paradigm Shift to Teach Neurobiology and the Nature of Science-a C.R.E.A.T.E.-based Approach.

PubMed

Hoskins, Sally G

2008-01-01

Decades ago, classic experiments established the phenomenon of "neural induction" (Spemann and Mangold, 1924; Holtfreter, 1933). It appeared clear that amphibian ectoderm was pre-programmed to form epidermis, and that the neural phenotype was induced by a chemical signal from mesoderm. The "ectoderm makes skin, unless induced to make nervous system" model appeared in many textbooks. This interpretation, however, was not simply incorrect but 180 degrees out of alignment with the actual situation. As subsequently demonstrated, the default state of amphibian ectoderm is neuronal, and the expression of the epidermal phenotype requires cell signaling (Hemmati-Brivanlou and Melton, 1992; 1994; 1997). In this activity, students are presented with key experiments in a stepwise fashion. At several points, they work in groups to devise models that explain particular experimental results. The stepwise presentation of results mirrors the history of discoveries in this experimental system. Eventually, faced with seemingly contradictory data, students must revise their models substantially and in doing so, experience the paradigm shift. The lesson also examines the history of this paradigm shift. Data inconsistent with the "epidermal default" model were published years before the "neural default" model was proposed, but the significance of the surprising new data was underemphasized by the scientists who made the discovery. Discussing this situation provides insight into how science works and highlights the possibility that working scientists may become entrenched in prevailing paradigms. Such "nature of science" discussions emphasize research as a human activity, and help to dispel student misconceptions about science and scientists.

CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation

PubMed Central

Kaji, Tomohiro; Hijikata, Atsushi; Ishige, Akiko; Kitami, Toshimori; Watanabe, Takashi; Ohara, Osamu; Yanaka, Noriyuki; Okada, Mariko; Shimoda, Michiko; Taniguchi, Masaru

2016-01-01

Memory CD4+ T cells promote protective humoral immunity; however, how memory T cells acquire this activity remains unclear. This study demonstrates that CD4+ T cells develop into antigen-specific memory T cells that can promote the terminal differentiation of memory B cells far more effectively than their naive T-cell counterparts. Memory T cell development requires the transcription factor B-cell lymphoma 6 (Bcl6), which is known to direct T-follicular helper (Tfh) cell differentiation. However, unlike Tfh cells, memory T cell development did not require germinal center B cells. Curiously, memory T cells that develop in the absence of cognate B cells cannot promote memory B-cell recall responses and this defect was accompanied by down-regulation of genes associated with homeostasis and activation and up-regulation of genes inhibitory for T-cell responses. Although memory T cells display phenotypic and genetic signatures distinct from Tfh cells, both had in common the expression of a group of genes associated with metabolic pathways. This gene expression profile was not shared to any great extent with naive T cells and was not influenced by the absence of cognate B cells during memory T cell development. These results suggest that memory T cell development is programmed by stepwise expression of gatekeeper genes through serial interactions with different types of antigen-presenting cells, first licensing the memory lineage pathway and subsequently facilitating the functional development of memory T cells. Finally, we identified Gdpd3 as a candidate genetic marker for memory T cells. PMID:26714588

Preparation, Characterization, and Antimicrobial Activities of Bimetallic Complexes of Sarcosine with Zn(II) and Sn(IV)

PubMed Central

Arafat, Yasir; Ali, Saqib; Shahzadi, Saira; Shahid, Muhammad

2013-01-01

Heterobimetallic complexes of Zn(II) and Sn(IV) with sarcosine have been synthesized at room temperature under stirring conditions by the reaction of sarcosine and zinc acetate in 2 : 1 molar ratio followed by the stepwise addition of CS2 and organotin(IV) halides, where R = Me, n-Bu, and Ph. The complexes were characterized by elemental analysis, FT-IR and NMR (1H, 13C) spectroscopy. IR data showed that the ligand acts in a bidentate manner. NMR data revealed the four coordinate geometry in solution state. In vitro antimicrobial activities data showed that complexes (3) and (4) were effective against bacterial and fungal strains with few exceptions. PMID:24235910

Multifaceted Modularity: A Key for Stepwise Building of Hierarchical Complexity in Actinide Metal–Organic Frameworks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dolgopolova, Ekaterina A.; Ejegbavwo, Otega A.; Martin, Corey R.

Growing necessity for efficient nuclear waste management is a driving force for development of alternative architectures towards fundamental understanding of mechanisms involved in actinide integration inside extended structures. In this manuscript, metal-organic frameworks (MOFs) were investigated as a model system for engineering radionuclide containing materials through utilization of unprecedented MOF modularity, which cannot be replicated in any other type of materials. Through the implementation of recent synthetic advances in the MOF field, hierarchical complexity of An-materials were built stepwise, which was only feasible due to preparation of the first examples of actinide-based frameworks with “unsaturated” metal nodes. The first successfulmore » attempts of solid-state metathesis and metal node extension in An-MOFs are reported, and the results of the former approach revealed drastic differences in chemical behavior of extended structures versus molecular species. Successful utilization of MOF modularity also allowed us to structurally characterize the first example of bimetallic An-An nodes. To the best of our knowledge, through combination of solid-state metathesis, guest incorporation, and capping linker installation, we were able to achieve the highest Th wt% in mono- and bi-actinide frameworks with minimal structural density. Overall, combination of a multistep synthetic approach with homogeneous actinide distribution and moderate solvothermal conditions could make MOFs an exceptionally powerful tool to address fundamental questions responsible for chemical behavior of An-based extended structures, and therefore, shed light on possible optimization of nuclear waste administration.« less

Assessing intravascular volume by difference in pulse pressure in pigs submitted to graded hemorrhage.

PubMed

Pestel, Gunther J; Hiltebrand, Luzius B; Fukui, Kimiko; Cohen, Delphine; Hager, Helmut; Kurz, Andrea M

2006-10-01

We assessed changes in intravascular volume monitored by difference in pulse pressure (dPP%) after stepwise hemorrhage in an experimental pig model. Six pigs (23-25 kg) were anesthetized (isoflurane 1.5 vol%) and mechanically ventilated to keep end-tidal CO2 (etCO2) at 35 mmHg. A PA-catheter and an arterial catheter were placed via femoral access. During and after surgery, animals received lactated Ringer's solution as long as they were considered volume responders (dPP>13%). Then animals were allowed to stabilize from the induction of anesthesia and insertion of catheters for 30 min. After stabilization, baseline measurements were taken. Five percent of blood volume was withdrawn, followed by another 5%, and then in 10%-increments until death from exsanguination occurred. After withdrawal of 5% of blood volume, all pigs were considered volume responders (dPP>13%); dPP rose significantly from 6.1+/-3.3% to 19.4+/-4.2%. The regression analysis of stepwise hemorrhage revealed a linear relation between blood loss (hemorrhage in %) and dPP (y=0.99*x+14; R2=0.7764; P<.0001). In addition, dPP was the only parameter that changed significantly between baseline and a blood loss of 5% (P<0.01), whereas cardiac output, stroke volume, heart rate, MAP, central venous pressure, pulmonary artery occlusion pressure, and systemic vascular resistance, respectively, remained unchanged. We conclude that in an experimental hypovolemic pig model, dPP correlates well with blood loss.

Multifaceted Modularity: A Key for Stepwise Building of Hierarchical Complexity in Actinide Metal-Organic Frameworks.

PubMed

Dolgopolova, Ekaterina A; Ejegbavwo, Otega A; Martin, Corey R; Smith, Mark D; Setyawan, Wahyu; Karakalos, Stavros G; Henager, Charles H; Zur Loye, Hans-Conrad; Shustova, Natalia B

2017-11-22

Growing necessity for efficient nuclear waste management is a driving force for development of alternative architectures toward fundamental understanding of mechanisms involved in actinide (An) integration inside extended structures. In this manuscript, metal-organic frameworks (MOFs) were investigated as a model system for engineering radionuclide containing materials through utilization of unprecedented MOF modularity, which cannot be replicated in any other type of materials. Through the implementation of recent synthetic advances in the MOF field, hierarchical complexity of An-materials was built stepwise, which was only feasible due to preparation of the first examples of actinide-based frameworks with "unsaturated" metal nodes. The first successful attempts of solid-state metathesis and metal node extension in An-MOFs are reported, and the results of the former approach revealed drastic differences in chemical behavior of extended structures versus molecular species. Successful utilization of MOF modularity also allowed us to structurally characterize the first example of bimetallic An-An nodes. To the best of our knowledge, through combination of solid-state metathesis, guest incorporation, and capping linker installation, we were able to achieve the highest Th wt % in mono- and biactinide frameworks with minimal structural density. Overall, the combination of a multistep synthetic approach with homogeneous actinide distribution and moderate solvothermal conditions could make MOFs an exceptionally powerful tool to address fundamental questions responsible for chemical behavior of An-based extended structures and, therefore, shed light on possible optimization of nuclear waste administration.

Quantifying Ciliary Dynamics during Assembly Reveals Step-wise Waveform Maturation in Airway Cells.

PubMed

Oltean, Alina; Schaffer, Andrew J; Bayly, Philip V; Brody, Steven L

2018-05-31

Motile cilia are essential for clearance of particulates and pathogens from airways. For effective transport, ciliary motor proteins and axonemal structures interact to generate the rhythmic, propulsive bending, but the mechanisms that produce a dynamic waveform remain incompletely understood. Biomechanical measures of human cilia motion and their relationships to cilia assembly are needed to illuminate the biophysics of normal cilia function, and to quantify dysfunction in ciliopathies. To these ends, we analyzed cilia motion from high-speed video microscopy of ciliated cells sampled from human lung airways compared to primary-culture cells that undergo ciliogenesis in vitro. Quantitative assessment of waveform parameters showed variations in waveform shape between individual cilia; however, general trends in waveform parameters emerged, associated with progression of cilia length and stage of differentiation. When cilia emerged from cultured cells, beat frequency was initially elevated, then fell and remained stable as cilia lengthened. In contrast, the average bending amplitude and the ability to generate force gradually increased and eventually approached values observed in ex vivo samples. Dynein arm motor proteins DNAH5, DNAH9, DNAH11, and DNAH6 were localized within specific regions of the axoneme in the ex vivo cells; however distinct stages of in vitro waveform development identified by biomechanical features were associated with the progressive movement of dyneins to the appropriate proximal or distal sections of the cilium. These observations suggest that the step-wise variation in waveform development during ciliogenesis is dependent on cilia length and potentially outer dynein arm assembly.

The osmotic stress response of split influenza vaccine particles in an acidic environment.

PubMed

Choi, Hyo-Jick; Kim, Min-Chul; Kang, Sang-Moo; Montemagno, Carlo D

2014-12-01

Oral influenza vaccine provides an efficient means of preventing seasonal and pandemic disease. In this work, the stability of envelope-type split influenza vaccine particles in acidic environments has been investigated. Owing to the fact that hyper-osmotic stress can significantly affect lipid assembly of vaccine, osmotic stress-induced morphological change of split vaccine particles, in conjunction with structural change of antigenic proteins, was investigated by the use of stopped-flow light scattering (SFLS), intrinsic fluorescence, transmission electron microscopy (TEM), and hemagglutination assay. Split vaccine particles were found to exhibit a step-wise morphological change in response to osmotic stress due to double-layered wall structure. The presence of hyper-osmotic stress in acidic medium (0.3 osmolarity, pH 2.0) induced a significant level of membrane perturbation as measured by SFLS and TEM, imposing more damage to antigenic proteins on vaccine envelope than can be caused by pH-induced conformational change at acidic iso-osmotic condition. Further supports were provided by the intrinsic fluorescence and hemagglutinin activity measurements. Thus, hyper-osmotic stress becomes an important factor for determining stability of split vaccine particles in acidic medium. These results are useful in better understanding the destabilizing mechanism of split influenza vaccine particles in gastric environment and in designing oral influenza vaccine formulations.

Role of the testis interstitial compartment in spermatogonial stem cell function

PubMed Central

Potter, Sarah J.; DeFalco, Tony

2017-01-01

Male fertility is maintained through intricate cellular and molecular interactions that ensure spermatogonial stem cells (SSCs) proceed in a step-wise differentiation process through spermatogenesis and spermiogenesis to produce sperm. SSCs lie within the seminiferous tubule compartment, which provides a nurturing environment for the development of sperm. Cells outside of the tubules, such as interstitial and peritubular cells, also help direct SSC activity. This review focuses on interstitial (interstitial macrophages, Leydig cells, and vasculature) and peritubular (peritubular macrophages, peritubular myoid cells) cells and their role in regulating SSC self-renewal and differentiation in mammals. Leydig cells, the major steroidogenic cells in the testis, influence SSCs through secreted factors, such as insulin growth factor 1 (IGF1) and colony stimulating factor 1 (CSF1). Macrophages interact with SSCs through various potential mechanisms, such as CSF1 and retinoic acid (RA), to induce proliferation or differentiation of SSCs, respectively. Vasculature influences SSC dynamics through CSF1, vascular endothelial growth factor (VEGF), and regulating oxygen levels. Lastly, peritubular myoid cells produce one of the most well-known factors that is required for SSC self-renewal, glial cell line derived neurotrophic factor (GDNF), as well as CSF1. Overall, SSC interactions with interstitial and peritubular cells are critical for SSC function and are an important underlying factor promoting male fertility. PMID:28115580

Dopamine cells respond to predicted events during classical conditioning: evidence for eligibility traces in the reward-learning network.

PubMed

Pan, Wei-Xing; Schmidt, Robert; Wickens, Jeffery R; Hyland, Brian I

2005-06-29

Behavioral conditioning of cue-reward pairing results in a shift of midbrain dopamine (DA) cell activity from responding to the reward to responding to the predictive cue. However, the precise time course and mechanism underlying this shift remain unclear. Here, we report a combined single-unit recording and temporal difference (TD) modeling approach to this question. The data from recordings in conscious rats showed that DA cells retain responses to predicted reward after responses to conditioned cues have developed, at least early in training. This contrasts with previous TD models that predict a gradual stepwise shift in latency with responses to rewards lost before responses develop to the conditioned cue. By exploring the TD parameter space, we demonstrate that the persistent reward responses of DA cells during conditioning are only accurately replicated by a TD model with long-lasting eligibility traces (nonzero values for the parameter lambda) and low learning rate (alpha). These physiological constraints for TD parameters suggest that eligibility traces and low per-trial rates of plastic modification may be essential features of neural circuits for reward learning in the brain. Such properties enable rapid but stable initiation of learning when the number of stimulus-reward pairings is limited, conferring significant adaptive advantages in real-world environments.

Psychophysiological responses to competition and the big five personality traits.

PubMed

Binboga, Erdal; Guven, Senol; Catıkkaş, Fatih; Bayazıt, Onur; Tok, Serdar

2012-06-01

This study examines the relationship between psychophysiological arousal, cognitive anxiety, and personality traits in young taekwondo athletes. A total of 20 male and 10 female taekwondo athletes (mean age = 18.6 years; ± 1.8) volunteered for the study. The Five Factor Personality Inventory and the state scale of the Spielberger State-Trait Anxiety Inventory (STAI) were used to measure personality and cognitive state anxiety. Electrodermal activity (EDA) was measured twice, one day and approximately one hour prior to the competition, to determine psychophysiological arousal. Descriptive statistics, Pearson product-moment correlations, and stepwise regression were used to analyze the data. Several "Big Five" facets were related to the EDA delta scores that were measured both one day and one hour before the competition. Two stepwise regressions were conducted to examine whether personality traits could significantly predict both EDA delta scores. The final model, containing only neuroticism from the Big Five factors, can significantly explain the variations in the EDA delta scores measured one day before the competition. Agreeableness can significantly explain variations in the EDA delta scores measured one hour before the competition. No relationship was found between cognitive anxiety and the EDA delta scores measured one hour before the competition. In conclusion, personality traits, especially agreeableness and neuroticism, might be useful in understanding arousal responses to competition.

Psychophysiological Responses to Competition and the Big Five Personality Traits

PubMed Central

Binboga, Erdal; Guven, Senol; Çatıkkaş, Fatih; Bayazıt, Onur; Tok, Serdar

2012-01-01

This study examines the relationship between psychophysiological arousal, cognitive anxiety, and personality traits in young taekwondo athletes. A total of 20 male and 10 female taekwondo athletes (mean age = 18.6 years; ± 1.8) volunteered for the study. The Five Factor Personality Inventory and the state scale of the Spielberger State-Trait Anxiety Inventory (STAI) were used to measure personality and cognitive state anxiety. Electrodermal activity (EDA) was measured twice, one day and approximately one hour prior to the competition, to determine psychophysiological arousal. Descriptive statistics, Pearson product-moment correlations, and stepwise regression were used to analyze the data. Several “Big Five” facets were related to the EDA delta scores that were measured both one day and one hour before the competition. Two stepwise regressions were conducted to examine whether personality traits could significantly predict both EDA delta scores. The final model, containing only neuroticism from the Big Five factors, can significantly explain the variations in the EDA delta scores measured one day before the competition. Agreeableness can significantly explain variations in the EDA delta scores measured one hour before the competition. No relationship was found between cognitive anxiety and the EDA delta scores measured one hour before the competition. In conclusion, personality traits, especially agreeableness and neuroticism, might be useful in understanding arousal responses to competition. PMID:23486906

Gas-saturated solution process to obtain microcomposite particles of alpha lipoic acid/hydrogenated colza oil in supercritical carbon dioxide.

PubMed

Mishima, Kenji; Honjo, Masatoshi; Sharmin, Tanjina; Ito, Shota; Kawakami, Ryo; Kato, Takafumi; Misumi, Makoto; Suetsugu, Tadashi; Orii, Hideaki; Kawano, Hiroyuki; Irie, Keiichi; Sano, Kazunori; Mishima, Kenichi; Harada, Takunori; Ouchi, Mikio

2016-09-01

Alpha lipoic acid (ALA), an active substance in anti-aging products and dietary supplements, need to be masked with an edible polymer to obscure its unpleasant taste. However, the high viscosity of the ALA molecules prevents them from forming microcomposites with masking materials even in supercritical carbon dioxide (scCO2). Therefore, the purpose of this study was to investigate and develop a novel production method for microcomposite particles for ALA in hydrogenated colza oil (HCO). Microcomposite particles of ALA/HCO were prepared by using a novel gas-saturated solution (PGSS) process in which the solid-dispersion method is used along with stepwise temperature control (PGSS-STC). Its high viscosity prevents the formation of microcomposites in the conventional PGSS process even under strong agitation. Here, we disperse the solid particles of ALA and HCO in scCO2 at low temperatures and change the temperature stepwise in order to mix the melted ALA and HCO in scCO2. As a result, a homogeneous dispersion of the droplets of ALA in melted HCO saturated with CO2 is obtained at high temperatures. After the rapid expansion of the saturated solution through a nozzle, microcomposite particles of ALA/HCO several micrometers in diameter are obtained.

Identification of molecular descriptors for design of novel Isoalloxazine derivatives as potential Acetylcholinesterase inhibitors against Alzheimer's disease.

