Generation Unbound: Drifting into Sex and Parenthood without Marriage

ERIC Educational Resources Information Center

Sawhill, Isabel V.

2014-01-01

Over half of all births to young adults in the United States now occur outside of marriage, and many are unplanned. The result is increased poverty and inequality for children. The left argues for more social support for unmarried parents; the right argues for a return to traditional marriage. In "Generation Unbound," Isabel V. Sawhill…

Detecting Intramolecular Conformational Dynamics of Single Molecules in Short Distance Range with Sub-Nanometer Sensitivity

PubMed Central

Zhou, Ruobo; Kunzelmann, Simone; Webb, Martin R.; Ha, Taekjip

2011-01-01

Single molecule detection is useful for characterizing nanoscale objects such as biological macromolecules, nano-particles and nano-devices with nano-meter spatial resolution. Fluorescence resonance energy transfer (FRET) is widely used as a single-molecule assay to monitor intramolecular dynamics in the distance range of 3–8 nm. Here we demonstrate that self-quenching of two rhodamine derivatives can be used to detect small conformational dynamics corresponding to sub-nanometer distance changes in a FRET-insensitive short range at the single molecule level. A ParM protein mutant labeled with two rhodamines works as a single molecule ADP sensor which has 20 times brighter fluorescence signal in the ADP bound state than the unbound state. Single molecule time trajectories show discrete transitions between fluorescence on and off states that can be directly ascribed to ADP binding and dissociation events. The conformational changes observed with 20:1 contrast are only 0.5 nm in magnitude and are between crystallographic distances of 1.6 nm and 2.1 nm, demonstrating exquisite sensitivity to short distance scale changes. The systems also allowed us to gain information on the photophysics of self-quenching induced by rhodamine stacking: (1) photobleaching of either of the two rhodamines eliminates quenching of the other rhodamine fluorophore and (2) photobleaching from the highly quenched, stacked state is only two-fold slower than from the unstacked state. PMID:22023515

Ground-state proton decay of 69Br and implications for the rp -process 68Se waiting-point

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

Rogers, Andrew M; Shapira, Dan; Lynch, William

2011-01-01

The first direct measurement of the proton separation energy, S p , for the proton-unbound nucleus 69Br is reported. Of interest is the exponential dependence of the 2 p-capture rate on S p which can bypass the 68Se waiting-point in the astrophysical rp process. An analysis of the observed proton decay spectrum is given in terms of the 69Se mirror nucleus and the influence of S p is explored within the context of a single-zone X-ray burst model.

Sound-absorbing slabs and structures based on granular materials (bound and unbound). [energy absorbing efficiency of porous material

NASA Technical Reports Server (NTRS)

Petre-Lazar, S.; Popeea, G.

1974-01-01

Sound absorbing slabs and structures made up of bound or unbound granular materials are considered and how to manufacture these elements at the building site. The raw material is a single grain powder (sand, expanded blast furnace slag, etc.) that imparts to the end products an apparent porosity of 25-45% and an energy dissipation within the structure leading to absorption coefficients that can be compared with those of mineral wool and urethane.

Large-scale single-chirality separation of single-wall carbon nanotubes by simple gel chromatography

PubMed Central

Liu, Huaping; Nishide, Daisuke; Tanaka, Takeshi; Kataura, Hiromichi

2011-01-01

Monostructured single-wall carbon nanotubes (SWCNTs) are important in both scientific research and electronic and biomedical applications; however, the bulk separation of SWCNTs into populations of single-chirality nanotubes remains challenging. Here we report a simple and effective method for the large-scale chirality separation of SWCNTs using a single-surfactant multicolumn gel chromatography method utilizing one surfactant and a series of vertically connected gel columns. This method is based on the structure-dependent interaction strength of SWCNTs with an allyl dextran-based gel. Overloading an SWCNT dispersion on the top column results in the adsorption sites of the column becoming fully occupied by the nanotubes that exhibit the strongest interaction with the gel. The unbound nanotubes flow through to the next column, and the nanotubes with the second strongest interaction with the gel are adsorbed in this stage. In this manner, 13 different (n, m) species were separated. Metallic SWCNTs were finally collected as unbound nanotubes because they exhibited the lowest interaction with the gel. PMID:21556063

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 1. Microdialysis Assessment of Brain Extracellular Fluid Concentrations in Patients with Acute Brain Injury

PubMed Central

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William

2014-01-01

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0–τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml−1. This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution. PMID:24277041

On the definition of the time evolution operator for time-independent Hamiltonians in non-relativistic quantum mechanics

NASA Astrophysics Data System (ADS)

Amaku, Marcos; Coutinho, Francisco A. B.; Masafumi Toyama, F.