PubMed

Gurung, Arun Bahadur; Aguan, Kripamoy; Mitra, Sivaprasad; Bhattacharjee, Atanu

2017-06-01

In Alzheimer's disease (AD), the level of Acetylcholine (ACh) neurotransmitter is reduced. Since Acetylcholinesterase (AChE) cleaves ACh, inhibitors of AChE are very much sought after for AD treatment. The side effects of current inhibitors necessitate development of newer AChE inhibitors. Isoalloxazine derivatives have proved to be promising (AChE) inhibitors. However, their structure-activity relationship studies have not been reported till date. In the present work, various quantitative structure-activity relationship (QSAR) building methods such as multiple linear regression (MLR), partial least squares ,and principal component regression were employed to derive 3D-QSAR models using steric and electrostatic field descriptors. Statistically significant model was obtained using MLR coupled with stepwise selection method having r 2  = .9405, cross validated r 2 (q 2 ) = .6683, and a high predictability (pred_r 2  = .6206 and standard error, pred_r 2 se = .2491). Steric and electrostatic contribution plot revealed three electrostatic fields E_496, E_386 and E_577 and one steric field S_60 contributing towards biological activity. A ligand-based 3D-pharmacophore model was generated consisting of eight pharmacophore features. Isoalloxazine derivatives were docked against human AChE, which revealed critical residues implicated in hydrogen bonds as well as hydrophobic interactions. The binding modes of docked complexes (AChE_IA1 and AChE_IA14) were validated by molecular dynamics simulation which showed their stable trajectories in terms of root mean square deviation and molecular mechanics/Poisson-Boltzmann surface area binding free energy analysis revealed key residues contributing significantly to overall binding energy. The present study may be useful in the design of more potent Isoalloxazine derivatives as AChE inhibitors.

Phorbol ester and hydrogen peroxide synergistically induce the interaction of diacylglycerol kinase gamma with the Src homology 2 and C1 domains of beta2-chimaerin.

PubMed

Yasuda, Satoshi; Kai, Masahiro; Imai, Shin-ichi; Kanoh, Hideo; Sakane, Fumio

2008-01-01

DGKgamma (diacylglycerol kinase gamma) was reported to interact with beta2-chimaerin, a GAP (GTPase-activating protein) for Rac, in response to epidermal growth factor. Here we found that PMA and H2O2 also induced the interaction of DGKgamma with beta2-chimaerin. It is noteworthy that simultaneous addition of PMA and H2O2 synergistically enhanced the interaction. In this case, PMA was replaceable by DAG (diacylglycerol). The beta2-chimaerin translocation from the cytoplasm to the plasma membrane caused by PMA plus H2O2 was further enhanced by the expression of DGKgamma. Moreover, DGKgamma apparently enhanced the beta2-chimaerin GAP activity upon cell stimulation with PMA. PMA was found to be mainly required for a conversion of beta2-chimaerin into an active form. On the other hand, H2O2 was suggested to induce a release of Zn2+ from the C1 domain of beta2-chimaerin. By stepwise deletion analysis, we demonstrated that the SH2 (Src homology 2) and C1 domains of beta2-chimaerin interacted with the N-terminal half of catalytic region of DGKgamma. Unexpectedly, the SH2 domain of beta2-chimaerin contributes to the interaction independently of phosphotyrosine. Taken together, these results suggest that the functional link between DGKgamma and beta2-chimaerin has a broad significance in response to a wide range of cell stimuli. Our work offers a novel mechanism of protein-protein interaction, that is, the phosphotyrosine-independent interaction of the SH2 domain acting in co-operation with the C1 domain.

Histopathological Effects of the Yen-Tc Toxin Complex from Yersinia entomophaga MH96 (Enterobacteriaceae) on the Costelytra zealandica (Coleoptera: Scarabaeidae) Larval Midgut

PubMed Central

Hares, Michelle C.; Jones, Sandra A.; Harper, Lincoln A.; Vernon, James R.; Harland, Duane P.; Jackson, Trevor A.; Hurst, Mark R. H.

2012-01-01

Yersinia entomophaga MH96, which was originally isolated from the New Zealand grass grub, Costelytra zealandica, produces an orally active proteinaceous toxin complex (Yen-Tc), and this toxin is responsible for mortality in a range of insect species, mainly within the Coleoptera and Lepidoptera. The genes encoding Yen-Tc are members of the toxin complex (Tc) family, with orthologs identified in several other bacterial species. As the mechanism of Yen-Tc activity remains unknown, a histopathological examination of C. zealandica larvae was undertaken in conjunction with cultured cells to identify the effects of Yen-Tc and to distinguish the contributions that its individual subunit components make upon intoxication. A progressive series of events that led to the deterioration of the midgut epithelium was observed. Additionally, experiments using a cell culture assay system were carried out to determine the cellular effects of intoxication on cells after topical application and the transient expression of Yen-Tc and its individual components. While observations were broadly consistent with those previously reported for other Tc family members, some differences were noted. In particular, the distinct stepwise disintegration of the midgut shared features associated with both apoptosis and necrotic programmed cell death pathways. Second, we observed, for the first time, a contribution of toxicity from two chitinases associated with the Yen-Tc complex. Our findings were suggestive of the activities encoded within the subunit components of Yen-Tc targeting different sites along putative programmed cell death pathways. Given the observed broad host range for Yen-Tc, these targeted loci are likely to be widely shared among insects. PMID:22544254

Multiple-Objective Stepwise Calibration Using Luca

USGS Publications Warehouse

Hay, Lauren E.; Umemoto, Makiko

2007-01-01

This report documents Luca (Let us calibrate), a multiple-objective, stepwise, automated procedure for hydrologic model calibration and the associated graphical user interface (GUI). Luca is a wizard-style user-friendly GUI that provides an easy systematic way of building and executing a calibration procedure. The calibration procedure uses the Shuffled Complex Evolution global search algorithm to calibrate any model compiled with the U.S. Geological Survey's Modular Modeling System. This process assures that intermediate and final states of the model are simulated consistently with measured values.

Mechanical factors and vitamin D deficiency in schoolchildren with low back pain: biochemical and cross-sectional survey analysis

PubMed Central

Alghadir, Ahmad H; Gabr, Sami A; Al-Eisa, Einas S

2017-01-01

Objective This study was designed to evaluate the role of vitamin D, muscle fatigue biomarkers, and mechanical factors in the progression of low back pain (LBP) in schoolchildren. Background Children and adolescents frequently suffer from LBP with no clear clinical causes, and >71% of schoolchildren aged 12–17 years will show at least one episode of LBP. Materials and methods A total of 250 schoolchildren aged 12–16 years were randomly enrolled in this study. For all schoolchildren height, weight, percentage of daily sun exposure and and areas of skin exposed to sun, method of carrying the bag, and bag weight and type were recorded over a typical school week. Pain scores, physical activity (PA), LBP, serum vitamin 25(OH)D level, serum bone-specific alkaline phosphatase, creatine kinase (CK), and lactate dehydrogenase (LDH) activities and calcium (Ca) concentrations were estimated using prevalidated Pain Rating Scale, modified Oswestry Low Back Pain Disability Questionnaire, short-form PA questionnaire, and colorimetric and immunoassay techniques. Results During the period of October 2013–May 2014, LBP was estimated in 52.2% of the schoolchildren. It was classified into moderate (34%) and severe (18%). Girls showed a higher LBP (36%) compared with boys (24%). In schoolchildren with moderate and severe LBP significantly higher (P=0.01) body mass index, waist, hip, and waist-to-hip ratio measurements were observed compared with normal schoolchildren. LBP significantly correlated with less sun exposure, lower PA, sedentary activity (TV/computer use), and overloaded school bags. In addition, schoolchildren with severe LBP showed lower levels of vitamin 25(OH)D and Ca and higher levels of CK, LDH, and serum bone-specific alkaline phosphatase compared with moderate and healthy schoolchildren. Stepwise regression analysis revealed that age, gender, demographic parameters, PA, vitamin D levels, Ca, CK, and LDH associated with ~56.8%–86.7% of the incidence of LBP among schoolchildren. Conclusion In children and adolescents, LBP was shown to be linked with limited sun exposure, inadequate vitamin D diets, adiposity, lower PA, sedentary lifestyles, vitamin 25 (OH) D deficiency, and lower levels of Ca, CK, and LDH. PMID:28442927

Mechanical factors and vitamin D deficiency in schoolchildren with low back pain: biochemical and cross-sectional survey analysis.

PubMed

Alghadir, Ahmad H; Gabr, Sami A; Al-Eisa, Einas S

2017-01-01

This study was designed to evaluate the role of vitamin D, muscle fatigue biomarkers, and mechanical factors in the progression of low back pain (LBP) in schoolchildren. Children and adolescents frequently suffer from LBP with no clear clinical causes, and >71% of schoolchildren aged 12-17 years will show at least one episode of LBP. A total of 250 schoolchildren aged 12-16 years were randomly enrolled in this study. For all schoolchildren height, weight, percentage of daily sun exposure and and areas of skin exposed to sun, method of carrying the bag, and bag weight and type were recorded over a typical school week. Pain scores, physical activity (PA), LBP, serum vitamin 25(OH)D level, serum bone-specific alkaline phosphatase, creatine kinase (CK), and lactate dehydrogenase (LDH) activities and calcium (Ca) concentrations were estimated using prevalidated Pain Rating Scale, modified Oswestry Low Back Pain Disability Questionnaire, short-form PA questionnaire, and colorimetric and immunoassay techniques. During the period of October 2013-May 2014, LBP was estimated in 52.2% of the schoolchildren. It was classified into moderate (34%) and severe (18%). Girls showed a higher LBP (36%) compared with boys (24%). In schoolchildren with moderate and severe LBP significantly higher ( P =0.01) body mass index, waist, hip, and waist-to-hip ratio measurements were observed compared with normal schoolchildren. LBP significantly correlated with less sun exposure, lower PA, sedentary activity (TV/computer use), and overloaded school bags. In addition, schoolchildren with severe LBP showed lower levels of vitamin 25(OH)D and Ca and higher levels of CK, LDH, and serum bone-specific alkaline phosphatase compared with moderate and healthy schoolchildren. Stepwise regression analysis revealed that age, gender, demographic parameters, PA, vitamin D levels, Ca, CK, and LDH associated with ~56.8%-86.7% of the incidence of LBP among schoolchildren. In children and adolescents, LBP was shown to be linked with limited sun exposure, inadequate vitamin D diets, adiposity, lower PA, sedentary lifestyles, vitamin 25 (OH) D deficiency, and lower levels of Ca, CK, and LDH.

The Acid-Base Properties, Hydrolytic Mechanism, and Susceptibility to O2 Oxidation of Fe4S4(SR)4-2 Clusters

PubMed Central

Bruice, Thomas C.; Maskiewicz, Richard; Job, Robert

1975-01-01

The iron-sulfur cluster compounds Fe4S4(SR)4-2 [where —SR = —SCH3, —S—C(CH3)3, and —S— CH2—CH(CH3)2] have been found to represent the base species of weak acids of pKa comparable to that of carboxylic acids. The acid species Fe4S4(SR)4H- is most subject to reaction with O2 and to acid-catalyzed solvolysis, while the base species Fe4S4(SR)4-2 most readily undergoes ligand exchange. The kinetics for hydrolysis of the isobutyl mercaptide cluster salt has been investigated in detail and a mechanism involving the stepwise process [Formula: see text] has been proposed. The importance of the acid-base equilibria in determining the reactivity of the iron-sulfur clusters and its possible importance as a factor in the determination of the potentials of ferredoxins and high potential iron protein are discussed. PMID:16592211

The role of hydrogels in the radical production of the Fricke-gel-dosimeter

NASA Astrophysics Data System (ADS)

Lazzaroni, S.; Liosi, G. M.; D'Agostino, G.; Marconi, R. P.; Mariani, M.; Buttafava, A.; Dondi, D.

2018-01-01

The radiolysis mechanism of the Fricke-gel-dosimeters has been investigated in order to evaluate the role of hydrogels in the radical production. For this purpose, electron paramagnetic resonance (EPR) spectra were acquired for samples frozen and irradiated at 77 K. The analysis was performed by increasing stepwise the temperature and acquiring the EPR spectra at 120 K in order to follow the radical reaction mechanism. The comparison between aqueous- and gel- dosimeters were performed. Both gelatin from porcine skin and PVA (polyvinyl alcohol) were investigated as gel matrix. Different radical species were identified and qualitatively compared. For gel matrix, peroxyl radicals, stemming from the hydrogel, play an important role in the survival of radicals at higher temperature. Moreover, the Fe3+ EPR signal has been studied and compared with the radicals concentration. From this comparison, it is evident the increase of Fe3+ concentration is shifted toward higher temperatures with respect to the radical decay. To explain this phenomenon, the intervention of EPR silent species like peroxides is supposed.

Recent studies on the developing human hepatocellular carcinoma.

PubMed

Gerber, M A

1986-01-01

From our knowledge of characteristic phenotypic changes of the preneoplastic lesions during the stepwise evolution of hepatocellular carcinoma (HCC) in experimental models, we are now beginning to define the structural, histochemical, biochemical, antigenic and molecular properties of early HCC and of the putative preneoplastic changes in human liver. Histological, ultrastructural, morphometric and immunohistochemical studies suggest that adenomatous nodules of regenerating and hyperplastic hepatocytes are more likely to represent direct precursors of HCC than dysplastic hepatocytes. Histochemical and immunomorphological investigations show appreciable functional and phenotypic heterogeneity of human HCC as previously recognized in experimental hepatocarcinogenesis. Studies of altered expression of oncogenes in the regenerating liver and HCC are beginning to define the molecular mechanisms in cell growth and malignant transformation. Although integration of Hepadna viral DNA sequences frequently occurs during persistent infection in man and animals, the exact mechanism of viral oncogenesis remains to be elucidated. It is likely that the development of monoclonal antibodies to surface antigens on transformed hepatocytes will be useful for exploring lineage relationships between the cell populations involved in hepatocarcinogenesis.

Removal of polybrominated diphenyl ethers by biomass carbon-supported nanoscale zerovalent iron particles: influencing factors, kinetics, and mechanism.

PubMed

Fu, Rongbing; Xu, Zhen; Peng, Lin; Bi, Dongsu

2016-12-01

In this study, nanoscale zerovalent iron (NZVI) immobilized on biomass carbon was used for the high efficient removal of BDE 209. NZVI supported on biomass carbon minimized the aggregation of NZVI particles resulting in the increased reaction performance. The proposed removal mechanism included the adsorption of BDE 209 on the surface or interior of the biomass carbon NZVI (BC-NZVI) particles and the subsequent debromination of BDE 209 by NZVI while biomass carbon served as an electron shuttle. BC-NZVI particles and the interaction between BC-NZVI particles and BDE 209 were characterized by TEM, XRD, and XPS. The removal reaction followed a pseudo-first-order rate expression under different reaction conditions, and the k obs was higher than that of other NZVI-supported materials. The debromination of BDE 209 by BC-NZVI was a stepwise process from nona-BDE to DE. A proposed pathway suggested that supporting NZVI on biomass carbon has potential as a promising technique for in situ organic-contaminated groundwater remediation.

Reactions of Criegee Intermediates with Non-Water Greenhouse Gases: Implications for Metal Free Chemical Fixation of Carbon Dioxide.

PubMed

Kumar, Manoj; Francisco, Joseph S

2017-09-07

High-level theoretical calculations suggest that a Criegee intermediate preferably interacts with carbon dioxide compared to two other greenhouse gases, nitrous oxide and methane. The results also suggest that the interaction between Criegee intermediates and carbon dioxide involves a cycloaddition reaction, which results in the formation of a cyclic carbonate-type adduct with a barrier of 6.0-14.0 kcal/mol. These results are in contrast to a previous assumption that the reaction occurs barrierlessly. The subsequent decomposition of the cyclic adduct into formic acid and carbon dioxide follows both concerted and stepwise mechanisms. The latter mechanism has been overlooked previously. Under formic acid catalysis, the concerted decomposition of the cyclic carbonate may be favored under tropospheric conditions. Considering that there is a strong nexus between carbon dioxide levels in the atmosphere and global warming, the high reactivity of Criegee intermediates could be utilized for designing efficient carbon capture technologies.

Exploration of a mechanism for the production of highly unsaturated fatty acids in Scenedesmus sp. at low temperature grown on oil crop residue based medium.

PubMed

Lu, Qian; Li, Jun; Wang, Jinghan; Li, Kun; Li, Jingjing; Han, Pei; Chen, Paul; Zhou, Wenguang

2017-11-01

The ability of algae to produce lipids comprising of unsaturated fatty acids varies with strains and culture conditions. This study investigates the effect of temperature on the production of unsaturated fatty acids in Scenedesmus sp. grown on oil crop residue based medium. At low temperature (10°C), synthesis of lipids compromising of high contents of unsaturated fatty acids took place primarily in the early stage while protein accumulation mainly occurred in the late stage. This stepwise lipid-protein synthesis process was found to be associated with the contents of acetyl-CoA and α-KG in the algal cells. A mechanism was proposed and tested through simulation experiments which quantified the carbon flux allocation in algal cells at different cultivation stages. It is concluded that low culture temperature such as 10°C is suitable for the production of lipids comprising of unsaturated fatty acids. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ferroelectric molecular field-switch based on double proton transfer process: Static and dynamical simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rode, Michał F.; Sobolewski, Andrzej L.; Jankowska, Joanna

2016-04-07

In this work, we present a reversible ferroelectric molecular switch controlled by an external electric field. The studied (2Z)-1-(6-((Z)-2-hydroxy-2-phenylvinyl)pyridin-3-yl)-2-(pyridin-2(1H) -ylidene)ethanone (DSA) molecule is polarized by two uniaxial intramolecular hydrogen bonds. Two protons can be transferred along hydrogen bonds upon an electric field applied along the main molecular axis. The process results in reversion of the dipole moment of the system. Static ab initio and on-the-fly dynamical simulations of the DSA molecule placed in an external electric field give insight into the mechanism of the double proton transfer (DPT) in the system and allow for estimation of the time scale ofmore » this process. The results indicate that with increasing strength of the electric field, the step-wise mechanism of DPT changes into the downhill barrierless process in which the synchronous and asynchronous DPTs compete with each other.« less

Terrorism as a process: a critical review of Moghaddam's "Staircase to Terrorism".

PubMed

Lygre, Ragnhild B; Eid, Jarle; Larsson, Gerry; Ranstorp, Magnus

2011-12-01

This study reviews empirical evidence for Moghaddam's model "Staircase to Terrorism," which portrays terrorism as a process of six consecutive steps culminating in terrorism. An extensive literature search, where 2,564 publications on terrorism were screened, resulted in 38 articles which were subject to further analysis. The results showed that while most of the theories and processes linked to Moghaddam's model are supported by empirical evidence, the proposed transitions between the different steps are not. These results may question the validity of a linear stepwise model and may suggest that a combination of mechanisms/factors could combine in different ways to produce terrorism. © 2011 The Authors. Scandinavian Journal of Psychology © 2011 The Scandinavian Psychological Associations.

Criegee intermediate-hydrogen sulfide chemistry at the air/water interface.

PubMed

Kumar, Manoj; Zhong, Jie; Francisco, Joseph S; Zeng, Xiao C

2017-08-01

We carry out Born-Oppenheimer molecular dynamic simulations to show that the reaction between the smallest Criegee intermediate, CH 2 OO, and hydrogen sulfide (H 2 S) at the air/water interface can be observed within few picoseconds. The reaction follows both concerted and stepwise mechanisms with former being the dominant reaction pathway. The concerted reaction proceeds with or without the involvement of one or two nearby water molecules. An important implication of the simulation results is that the Criegee-H 2 S reaction can provide a novel non-photochemical pathway for the formation of a C-S linkage in clouds and could be a new oxidation pathway for H 2 S in terrestrial, geothermal and volcanic regions.

Villification of the gut

NASA Astrophysics Data System (ADS)

Tallinen, Tuomas; Shyer, Amy E.; Tabin, Clifford J.; Mahadevan, L.

2014-03-01

The villi of the human and chick gut are formed in similar stepwise progressions, wherein the mesenchyme and attached epithelium first fold into longitudinal ridges, then a zigzag pattern, and lastly individual villi. We combine biological manipulations and quantitative modeling to show that these steps of villification depend on the sequential differentiation of the distinct smooth muscle layers of the gut, which restrict the expansion of the growing endoderm and mesenchyme, generating compressive stresses that lead to their buckling and folding. Our computational model incorporates measured elastic properties and growth rates in the developing gut, recapitulating the morphological patterns seen during villification in a variety of species. Our study provides a mechanical basis for the genesis of these epithelial protrusions that are essential for providing sufficient surface area for nutrient absorption.

Chromanyl-isoxazolidines as Antibacterial agents: Synthesis, Biological Evaluation, Quantitative Structure Activity Relationship, and Molecular Docking Studies.

PubMed

Singh, Gagandeep; Sharma, Anuradha; Kaur, Harpreet; Ishar, Mohan Paul S

2016-02-01

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (N) with different mono-substituted, disubstituted, and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3'-(chrom-4-one-3-yl)-isoxazolidines (1-40). All the synthesized compounds were assayed for their in vitro antibacterial activity and display significant inhibitory potential; in particular, compound 32 exhibited good inhibitory activity against Salmonella typhymurium-1 & Salmonella typhymurium-2 with minimum inhibitory concentration value of 1.56 μg/mL and also showed good potential against methicillin-resistant Staphylococcus aureus with minimum inhibitory concentration 3.12 μg/mL. Quantitative structure activity relationship investigations with stepwise multiple linear regression analysis and docking simulation studies have been performed for validation of the observed antibacterial potential of the investigated compounds for determination of the most important parameters regulating antibacterial activities. © 2015 John Wiley & Sons A/S.

Association between masseter muscle activity levels recorded during sleep and signs and symptoms of temporomandibular disorders in healthy young adults.

PubMed

Baba, Kazuyoshi; Haketa, Tadasu; Sasaki, Yoshiyuki; Ohyama, Takashi; Clark, Glenn T

2005-01-01

To examine whether any signs and symptoms of temporomandibular disorders were significantly associated with masseter muscle activity levels during sleep. One hundred three healthy adult subjects (age range, 22 to 32 years) participated in the study. They were asked to fill out questionnaires, undergo a calibrated clinical examination of their jaws and teeth, and perform 6 consecutive nightly masseter electromyographic (EMG) recordings with a portable EMG recording system in their home. The EMG data were considered dependent variables, while the questionnaire and examination data were considered independent variables. Multiple stepwise linear regression analysis was utilized to assess possible associations between these variables. Both gender and joint sound scores were significantly related to the duration of EMG activity. None of the other independent variables were found to be related to any of the muscle activity variables. The results suggest that both gender and clicking are significantly related to duration of masseter EMG activity during sleep.

Stepwise management of asthma.

PubMed

Khalid, Ayesha N

2015-09-01

Stepwise management of asthma remains an area of evolving research. Asthma is one of the most expensive chronic diseases in the United States; stepwise management is an important area of focus, with several recent guidelines recommending management. This is a review of published English language literature, focusing on management guidelines for asthma in adult and pediatric patients. Asthma is a chronic disease whose assessment of severity allows for therapeutic goals to match the impairment noted. Good evidence exists to aid risk reduction, leading to decreased emergency room visits, preventing loss of lung function in adults and lung growth in children, and optimizing pharmacotherapy with reduced side effects profile. Recent asthma management guidelines incorporate 4 components of asthma care including: monitoring of severity, patient education, controlling external triggers, and medications, including recent attention to medication adherence. Asthma is an expensive chronic disease with preventive measures leading to reduced healthcare costs. Future targeted cytokine therapy to decrease serum and blood eosinophils may become an integral part of asthma management. © 2015 ARS-AAOA, LLC.

Response kinetics of tethered bacteria to stepwise changes in nutrient concentration.

PubMed

Chernova, Anna A; Armitage, Judith P; Packer, Helen L; Maini, Philip K

2003-09-01

We examined the changes in swimming behaviour of the bacterium Rhodobacter sphaeroides in response to stepwise changes in a nutrient (propionate), following the pre-stimulus motion, the initial response and the adaptation to the sustained concentration of the chemical. This was carried out by tethering motile cells by their flagella to glass slides and following the rotational behaviour of their cell bodies in response to the nutrient change. Computerised motion analysis was used to analyse the behaviour. Distributions of run and stop times were obtained from rotation data for tethered cells. Exponential and Weibull fits for these distributions, and variability in individual responses are discussed. In terms of parameters derived from the run and stop time distributions, we compare the responses to stepwise changes in the nutrient concentration and the long-term behaviour of 84 cells under 12 propionate concentration levels from 1 nM to 25 mM. We discuss traditional assumptions for the random walk approximation to bacterial swimming and compare them with the observed R. sphaeroides motile behaviour.

Stepwise Assembly and Characterization of DNA Linked Two-Color Quantum Dot Clusters.

PubMed

Coopersmith, Kaitlin; Han, Hyunjoo; Maye, Mathew M

2015-07-14

The DNA-mediated self-assembly of multicolor quantum dot (QD) clusters via a stepwise approach is described. The CdSe/ZnS QDs were synthesized and functionalized with an amphiphilic copolymer, followed by ssDNA conjugation. At each functionalization step, the QDs were purified via gradient ultracentrifugation, which was found to remove excess polymer and QD aggregates, allowing for improved conjugation yields and assembly reactivity. The QDs were then assembled and disassembled in a stepwise manner at a ssDNA functionalized magnetic colloid, which provided a convenient way to remove unreacted QDs and ssDNA impurities. After assembly/disassembly, the clusters' optical characteristics were studied by fluorescence spectroscopy and the assembly morphology and stoichiometry was imaged via electron microscopy. The results indicate that a significant amount of QD-to-QD energy transfer occurred in the clusters, which was studied as a function of increasing acceptor-to-donor ratios, resulting in increased QD acceptor emission intensities compared to controls.

Stepwise detection of recombination breakpoints in sequence alignments.

PubMed

Graham, Jinko; McNeney, Brad; Seillier-Moiseiwitsch, Françoise

2005-03-01

We propose a stepwise approach to identify recombination breakpoints in a sequence alignment. The approach can be applied to any recombination detection method that uses a permutation test and provides estimates of breakpoints. We illustrate the approach by analyses of a simulated dataset and alignments of real data from HIV-1 and human chromosome 7. The presented simulation results compare the statistical properties of one-step and two-step procedures. More breakpoints are found with a two-step procedure than with a single application of a given method, particularly for higher recombination rates. At higher recombination rates, the additional breakpoints were located at the cost of only a slight increase in the number of falsely declared breakpoints. However, a large proportion of breakpoints still go undetected. A makefile and C source code for phylogenetic profiling and the maximum chi2 method, tested with the gcc compiler on Linux and WindowsXP, are available at http://stat-db.stat.sfu.ca/stepwise/ jgraham@stat.sfu.ca.

Stepwise Iterative Fourier Transform: The SIFT

NASA Technical Reports Server (NTRS)

Benignus, V. A.; Benignus, G.

1975-01-01

A program, designed specifically to study the respective effects of some common data problems on results obtained through stepwise iterative Fourier transformation of synthetic data with known waveform composition, was outlined. Included in this group were the problems of gaps in the data, different time-series lengths, periodic but nonsinusoidal waveforms, and noisy (low signal-to-noise) data. Results on sinusoidal data were also compared with results obtained on narrow band noise with similar characteristics. The findings showed that the analytic procedure under study can reliably reduce data in the nature of (1) sinusoids in noise, (2) asymmetric but periodic waves in noise, and (3) sinusoids in noise with substantial gaps in the data. The program was also able to analyze narrow-band noise well, but with increased interpretational problems. The procedure was shown to be a powerful technique for analysis of periodicities, in comparison with classical spectrum analysis techniques. However, informed use of the stepwise procedure nevertheless requires some background of knowledge concerning characteristics of the biological processes under study.

Improved efficiency in blue phosphorescent organic light-emitting diodes by the stepwise doping structure

NASA Astrophysics Data System (ADS)

Yang, Liping; Wang, Xiaoping; Kou, Zhiqi; Ji, Changyan

2017-04-01

The electro-optical properties of the blue phosphorescent organic light-emitting diodes (PHOLEDs) can be affected by the stepwise doping structure in the emitting layer (EML). A series of multi-EML devices with different doping concentration of blue dopant (FIrpic) are fabricated. The effect of the stepwise doping structure close to the electron transport layer is more obvious than that close to the hole transport layer. When the doping concentration increases gradually from the hole injection side to the electron injection side, the maximum values of the luminance, current and power efficiency can reach to 9745 cd/m2 (at 9 V), 32.0 cd/A and 25.1 lm/W in the device with the asymmetric tri-EML structure, which is improved by about 10% compared with that in the bi-EML device. When the number of the EML is four, the performance of the device becomes worse because of the interface effect resulting from different concentration of dopant.

Stepwise self-assembly of C60 mediated by atomic scale moiré magnifiers

NASA Astrophysics Data System (ADS)

Gruznev, D. V.; Matetskiy, A. V.; Bondarenko, L. V.; Utas, O. A.; Zotov, A. V.; Saranin, A. A.; Chou, J. P.; Wei, C. M.; Lai, M. Y.; Wang, Y. L.

2013-04-01

Self-assembly of atoms or molecules on a crystal surface is considered one of the most promising methods to create molecular devices. Here we report a stepwise self-assembly of C60 molecules into islands with unusual shapes and preferred sizes on a gold-indium-covered Si(111) surface. Specifically, 19-mer islands prefer a non-compact boomerang shape, whereas hexagonal 37-mer islands exhibit extraordinarily enhanced stability and abundance. The stepwise self-assembly is mediated by the moiré interference between an island with its underlying lattice, which essentially maps out the adsorption-energy landscape of a C60 on different positions of the surface with a lateral magnification factor and dictates the probability for the subsequent attachment of C60 to an island’s periphery. Our discovery suggests a new method for exploiting the moiré interference to dynamically assist the self-assembly of particles and provides an unexplored tactic of engineering atomic scale moiré magnifiers to facilitate the growth of monodispersed mesoscopic structures.

Prediction of troponin-T degradation using color image texture features in 10d aged beef longissimus steaks.

PubMed

Sun, X; Chen, K J; Berg, E P; Newman, D J; Schwartz, C A; Keller, W L; Maddock Carlin, K R

2014-02-01

The objective was to use digital color image texture features to predict troponin-T degradation in beef. Image texture features, including 88 gray level co-occurrence texture features, 81 two-dimension fast Fourier transformation texture features, and 48 Gabor wavelet filter texture features, were extracted from color images of beef strip steaks (longissimus dorsi, n = 102) aged for 10d obtained using a digital camera and additional lighting. Steaks were designated degraded or not-degraded based on troponin-T degradation determined on d 3 and d 10 postmortem by immunoblotting. Statistical analysis (STEPWISE regression model) and artificial neural network (support vector machine model, SVM) methods were designed to classify protein degradation. The d 3 and d 10 STEPWISE models were 94% and 86% accurate, respectively, while the d 3 and d 10 SVM models were 63% and 71%, respectively, in predicting protein degradation in aged meat. STEPWISE and SVM models based on image texture features show potential to predict troponin-T degradation in meat. © 2013.

Stepwise heating in Stille polycondensation toward no batch-to-batch variations in polymer solar cell performance.

PubMed

Lee, Sang Myeon; Park, Kwang Hyun; Jung, Seungon; Park, Hyesung; Yang, Changduk

2018-05-14

For a given π-conjugated polymer, the batch-to-batch variations in molecular weight (M w ) and polydispersity index (Ð) can lead to inconsistent process-dependent material properties and consequent performance variations in the device application. Using a stepwise-heating protocol in the Stille polycondensation in conjunction with optimized processing, we obtained an ultrahigh-quality PTB7 polymer having high M w and very narrow Ð. The resulting ultrahigh-quality polymer-based solar cells demonstrate up to 9.97% power conversion efficiencies (PCEs), which is over 24% enhancement from the control devices fabricated with commercially available PTB7. Moreover, we observe almost negligible batch-to-batch variations in the overall PCE values from ultrahigh-quality polymer-based devices. The proposed stepwise polymerization demonstrates a facile and effective strategy for synthesizing high-quality semiconducting polymers that can significantly improve device yield in polymer-based solar cells, an important factor for the commercialization of organic solar cells, by mitigating device-to-device variations.

Renewable platform chemicals from directional microwave-assisted liquefaction coupling stepwise extraction of waste biomass.

PubMed

Feng, Junfeng; Hse, Chungyun; Yang, Zhongzhi; Wang, Kui; Jiang, Jianchun; Xu, Junming

2017-11-01

Directional microwave-assisted liquefaction and stepwise extraction are introduced for producing platform chemicals: aromatics and monosaccharides. When sulfuric acid was used as a catalyst, a 45% monosaccharides yield and a 29% aromatics yield were obtained from bamboo with 0.3g catalyst per 18g methanol and 2g bamboo at 160°C with 10min. Approximately 78-86wt% of the six biomass materials were converted into liquid products. After the stepwise extraction and precipitation process, the yields of monosaccharide derivatives and three phenolic compound fractions were 39-45% and 28-32%, respectively. Monosaccharides from holocellulose collected with a high purity of methyl glycosides were higher than 90%. Aromatic derivatives with different weight-molecular distributions were separated into three fractions with more than 80% phenolics. As their similar chemical properties within each fraction, platform chemicals have great commercial potential for producing high-quality chemicals and biofuels using mild upgrading conditions. Copyright © 2017. Published by Elsevier Ltd.

Structuring in fast-quenched ferrite compositions under plasma spraying

NASA Astrophysics Data System (ADS)

Lepeshev, A. A.; Karpov, I. V.; Ushakov, A. V.; Nagibin, G. E.; Dorozhkina, E. A.; Karpova, O. N.; Demin, V. G.; Shaikhadinov, A. A.

2017-06-01

The influence of the quench rate on structuring in spinel ferrites has been studied. It has been found that, when the quench rate is increased, the equilibrium spinel structure gradually becomes disordered. At the first stage, the statistically homogeneous (or almost homogeneous) redistribution of cations over crystal lattice sites has been observed. Then, the fcc lattice of the anion framework breaks down, the translational symmetry disappears, and topological chaos arises. The resulting cluster structural state is thermodynamically unstable, and heating of quenched ferrites causes stepwise energy liberation. As a result, the activity of ferrite powders in solid-state and catalytic reactions rises.

A stable solid acid material: Sulfated ZrO2 dispersed on alumina nanotubes

NASA Astrophysics Data System (ADS)

Feng, Yu; Jiaqi, Chen; Xu, Wang; Rui-Feng, Li

2017-02-01

A tubular solid acid catalyst was designed by loading sulfated zirconia into γ-Al2O3 nanotubes using the method of stepwise deposition. The XRD, N2 adsorption-desorption characterization demonstrated that introducing alumina nanotube and SO4 2- anions have played an important role in stabilizing the metastable tetragonal ZrO2 phase, and the sulfated zirconia on the surface of the γ-Al2O3 nanotube has high dispersion and stability. The catalyst reused repeatedly possesses large amounts of acid sites and good acidity, exhibiting high catalytic activity and stability for isopropylbenzene cracking.

Regional danger assessment of Debris flow and its engineering mitigation practice in Sichuan-Tibet highway

NASA Astrophysics Data System (ADS)

Su, Pengcheng; Sun, Zhengchao; li, Yong

2017-04-01

Luding-Kangding highway cross the eastern edge of Qinghai-Tibet Plateau where belong to the most deep canyon area of plateau and mountains in western Sichuan with high mountain and steep slope. This area belongs to the intersection among Xianshuihe, Longmenshan and Anninghe fault zones which are best known in Sichuan province. In the region, seismic intensity is with high frequency and strength, new tectonic movement is strong, rock is cracked, there are much loose solid materials. Debris flow disaster is well developed under the multiple effects of the earthquake, strong rainfall and human activity which poses a great threat to the local people's life and property security. So this paper chooses Kangding and LuDing as the study area to do the debris flow hazard assessment through the in-depth analysis of development characteristics and formation mechanism of debris flow. Which can provide important evidence for local disaster assessment and early warning forecast. It also has the important scientific significance and practical value to safeguard the people's life and property safety and the security implementation of the national major project. In this article, occurrence mechanism of debris flow disasters in the study area is explored, factor of evaluation with high impact to debris flow hazards is identified, the database of initial evaluation factors is made by the evaluation unit of basin. The factors with high impact to hazards occurrence are selected by using the stepwise regression method of logistic regression model, at the same time the factors with low impact are eliminated, then the hazard evaluation factor system of debris flow is determined in the study area. Then every factors of evaluation factor system are quantified, and the weights of all evaluation factors are determined by using the analysis of stepwise regression. The debris flows hazard assessment and regionalization of all the whole study area are achieved eventually after establishing the hazard assessment model. In this paper, regional debris flows hazard assessment method with strong universality and reliable evaluation result is presented. The whole study area is divided into 1674 units by automatically extracting and artificial identification, and then 11 factors are selected as the initial assessment factors of debris flow hazard assessment in the study area. The factors of the evaluation index system are quantified using the method of standardized watershed unit amount ratio. The relationship between debris flow occurrence and each evaluation factor is simulated using logistic regression model. The weights of evaluation factors are determined, and the model of debris flows hazard assessment is established in the study area. Danger assessment result of debris flow was applied in line optimization and engineering disaster reduction of Sichuan-Tibet highway (section of Luding-Kangding).

Improving prediction of metal uptake by Chinese cabbage (Brassica pekinensis L.) based on a soil-plant stepwise analysis.

PubMed

Zhang, Sha; Song, Jing; Gao, Hui; Zhang, Qiang; Lv, Ming-Chao; Wang, Shuang; Liu, Gan; Pan, Yun-Yu; Christie, Peter; Sun, Wenjie

2016-11-01

It is crucial to develop predictive soil-plant transfer (SPT) models to derive the threshold values of toxic metals in contaminated arable soils. The present study was designed to examine the heavy metal uptake pattern and to improve the prediction of metal uptake by Chinese cabbage grown in agricultural soils with multiple contamination by Cd, Cu, Ni, Pb, and Zn. Pot experiments were performed with 25 historically contaminated soils to determine metal accumulation in different parts of Chinese cabbage. Different soil bioavailable metal fractions were determined using different extractants (0.43M HNO3, 0.01M CaCl2, 0.005M DTPA, and 0.01M LWMOAs), soil moisture samplers, and diffusive gradients in thin films (DGT), and the fractions were compared with shoot metal uptake using both direct and stepwise multiple regression analysis. The stepwise approach significantly improved the prediction of metal uptake by cabbage over the direct approach. Strongly pH dependent or nonlinear relationships were found for the adsorption of root surfaces and in root-shoot uptake processes. Metals were linearly translocated from the root surface to the root. Therefore, the nonlinearity of uptake pattern is an important explanation for the inadequacy of the direct approach in some cases. The stepwise approach offers an alternative and robust method to study the pattern of metal uptake by Chinese cabbage (Brassica pekinensis L.). Copyright © 2016. Published by Elsevier B.V.

Acoustic emission from trabecular bone during mechanical testing: the effect of osteoporosis and osteoarthritis.

PubMed

Leichter, I; Bivas, A; Margulies, J Y; Roman, I; Simkin, A

1990-01-01

This study examines the relation between the nature of acoustic emission signals emitted from cancellous bone under compression and the mechanical properties of the tissue. The examined bone specimens were taken from 12 normal, 31 osteoporotic and six osteoarthritic femoral heads. The mechanical behaviour of the osteoporotic bone specimens was found to be significantly different from that of the normal specimens both in the pre-yield and post-yield ranges. In the osteoarthritic bones only the elastic behaviour was significantly different. The rates of acoustic events before yield and beyond it were found to be significantly higher both in the osteoporotic and osteoarthritic bone specimens. The average peak amplitude of the signals was also significantly higher in the diseased bones. Stepwise regression analysis showed that a combination of the acoustic emission parameters could significantly predict some mechanical properties of the bone. The energy absorbed during compression and the ultimate compressive stress of the specimens could be estimated from the rate of pre-yield acoustic events, the average amplitude of the signals and the rate of post-yield events. However, the explanation power of the acoustic emission parameters was only moderate. The nature of acoustic emission signals was thus demonstrated to be a potential tool for assessing bone quality.