2017-09-01

The usual definition of the time evolution operator e-i H t /ℏ=∑n=0∞1/n ! (-i/ℏHt ) n , where H is the Hamiltonian of the system, as given in almost every book on quantum mechanics, causes problems in some situations. The operators that appear in quantum mechanics are either bounded or unbounded. Unbounded operators are not defined for all the vectors (wave functions) of the Hilbert space of the system; when applied to some states, they give a non-normalizable state. Therefore, if H is an unbounded operator, the definition in terms of the power series expansion does not make sense because it may diverge or result in a non-normalizable wave function. In this article, we explain why this is so and suggest, as an alternative, another definition used by mathematicians.

Approximation methods for control of structural acoustics models with piezoceramic actuators

NASA Astrophysics Data System (ADS)

Banks, H. T.; Fang, W.; Silcox, R. J.; Smith, R. C.

1993-01-01

The active control of acoustic pressure in a 2-D cavity with a flexible boundary (a beam) is considered. Specifically, this control is implemented via piezoceramic patches on the beam which produces pure bending moments. The incorporation of the feedback control in this manner leads to a system with an unbounded input term. Approximation methods in this manner leads to a system with an unbounded input term. Approximation methods in this manner leads to a system with an unbounded input team. Approximation methods in the context of linear quadratic regulator (LQR) state space control formulation are discussed and numerical results demonstrating the effectiveness of this approach in computing feedback controls for noise reduction are presented.

Two-proton radioactivity with 2p halo in light mass nuclei A = 18-34

NASA Astrophysics Data System (ADS)

Saxena, G.; Kumawat, M.; Kaushik, M.; Jain, S. K.; Aggarwal, Mamta

2017-12-01

Two-proton radioactivity with 2p halo is reported theoretically in light mass nuclei A = 18- 34. We predict 19Mg, 22Si, 26S, 30Ar and 34Ca as promising candidates of ground state 2p-radioactivity with S2p < 0 and Sp > 0. Observation of extended tail of spatial charge density distribution, larger charge radius and study of proton single particle states, Fermi energy and the wave functions indicate 2p halo like structure which supports direct 2p emission. The Coulomb and centrifugal barriers in experimentally identified 2p unbound 22Si show a quasi-bound state that ensures enough life time for such experimental probes. Our predictions are in good accord with experimental and other theoretical data available so far.

Helicons in Unbounded Plasmas.

PubMed

Stenzel, R L; Urrutia, J M

2015-05-22

Helicons are whistler modes with helical phase fronts. They have been studied in solid state plasmas and in discharge tubes where boundaries and nonuniformities are ever present. The present work shows that helicons also exist in unbounded and uniform plasmas, thereby bridging the fields of laboratory and space plasma physics. First measurements of helicon field lines in three dimensional space are presented. Helicons with negative and positive mode numbers can propagate with equal amplitudes.

Approximate Model Checking of PCTL Involving Unbounded Path Properties

NASA Astrophysics Data System (ADS)

Basu, Samik; Ghosh, Arka P.; He, Ru

We study the problem of applying statistical methods for approximate model checking of probabilistic systems against properties encoded as PCTL formulas. Such approximate methods have been proposed primarily to deal with state-space explosion that makes the exact model checking by numerical methods practically infeasible for large systems. However, the existing statistical methods either consider a restricted subset of PCTL, specifically, the subset that can only express bounded until properties; or rely on user-specified finite bound on the sample path length. We propose a new method that does not have such restrictions and can be effectively used to reason about unbounded until properties. We approximate probabilistic characteristics of an unbounded until property by that of a bounded until property for a suitably chosen value of the bound. In essence, our method is a two-phase process: (a) the first phase is concerned with identifying the bound k 0; (b) the second phase computes the probability of satisfying the k 0-bounded until property as an estimate for the probability of satisfying the corresponding unbounded until property. In both phases, it is sufficient to verify bounded until properties which can be effectively done using existing statistical techniques. We prove the correctness of our technique and present its prototype implementations. We empirically show the practical applicability of our method by considering different case studies including a simple infinite-state model, and large finite-state models such as IPv4 zeroconf protocol and dining philosopher protocol modeled as Discrete Time Markov chains.