Relationships between surface coverage ratio and powder mechanics of binary adhesive mixtures for dry powder inhalers.

PubMed

Rudén, Jonas; Frenning, Göran; Bramer, Tobias; Thalberg, Kyrre; Alderborn, Göran

2018-04-25

The aim of this paper was to study relationships between the content of fine particles and the powder mechanics of binary adhesive mixtures and link these relationships to the blend state. Mixtures with increasing amounts of fine particles (increasing surface coverage ratios (SCR)) were prepared using Lactopress SD as carrier and micro particles of lactose as fines (2.7 µm). Indicators of unsettled bulk density, compressibility and flowability were derived and the blend state was visually examined by imaging. The powder properties studied showed relationships to the SCR characterised by stages. At low SCR, the fine particles predominantly gathered in cavities of the carriers, giving increased bulk density and unchanged or improved flow. Thereafter, increased SCR gave a deposition of particles at the enveloped carrier surface with a gradually more irregular adhesion layer leading to a reduced bulk density and a step-wise reduced flowability. The mechanics of the mixtures at a certain stage were dependent on the structure and the dynamics of the adhesion layer and transitions between the stages were controlled by the evolution of the adhesion layer. It is advisable to use techniques based on different types of flow in order to comprehensively study the mechanics of adhesive mixtures. Copyright © 2018 Elsevier B.V. All rights reserved.

The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands

NASA Astrophysics Data System (ADS)

Tebib, Souhail; Bourguignon, Jean-Jacques; Wermuth, Camille-Georges

1987-07-01

Applied to seven potent benzodiazepine-receptor ligands belonging to chemically different classes, the active analog approach allowed the stepwise identification of the pharmacophoric pattern associated with the recognition by the benzodiazepine receptor. A unique pharmacophore model was derived which involves six critical zones: (a) a π-electron rich aromatic (PAR) zone; (b) two electron-rich zones δ1 and δ2 placed at 5.0 and 4.5 Å respectively from the reference centroid in the PAR zone; (c) a freely rotating aromatic ring (FRA) region; (d) an out-of-plane region (OPR), strongly associated with agonist properties; and (e) an additional hydrophobic region (AHR). The model accommodates all presently known ligands of the benzodiazepine receptor, identifies sensitivity to steric hindrance close to the δ1 zone, accounts for R and S differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.

Synthesis and antibacterial activity of Schiff bases and amines derived from alkyl 2-(2-formyl-4-nitrophenoxy)alkanoates.

PubMed

Goszczyńska, Agata; Kwiecień, Halina; Fijałkowski, Karol

A series of novel Schiff bases and secondary amines were obtained in good yields, as a result of the reductive amination of alkyl 2-(2-formyl-4-nitrophenoxy)alkanoates with both aniline and 4-methoxyaniline under established mild reaction conditions. Sodium triacetoxyborohydride as well as hydrogen in the presence of palladium on carbon were used as efficient reducing agents of the Schiff bases, in both direct and stepwise reductive amination processes. The Schiff bases, amines, and amine hydrochlorides were designed as potential antibacterial agents, and structure-activity relationship could be established following in vitro assays against Gram-positive and Gram-negative bacteria. The minimal inhibitory concentration and zone of inhibition were also determined. In these tests, some of Schiff bases and secondary amine hydrochlorides showed moderate-to-good activity against Gram-positive bacteria, including S. aureus , M. luteus , and S. mutans .

Wavelength dependence of biological damage induced by UV radiation on bacteria.

PubMed

Santos, Ana L; Oliveira, Vanessa; Baptista, Inês; Henriques, Isabel; Gomes, Newton C M; Almeida, Adelaide; Correia, António; Cunha, Ângela

2013-01-01

The biological effects of UV radiation of different wavelengths (UVA, UVB and UVC) were assessed in nine bacterial isolates displaying different UV sensitivities. Biological effects (survival and activity) and molecular markers of oxidative stress [DNA strand breakage (DSB), generation of reactive oxygen species (ROS), oxidative damage to proteins and lipids, and the activity of antioxidant enzymes catalase and superoxide dismutase] were quantified and statistically analyzed in order to identify the major determinants of cell inactivation under the different spectral regions. Survival and activity followed a clear wavelength dependence, being highest under UVA and lowest under UVC. The generation of ROS, as well as protein and lipid oxidation, followed the same pattern. DNA damage (DSB) showed the inverse trend. Multiple stepwise regression analysis revealed that survival under UVA, UVB and UVC wavelengths was best explained by DSB, oxidative damage to lipids, and intracellular ROS levels, respectively.

Concussion evaluation and management in pediatrics.

PubMed

Rivera, Robin G; Roberson, Susan P; Whelan, Margaret; Rohan, Annie

2015-01-01

Concussions are among the most complex injuries to assess and manage in sports medicine and primary care. Sports concussion in youth has received much attention in recent years because research shows that improperly managed concussion can lead to long-term cognitive deficits and mental health problems. There are several notable risk factors affecting the incidence and severity of concussion in school-age children and adolescents, including a history of a previous concussion. A more conservative approach for return to activities following concussion has been proposed for children and adolescents. Programs of individualized, stepwise increases in physical activity have largely replaced use of algorithms for assigning a grade and activity expectations to concussions. Although validity and reliability testing is ongoing to support use of concussion assessment instruments in pediatric patients, it is practical and appropriate that clinicians incorporate symptom checklists, sideline and balance assessment tools, and neurocognitive assessment instruments into their practice in accordance with evidence-based guidelines.

Biotechnology and genetic engineering in the new drug development. Part III. Biocatalysis, metabolic engineering and molecular modelling.

PubMed

Stryjewska, Agnieszka; Kiepura, Katarzyna; Librowski, Tadeusz; Lochyński, Stanisław

2013-01-01

Industrial biotechnology has been defined as the use and application of biotechnology for the sustainable processing and production of chemicals, materials and fuels. It makes use of biocatalysts such as microbial communities, whole-cell microorganisms or purified enzymes. In the review these processes are described. Drug design is an iterative process which begins when a chemist identifies a compound that displays an interesting biological profile and ends when both the activity profile and the chemical synthesis of the new chemical entity are optimized. Traditional approaches to drug discovery rely on a stepwise synthesis and screening program for large numbers of compounds to optimize activity profiles. Over the past ten to twenty years, scientists have used computer models of new chemical entities to help define activity profiles, geometries and relativities. This article introduces inter alia the concepts of molecular modelling and contains references for further reading.

Structural definition of a potent macrophage activating factor derived from vitamin D3-binding protein with adjuvant activity for antibody production.

PubMed

Yamamoto, N

1996-10-01

Incubation of human vitamin D3-binding protein (Gc protein), with a mixture of immobilized beta-galactosidase and sialidase, efficiently generated a potent macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar. Stepwise incubation of Gc protein with immobilized beta-galactosidase and sialidase, and isolation of the intermediates with immobilized lectins, revealed that either sequence of hydrolysis of Gc glycoprotein by these glycosidases yields the macrophage-activating factor, implying that Gc protein carries a trisaccharide composed of N-acetylgalactosamine and dibranched galactose and sialic acid termini. A 3 hr incubation of mouse peritoneal macrophages with picomolar amounts of the enzymatically generated macrophage-activating factor (GcMAF) resulted in a greatly enhanced phagocytic activity. Administration of a minute amount (10-50 pg/mouse) of GcMAF resulted in a seven- to nine-fold enhanced phagocytic activity of macrophages. Injection of sheep red blood cells (SRBC) along with GcMAF into mice produced a large number of anti-SRBC antibody secreting splenic cells in 2-4 days.

First order phase transitions resulted from collective Jahn-Teller effect

NASA Astrophysics Data System (ADS)

Rosenfeld, E. V.

2018-01-01

Generally, in case of the collective Jahn-Teller effect, a high-symmetry structure of a matrix in which quantum systems with degenerate ground state are inserted becomes distorted. This usually smooth transition can become abrupt only if the matrix by itself is a trigger and JTE merely activates its switching. It is shown in this paper that proper insertion into matrix of quantum systems with the singlet ground state and degenerate excited state leads to the formation of a new metastable state of the whole system and a stepwise appearance of JTE. Using nanotechnology, a matrix of any nature can be transformed into trigger in this way if one manages to synthesize and insert into it proper quantity of quantum JT-active centers with appropriate energy spectrum.

Efficient generation of functional CFTR-expressing airway epithelial cells from human pluripotent stem cells.

PubMed

Wong, Amy P; Chin, Stephanie; Xia, Sunny; Garner, Jodi; Bear, Christine E; Rossant, Janet

2015-03-01

Airway epithelial cells are of great interest for research on lung development, regeneration and disease modeling. This protocol describes how to generate cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR)-expressing airway epithelial cells from human pluripotent stem cells (PSCs). The stepwise approach from PSC culture to differentiation into progenitors and then mature epithelia with apical CFTR activity is outlined. Human PSCs that were inefficient at endoderm differentiation using our previous lung differentiation protocol were able to generate substantial lung progenitor cell populations. Augmented CFTR activity can be observed in all cultures as early as at 35 d of differentiation, and full maturation of the cells in air-liquid interface cultures occurs in <5 weeks. This protocol can be used for drug discovery, tissue regeneration or disease modeling.

Total energy expenditure in adults with cerebral palsy as assessed by doubly labeled water.

PubMed

Johnson, R K; Hildreth, H G; Contompasis, S H; Goran, M I

1997-09-01

To characterize total energy expenditure (TEE) in free-living adults with cerebral palsy (CP) using the doubly labeled water technique, and to determine those physiologic variables and characteristics of CP that were markers of TEE in adults with CP. TEE was measured using the doubly labeled water technique in 30 free-living adults with CP (12 women, 18 men). To determine the best markers of TEE, the following factors were examined: CP status, resting metabolic rate (RMR), anthropometric characteristics and body composition by means of dual-energy x-ray absorptiometry (DXA) and skinfold thickness measurements, energy cost of leisure-time activities, and oral-motor impairment. Means +/- standard deviations, t tests, Pearson product-moment correlation coefficients, Spearman rank correlation coefficients, chi 2, stepwise multiple-correlation regression analysis, and analysis of covariance were used to examine the relationships among variables of interest. TEE was highly variable in the sample (mean = 2,455 +/- 622 kcal/day for men and 1,986 +/- 363 kcal/day for women). Stepwise regression analysis showed that TEE was best predicted in the sample by RMR, percentage body fat determined by DXA, ambulation status, and sex (multiple R = .68, P = .003). When practical, easily measured variables were used, TEE was best predicted by height, ambulation status, percentage body fat by skinfold thickness measurements, and sex (multiple R = .61, P. = 018). The contribution of energy expended in physical activity to TEE was significantly higher in the ambulatory subjects than the nonambulatory subjects (25% vs 16%, respectively; P = .009). The high degree of variability in TEE, largely attributable to high interindividual variation in energy expended in physical activity, makes it difficult to provide general guidelines for energy requirements for adults with CP. Because ambulation status was an important predictor of TEE, it must be accounted for in estimating energy requirements in this population.

Stepwise Elastic Behavior in a Model Elastomer

NASA Astrophysics Data System (ADS)

Bhawe, Dhananjay M.; Cohen, Claude; Escobedo, Fernando A.

2004-12-01

MonteCarlo simulations of an entanglement-free cross-linked polymer network of semiflexible chains reveal a peculiar stepwise elastic response. For increasing stress, step jumps in strain are observed that do not correlate with changes in the number of aligned chains. We show that this unusual behavior stems from the ability of the system to form multiple ordered chain domains that exclude the cross-linking species. This novel elastomer shows a toughening behavior similar to that observed in biological structural materials, such as muscle proteins and abalone shell adhesive.

Low thrust spacecraft transfers optimization method with the stepwise control structure in the Earth-Moon system in terms of the L1-L2 transfer

NASA Astrophysics Data System (ADS)

Fain, M. K.; Starinova, O. L.

2016-04-01

The paper outlines the method for determination of the locally optimal stepwise control structure in the problem of the low thrust spacecraft transfer optimization in the Earth-Moon system, including the L1-L2 transfer. The total flight time as an optimization criterion is considered. The optimal control programs were obtained by using the Pontryagin's maximum principle. As a result of optimization, optimal control programs, corresponding trajectories, and minimal total flight times were determined.

Formation of intermediate products during the resonance stepwise polarization of dibenzyl ketone and benzil molecules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Polevoi, A.V.; Matyuk, V.M.; Grigor'eva, G.A.

1987-07-01

The processes resulting in the intramolecular redistribution of energy in electronically excited S/sub ..pi pi..*/ states of dibenzyl ketone and benzil molecules have been investigated by laser mass spectrometry. The decisive role of dissociation under the conditions of the resonance stepwise photoionization of these molecules upon excitation by radiation with lambda = 266 nm has been demonstrated. The ionization potentials of the molecules and the appearance potentials of fragment ions from dibenzyl ketone and benzil have been determined on the basis of an analysis of photoionization efficiency curves.

Placebo influences on dyskinesia in Parkinson's disease.

PubMed

Goetz, Christopher G; Laska, Eugene; Hicking, Christine; Damier, Philippe; Müller, Thomas; Nutt, John; Warren Olanow, C; Rascol, Olivier; Russ, Hermann

2008-04-15

Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents. 2007 Movement Disorder Society

Placebo Influences on Dyskinesia in Parkinson's Disease

PubMed Central

Goetz, Christopher G.; Laska, Eugene; Hicking, Christine; Damier, Philippe; Müller, Thomas; Nutt, John; Olanow, C. Warren; Rascol, Olivier; Russ, Hermann

2009-01-01

Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents. PMID:18175337

A combined model of sensory and cognitive representations underlying tonal expectations in music: from audio signals to behavior.

PubMed

Collins, Tom; Tillmann, Barbara; Barrett, Frederick S; Delbé, Charles; Janata, Petr

2014-01-01

Listeners' expectations for melodies and harmonies in tonal music are perhaps the most studied aspect of music cognition. Long debated has been whether faster response times (RTs) to more strongly primed events (in a music theoretic sense) are driven by sensory or cognitive mechanisms, such as repetition of sensory information or activation of cognitive schemata that reflect learned tonal knowledge, respectively. We analyzed over 300 stimuli from 7 priming experiments comprising a broad range of musical material, using a model that transforms raw audio signals through a series of plausible physiological and psychological representations spanning a sensory-cognitive continuum. We show that RTs are modeled, in part, by information in periodicity pitch distributions, chroma vectors, and activations of tonal space--a representation on a toroidal surface of the major/minor key relationships in Western tonal music. We show that in tonal space, melodies are grouped by their tonal rather than timbral properties, whereas the reverse is true for the periodicity pitch representation. While tonal space variables explained more of the variation in RTs than did periodicity pitch variables, suggesting a greater contribution of cognitive influences to tonal expectation, a stepwise selection model contained variables from both representations and successfully explained the pattern of RTs across stimulus categories in 4 of the 7 experiments. The addition of closure--a cognitive representation of a specific syntactic relationship--succeeded in explaining results from all 7 experiments. We conclude that multiple representational stages along a sensory-cognitive continuum combine to shape tonal expectations in music. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Stepwise metamorphosis of the tubeworm Hydroides elegans is mediated by a bacterial inducer and MAPK signaling.

PubMed

Shikuma, Nicholas J; Antoshechkin, Igor; Medeiros, João M; Pilhofer, Martin; Newman, Dianne K

2016-09-06

Diverse animal taxa metamorphose between larval and juvenile phases in response to bacteria. Although bacteria-induced metamorphosis is widespread among metazoans, little is known about the molecular changes that occur in the animal upon stimulation by bacteria. Larvae of the tubeworm Hydroides elegans metamorphose in response to surface-bound Pseudoalteromonas luteoviolacea bacteria, producing ordered arrays of phage tail-like metamorphosis-associated contractile structures (MACs). Sequencing the Hydroides genome and transcripts during five developmental stages revealed that MACs induce the regulation of groups of genes important for tissue remodeling, innate immunity, and mitogen-activated protein kinase (MAPK) signaling. Using two MAC mutations that block P. luteoviolacea from inducing settlement or metamorphosis and three MAPK inhibitors, we established a sequence of bacteria-induced metamorphic events: MACs induce larval settlement; then, particular properties of MACs encoded by a specific locus in P. luteoviolacea initiate cilia loss and activate metamorphosis-associated transcription; finally, signaling through p38 and c-Jun N-terminal kinase (JNK) MAPK pathways alters gene expression and leads to morphological changes upon initiation of metamorphosis. Our results reveal that the intricate interaction between Hydroides and P. luteoviolacea can be dissected using genomic, genetic, and pharmacological tools. Hydroides' dependency on bacteria for metamorphosis highlights the importance of external stimuli to orchestrate animal development. The conservation of Hydroides genome content with distantly related deuterostomes (urchins, sea squirts, and humans) suggests that mechanisms of bacteria-induced metamorphosis in Hydroides may have conserved features in diverse animals. As a major biofouling agent, insight into the triggers of Hydroides metamorphosis might lead to practical strategies for fouling control.

Molecular dynamics modeling the synthetic and biological polymers interactions pre-studied via docking

NASA Astrophysics Data System (ADS)

Tsvetkov, Vladimir B.; Serbin, Alexander V.

2014-06-01

In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 ( HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [ HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics ( MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.

Role of the heme oxygenases in abnormalities of the mesenteric circulation in cirrhotic rats.

PubMed

Sacerdoti, David; Abraham, Nader G; Oyekan, Adebayo O; Yang, Liming; Gatta, Angelo; McGiff, John C

2004-02-01

Carbon monoxide (CO), a product of heme metabolism by heme-oxygenase (HO), has biological actions similar to those of nitric oxide (NO). The role of CO in decreasing vascular responses to constrictor agents produced by experimental cirrhosis induced by carbon tetrachloride was evaluated before and after inhibition of HO with tin-mesoporphyrin (SnMP) in the perfused superior mesenteric vasculature (SMV) of cirrhotic and normal rats and in normal rats transfected with the human HO-1 (HHO-1) gene. Perfusion pressure and vasoconstrictor responses of the SMV to KCl, phenylephrine (PE), and endothelin-1 (ET-1) were decreased in cirrhotic rats. SnMP increased SMV perfusion pressure and restored the constrictor responses of the SMV to KCl, PE, and ET-1 in cirrhotic rats. The relative roles of NO and CO in producing hyporeactivity of the SMV to PE in cirrhotic rats were examined. Vasoconstrictor responses to PE were successively augmented by stepwise inhibition of CO and NO production, suggesting a complementary role for these gases in the regulation of reactivity of the SMV. Expression of constitutive but not of inducible HO (HO-1) was increased in the SMV of cirrhotic rats as was HO activity. Administration of adenovirus containing HHO-1 gene produced detection of HHO-1 RNA and increased HO activity in the SMV within 7 days. Rats transfected with HO-1 demonstrated reduction in both perfusion pressure and vasoconstrictor responses to PE in the SMV. We propose that HO is an essential component in mechanisms that modulate reactivity of the mesenteric circulation in experimental hepatic cirrhosis in rats.

Electrically-inactive phosphorus re-distribution during low temperature annealing

NASA Astrophysics Data System (ADS)

Peral, Ana; Youssef, Amanda; Dastgheib-Shirazi, Amir; Akey, Austin; Peters, Ian Marius; Hahn, Giso; Buonassisi, Tonio; del Cañizo, Carlos

2018-04-01

An increased total dose of phosphorus (P dose) in the first 40 nm of a phosphorus diffused emitter has been measured after Low Temperature Annealing (LTA) at 700 °C using the Glow Discharge Optical Emission Spectrometry technique. This evidence has been observed in three versions of the same emitter containing different amounts of initial phosphorus. A stepwise chemical etching of a diffused phosphorus emitter has been carried out to prepare the three types of samples. The total P dose in the first 40 nm increases during annealing by 1.4 × 1015 cm-2 for the sample with the highly doped emitter, by 0.8 × 1015 cm-2 in the middle-doped emitter, and by 0.5 × 1015 cm-2 in the lowest-doped emitter. The presence of surface dislocations in the first few nanometers of the phosphorus emitter might play a role as preferential sites of local phosphorus gettering in phosphorus re-distribution, because the phosphorus gettering to the first 40 nm is lower when this region is etched stepwise. This total increase in phosphorus takes place even though the calculated electrically active phosphorus concentration shows a reduction, and the measured sheet resistance shows an increase after annealing at a low temperature. The reduced electrically active P dose is around 0.6 × 1015 cm-2 for all the emitters. This can be explained with phosphorus-atoms diffusing towards the surface during annealing, occupying electrically inactive configurations. An atomic-scale visual local analysis is carried out with needle-shaped samples of tens of nm in diameter containing a region of the highly doped emitter before and after LTA using Atom Probe Tomography, showing phosphorus precipitates of 10 nm and less before annealing and an increased density of larger precipitates after annealing (25 nm and less).

Neurophysiological capacity in a working memory task differentiates dependent from nondependent heavy drinkers and controls.

PubMed

Wesley, Michael J; Lile, Joshua A; Fillmore, Mark T; Porrino, Linda J

2017-06-01

Determining the neurobehavioral profiles that differentiate heavy drinkers who are and are not alcohol dependent will inform treatment efforts. Working memory is linked to substance use disorders and can serve as a representation of the demand placed on the neurophysiology associated with cognitive control. Behavior and brain activity (via fMRI) were recorded during an N-Back working memory task in controls (CTRL), nondependent heavy drinkers (A-ND) and dependent heavy drinkers (A-D). Typical and novel step-wise analyses examined profiles of working memory load and increasing task demand, respectively. Performance was significantly decreased in A-D during high working memory load (2-Back), compared to CTRL and A-ND. Analysis of brain activity during high load (0-Back vs. 2- Back) showed greater responses in the dorsal lateral and medial prefrontal cortices of A-D than CTRL, suggesting increased but failed compensation. The step-wise analysis revealed that the transition to Low Demand (0-Back to 1-Back) was associated with robust increases and decreases in cognitive control and default-mode brain regions, respectively, in A-D and A-ND but not CTRL. The transition to High Demand (1-Back to 2-Back) resulted in additional engagement of these networks in A-ND and CTRL, but not A-D. Heavy drinkers engaged working memory neural networks at lower demand than controls. As demand increased, nondependent heavy drinkers maintained control performance but relied on additional neurophysiological resources, and dependent heavy drinkers did not display further resource engagement and had poorer performance. These results support targeting these brain areas for treatment interventions. Copyright © 2017 Elsevier B.V. All rights reserved.

A stepwise approach for the reproducible optimization of PAMO expression in Escherichia coli for whole-cell biocatalysis

PubMed Central

2012-01-01

Background Baeyer-Villiger monooxygenases (BVMOs) represent a group of enzymes of considerable biotechnological relevance as illustrated by their growing use as biocatalyst in a variety of synthetic applications. However, due to their increased use the reproducible expression of BVMOs and other biotechnologically relevant enzymes has become a pressing matter while knowledge about the factors governing their reproducible expression is scattered. Results Here, we have used phenylacetone monooxygenase (PAMO) from Thermobifida fusca, a prototype Type I BVMO, as a model enzyme to develop a stepwise strategy to optimize the biotransformation performance of recombinant E. coli expressing PAMO in 96-well microtiter plates in a reproducible fashion. Using this system, the best expression conditions of PAMO were investigated first, including different host strains, temperature as well as time and induction period for PAMO expression. This optimized system was used next to improve biotransformation conditions, the PAMO-catalyzed conversion of phenylacetone, by evaluating the best electron donor, substrate concentration, and the temperature and length of biotransformation. Combining all optimized parameters resulted in a more than four-fold enhancement of the biocatalytic performance and, importantly, this was highly reproducible as indicated by the relative standard deviation of 1% for non-washed cells and 3% for washed cells. Furthermore, the optimized procedure was successfully adapted for activity-based mutant screening. Conclusions Our optimized procedure, which provides a comprehensive overview of the key factors influencing the reproducible expression and performance of a biocatalyst, is expected to form a rational basis for the optimization of miniaturized biotransformations and for the design of novel activity-based screening procedures suitable for BVMOs and other NAD(P)H-dependent enzymes as well. PMID:22720747

Gold catalyzed nickel disilicide formation: a new solid-liquid-solid phase growth mechanism.

PubMed

Tang, Wei; Picraux, S Tom; Huang, Jian Yu; Liu, Xiaohua; Tu, K N; Dayeh, Shadi A

2013-01-01

The vapor-liquid-solid (VLS) mechanism is the predominate growth mechanism for semiconductor nanowires (NWs). We report here a new solid-liquid-solid (SLS) growth mechanism of a silicide phase in Si NWs using in situ transmission electron microcopy (TEM). The new SLS mechanism is analogous to the VLS one in relying on a liquid-mediating growth seed, but it is fundamentally different in terms of nucleation and mass transport. In SLS growth of Ni disilicide, the Ni atoms are supplied from remote Ni particles by interstitial diffusion through a Si NW to the pre-existing Au-Si liquid alloy drop at the tip of the NW. Upon supersaturation of both Ni and Si in Au, an octahedral nucleus of Ni disilicide (NiSi2) forms at the center of the Au liquid alloy, which thereafter sweeps through the Si NW and transforms Si into NiSi2. The dissolution of Si by the Au alloy liquid mediating layer proceeds with contact angle oscillation at the triple point where Si, oxide of Si, and the Au alloy meet, whereas NiSi2 is grown from the liquid mediating layer in an atomic stepwise manner. By using in situ quenching experiments, we are able to measure the solubility of Ni and Si in the Au-Ni-Si ternary alloy. The Au-catalyzed mechanism can lower the formation temperature of NiSi2 by 100 °C compared with an all solid state reaction.

General morphological and biological features of neoplasms: integration of molecular findings.

PubMed

Diaz-Cano, S J

2008-07-01

This review highlights the importance of morphology-molecular correlations for a proper implementation of new markers. It covers both general aspects of tumorigenesis (which are normally omitted in papers analysing molecular pathways) and the general mechanisms for the acquired capabilities of neoplasms. The mechanisms are also supported by appropriate diagrams for each acquired capability that include overlooked features such as mobilization of cellular resources and changes in chromatin, transcription and epigenetics; fully accepted oncogenes and tumour suppressor genes are highlighted, while the pathways are also presented as activating or inactivating with appropriate colour coding. Finally, the concepts and mechanisms presented enable us to understand the basic requirements for the appropriate implementation of molecular tests in clinical practice. In summary, the basic findings are presented to serve as a bridge to clinical applications. The current definition of neoplasm is descriptive and difficult to apply routinely. Biologically, neoplasms develop through acquisition of capabilities that involve tumour cell aspects and modified microenvironment interactions, resulting in unrestricted growth due to a stepwise accumulation of cooperative genetic alterations that affect key molecular pathways. The correlation of these molecular aspects with morphological changes is essential for better understanding of essential concepts as early neoplasms/precancerous lesions, progression/dedifferentiation, and intratumour heterogeneity. The acquired capabilities include self-maintained replication (cell cycle dysregulation), extended cell survival (cell cycle arrest, apoptosis dysregulation, and replicative lifespan), genetic instability (chromosomal and microsatellite), changes of chromatin, transcription and epigenetics, mobilization of cellular resources, and modified microenvironment interactions (tumour cells, stromal cells, extracellular, endothelium). The acquired capabilities defining neoplasms are the hallmarks of cancer, but they also comprise useful tools to improve diagnosis and prognosis, as well as potential therapeutic targets. The application of these concepts in oncological pathology leads to consideration of the molecular test requirements (Molecular Test Score System) for reliable implementation; these requirements should cover biological effects, molecular pathway, biological validation, and technical validation. Sensible application of molecular markers in tumour pathology always needs solid morphological support.

Rotavirus NSP1 Requires Casein Kinase II-Mediated Phosphorylation for Hijacking of Cullin-RING Ligases.

PubMed

Davis, Kaitlin A; Morelli, Marco; Patton, John T

2017-08-29

The rotavirus nonstructural protein NSP1 repurposes cullin-RING E3 ubiquitin ligases (CRLs) to antagonize innate immune responses. By functioning as substrate adaptors of hijacked CRLs, NSP1 causes ubiquitination and proteasomal degradation of host proteins that are essential for expression of interferon (IFN) and IFN-stimulated gene products. The target of most human and porcine rotaviruses is the β-transducin repeat-containing protein (β-TrCP), a regulator of NF-κB activation. β-TrCP recognizes a phosphorylated degron (DSGΦXS) present in the inhibitor of NF-κB (IκB); phosphorylation of the IκB degron is mediated by IκB kinase (IKK). Because NSP1 contains a C-terminal IκB-like degron (ILD; DSGXS) that recruits β-TrCP, we investigated whether the NSP1 ILD is similarly activated by phosphorylation and whether this modification is required to trigger the incorporation of NSP1 into CRLs. Based on mutagenesis and phosphatase treatment studies, we found that both serine residues of the NSP1 ILD are phosphorylated, a pattern mimicking phosphorylation of IκB. A three-pronged approach using small-molecule inhibitors, small interfering RNAs, and mutagenesis demonstrated that NSP1 phosphorylation is mediated by the constitutively active casein kinase II (CKII), rather than IKK. In coimmunoprecipitation assays, we found that this modification was essential for NSP1 recruitment of β-TrCP and induced changes involving the NSP1 N-terminal RING motif that allowed formation of Cul3-NSP1 complexes. Taken together, our results indicate a highly regulated stepwise process in the formation of NSP1-Cul3 CRLs that is initiated by CKII phosphorylation of NSP1, followed by NSP1 recruitment of β-TrCP and ending with incorporation of the NSP1-β-TrCP complex into the CRL via interactions dependent on the highly conserved NSP1 RING motif. IMPORTANCE Rotavirus is a segmented double-stranded RNA virus that causes severe diarrhea in young children. A primary mechanism used by the virus to inhibit host innate immune responses is to hijack cellular cullin-RING E3 ubiquitin ligases (CRLs) and redirect their targeting activity to the degradation of cellular proteins crucial for interferon expression. This task is accomplished through the rotavirus nonstructural protein NSP1, which incorporates itself into a CRL and serves as a substrate recognition subunit. The substrate recognized by the NSP1 of many human and porcine rotaviruses is β-TrCP, a protein that regulates the transcription factor NF-κB. In this study, we show that formation of NSP1 CRLs is a highly regulated stepwise process initiated by CKII phosphorylation of the β-TrCP recognition motif in NSP1. This modification triggers recruitment of the β-TrCP substrate and induces subsequent changes in a highly conserved NSP1 RING domain that allow anchoring of the NSP1-β-TrCP complex to a cullin scaffold. Copyright © 2017 Davis et al.

Exploring the facilitators and barriers to engagement in physical activity for people with multiple sclerosis.

PubMed

Kayes, Nicola M; McPherson, Kathryn M; Schluter, Philip; Taylor, Denise; Leete, Marta; Kolt, Gregory S

2011-01-01

To explore the relationship that cognitive behavioural and other previously identified variables have with physical activity engagement in people with multiple sclerosis (MS). This study adopted a cross-sectional questionnaire design. Participants were 282 individuals with MS. Outcome measures included the Physical Activity Disability Survey--Revised, Cognitive and Behavioural Responses to Symptoms Questionnaire, Barriers to Health Promoting Activities for Disabled Persons Scale, Multiple Sclerosis Self-efficacy Scale, Self-Efficacy for Chronic Diseases Scales and Chalder Fatigue Questionnaire. Multivariable stepwise regression analyses found that greater self-efficacy, greater reported mental fatigue and lower number of perceived barriers to physical activity accounted for a significant proportion of variance in physical activity behaviour, over that accounted for by illness-related variables. Although fear-avoidance beliefs accounted for a significant proportion of variance in the initial analyses, its effect was explained by other factors in the final multivariable analyses. Self-efficacy, mental fatigue and perceived barriers to physical activity are potentially modifiable variables which could be incorporated into interventions designed to improve physical activity engagement. Future research should explore whether a measurement tool tailored to capture beliefs about physical activity identified by people with MS would better predict participation in physical activity.

Active-learning implementation in an advanced elective course on infectious diseases.

PubMed

Hidayat, Levita; Patel, Shreya; Veltri, Keith

2012-06-18

To describe the development, implementation, and assessment of an advanced elective course on infectious diseases using active-learning strategies. Pedagogy for active learning was incorporated by means of mini-lecture, journal club, and debate with follow-up discussion. Forty-eight students were enrolled in this 4-week elective course, in which 30% of course time was allocated for active-learning exercises. All activities were fundamentally designed as a stepwise approach in complementing each active-learning exercise. Achievement of the course learning objectives was assessed using a 5-point Likert scale survey instrument. Students' awareness of the significance of antimicrobial resistance was improved (p ≤ 0.05). Students' ability to critically evaluate the infectious-disease literature and its application in informed clinical judgments was also enhanced through these active-learning exercises (p ≤ 0.05). Students agreed that active learning should be part of the pharmacy curriculum and that active-learning exercises improved their critical-thinking, literature-evaluation, and self-learning skills. An elective course using active-learning strategies allowed students to combine information gained from the evaluation of infectious-disease literature, critical thinking, and informed clinical judgment. This blended approach ultimately resulted in an increased knowledge and awareness of infectious diseases.

QSAR Analysis of 2-Amino or 2-Methyl-1-Substituted Benzimidazoles Against Pseudomonas aeruginosa

PubMed Central

Podunavac-Kuzmanović, Sanja O.; Cvetković, Dragoljub D.; Barna, Dijana J.

2009-01-01

A set of benzimidazole derivatives were tested for their inhibitory activities against the Gram-negative bacterium Pseudomonas aeruginosa and minimum inhibitory concentrations were determined for all the compounds. Quantitative structure activity relationship (QSAR) analysis was applied to fourteen of the abovementioned derivatives using a combination of various physicochemical, steric, electronic, and structural molecular descriptors. A multiple linear regression (MLR) procedure was used to model the relationships between molecular descriptors and the antibacterial activity of the benzimidazole derivatives. The stepwise regression method was used to derive the most significant models as a calibration model for predicting the inhibitory activity of this class of molecules. The best QSAR models were further validated by a leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. To confirm the predictive power of the models, an external set of molecules was used. High agreement between experimental and predicted inhibitory values, obtained in the validation procedure, indicated the good quality of the derived QSAR models. PMID:19468332

The QSAR study of flavonoid-metal complexes scavenging rad OH free radical

NASA Astrophysics Data System (ADS)

Wang, Bo-chu; Qian, Jun-zhen; Fan, Ying; Tan, Jun

2014-10-01

Flavonoid-metal complexes have antioxidant activities. However, quantitative structure-activity relationships (QSAR) of flavonoid-metal complexes and their antioxidant activities has still not been tackled. On the basis of 21 structures of flavonoid-metal complexes and their antioxidant activities for scavenging rad OH free radical, we optimised their structures using Gaussian 03 software package and we subsequently calculated and chose 18 quantum chemistry descriptors such as dipole, charge and energy. Then we chose several quantum chemistry descriptors that are very important to the IC50 of flavonoid-metal complexes for scavenging rad OH free radical through method of stepwise linear regression, Meanwhile we obtained 4 new variables through the principal component analysis. Finally, we built the QSAR models based on those important quantum chemistry descriptors and the 4 new variables as the independent variables and the IC50 as the dependent variable using an Artificial Neural Network (ANN), and we validated the two models using experimental data. These results show that the two models in this paper are reliable and predictable.

Stepwise Adaptations to Low Temperature as Revealed by Multiple Mutants of Psychrophilic α-Amylase from Antarctic Bacterium*

PubMed Central

Cipolla, Alexandre; D'Amico, Salvino; Barumandzadeh, Roya; Matagne, André; Feller, Georges

2011-01-01

The mutants Mut5 and Mut5CC from a psychrophilic α-amylase bear representative stabilizing interactions found in the heat-stable porcine pancreatic α-amylase but lacking in the cold-active enzyme from an Antarctic bacterium. From an evolutionary perspective, these mutants can be regarded as structural intermediates between the psychrophilic and the mesophilic enzymes. We found that these engineered interactions improve all the investigated parameters related to protein stability as follows: compactness; kinetically driven stability; thermodynamic stability; resistance toward chemical denaturation, and the kinetics of unfolding/refolding. Concomitantly to this improved stability, both mutants have lost the kinetic optimization to low temperature activity displayed by the parent psychrophilic enzyme. These results provide strong experimental support to the hypothesis assuming that the disappearance of stabilizing interactions in psychrophilic enzymes increases the amplitude of concerted motions required by catalysis and the dynamics of active site residues at low temperature, leading to a higher activity. PMID:21900238

Social cognitive theory as a predictor of dietary behavior and leisure time physical activity behavior in middle-aged Asian Indian women residing in United States.

PubMed

Mehta, Purvi; Sharma, Manoj; Bernard, Amy

The purpose of the study was to determine to what extent expectations, self-control, and self-efficacy from the social cognitive theory account for variance in the dietary behaviors and leisure time physical activity of middle-aged Asian Indian women residing in Chicago. Dietary behavior was broken down into fruit and vegetable consumption and number of portions consumed. Data was collected from a sample of 200 participants in Chicago over a span of 1 month. Valid and reliable subscales were developed for the study. Descriptive statistics, stepwise multiple regressions, and Pearson correlations were used to analyze the data. Results indicated expectations for leisure time physical activity and self-control as predictive for leisure time physical activity (adjusted R² = 0.14). No relationships were seen with the constructs of the social cognitive theory with number of portions and fruit and vegetable consumption. Recommendations have been included for future studies.

Participation in community and political life of persons with severe disabilities.

PubMed

Puumalainen, Jouni

2011-12-01

Participation as a citizen, that is, engaging in social, political, and governmental life, has been rarely seen as an important domain when studying social participation of disabled persons. The purpose of this study was to depict the participation in community and political life of persons with severe or multiple disabilities and to determine which individual and social factors were associated with their participation. Altogether, 818 persons, who had participated in rehabilitation for persons with severe disabilities, answered the questionnaire survey. They reported how actively they participated in associations, local congregations, political parties, or public elections. Active participation in community and political life was strongly connected to participation in work, social, and leisure activities, as well as to the use of computers. According to stepwise multiple logistic regression analysis, the strongest predictors for active participation in community and political life were age of disablement, the individual's present age, self-rated income, self-rated quality of life, use of assistive devices, and the ability to communicate.

A step-wise steerable source of illumination for low-noise “Violin-Mode” shadow sensors, intended for use in interferometric gravitational wave detectors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lockerbie, N. A.; Tokmakov, K. V.