Strong γ-ray emission from neutron unbound states populated in β-decay: Impact on (n,γ) cross-section estimates

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

Tain, J. L.; Guadilla, V.; Valencia, E.

Total absorption gamma-ray spectroscopy is used to measure accurately the intensity of γ emission from neutron-unbound states populated in the β-decay of delayed-neutron emitters. From the comparison of this intensity with the intensity of neutron emission one can deduce information on the (n,γ) cross section for unstable neutron-rich nuclei of interest in r process abundance calculations. A surprisingly large γ branching was observed for a number of isotopes. Here, the results are compared with Hauser-Feshbach calculations and discussed.

Strong γ-ray emission from neutron unbound states populated in β-decay: Impact on (n,γ) cross-section estimates

DOE PAGES

Tain, J. L.; Guadilla, V.; Valencia, E.; ...

2017-09-13

Total absorption gamma-ray spectroscopy is used to measure accurately the intensity of γ emission from neutron-unbound states populated in the β-decay of delayed-neutron emitters. From the comparison of this intensity with the intensity of neutron emission one can deduce information on the (n,γ) cross section for unstable neutron-rich nuclei of interest in r process abundance calculations. A surprisingly large γ branching was observed for a number of isotopes. Here, the results are compared with Hauser-Feshbach calculations and discussed.

A limited sampling model for estimation of total and unbound mycophenolic acid (MPA) area under the curve (AUC) in hematopoietic cell transplantation (HCT).

PubMed

Ng, Juki; Rogosheske, John; Barker, Juliet; Weisdorf, Daniel; Jacobson, Pamala A

2006-06-01

Renal transplant patients with suboptimal mycophenolic acid (MPA) areas under the curves (AUCs) are at greater risk of acute rejection. In hematopoietic cell transplantation, a low MPA AUC is also associated with a higher incidence of acute graft versus host disease. Therefore, a limited sampling model was developed and validated to simultaneously estimate total and unbound MPA AUC0-12 in hematopoietic cell transplantation patients. Intensive pharmacokinetic sampling was performed at steady state between days 3 to 7 posttransplant in 73 adult subjects while receiving prophylactic mycophenolate mofetil 1 g per 12 hours orally or intravenously plus cyclosporine. Total and unbound MPA plasma concentrations were measured, and total and unbound AUC0-12 was determined using noncompartmental analysis. Regression analysis was then performed to build IV and PO, total and unbound AUC0-12 models from the first 34 subjects. The predictive performance of these models was tested in the next 39 subjects. Trough concentrations poorly estimate observed total and unbound AUC0-12 (r<0.48). A model with 3 concentrations (2-, 4-, and 6-hour post start of infusion) best estimated observed total and unbound AUC0-12 after IV dosing (r>0.99). Oral total and unbound AUC0-12 was more difficult to estimate and required at least 4 concentrations (0-, 1-, 2-, and 6-hour post dose) in the model (r>0.85). The predictive performance of the final models was good. Eighty-three percent of IV and 70% of PO AUC0-12 predictions fell within +/-20% of the observed values without significant bias. Trough MPA concentrations do not accurately describe MPA AUC0-12. Three intravenous (2-, 4-, 6-hour post start of infusion) or 4 oral (0-, 1-, 2-, and 6-hour post dose) MPA plasma concentrations measured over a 12-hour dosing interval will estimate the total and unbound AUC0-12 nearly as well as intensive pharmacokinetic sampling with good precision and low bias. This approach simplifies AUC0-12 targeting of MPA post hematopoietic cell transplantation.

Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients

PubMed Central

Foster, David J R; Somogyi, Andrew A; Dyer, Kyle R; White, Jason M; Bochner, Felix

2000-01-01

Aims To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. Methods Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma α1-acid glycoprotein concentrations were quantified by radial immunoassay. Results (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCτSS, (167%) was significantly (P < 0.001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCτSS, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. Conclusions Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence. PMID:11069437

Efficient Computation of Small-Molecule Configurational Binding Entropy and Free Energy Changes by Ensemble Enumeration