A steerable low-noise source of illumination is described for shadow-sensors having a displacement sensitivity of ∼100 pm (rms)/√Hz, at 500 Hz, over a measuring span of at least ±0.5 mm. These sensors were designed to detect lateral “Violin-Mode” resonances in the highly tensioned fused-silica suspension fibres of the test-masses/mirrors for the Advanced Laser Interferometer Gravitational Wave Observatory gravitational wave detectors. The shadow sensors—one intended for each of the four fibres in a suspension—comprised a source of Near InfraRed (NIR) radiation (emitter) and a differential shadow-displacement sensor (detector), these bracketing the fibre under test. The suspension fibres themselves were approximately 600more » mm long by 0.4 mm in diameter, and when illuminated from the side, they cast narrow, vertical, shadows onto their respective detectors—these being located at an effective distance of 50 fibre diameters behind the axes of the fibres themselves. The emitter described here was designed to compensate for a significant degree of mechanical drift or creep over time in the mean position of its suspension fibre. This was achieved by employing five adjacent columns of 8  × miniature NIR LEDs (Light Emitting Diodes, λ = 890 nm), with one column being activated at a time. When used in conjunction with a “reverse Galilean” telescope, the LED sources allowed the collimated beam from the emitter to be steered azimuthally in fine angular increments (0.65°), causing the fibre’s shadow to move laterally, in a step-wise manner, across the plane of its facing detector. Each step in shadow position was approximately 0.23 mm in size, and this allowed the fibre’s shadow to be re-centred, so as to bridge once again both elements of its photodiode detector—even if the fibre was off-centred by as much as ±0.5 mm. Re-centring allowed Violin-Mode vibrations of the fibre to be sensed once again as differential AC photocurrents, these flowing in anti-phase in the two elements of the “split-photodiode” detector.« less

Disequilibrium dihedral angles in layered intrusions: the microstructural record of fractionation

NASA Astrophysics Data System (ADS)

Holness, Marian; Namur, Olivier; Cawthorn, Grant

2013-04-01

The dihedral angle formed at junctions between two plagioclase grains and a grain of augite is only rarely in textural equilibrium in gabbros from km-scale crustal layered intrusions. The median of a population of these disequilibrium angles, Θcpp, varies systematically within individual layered intrusions, remaining constant over large stretches of stratigraphy with significant increases or decreases associated with the addition or reduction respectively of the number of phases on the liquidus of the bulk magma. The step-wise changes in Θcpp are present in Upper Zone of the Bushveld Complex, the Megacyclic Unit I of the Sept Iles Intrusion, and the Layered Series of the Skaergaard Intrusion. The plagioclase-bearing cumulates of Rum have a bimodal distribution of Θcpp, dependent on whether the cumulus assemblage includes clinopyroxene. The presence of the step-wise changes is independent of the order of arrival of cumulus phases and of the composition of either the cumulus phases or the interstitial liquid inferred to be present in the crystal mush. Step-wise changes in the rate of change in enthalpy with temperature (ΔH) of the cooling and crystallizing magma correspond to the observed variation of Θcpp, with increases of both ΔH and Θcpp associated with the addition of another liquidus phase, and decreases of both associated with the removal of a liquidus phase. The replacement of one phase by another (e.g. olivine ⇔ orthpyroxene) has little effect on ΔH and no discernible effect on Θcpp. An increase of ΔH is manifest by an increase in the fraction of the total enthalpy budget that is the latent heat of crystallization (the fractional latent heat). It also results in an increase in the amount crystallized in each incremental temperature drop (the crystal productivity). An increased fractional latent heat and crystal productivity result in an increased rate of plagioclase growth compared to that of augite during the final stages of solidification, causing a step-wise increase in Θcpp. Step-wise changes in the geometry of three-grain junctions in fully solidified gabbros thus provide a clear microstructural marker for the progress of fractionation.

Causal correlation of foliar biochemical concentrations with AVIRIS spectra using forced entry linear regression

NASA Technical Reports Server (NTRS)

Dawson, Terence P.; Curran, Paul J.; Kupiec, John A.

1995-01-01

A major goal of airborne imaging spectrometry is to estimate the biochemical composition of vegetation canopies from reflectance spectra. Remotely-sensed estimates of foliar biochemical concentrations of forests would provide valuable indicators of ecosystem function at regional and eventually global scales. Empirical research has shown a relationship exists between the amount of radiation reflected from absorption features and the concentration of given biochemicals in leaves and canopies (Matson et al., 1994, Johnson et al., 1994). A technique commonly used to determine which wavelengths have the strongest correlation with the biochemical of interest is unguided (stepwise) multiple regression. Wavelengths are entered into a multivariate regression equation, in their order of importance, each contributing to the reduction of the variance in the measured biochemical concentration. A significant problem with the use of stepwise regression for determining the correlation between biochemical concentration and spectra is that of 'overfitting' as there are significantly more wavebands than biochemical measurements. This could result in the selection of wavebands which may be more accurately attributable to noise or canopy effects. In addition, there is a real problem of collinearity in that the individual biochemical concentrations may covary. A strong correlation between the reflectance at a given wavelength and the concentration of a biochemical of interest, therefore, may be due to the effect of another biochemical which is closely related. Furthermore, it is not always possible to account for potentially suitable waveband omissions in the stepwise selection procedure. This concern about the suitability of stepwise regression has been identified and acknowledged in a number of recent studies (Wessman et al., 1988, Curran, 1989, Curran et al., 1992, Peterson and Hubbard, 1992, Martine and Aber, 1994, Kupiec, 1994). These studies have pointed to the lack of a physical link between wavelengths chosen by stepwise regression and the biochemical of interest, and this in turn has cast doubts on the use of imaging spectrometry for the estimation of foliar biochemical concentrations at sites distant from the training sites. To investigate this problem, an analysis was conducted on the variation in canopy biochemical concentrations and reflectance spectra using forced entry linear regression.

A stepwise under-prepared osteotomy technique improves primary stability in shallow-placed implants: a preliminary study for simultaneous vertical ridge augmentation.

PubMed

Ueno, Daisuke; Nakamura, Kei; Kojima, Kousuke; Toyoshima, Takeshi; Tanaka, Hideaki; Ueda, Kazuhiko; Koyano, Kiyoshi; Kodama, Toshiro

2018-04-01

Simultaneous vertical ridge augmentation (VRA) can reduce treatment procedures and surgery time, but the concomitant reduction in primary stability (PS) of a shallow-placed implant imparts risk to its prognosis. Although several studies have reported improvements in PS, there is little information from any simultaneous VRA model. This study aimed to evaluate whether tapered implants with stepwise under-prepared osteotomy could improve the PS of shallow-placed implants in an in vitro model of simultaneous VRA. Tapered implants (Straumann ® Bone Level Tapered implant; BLT) and hybrid implants (Straumann ® Bone Level implant; BL) were investigated in this study. A total of 80 osteotomies of different depths (4, 6, 8, 10 mm) were created in rigid polyurethane foam blocks, and each BLT and BL was inserted by either standard (BLT-S, BL-S) or a stepwise under-prepared (BLT-U, BL-U) osteotomy protocol. The PS was evaluated by measuring maximum insertion torque (IT), implant stability quotient (ISQ), and removal torque (RT). The significance level was set at P < 0.05. There were no significant differences in IT, ISQ or RT when comparing BLT-S and BL-S or BLT-U and BL-U at placement depths of 6 and 8 mm. When comparison was made between osteotomy protocols, IT was significantly greater in BLT-U than in BLT-S at all placement depths. A stepwise under-prepared osteotomy protocol improves initial stability of a tapered implant even in a shallow-placed implant model. BLT-U could be a useful protocol for simultaneous VRA.

A stepwise recovery of metals from hybrid cathodes of spent Li-ion batteries with leaching-flotation-precipitation process

NASA Astrophysics Data System (ADS)

Huang, Yanfang; Han, Guihong; Liu, Jiongtian; Chai, Wencui; Wang, Wenjuan; Yang, Shuzhen; Su, Shengpeng

2016-09-01

The recovering of valuable metals in spent lithium-ion battery cathodes brings about economic and environmental benefits. A stepwise leaching-flotation-precipitation process is adopted to separate and recover Li/Fe/Mn from the mixed types of cathode materials (hybrid wastes of LiFePO4 and LiMn2O4). The optimal operating conditions for the stepwise recovery process are determined and analyzed by factorial design, thermodynamics calculation, XRD and SEM characterization in this study. First, Li/Fe/Mn ions are released from the cathode using HCl assisted with H2O2 in the acid leaching step. The leachability of metals follows the series Li > Fe > Mn in the acidic environment. Then Fe3+ ions are selectively floated and recovered as FeCl3 from the leachate in the flotation step. Finally, Mn2+/Mn3+ and Li+ ions are sequentially precipitated and separated as MnO2/Mn2O3 and Li3PO4 using saturated KMnO4 solution and hot saturated Na3PO4 solution, respectively. Under the optimized and advisable conditions, the total recovery of Li, Fe and Mn is respectively 80.93 ± 0.16%, 85.40 ± 0.12% and 81.02 ± 0.08%. The purity for lithium, ferrum and manganese compounds is respectively 99.32 ± 0.07%, 97.91 ± 0.05% and 98.73 ± 0.05%. This stepwise process could provide an alternative way for the effective separation and recovery of metal values from spent Li-ion battery cathodes in industry.

Application of the modified chi-square ratio statistic in a stepwise procedure for cascade impactor equivalence testing.

PubMed

Weber, Benjamin; Lee, Sau L; Delvadia, Renishkumar; Lionberger, Robert; Li, Bing V; Tsong, Yi; Hochhaus, Guenther

2015-03-01

Equivalence testing of aerodynamic particle size distribution (APSD) through multi-stage cascade impactors (CIs) is important for establishing bioequivalence of orally inhaled drug products. Recent work demonstrated that the median of the modified chi-square ratio statistic (MmCSRS) is a promising metric for APSD equivalence testing of test (T) and reference (R) products as it can be applied to a reduced number of CI sites that are more relevant for lung deposition. This metric is also less sensitive to the increased variability often observed for low-deposition sites. A method to establish critical values for the MmCSRS is described here. This method considers the variability of the R product by employing a reference variance scaling approach that allows definition of critical values as a function of the observed variability of the R product. A stepwise CI equivalence test is proposed that integrates the MmCSRS as a method for comparing the relative shapes of CI profiles and incorporates statistical tests for assessing equivalence of single actuation content and impactor sized mass. This stepwise CI equivalence test was applied to 55 published CI profile scenarios, which were classified as equivalent or inequivalent by members of the Product Quality Research Institute working group (PQRI WG). The results of the stepwise CI equivalence test using a 25% difference in MmCSRS as an acceptance criterion provided the best matching with those of the PQRI WG as decisions of both methods agreed in 75% of the 55 CI profile scenarios.

Serum chemerin levels are independently associated with quality of life in colorectal cancer survivors: A pilot study

PubMed Central

Lee, Jee-Yon; Lee, Mi-Kyung; Kim, Nam-Kyu; Chu, Sang-Hui; Lee, Duk-Chul; Lee, Hye-Sun

2017-01-01

Background Colorectal cancer (CRC) survivors are known to experience various symptoms that significantly affect their quality of life (QOL); therefore, it is important to identify clinical markers related with CRC survivor QOL. Here we investigated the relationship between serum chemerin levels, a newly identified proinflammatory adipokine, and QOL in CRC survivors. Methods A data of total of 110 CRC survivors were analysed in the study. Serum chemerin levels were measured with an enzyme immunoassay analyser. Functional Assessment of Cancer Therapy (FACT) scores were used as an indicator of QOL in CRC survivors. Results Weak but not negligible relationships were observed between serum chemerin levels and FACT-General (G) (r = -0.22, p<0.02), FACT-Colorectal cancer (C) (r = -0.23, p<0.02) and FACT-Fatigue (F) scores (r = -0.27, p<0.01) after adjusting for confounding factors. Both stepwise and enter method multiple linear regression analyses confirmed that serum chemerin levels were independently associated with FACT-G (stepwise: β = -0.15, p<0.01; enter: β = -0.12, p = 0.02), FACT-C (stepwise: β = -0.19, p<0.01; enter; β = -0.14, p = 0.02) and FACT-F scores (stepwise: β = -0.23, p<0.01; enter: β = -0.20, p<0.01). Conclusions Our results demonstrate a weak inverse relationship between serum chemerin and CRC survivor QOL. Although it is impossible to determine causality, our findings suggest that serum chemerin levels may have a significant association with CRC survivor QOL. Further prospective studies are required to confirm the clinical significance of our pilot study. PMID:28475614

A survey of variable selection methods in two Chinese epidemiology journals

PubMed Central

2010-01-01

Background Although much has been written on developing better procedures for variable selection, there is little research on how it is practiced in actual studies. This review surveys the variable selection methods reported in two high-ranking Chinese epidemiology journals. Methods Articles published in 2004, 2006, and 2008 in the Chinese Journal of Epidemiology and the Chinese Journal of Preventive Medicine were reviewed. Five categories of methods were identified whereby variables were selected using: A - bivariate analyses; B - multivariable analysis; e.g. stepwise or individual significance testing of model coefficients; C - first bivariate analyses, followed by multivariable analysis; D - bivariate analyses or multivariable analysis; and E - other criteria like prior knowledge or personal judgment. Results Among the 287 articles that reported using variable selection methods, 6%, 26%, 30%, 21%, and 17% were in categories A through E, respectively. One hundred sixty-three studies selected variables using bivariate analyses, 80% (130/163) via multiple significance testing at the 5% alpha-level. Of the 219 multivariable analyses, 97 (44%) used stepwise procedures, 89 (41%) tested individual regression coefficients, but 33 (15%) did not mention how variables were selected. Sixty percent (58/97) of the stepwise routines also did not specify the algorithm and/or significance levels. Conclusions The variable selection methods reported in the two journals were limited in variety, and details were often missing. Many studies still relied on problematic techniques like stepwise procedures and/or multiple testing of bivariate associations at the 0.05 alpha-level. These deficiencies should be rectified to safeguard the scientific validity of articles published in Chinese epidemiology journals. PMID:20920252

Characterization and Regulation of the Osmolyte Betaine Synthesizing Enzymes GSMT and SDMT from Halophilic Methanogen Methanohalophilus portucalensis

PubMed Central

Lai, Shu-Jung; Lai, Mei-Chin

2011-01-01

The halophilic methanoarchaeon Methanohalophilus portucalensis can synthesize the osmolyte betaine de novo in response to extracellular salt stress. Betaine is generated by the stepwise methylation of glycine to form sarcosine, N, N-dimethylglycine and betaine by using S-adenosyl-L-methionine (AdoMet) as the methyl donor. The complete gene cluster of Mpgsmt-sdmt was cloned from Southern hybridization and heterologous expressed in E. coli respectively. The recombinant MpGSMT and MpSDMT both retained their in vivo functional activities in E. coli BL21(DE3)RIL to synthesize and accumulate betaine and conferred elevated survival ability in betaine transport deficient mutant E. coli MKH13 under high salt stress. The dramatic activating effects of sodium and potassium ions on the in vitro methyltransferase activities of MpGSMT, but not MpSDMT or bacterial GSMT and SDMT, revealed that GSMT from halophilic methanoarchaeon possesses novel regulate mechanism in betaine biosynthesis pathway. The circular dichroism spectra showed the fluctuated peaks at 206 nm were detected in the MpGSMT under various concentrations of potassium or sodium ions. This fluctuated difference may cause by a change in the β-turn structure located at the conserved glycine- and sarcosine-binding residue Arg167 of MpGSMT. The analytical ultracentrifugation analysis indicated that the monomer MpGSMT switched to dimeric form increased from 7.6% to 70% with KCl concentration increased from 0 to 2.0 M. The level of potassium and sodium ions may modulate the substrate binding activity of MpGSMT through the conformational change. Additionally, MpGSMT showed a strong end product, betaine, inhibitory effect and was more sensitive to the inhibitor AdoHcy. The above results indicated that the first enzymatic step involved in synthesizing the osmolyte betaine in halophilic archaea, namely, GSMT, may also play a major role in coupling the salt-in and compatible solute (osmolyte) osmoadaptative strategies in halophilic methanogens for adapting to high salt environments. PMID:21949863

Cryotherapy with concurrent CpG oligonucleotide treatment controls local tumor recurrence and modulates HER2/neu immunity.

PubMed

Veenstra, Jesse J; Gibson, Heather M; Littrup, Peter J; Reyes, Joyce D; Cher, Michael L; Takashima, Akira; Wei, Wei-Zen

2014-10-01

Percutaneous cryoablation is a minimally invasive procedure for tumor destruction, which can potentially initiate or amplify antitumor immunity through the release of tumor-associated antigens. However, clinically efficacious immunity is lacking and regional recurrences are a limiting factor relative to surgical excision. To understand the mechanism of immune activation by cryoablation, comprehensive analyses of innate immunity and HER2/neu humoral and cellular immunity following cryoablation with or without peritumoral CpG injection were conducted using two HER2/neu(+) tumor systems in wild-type (WT), neu-tolerant, and SCID mice. Cryoablation of neu(+) TUBO tumor in BALB/c mice resulted in systemic immune priming, but not in neu-tolerant BALB NeuT mice. Cryoablation of human HER2(+) D2F2/E2 tumor enabled the functionality of tumor-induced immunity, but secondary tumors were refractory to antitumor immunity if rechallenge occurred during the resolution phase of the cryoablated tumor. A step-wise increase in local recurrence was observed in WT, neu-tolerant, and SCID mice, indicating a role of adaptive immunity in controlling residual tumor foci. Importantly, local recurrences were eliminated or greatly reduced in WT, neu tolerant, and SCID mice when CpG was incorporated in the cryoablation regimen, showing significant local control by innate immunity. For long-term protection, however, adaptive immunity was required because most SCID mice eventually succumbed to local tumor recurrence even with combined cryoablation and CpG treatment. This improved understanding of the mechanisms by which cryoablation affects innate and adaptive immunity will help guide appropriate combination of therapeutic interventions to improve treatment outcomes. ©2014 American Association for Cancer Research.

On the mechanism of transverse-mode beatings in a Fabry - Perot laser

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, N; Ledenev, V I

2010-06-23

The mechanism of emergence of fundamental-mode and first-mode beatings in the case of a step-wise increase in the pump rate is studied under the stationary single-mode lasing conditions. Investigation is based on the numerical solution of nonstationary wave equations in a resonator in the quasi-optic approximation and on the equation for a relaxation-type medium as well as on the use of the first two Hermite - Gaussian polynomials {psi}{sub 0,1}(x) to obtain the distribution projections I{sub 0,1}(t), g{sub 0,1}(t) of the radiation intensity and gain, respectively. It is shown that the transverse-mode beatings emerge at early stages of two-mode lasing,more » the appearance of radiation intensity oscillations in the active medium preceding the development of the gain oscillations. The time of the passage of two-mode lasing to the stationary regime is determined. The phase shift {pi}/2 between the oscillations I{sub 1}(t) and g{sub 1}(t) is found for the established beating regime and the modulation depth {Delta}I averaged over the output aperture of the radiation intensity in the established two-mode regime is shown to be proportional to the pump rate excess k over the single-mode lasing threshold. A scheme for controlling the mode composition of laser radiation is proposed, which is based on the rules for determining I{sub 0,1}(t) by the sensor signals. The efficiency of the scheme is studied. The scheme employs two field intensity sensors mounted inside the resonator behind the output aperture. (resonators. modes)« less

Simulating the roles of crevasse routing of surface water and basal friction on the surge evolution of Basin 3, Austfonna ice cap

NASA Astrophysics Data System (ADS)

Gong, Yongmei; Zwinger, Thomas; Åström, Jan; Altena, Bas; Schellenberger, Thomas; Gladstone, Rupert; Moore, John C.

2018-05-01

The marine-terminating outlet in Basin 3, Austfonna ice cap, has been accelerating since the mid-1990s. Stepwise multi-annual acceleration associated with seasonal summer speed-up events was observed before the outlet entered the basin-wide surge in autumn 2012. We used multiple numerical models to explore hydrologic activation mechanisms for the surge behaviour. A continuum ice dynamic model was used to invert basal friction coefficient distributions using the control method and observed surface velocity data between April 2012 and July 2014. This has provided input to a discrete element model capable of simulating individual crevasses, with the aim of finding locations where meltwater entered the glacier during the summer and reached the bed. The possible flow paths of surface meltwater reaching the glacier bed as well as those of meltwater produced at the bed were calculated according to the gradient of the hydraulic potential. The inverted friction coefficients show the unplugging of the stagnant ice front and expansion of low-friction regions before the surge reached its peak velocity in January 2013. Crevasse distribution reflects the basal friction pattern to a high degree. The meltwater reaches the bed through the crevasses located above the margins of the subglacial valley and the basal melt that is generated mainly by frictional heating flows either to the fast-flowing units or potentially accumulates in an overdeepened region. Based on these results, the mechanisms facilitated by basal meltwater production, crevasse opening and the routing of meltwater to the bed are discussed for the surge in Basin 3.

JNK1/2-dependent phosphorylation of angulin-1/LSR is required for the exclusive localization of angulin-1/LSR and tricellulin at tricellular contacts in EpH4 epithelial sheet.

PubMed

Nakatsu, Daiki; Kano, Fumi; Taguchi, Yuki; Sugawara, Taichi; Nishizono, Takashi; Nishikawa, Kiyotaka; Oda, Yukako; Furuse, Mikio; Murata, Masayuki

2014-07-01

Tricellular tight junctions (tTJs) are specialized structural variants of tight junctions within tricellular contacts of an epithelial sheet and comprise several transmembrane proteins including lipolysis-stimulated lipoprotein receptor (angulin-1/LSR) and tricellulin. To elucidate the mechanism of its formation, we carried out stepwise screening of kinase inhibitors followed by RNAi screening to identify kinases that regulate intracellular localization of angulin-1/LSR to the tTJs using a fluorescence image-based screen. We found that the activity of JNK1 and JNK2, but not JNK3, was required for the exclusive localization of angulin-1/LSR at the tTJs. Based on a bioinformatics approach, we estimated the potential phosphorylation site of angulin-1/LSR by JNK1 to be serine 288 and experimentally confirmed that JNK1 directly phosphorylates angulin-1/LSR at this site. We found that JNK2 was also involved in the phosphorylation of angulin-1/LSR. Furthermore, GFP-tagged angulin-1/LSR(S288A), in which serine 288 was substituted by alanine, was observed to be dispersed to bicellular junctions, indicating that phosphorylation of Ser288 is crucial for the exclusive localization of angulin-1/LSR and tricellulin at tTJs. Our fluorescence image-based screening for kinases inhibitor or siRNAs combined with the phosphorylation site prediction could become a versatile and useful tool to elucidate the mechanisms underlying the maintenance of tTJs regulated by kinase networks. © 2014 The Authors Genes to Cells © 2014 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

On non-autonomous dynamical systems

NASA Astrophysics Data System (ADS)

Anzaldo-Meneses, A.

2015-04-01

In usual realistic classical dynamical systems, the Hamiltonian depends explicitly on time. In this work, a class of classical systems with time dependent nonlinear Hamiltonians is analyzed. This type of problems allows to find invariants by a family of Veronese maps. The motivation to develop this method results from the observation that the Poisson-Lie algebra of monomials in the coordinates and momenta is clearly defined in terms of its brackets and leads naturally to an infinite linear set of differential equations, under certain circumstances. To perform explicit analytic and numerical calculations, two examples are presented to estimate the trajectories, the first given by a nonlinear problem and the second by a quadratic Hamiltonian with three time dependent parameters. In the nonlinear problem, the Veronese approach using jets is shown to be equivalent to a direct procedure using elliptic functions identities, and linear invariants are constructed. For the second example, linear and quadratic invariants as well as stability conditions are given. Explicit solutions are also obtained for stepwise constant forces. For the quadratic Hamiltonian, an appropriated set of coordinates relates the geometric setting to that of the three dimensional manifold of central conic sections. It is shown further that the quantum mechanical problem of scattering in a superlattice leads to mathematically equivalent equations for the wave function, if the classical time is replaced by the space coordinate along a superlattice. The mathematical method used to compute the trajectories for stepwise constant parameters can be applied to both problems. It is the standard method in quantum scattering calculations, as known for locally periodic systems including a space dependent effective mass.

Stepwise O-Atom Transfer in Heme-Based Tryptophan Dioxygenase: Role of Substrate Ammonium in Epoxide Ring Opening.

PubMed

Shin, Inchul; Ambler, Brett R; Wherritt, Daniel; Griffith, Wendell P; Maldonado, Amanda C; Altman, Ryan A; Liu, Aimin

2018-03-28

Heme-based tryptophan dioxygenases are established immunosuppressive metalloproteins with significant biomedical interest. Here, we synthesized two mechanistic probes to specifically test if the α-amino group of the substrate directly participates in a critical step of the O atom transfer during catalysis in human tryptophan 2,3-dioxygenase (TDO). Substitution of the nitrogen atom of the substrate to a carbon (probe 1) or oxygen (probe 2) slowed the catalytic step following the first O atom transfer such that transferring the second O atom becomes less likely to occur, although the dioxygenated products were observed with both probes. A monooxygenated product was also produced from probe 2 in a significant quantity. Analysis of this new product by HPLC coupled UV-vis spectroscopy, high-resolution mass spectrometry, 1 H NMR, 13 C NMR, HSQC, HMBC, and infrared (IR) spectroscopies concluded that this monooxygenated product is a furoindoline compound derived from an unstable epoxyindole intermediate. These results prove that small molecules can manipulate the stepwise O atom transfer reaction of TDO and provide a showcase for a tunable mechanism by synthetic compounds. The product analysis results corroborate the presence of a substrate-based epoxyindole intermediate during catalysis and provide the first substantial experimental evidence for the involvement of the substrate α-amino group in the epoxide ring-opening step during catalysis. This combined synthetic, biochemical, and biophysical study establishes the catalytic role of the α-amino group of the substrate during the O atom transfer reactions and thus represents a substantial advance to the mechanistic comprehension of the heme-based tryptophan dioxygenases.

The SARE tool for rabies control: Current experience in Ethiopia.

PubMed

Coetzer, A; Kidane, A H; Bekele, M; Hundera, A D; Pieracci, E G; Shiferaw, M L; Wallace, R; Nel, L H

2016-11-01

The Stepwise Approach towards Rabies Elimination (SARE) tool was developed through a joint effort of the Food and Agriculture Organization (FAO) of the United Nations and the Global Alliance for Rabies Control (GARC), to provide a standard mechanism for countries to assess their rabies situation and measure progress in eliminating the disease. Because the African continent has the highest per capita death rate from rabies, and Ethiopia is estimated to have the second largest number of rabies deaths of all African countries, Ethiopia undertook a self-assessment by means of the Stepwise Approach towards Rabies Elimination (SARE) tool. In February 2016, the Ethiopian government hosted an intersectoral consultative meeting in an effort to assess the progress that has been made towards the control and elimination of canine rabies. The SARE assessment identified a number of critical gaps, including poor inter-sectoral collaboration and limited availability and access to dog vaccine, while the existence of a surveillance system for rabies and legislation for outbreak declaration and response were among the strengths identified. The SARE tool enabled key criteria to be prioritized, thereby accelerating the National Strategy and ensuring that Ethiopia will progress rapidly in line with the goals set by the global community for the elimination of human rabies deaths by 2030. Although the analysis showed that Ethiopia is still in the early stages of rabies control (Stage 0.5/5), the country shows great promise in terms of developing a SARE-guided National Rabies Prevention and Control Strategy. Copyright © 2016 Elsevier B.V. All rights reserved.

A Population Biology Perspective on the Stepwise Infection Process of the Bacterial Pathogen Pasteuria ramosa in Daphnia.

PubMed

Ebert, Dieter; Duneau, David; Hall, Matthew D; Luijckx, Pepijn; Andras, Jason P; Du Pasquier, Louis; Ben-Ami, Frida

2016-01-01

The infection process of many diseases can be divided into series of steps, each one required to successfully complete the parasite's life and transmission cycle. This approach often reveals that the complex phenomenon of infection is composed of a series of more simple mechanisms. Here we demonstrate that a population biology approach, which takes into consideration the natural genetic and environmental variation at each step, can greatly aid our understanding of the evolutionary processes shaping disease traits. We focus in this review on the biology of the bacterial parasite Pasteuria ramosa and its aquatic crustacean host Daphnia, a model system for the evolutionary ecology of infectious disease. Our analysis reveals tremendous differences in the degree to which the environment, host genetics, parasite genetics and their interactions contribute to the expression of disease traits at each of seven different steps. This allows us to predict which steps may respond most readily to selection and which steps are evolutionarily constrained by an absence of variation. We show that the ability of Pasteuria to attach to the host's cuticle (attachment step) stands out as being strongly influenced by the interaction of host and parasite genotypes, but not by environmental factors, making it the prime candidate for coevolutionary interactions. Furthermore, the stepwise approach helps us understanding the evolution of resistance, virulence and host ranges. The population biological approach introduced here is a versatile tool that can be easily transferred to other systems of infectious disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Bone stress in runners with tibial stress fracture.

PubMed

Meardon, Stacey A; Willson, John D; Gries, Samantha R; Kernozek, Thomas W; Derrick, Timothy R

2015-11-01

Combinations of smaller bone geometry and greater applied loads may contribute to tibial stress fracture. We examined tibial bone stress, accounting for geometry and applied loads, in runners with stress fracture. 23 runners with a history of tibial stress fracture & 23 matched controls ran over a force platform while 3-D kinematic and kinetic data were collected. An elliptical model of the distal 1/3 tibia cross section was used to estimate stress at 4 locations (anterior, posterior, medial and lateral). Inner and outer radii for the model were obtained from 2 planar x-ray images. Bone stress differences were assessed using two-factor ANOVA (α=0.05). Key contributors to observed stress differences between groups were examined using stepwise regression. Runners with tibial stress fracture experienced greater anterior tension and posterior compression at the distal tibia. Location, but not group, differences in shear stress were observed. Stepwise regression revealed that anterior-posterior outer diameter of the tibia and the sagittal plane bending moment explained >80% of the variance in anterior and posterior bone stress. Runners with tibial stress fracture displayed greater stress anteriorly and posteriorly at the distal tibia. Elevated tibial stress was associated with smaller bone geometry and greater bending moments about the medial-lateral axis of the tibia. Future research needs to identify key running mechanics associated with the sagittal plane bending moment at the distal tibia as well as to identify ways to improve bone geometry in runners in order to better guide preventative and rehabilitative efforts. Copyright © 2015 Elsevier Ltd. All rights reserved.

Characterization of bovine cartilage by fiber Bragg grating-based stress relaxation measurements

NASA Astrophysics Data System (ADS)

Baier, V.; Marchi, G.; Foehr, P.; Burgkart, R.; Roths, J.

2017-04-01

A fiber-based device for testing mechanical properties of cartilage is presented within this study. The measurement principle is based on stepwise indentation into the tissue and observing of corresponding relaxation of the stress. The indenter tip is constituted of a cleaved optical fiber that includes a fiber Bragg grating which is used as the force sensor. Stress relaxation measurements at 25 different positions on a healthy bovine cartilage sample were performed to assess the behavior of healthy cartilage. For each indentation step a good agreement was found with a viscoelastic model that included two time constants. The model parameters showed low variability and a clear dependence with indentation depth. The parameters can be used as reference values for discriminating healthy and degenerated cartilage.

LANDING QUALITY IN ARTISTIC GYMNASTICS IS RELATED TO LANDING SYMMETRY

PubMed Central

Marinšek, M.

2013-01-01

In gymnastics every exercise finishes with a landing. The quality of landing depends on subjective (e.g. biomechanical) and objective (e.g. mechanical characteristics of landing area) factors. The aim of our research was to determine which biomechanical (temporal, kinematic and dynamic) characteristics of landing best predict the quality of landing. Twelve male gymnasts performed a stretched forward and backward salto; also with 1/2, 1/1 and 3/2 turns. Stepwise multiple regression extracted five predictors which explained 51.5% of landing quality variance. All predictors were defining asymmetries between legs (velocities, angles). To avoid asymmetric landings, gymnasts need to develop enough height; they need higher angular momentum around the transverse and longitudinal axis and they need to better control angular velocity in the longitudinal axis. PMID:24744462

Cushing’s Syndrome: All variants, detection, and treatment

PubMed Central

Sharma, Susmeeta T.; Nieman, Lynnette K.

2010-01-01

Synopsis Cushing’s syndrome is caused by prolonged exposure to excess glucocorticoids. Diagnosis of Cushing’s syndrome involves a step-wise approach and establishing the cause can be challenging in some cases. Hypertension is present in about 80% of patients with Cushing’s syndrome and can lead to significant morbidity and mortality. Several pathogenic mechanisms have been proposed for glucocorticoid-induced hypertension including a functional mineralocorticoid excess state, up-regulation of the renin angiotensin system and deleterious effects of cortisol on the vasculature. Surgical excision of the cause of excess glucocorticoids remains the optimal treatment for Cushing’s syndrome. Anti-glucocorticoid and antihypertensive agents and steroidogenesis inhibitors can be used as adjunctive treatment modalities in preparation for surgery, and in cases where surgery is contraindicated or has not led to cure. PMID:21565673

Inconstancy in predator/prey ratios in Quaternary large mammal communities of Italy, with an appraisal of mechanisms

NASA Astrophysics Data System (ADS)

Raia, Pasquale; Meloro, Carlo; Barbera, Carmela

2007-03-01

Constancy in predator/prey ratio (PPR) is a controversial issue in ecological research. Published reports support both constancy and inconstancy of the ratio in animal communities. Only a few studies, however, specifically address its course through time. Here we study the course of predator/prey ratio in communities of large Plio-Pleistocene mammals in Italy. After controlling for taphonomic biases, we find strong support for PPR inconstancy through time. Extinction, dispersal events, and differences in body size trends between predators and their prey were found to affect the ratio, which was distributed almost bimodally. We suggest that this stepwise dynamic in PPR indicates changes in ecosystem functioning. Prey richness was controlled by predation when PPR was high and by resources when PPR was low.

Inverse relationship between physical activity and arterial stiffness in adults with hypertension.

PubMed

O'Donovan, Cuisle; Lithander, Fiona E; Raftery, Tara; Gormley, John; Mahmud, Azra; Hussey, Juliette

2014-02-01

Physical activity has beneficial effects on arterial stiffness among healthy adults. There is a lack of data on this relationship in adults with hypertension. The majority of studies which have examined physical activity and arterial stiffness have used subjective measures of activity. The aim of this study was to investigate the relationship between objectively measured habitual physical activity and arterial stiffness in individuals with newly diagnosed essential hypertension. Adults attending an outpatient hypertension clinic were recruited into this cross sectional study. Physical activity was measured using a triaxial accelerometer. Pulse wave velocity (PWV) and augmentation index (AIx) were measured using applanation tonometry. Participant's full lipid profile and glucose were determined through the collection of a fasting blood sample. Fifty-three adults [51(14) years, 26 male] participated, 16 of whom had the metabolic syndrome. Inactivity was positively correlated with PWV (r = .53, P < .001) and AIx (r = .48, P < .001). There were significant inverse associations between habitual physical activity of all intensities and both AIx and PWV. In stepwise regression, after adjusting for potential confounders, physical activity was a significant predictor of AIx and PWV. Habitual physical activity of all intensities is associated with reduced arterial stiffness among adults with hypertension.

Biomechanical correlates of symptomatic and asymptomatic neurophysiological impairment in high school football.

PubMed

Breedlove, Evan L; Robinson, Meghan; Talavage, Thomas M; Morigaki, Katherine E; Yoruk, Umit; O'Keefe, Kyle; King, Jeff; Leverenz, Larry J; Gilger, Jeffrey W; Nauman, Eric A

2012-04-30

Concussion is a growing public health issue in the United States, and chronic traumatic encephalopathy (CTE) is the chief long-term concern linked to repeated concussions. Recently, attention has shifted toward subconcussive blows and the role they may play in the development of CTE. We recruited a cohort of high school football players for two seasons of observation. Acceleration sensors were placed in the helmets, and all contact activity was monitored. Pre-season computer-based neuropsychological tests and functional magnetic resonance imaging (fMRI) tests were also obtained in order to assess cognitive and neurophysiological health. In-season follow-up scans were then obtained both from individuals who had sustained a clinically-diagnosed concussion and those who had not. These changes were then related through stepwise regression to history of blows recorded throughout the football season up to the date of the scan. In addition to those subjects who had sustained a concussion, a substantial portion of our cohort who did not sustain concussions showed significant neurophysiological changes. Stepwise regression indicated significant relationships between the number of blows sustained by a subject and the ensuing neurophysiological change. Our findings reinforce the hypothesis that the effects of repetitive blows to the head are cumulative and that repeated exposure to subconcussive blows is connected to pathologically altered neurophysiology. Copyright © 2012 Elsevier Ltd. All rights reserved.

The influence of attention deficits on functional recovery post stroke during the first 12 months after discharge from hospital.

PubMed

Hyndman, D; Pickering, R M; Ashburn, A

2008-06-01

Attention deficits have been linked to poor recovery after stroke and may predict outcome. We explored the influence of attention on functional recovery post stroke in the first 12 months after discharge from hospital. People with stroke completed measures of attention, balance, mobility and activities of daily living (ADL) ability at the point of discharge from hospital, and 6 and 12 months later. We used correlational analysis and stepwise linear regression to explore potential predictors of outcome. We recruited 122 men and women, mean age 70 years. At discharge, 56 (51%) had deficits of divided attention, 45 (37%) of sustained attention, 43 (36%) of auditory selective attention and 41 (37%) had visual selective attention deficits. Attention at discharge correlated with mobility, balance and ADL outcomes 12 months later. After controlling for the level of the outcome at discharge, correlations remained significant in only five of the 12 relationships. Stepwise linear regression revealed that the outcome measured at discharge, days until discharge and number of medications were better predictors of outcome: in no case was an attention variable at discharge selected as a predictor of outcome at 12 months. Although attention and function correlated significantly, this correlation was reduced after controlling for functional ability at discharge. Furthermore, side of lesion and the attention variables were not demonstrated as important predictors of outcome 12 months later.

Mapping wildfire vulnerability in Mediterranean Europe. Testing a stepwise approach for operational purposes.

PubMed

Oliveira, Sandra; Félix, Fernando; Nunes, Adélia; Lourenço, Luciano; Laneve, Giovanni; Sebastián-López, Ana

2018-01-15

Vulnerability assessment is a vital component of wildfire management. This research focused on the development of a framework to measure and map vulnerability levels in several areas within Mediterranean Europe, where wildfires are a major concern. The framework followed a stepwise approach to evaluate its main components, expressed by exposure, sensitivity and coping capacity. Data on population density, fuel types, protected areas location, roads infrastructure and surveillance activities, among others, were integrated to create composite indices, representing each component and articulated in multiple dimensions. Maps were created for several test areas, in northwest Portugal, southwest Sardinia in Italy and northeast Corsica in France, with the contribution of local participants from civil protection institutions and forest services. Results showed the influence of fuel sensitivity levels, population distribution and protected areas coverage for the overall vulnerability classes. Reasonable levels of accuracy were found on the maps provided through the validation procedure, with an overall match above 72% for the several sites. The systematic and flexible approach applied allowed for adjustments to local circumstances with regards to data availability and fire management procedures, without compromising its consistency and with substantial operational capabilities. The results obtained and the positive feedback of end-users encourage its further application, as a means to improve wildfire management strategies at multiple levels with the latest scientific outputs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stepwise microhydration of aromatic amide cations: water solvation networks revealed by the infrared spectra of acetanilide+-(H2O)n clusters (n ≤ 3).