PubMed Central

2013-01-01

Here we present a novel, end-point method using the dead-end-elimination and A* algorithms to efficiently and accurately calculate the change in free energy, enthalpy, and configurational entropy of binding for ligand–receptor association reactions. We apply the new approach to the binding of a series of human immunodeficiency virus (HIV-1) protease inhibitors to examine the effect ensemble reranking has on relative accuracy as well as to evaluate the role of the absolute and relative ligand configurational entropy losses upon binding in affinity differences for structurally related inhibitors. Our results suggest that most thermodynamic parameters can be estimated using only a small fraction of the full configurational space, and we see significant improvement in relative accuracy when using an ensemble versus single-conformer approach to ligand ranking. We also find that using approximate metrics based on the single-conformation enthalpy differences between the global minimum energy configuration in the bound as well as unbound states also correlates well with experiment. Using a novel, additive entropy expansion based on conditional mutual information, we also analyze the source of ligand configurational entropy loss upon binding in terms of both uncoupled per degree of freedom losses as well as changes in coupling between inhibitor degrees of freedom. We estimate entropic free energy losses of approximately +24 kcal/mol, 12 kcal/mol of which stems from loss of translational and rotational entropy. Coupling effects contribute only a small fraction to the overall entropy change (1–2 kcal/mol) but suggest differences in how inhibitor dihedral angles couple to each other in the bound versus unbound states. The importance of accounting for flexibility in drug optimization and design is also discussed. PMID:24250277

Global-Local Finite Element Analysis of Bonded Single-Lap Joints

NASA Technical Reports Server (NTRS)

Kilic, Bahattin; Madenci, Erdogan; Ambur, Damodar R.

2004-01-01

Adhesively bonded lap joints involve dissimilar material junctions and sharp changes in geometry, possibly leading to premature failure. Although the finite element method is well suited to model the bonded lap joints, traditional finite elements are incapable of correctly resolving the stress state at junctions of dissimilar materials because of the unbounded nature of the stresses. In order to facilitate the use of bonded lap joints in future structures, this study presents a finite element technique utilizing a global (special) element coupled with traditional elements. The global element includes the singular behavior at the junction of dissimilar materials with or without traction-free surfaces.

Backcalculation of unbound granular layer moduli.

DOT National Transportation Integrated Search

2011-03-01

The state of Michigan is geographically located within the wet-freeze zone identified by the : American Association of States and Highway Transportation Officials (AASHTO). The frost : depth in the State ranges from 2.5 feet near the Ohio and Indiana...

50 CFR 679.61 - Formation and operation of fishery cooperatives.

Code of Federal Regulations, 2010 CFR

2010-10-01

... ECONOMIC ZONE OFF ALASKA American Fisheries Act and Aleutian Island Directed Pollock Fishery Management... duplication on unbound single-sided 8.5- by-11-inch paper, or in an alternative format approved in advance by...

Impact of fraction unbound, CYP3A, and CYP2D6 in vivo activities, and other potential covariates to the clearance of tramadol enantiomers in patients with neuropathic pain.

PubMed

de Moraes, Natália V; Lauretti, Gabriela R; Coelho, Eduardo B; Godoy, Ana Leonor P C; Neves, Daniel V; Lanchote, Vera L

2016-04-01

The pharmacokinetics of tramadol is characterized by a large interindividual variability, which is partially attributed to polymorphic CYP2D6 metabolism. The contribution of CYP3A, CYP2B6, fraction unbound, and other potential covariates remains unknown. This study aimed to investigate the contribution of in vivo activities of cytochrome P450 (CYP) 2D6 and 3A as well as other potential covariates (CYP2B6 genotype to the SNP g.15631G>T, fraction unbound, age, body weight, creatinine clearance) to the enantioselective pharmacokinetics of tramadol. Thirty patients with neuropathic pain and phenotyped as CYP2D6 extensive metabolizers were treated with a single oral dose of 100 mg tramadol. Multiple linear regressions were performed to determine the contribution of CYP activities and other potential covariates to the clearance of tramadol enantiomers. The apparent total clearances were 44.9 (19.1-102-2) L/h and 55.2 (14.8-126.0) L/h for (+)- and (-)-tramadol, respectively [data presented as median (minimum-maximum)]. Between 79 and 83% of the overall variation in apparent clearance of tramadol enantiomers was explained by fraction unbound, CYP2D6, and CYP3A in vivo activities and body weight. Fraction unbound explained 47 and 41% of the variation in clearance of (+)-tramadol and (-)-tramadol, respectively. Individually, CYP2D6 and CYP3A activities were shown to have moderate contribution on clearance of tramadol enantiomers (11-16% and 11-18%, respectively). In conclusion, factors affecting fraction unbound of drugs (such as hyperglycemia or co-administration of drugs highly bound to plasma proteins) should be monitored, because this parameter dominates the elimination of tramadol enantiomers. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

PubMed Central

Ruslami, R.; Later-Nijland, H.; Mooren, F.; Teulen, M.; Apriani, L.; Koenderink, J. B.; Russel, F. G.; Burger, D. M.; Alisjahbana, B.; Wieringa, F.; van Crevel, R.; Aarnoutse, R. E.

2015-01-01

Nutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m2), malnourished (BMI of <18.5 kg/m2), and well-nourished (BMI of ≥18.5 kg/m2) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n = 7), malnourished (n = 11), and well-nourished (n = 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0–24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0–24 (geometric mean, 59.2 versus 48.2 h · mg/liter; P = 0.02) and higher unbound AUC0–24 (geometric mean, 6.2 versus 4.8 h · mg/liter; P = 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n = 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships. PMID:25801554

HIV envelope glycoprotein imaged at high resolution | Center for Cancer Research

Cancer.gov

The outer surface of the human immunodeficiency virus (HIV) is surrounded by an envelope studded with spike-shaped glycoproteins called Env that help the deadly virus identify, bind, and infect cells. When unbound, Env exists in a “closed” conformational state. Upon binding with target cells, such as CD4+ T cells, the protein transitions to an “open” configuration. Given that Env is the only viral protein expressed on HIV’s surface, knowing its detailed structure—especially in the unbound state—may be critical for designing antibodies and vaccines against HIV.

Fluorescence lifetime imaging to differentiate bound from unbound ICG-cRGD both in vitro and in vivo

NASA Astrophysics Data System (ADS)

Stegehuis, Paulien L.; Boonstra, Martin C.; de Rooij, Karien E.; Powolny, François E.; Sinisi, Riccardo; Homulle, Harald; Bruschini, Claudio; Charbon, Edoardo; van de Velde, Cornelis J. H.; Lelieveldt, Boudewijn P. F.; Vahrmeijer, Alexander L.; Dijkstra, Jouke; van de Giessen, Martijn

2015-03-01

Excision of the whole tumor is crucial, but remains difficult for many tumor types. Fluorescence lifetime imaging could be helpful intraoperative to differentiate normal from tumor tissue. In this study we investigated the difference in fluorescence lifetime imaging of indocyanine green coupled to cyclic RGD free in solution/serum or bound to integrins e.g. in tumors. The U87-MG glioblastoma cell line, expressing high integrin levels, was cultured to use in vitro and to induce 4 subcutaneous tumors in a-thymic mice (n=4). Lifetimes of bound and unbound probe were measured with an experimental time-domain single-photon avalanche diode array (time resolution <100ps). In vivo measurements were taken 30-60 minutes after intravenous injection, and after 24 hours. The in vitro lifetime of the fluorophores was similar at different concentrations (20, 50 and 100μM) and showed a statistically significant higher lifetime (p<0.001) of bound probe compared to unbound probe. In vivo, lifetimes of the fluorophores in tumors were significantly higher (p<0.001) than at the control site (tail) at 30-60 minutes after probe injection. Lifetimes after 24 hours confirmed tumor-specific binding (also validated by fluorescence intensity images). Based on the difference in lifetime imaging, it can be concluded that it is feasible to separate between bound and unbound probes in vivo.

Hole pairing and thermodynamic properties of the two dimensional frustrated t-J model

NASA Astrophysics Data System (ADS)

Roy, K.; Pal, P.; Nath, S.; Ghosh, N. K.

2018-04-01

The frustrated t-J model is investigated by using the exact-diagonalization (ED) method on an 8-site cluster. The effect on next-nearest-neighbor (NNN) exchange interaction J' (frustration) on the hole pairing and the thermodynamic properties of the system is considered. Two holes initially remain unbound at smaller value of J'/t, but tend to bind at larger value. The maximum possibility of pair formation has been observed to be at NNN sites. Entropy calculation shows that the system goes to more disordered state with J'. The specific heat curves show a single peak structure. A decrease in effective exchange energy is observed due to the frustration.

Competing decay modes of a high-spin isomer in the proton-unbound nucleus ¹⁵⁸Ta*

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

Carroll, R. J.; Page, R. D.; Joss, D. T.