PubMed

Klyne, Johanna; Schmies, Matthias; Miyazaki, Mitsuhiko; Fujii, Masaaki; Dopfer, Otto

2018-01-31

The structure and activity of peptides and proteins strongly rely on their charge state and the interaction with their hydration environment. Here, infrared photodissociation (IRPD) spectra of size-selected microhydrated clusters of cationic acetanilide (AA + , N-phenylacetamide), AA + -(H 2 O) n with n ≤ 3, are analysed by dispersion-corrected density functional theory calculations at the ωB97X-D/aug-cc-pVTZ level to determine the stepwise microhydration process of this aromatic peptide model. The IRPD spectra are recorded in the informative X-H stretch (ν OH , ν NH , ν CH , amide A, 2800-3800 cm -1 ) and fingerprint (amide I-II, 1000-1900 cm -1 ) ranges to probe the preferred hydration motifs and the cluster growth. In the most stable AA + -(H 2 O) n structures, the H 2 O ligands solvate the acidic NH proton of the amide by forming a hydrogen-bonded solvent network, which strongly benefits from cooperative effects arising from the excess positive charge. Comparison with neutral AA-H 2 O reveals the strong impact of ionization on the acidity of the NH proton and the topology of the interaction potential. Comparison with related hydrated formanilide clusters demonstrates the influence of methylation of the amide group (H → CH 3 ) on the shape of the intermolecular potential and the structure of the hydration shell.

Hyperspectral Image Classification via Multitask Joint Sparse Representation and Stepwise MRF Optimization.

PubMed

Yuan, Yuan; Lin, Jianzhe; Wang, Qi

2016-12-01

Hyperspectral image (HSI) classification is a crucial issue in remote sensing. Accurate classification benefits a large number of applications such as land use analysis and marine resource utilization. But high data correlation brings difficulty to reliable classification, especially for HSI with abundant spectral information. Furthermore, the traditional methods often fail to well consider the spatial coherency of HSI that also limits the classification performance. To address these inherent obstacles, a novel spectral-spatial classification scheme is proposed in this paper. The proposed method mainly focuses on multitask joint sparse representation (MJSR) and a stepwise Markov random filed framework, which are claimed to be two main contributions in this procedure. First, the MJSR not only reduces the spectral redundancy, but also retains necessary correlation in spectral field during classification. Second, the stepwise optimization further explores the spatial correlation that significantly enhances the classification accuracy and robustness. As far as several universal quality evaluation indexes are concerned, the experimental results on Indian Pines and Pavia University demonstrate the superiority of our method compared with the state-of-the-art competitors.

Development and Application of a Stepwise Assessment Process for Rational Redesign of Sequential Skills-Based Courses.

PubMed

Gallimore, Casey E; Porter, Andrea L; Barnett, Susanne G

2016-10-25

Objective. To develop and apply a stepwise process to assess achievement of course learning objectives related to advanced pharmacy practice experiences (APPEs) preparedness and inform redesign of sequential skills-based courses. Design. Four steps comprised the assessment and redesign process: (1) identify skills critical for APPE preparedness; (2) utilize focus groups and course evaluations to determine student competence in skill performance; (3) apply course mapping to identify course deficits contributing to suboptimal skill performance; and (4) initiate course redesign to target exposed deficits. Assessment. Focus group participants perceived students were least prepared for skills within the Accreditation Council for Pharmacy Education's pre-APPE core domains of Identification and Assessment of Drug-related Problems and General Communication Abilities. Course mapping identified gaps in instruction, performance, and assessment of skills within aforementioned domains. Conclusions. A stepwise process that identified strengths and weaknesses of a course, was used to facilitate structured course redesign. Strengths of the process included input and corroboration from both preceptors and students. Limitations included feedback from a small number of pharmacy preceptors and increased workload on course coordinators.

Effect of feeding mode and dilution on the performance and microbial community population in anaerobic digestion of food waste.

PubMed

Park, Jong-Hun; Kumar, Gopalakrishnan; Yun, Yeo-Myeong; Kwon, Joong-Chun; Kim, Sang-Hyoun

2018-01-01

The effect of feeding mode and dilution was studied in anaerobic digestion of food waste. An upflow anaerobic digester with a settler was fed at six different organic loading rates (OLRs) from 4.6 to 8.6kgCOD/m 3 /d for 200days. The highest methane productivity of 2.78LCH 4 /L/d was achieved at 8.6kgCOD/m 3 /d during continuous feeding of diluted FW. Continuous feeding of diluted food waste showed more stable and efficient performance than stepwise feeding of undiluted food waste. Sharp increase in propionate concentration attributed towards deterioration of the digester performances in stepwise feeding of undiluted food waste. Microbial communities at various OLRs divulged that the microbial distribution in the continuous feeding of diluted food waste was not significantly perturbed despite the increase of OLR up to 8.6kgCOD/m 3 /d, which was contrast to the unstable distribution in stepwise feeding of undiluted food waste at 6.1kgCOD/m 3 /d. Copyright © 2017 Elsevier Ltd. All rights reserved.

Step-by-step training in basic laparoscopic skills using two-way web conferencing software for remote coaching: A multicenter randomized controlled study.

PubMed

Mizota, Tomoko; Kurashima, Yo; Poudel, Saseem; Watanabe, Yusuke; Shichinohe, Toshiaki; Hirano, Satoshi

2018-07-01

Despite its advantages, few trainees outside of North America have access to simulation training. We hypothesized that a stepwise training method using tele-mentoring system would be an efficient technique for training in basic laparoscopic skills. Residents were randomized into two groups and trained to proficiency in intracorporeal suturing. The stepwise group (SG) practiced the task step-by-step, while the other group practiced comprehensively (CG). Each participant received weekly coaching via two-way web conferencing software. The duration of the coaching sessions and self-practice time were compared between the two groups. Twenty residents from 15 institutions participated, and all achieved proficiency. Coaching sessions using tele-mentoring system were completed without difficulties. The SG required significantly shorter coaching time per session than the CG (p = .002). There was no significant difference in self-practice time. The stepwise training method with the tele-mentoring system appears to make efficient use of surgical trainees' and trainers' time. Copyright © 2017 Elsevier Inc. All rights reserved.

Optimization of elution salt concentration in stepwise elution of protein chromatography using linear gradient elution data. Reducing residual protein A by cation-exchange chromatography in monoclonal antibody purification.

PubMed

Ishihara, Takashi; Kadoya, Toshihiko; Endo, Naomi; Yamamoto, Shuichi

2006-05-05

Our simple method for optimization of the elution salt concentration in stepwise elution was applied to the actual protein separation system, which involves several difficulties such as detection of the target. As a model separation system, reducing residual protein A by cation-exchange chromatography in human monoclonal antibody (hMab) purification was chosen. We carried out linear gradient elution experiments and obtained the data for the peak salt concentration of hMab and residual protein A, respectively. An enzyme-linked immunosorbent assay was applied to the measurement of the residual protein A. From these data, we calculated the distribution coefficient of the hMab and the residual protein A as a function of salt concentration. The optimal salt concentration of stepwise elution to reduce the residual protein A from the hMab was determined based on the relationship between the distribution coefficient and the salt concentration. Using the optimized condition, we successfully performed the separation, resulting in high recovery of hMab and the elimination of residual protein A.

Computational technique for stepwise quantitative assessment of equation correctness

NASA Astrophysics Data System (ADS)

Othman, Nuru'l Izzah; Bakar, Zainab Abu

2017-04-01

Many of the computer-aided mathematics assessment systems that are available today possess the capability to implement stepwise correctness checking of a working scheme for solving equations. The computational technique for assessing the correctness of each response in the scheme mainly involves checking the mathematical equivalence and providing qualitative feedback. This paper presents a technique, known as the Stepwise Correctness Checking and Scoring (SCCS) technique that checks the correctness of each equation in terms of structural equivalence and provides quantitative feedback. The technique, which is based on the Multiset framework, adapts certain techniques from textual information retrieval involving tokenization, document modelling and similarity evaluation. The performance of the SCCS technique was tested using worked solutions on solving linear algebraic equations in one variable. 350 working schemes comprising of 1385 responses were collected using a marking engine prototype, which has been developed based on the technique. The results show that both the automated analytical scores and the automated overall scores generated by the marking engine exhibit high percent agreement, high correlation and high degree of agreement with manual scores with small average absolute and mixed errors.

Dealing with office emergencies. Stepwise approach for family physicians.

PubMed Central

Sempowski, Ian P.; Brison, Robert J.

2002-01-01

OBJECTIVE: To develop a simple stepwise approach to initial management of emergencies in family physicians' offices; to review how to prepare health care teams and equipment; and to illustrate a general approach to three of the most common office emergencies. QUALITY OF EVIDENCE: MEDLINE was searched from January 1980 to December 2001. Articles were selected based on their clinical relevance, quality of evidence, and date of publication. We reviewed American family medicine, pediatric, dental, and dermatologic articles, but found that the area has not been well studied from a Canadian family medicine perspective. Consensus statements by specialty professional groups were used to identify accepted emergency medical treatments. MAIN MESSAGE: Family medicine offices are frequently poorly equipped and inadequately prepared to deal with emergencies. Straightforward emergency response plans can be designed and tailored to an office's risk profile. A systematic team approach and effective use of skills, support staff, and equipment is important. The general approach can be modified for specific patients or conditions. CONCLUSION: Family physicians can plan ahead and use a team approach to develop a simple stepwise response to emergency situations in the office. PMID:12371305

Chemical synthesis of the tetrasaccharide repeating unit of the O-polysaccharide isolated from Azospirillum brasilense SR80.

PubMed

Sarkar, Vikramjit; Mukhopadhyay, Balaram

2015-04-10

A linear strategy has been developed for the synthesis of the tetrasaccharide repeating unit of the O-polysaccharide from Azospirillum brasilense SR80. Stepwise glycosylation of the rationally protected thioglycoside donors activated by NIS in the presence of La(OTf)3 furnished the target tetrasaccharide. The glycosylation reactions resulted in the formation of the desired linkage with absolute stereoselectivity and afforded the required derivatives in good to excellent yields. The phthalimido group has been used as the precursor of the desired acetamido group to meet the requirement of 1,2-trans glycosidic linkage. Copyright © 2015 Elsevier Ltd. All rights reserved.

Risk factors of major noncommunicable diseases in Bahrain. The need for a surveillance system.

PubMed

Hamadeh, Randah R

2004-09-01

Noncommunicable diseases NCDs are the major cause of morbidity and mortality in Bahrain. The review examines the prevalence of risk factors of major NCDs from the available literature and determines the impact of the rapid socio economic changes on their burden. It further recommends ways of improving their reporting and monitoring. Smoking, obesity, diabetes, hypertension, hyperlipidemia, physical activity and nutrition are considered. The review points out that data on some of the factors is available but deficient for others. The call for the establishment of an integrated surveillance system using the World Health Organization STEPwise approach is stressed.

Current correlations for the transport of interacting electrons through parallel quantum dots in a photon cavity

NASA Astrophysics Data System (ADS)

Gudmundsson, Vidar; Abdullah, Nzar Rauf; Sitek, Anna; Goan, Hsi-Sheng; Tang, Chi-Shung; Manolescu, Andrei

2018-06-01

We calculate the current correlations for the steady-state electron transport through multi-level parallel quantum dots embedded in a short quantum wire, that is placed in a non-perfect photon cavity. We account for the electron-electron Coulomb interaction, and the para- and diamagnetic electron-photon interactions with a stepwise scheme of configuration interactions and truncation of the many-body Fock spaces. In the spectral density of the temporal current-current correlations we identify all the transitions, radiative and non-radiative, active in the system in order to maintain the steady state. We observe strong signs of two types of Rabi oscillations.

Indicators of commitment to the church: a longitudinal study of church-affiliated youth.

PubMed

Dudley, R L

1993-01-01

In an attempt to discover the factors that determine which late adolescents drop out of the church and which remain committed to it, a broad sample of Seventh-day Adventist youth was surveyed. These youth were part of a ten-year study which originally involved over 1,500 subjects distributed throughout the United States and Canada. Commitment was found to be related to cognitive, experiential, and activity dimensions of religion. Ethical considerations, a perception of one's importance to the local congregation, and peer influence also played a part in the stepwise regression package, which accounted for half of the variance in commitment scores.

Stepwise sequential redox potential modulation possible on a single platform.

PubMed

Pepiol, Ariadna; Teixidor, Francesc; Sillanpää, Reijo; Lupu, Marius; Viñas, Clara

2011-12-23

Step by step: The cluster [3,3'-Co(1,2-C(2)B(9)H(11))(2)](-) is an excellent platform for making a stepwise tunable redox potential system by dehydroiodination. With the addition of up to eight iodine substituents (purple; see picture), there is a fall in the E(1/2)(Co(III)/Co(II)) value from -1.80 V to -0.68 V (vs. Fc(+)/Fc; Fc = ferrocene). A practical application of this tunability has been observed in the growth of polypyrrole. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Stepwise Bay Annulation of Indigo for the Synthesis of Desymmetrized Electron Acceptors and Donor–Acceptor Constructs

DOE PAGES

Kolaczkowski, Matthew A.; He, Bo; Liu, Yi

2016-10-10

In this work, a selective stepwise annulation of indigo has been demonstrated as a means of providing both monoannulated and differentially double-annulated indigo derivatives. Disparate substitution of the electron accepting bay-annulated indigo system allows for fine control over both the electronic properties as well as donor-acceptor structural architectures. Optical and electronic properties were characterized computationally as well as through UV-vis absorption spectroscopy and cyclic voltammetry. Finally, this straightforward method provides a modular approach for the design of indigo-based materials with tailored optoelectronic properties.

Solid-phase synthesis of a nucleopeptide from the linking site of adenovirus-2 nucleoprotein, -Ser(p5'CATCAT)-Gly-Asp-. Convergent versus stepwise strategy.

PubMed Central

Robles, J; Pedroso, E; Grandas, A

1995-01-01

The synthesis of a nucleopeptide with the sequence -Ser(p5'CATCAT)-Gly-Asp- has been undertaken by either convergent or stepwise solid-phase strategies, both of which use base-labile permanent protecting groups. The coupling of phosphitylated protected peptides onto oligonucleotide-resins did not afford the desired nucleopeptide, which was nevertheless obtained after oligonucleotide elongation at the hydroxyl group of the resin-bound peptide and deprotection under mild basic conditions. A preliminary study on the stability of different nucleopeptides to bases is also reported. PMID:7479079

[Correlation Between Functional Groups and Radical Scavenging Activities of Acidic Polysaccharides from Dendrobium].

PubMed

Liao, Ying; Yuan, Wen-yu; Zheng, Wen-ke; Luo, Ao-xue; Fan, Yi-jun

2015-11-01

To compare the radical scavenging activity of five different acidic polysaccharides, and to find the correlation with the functional groups. Alkali extraction method and Stepwise ethanol precipitation method were used to extract and concentrate the five Dendrobium polysaccharides, and to determine the contents of sulfuric acid and uronic acid of each kind of acidic polysaccharides, and the scavenging activity to ABTS+ radical and hydroxyl radical. Functional group structures were examined by FTIR Spectrometer. Five kinds of Dendrobium polysaccharides had different ability of scavenging ABTS+ free radical and hydroxyl free radical. Moreover, the study had shown that five kinds of antioxidant activity of acidic polysaccharides had obvious correlation withuronic acid and sulfuric acid. The antioxidant activity of each sample was positively correlated with the content of uronic acid, and negatively correlated with the content of sulfuric acid. Sulfuric acid can inhibit the antioxidant activity of acidic polysaccharide but uronic acid can enhance the free radical scavenging activity. By analyzing the structure characteristics of five acidic polysaccharides, all samples have similar structures, however, Dendrobium denneanum, Dendrobium devonianum and Dendrobium officinale which had β configuration have higher antioxidant activity than Dendrobium nobile and Dendrobium fimbriatum which had a configuration.

Resistance of a soybean cell line to oxyfluorfen by overproduction of mitochondrial protoporphyrinogen oxidase.

PubMed

Warabi, E; Usui, K; Tanaka, Y; Matsumoto, H

2001-08-01

The diphenyl ether herbicide oxyfluorfen (2-chloro-4-trifluoromethylphenyl 3-ethoxy-4-nitrophenyl ether) inhibits protoporphyrinogen oxidase (Protox) which catalyzes the oxidation of protoporphyrinogen IX (Protogen) to protoporphyrin IX (Proto IX), the last step of the common pathway to chlorophyll and haeme biosynthesis. We have selected an oxyfluorfen-resistant soybean cell line by stepwise selection methods, and the resistance mechanism has been investigated. No growth inhibition was observed in resistant cells at a concentration of 10(-7) M oxyfluorfen, a concentration at which normal cells did not survive. While the degree of inhibition of total extractable Protox by oxyfluorfen was the same in both cell types, the enzyme activity in the mitochondrial fraction from non-treated resistant cells was about nine-fold higher than that from normal cells. Northern analysis of mitochondrial Protox revealed that the concentration of mitochondrial Protox mRNA was much higher in resistant cells than that in normal cells. There were no differences in the absorption and metabolic breakdown of oxyfluorfen. The growth of resistant cells was also insensitive to oxadiazon [5-tert-butyl-3-(2,4-dichloro-5-isopropoxyphenyl)-1,3,4-oxadiazol-2-(3H)- one], the other chemical class of Protox inhibitor. Therefore, the resistance of the selected soybean cell line to oxyfluorfen is probably mainly due to the overproduction of mitochondrial Protox.

Structure-guided engineering of Anticalins with improved binding behavior and biochemical characteristics for application in radio-immuno imaging and/or therapy.

PubMed

Eggenstein, E; Eichinger, A; Kim, H-J; Skerra, A

2014-02-01

Modern strategies in radio-immuno therapy and in vivo imaging require robust, small, and specific ligand-binding proteins. In this context we have previously developed artificial lipocalins, so-called Anticalins, with high binding activity toward rare-earth metal-chelate complexes using combinatorial protein design. Here we describe further improvement of the Anticalin C26 via in vitro affinity maturation to yield CL31, which has a fourfold slower dissociation half-life above 2h. Also, we present the crystallographic analyses of both the initial and the improved Anticalin, providing insight into the molecular mechanism of chelated metal binding and the role of amino acid substitutions during the step-wise affinity maturation. Notably, one of the four structurally variable loops that form the ligand pocket in the lipocalin scaffold undergoes a significant conformational change from C26 to CL31, acting as a lid that closes over the accommodated metal-chelate ligand. A systematic mutational study indicated that further improvement of ligand affinity is difficult to achieve while providing clues on the contribution of relevant side chains in the engineered binding pocket. Unexpectedly, some of the amino acid replacements led to strong increases - more then 10-fold - in the yield of soluble protein from periplasmic secretion in Escherichia coli. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of protein tyrosine phosphatase-PEST are reversed by Akt in T cells.

PubMed

Arimura, Yutaka; Shimizu, Kazuhiko; Koyanagi, Madoka; Yagi, Junji

2014-12-01

T cell activation is regulated by a balance between phosphorylation and dephosphorylation that is under the control of kinases and phosphatases. Here, we examined the role of a non-receptor-type protein tyrosine phosphatase, PTP-PEST, using retrovirus-mediated gene transduction into murine T cells. Based on observations of vector markers (GFP or Thy1.1), exogenous PTP-PEST-positive CD4(+) T cells appeared within 2 days after gene transduction; the percentage of PTP-PEST-positive cells tended to decrease during a resting period in the presence of IL-2 over the next 2 days. These vector markers also showed much lower expression intensities, compared with control cells, suggesting a correlation between the percent reduction and the low marker expression intensity. A catalytically inactive PTP-PEST mutant also showed the same tendency, and stepwise deletion mutants gradually lost their ability to induce the above phenomenon. On the other hand, these PTP-PEST-transduced cells did not have an apoptotic phenotype. No difference in the total cell numbers was found in the wells of a culture plate containing VEC- and PTP-PEST-transduced T cells. Moreover, serine/threonine kinase Akt, but not the anti-apoptotic molecules Bcl-2 and Bcl-XL, reversed the phenotype induced by PTP-PEST. We discuss the novel mechanism by which Akt interferes with PTP-PEST. Copyright © 2014 Elsevier Inc. All rights reserved.