2015-01-01

An isomeric state at high spin and excitation energy was recently observed in the proton-unbound nucleus 158Ta. This state was observed to decay by both α and γ decay modes. The large spin change required to decay via γ-ray emission incurs a lifetime long enough for α decay to compete. The α decay has an energy of 8644(11) keV, which is among the highest observed in the region, a partial half-life of 440(70) μs and changes the spin by 11ℏ. In this study, additional evidence supporting the assignment of this α decay to the high-spin isomer in 158Ta will bemore » presented.« less

Exact, E = 0, classical and quantum solutions for general power-law oscillators

NASA Technical Reports Server (NTRS)

Nieto, Michael Martin; Daboul, Jamil

1995-01-01

For zero energy, E = 0, we derive exact, classical and quantum solutions for all power-law oscillators with potentials V(r) = -gamma/r(exp nu), gamma greater than 0 and -infinity less than nu less than infinity. When the angular momentum is non-zero, these solutions lead to the classical orbits (p(t) = (cos mu(phi(t) - phi(sub 0)t))(exp 1/mu) with mu = nu/2 - 1 does not equal 0. For nu greater than 2, the orbits are bound and go through the origin. We calculate the periods and precessions of these bound orbits, and graph a number of specific examples. The unbound orbits are also discussed in detail. Quantum mechanically, this system is also exactly solvable. We find that when nu is greater than 2 the solutions are normalizable (bound), as in the classical case. Further, there are normalizable discrete, yet unbound, states. They correspond to unbound classical particles which reach infinity in a finite time. Finally, the number of space dimensions of the system can determine whether or not an E = 0 state is bound. These and other interesting comparisons to the classical system will be discussed.

Modeling of the gate-controlled Kondo effect at carbon point defects in graphene

NASA Astrophysics Data System (ADS)

May, Daniel; Lo, Po-Wei; Deltenre, Kira; Henke, Anika; Mao, Jinhai; Jiang, Yuhang; Li, Guohong; Andrei, Eva Y.; Guo, Guang-Yu; Anders, Frithjof B.

2018-04-01

We study the magnetic properties in the vicinity of a single carbon defect in a monolayer of graphene. We include the unbound σ orbital and the vacancy-induced bound π state in an effective two-orbital single-impurity model. The local magnetic moments are stabilized by the Coulomb interaction as well as a significant ferromagnetic Hund's rule coupling between the orbitals predicted by a density functional theory calculation. A hybridization between the orbitals and the Dirac fermions is generated by the curvature of the graphene sheet in the vicinity of the vacancy. We present results for the local spectral function calculated using Wilson's numerical renormalization group approach for a realistic graphene band structure and find three different regimes depending on the filling, the controlling chemical potential, and the hybridization strength. These different regions are characterized by different magnetic properties. The calculated spectral functions qualitatively agree with recent scanning tunneling spectra on graphene vacancies.

Hot Spots in a Network of Functional Sites

PubMed Central

Ozbek, Pemra; Soner, Seren; Haliloglu, Turkan

2013-01-01

It is of significant interest to understand how proteins interact, which holds the key phenomenon in biological functions. Using dynamic fluctuations in high frequency modes, we show that the Gaussian Network Model (GNM) predicts hot spot residues with success rates ranging between S 8–58%, C 84–95%, P 5–19% and A 81–92% on unbound structures and S 8–51%, C 97–99%, P 14–50%, A 94–97% on complex structures for sensitivity, specificity, precision and accuracy, respectively. High specificity and accuracy rates with a single property on unbound protein structures suggest that hot spots are predefined in the dynamics of unbound structures and forming the binding core of interfaces, whereas the prediction of other functional residues with similar dynamic behavior explains the lower precision values. The latter is demonstrated with the case studies; ubiquitin, hen egg-white lysozyme and M2 proton channel. The dynamic fluctuations suggest a pseudo network of residues with high frequency fluctuations, which could be plausible for the mechanism of biological interactions and allosteric regulation. PMID:24023934

Structure of the exotic 9He nucleus from the no-core shell model with continuum

NASA Astrophysics Data System (ADS)

Vorabbi, Matteo; Calci, Angelo; Navrátil, Petr; Kruse, Michael K. G.; Quaglioni, Sofia; Hupin, Guillaume

2018-03-01

Background: The exotic 9He nucleus, which presents one of the most extreme neutron-to-proton ratios, belongs to the N =7 isotonic chain famous for the phenomenon of ground-state parity inversion with decreasing number of protons. Consequently, it would be expected to have an unnatural (positive) parity ground state similar to 11Be and 10Li. Despite many experimental and theoretical investigations, its structure remains uncertain. Apart from the fact that it is unbound, other properties including the spin and parity of its ground state, and the very existence of additional low-lying resonances are still a matter of debate. Purpose: In this work, we study the properties of 9He by analyzing the n +8He continuum in the context of the ab initio no-core shell model with continuum (NCSMC) formalism with chiral nucleon-nucleon interactions as the only input. Methods: The NCSMC is a state-of-the-art approach for the ab initio description of light nuclei. With its capability to predict properties of bound states, resonances, and scattering states in a unified framework, the method is particularly well suited for the study of unbound nuclei such as 9He. Results: Our analysis produces an unbound 9He nucleus. Two resonant states are found at the energies of ˜1 and ˜3.5 MeV, respectively, above the n +8He breakup threshold. The first state has a spin-parity assignment of Jπ=1/2 - and can be associated with the ground state of 9He, while the second, broader state has a spin parity of 3/2 -. No resonance is found in the 1/2 + channel, only a very weak attraction. Conclusions: We find that the 9He ground-state resonance has a negative parity and thus breaks the parity-inversion mechanism found in the 11Be and 10Li nuclei of the same N =7 isotonic chain.

The quantum holonomy-diffeomorphism algebra and quantum gravity

NASA Astrophysics Data System (ADS)

Aastrup, Johannes; Grimstrup, Jesper Møller

2016-03-01

We introduce the quantum holonomy-diffeomorphism ∗-algebra, which is generated by holonomy-diffeomorphisms on a three-dimensional manifold and translations on a space of SU(2)-connections. We show that this algebra encodes the canonical commutation relations of canonical quantum gravity formulated in terms of Ashtekar variables. Furthermore, we show that semiclassical states exist on the holonomy-diffeomorphism part of the algebra but that these states cannot be extended to the full algebra. Via a Dirac-type operator we derive a certain class of unbounded operators that act in the GNS construction of the semiclassical states. These unbounded operators are the type of operators, which we have previously shown to entail the spatial three-dimensional Dirac operator and Dirac-Hamiltonian in a semiclassical limit. Finally, we show that the structure of the Hamilton constraint emerges from a Yang-Mills-type operator over the space of SU(2)-connections.

Unbound states in quantum heterostructures

PubMed Central

Bastard, G

2006-01-01

We report in this review on the electronic continuum states of semiconductor Quantum Wells and Quantum Dots and highlight the decisive part played by the virtual bound states in the optical properties of these structures. The two particles continuum states of Quantum Dots control the decoherence of the excited electron – hole states. The part played by Auger scattering in Quantum Dots is also discussed.

Measurement of plasma unbound unconjugated bilirubin.

PubMed

Ahlfors, C E

2000-03-15

A method is described for measuring the unconjugated fraction of the unbound bilirubin concentration in plasma by combining the peroxidase method for determining unbound bilirubin with a diazo method for measuring conjugated and unconjugated bilirubin. The accuracy of the unbound bilirubin determination is improved by decreasing sample dilution, eliminating interference by conjugated bilirubin, monitoring changes in bilirubin concentration using diazo derivatives, and correcting for rate-limiting dissociation of bilirubin from albumin. The unbound unconjugated bilirubin concentration by the combined method in plasma from 20 jaundiced newborns was significantly greater than and poorly correlated with the unbound bilirubin determined by the existing peroxidase method (r = 0.7), possibly due to differences in sample dilution between the methods. The unbound unconjugated bilirubin was an unpredictable fraction of the unbound bilirubin in plasma samples from patients with similar total bilirubin concentrations but varying levels of conjugated bilirubin. A bilirubin-binding competitor was readily detected at a sample dilution typically used for the combined test but not at the dilution used for the existing peroxidase method. The combined method is ideally suited to measuring unbound unconjugated bilirubin in jaundiced human newborns or animal models of kernicterus. Copyright 2000 Academic Press.

Coherent control of the formation of cold heteronuclear molecules by photoassociation

NASA Astrophysics Data System (ADS)

de Lima, Emanuel F.

2017-01-01

We consider the formation of cold diatomic molecules in the electronic ground state by photoassociation of atoms of dissimilar species. A combination of two transition pathways from the free colliding pair of atoms to a bound vibrational level of the electronic molecular ground state is envisioned. The first pathway consists of a pump-dump scheme with two time-delayed laser pulses in the near-infrared frequency domain. The pump pulse drives the transition to a bound vibrational level of an excited electronic state, while the dump pulse transfers the population to a bound vibrational level of the electronic ground state. The second pathway takes advantage of the existing permanent dipole moment and employs a single pulse in the far-infrared domain to drive the transition from the unbound atoms directly to a bound vibrational level in the electronic ground state. We show that this scheme offers the possibility to coherently control the photoassociation yield by manipulating the relative phase and timing of the pulses. The photoassociation mechanism is illustrated for the formation of cold LiCs molecules.

Lactose binding to galectin-1 modulates structural dynamics, increases conformational entropy, and occurs with apparent negative cooperativity.

PubMed

Nesmelova, Irina V; Ermakova, Elena; Daragan, Vladimir A; Pang, Mabel; Menéndez, Margarita; Lagartera, Laura; Solís, Dolores; Baum, Linda G; Mayo, Kevin H

2010-04-16

Galectins are a family of lectins with a conserved carbohydrate recognition domain that interacts with beta-galactosides. By binding cell surface glycoconjugates, galectin-1 (gal-1) is involved in cell adhesion and migration processes and is an important regulator of tumor angiogenesis. Here, we used heteronuclear NMR spectroscopy and molecular modeling to investigate lactose binding to gal-1 and to derive solution NMR structures of gal-1 in the lactose-bound and unbound states. Structure analysis shows that the beta-strands and loops around the lactose binding site, which are more open and dynamic in the unbound state, fold in around the bound lactose molecule, dampening internal motions at that site and increasing motions elsewhere throughout the protein to contribute entropically to the binding free energy. CD data support the view of an overall more open structure in the lactose-bound state. Analysis of heteronuclear single quantum coherence titration binding data indicates that lactose binds the two carbohydrate recognition domains of the gal-1 dimer with negative cooperativity, in that the first lactose molecule binds more strongly (K(1)=21+/-6 x 10(3) M(-1)) than the second (K(2)=4+/-2 x 10(3) M(-1)). Isothermal calorimetry data fit using a sequential binding model present a similar picture, yielding K(1)=20+/-10 x 10(3) M(-1) and K(2)=1.67+/-0.07 x 10(3) M(-1). Molecular dynamics simulations provide insight into structural dynamics of the half-loaded lactose state and, together with NMR data, suggest that lactose binding at one site transmits a signal through the beta-sandwich and loops to the second binding site. Overall, our results provide new insight into gal-1 structure-function relationships and to protein-carbohydrate interactions in general. Copyright (c) 2010. Published by Elsevier Ltd.

On the possibility of using polycrystalline material in the development of structure-based generic assays

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

Allaire, Marc, E-mail: allaire@bnl.gov; Moiseeva, Natalia; Botez, Cristian E.

The correlation coefficients calculated between raw powder diffraction profiles can be used to identify ligand-bound/unbound states of lysozyme. The discovery of ligands that bind specifically to a targeted protein benefits from the development of generic assays for high-throughput screening of a library of chemicals. Protein powder diffraction (PPD) has been proposed as a potential method for use as a structure-based assay for high-throughput screening applications. Building on this effort, powder samples of bound/unbound states of soluble hen-egg white lysozyme precipitated with sodium chloride were compared. The correlation coefficients calculated between the raw diffraction profiles were consistent with the known bindingmore » properties of the ligands and suggested that the PPD approach can be used even prior to a full description using stereochemically restrained Rietveld refinement.« less

Shock/vortex interaction and vortex-breakdown modes

NASA Technical Reports Server (NTRS)

Kandil, Osama A.; Kandil, H. A.; Liu, C. H.

1992-01-01

Computational simulation and study of shock/vortex interaction and vortex-breakdown modes are considered for bound (internal) and unbound (external) flow domains. The problem is formulated using the unsteady, compressible, full Navier-Stokes (NS) equations which are solved using an implicit, flux-difference splitting, finite-volume scheme. For the bound flow domain, a supersonic swirling flow is considered in a configured circular duct and the problem is solved for quasi-axisymmetric and three-dimensional flows. For the unbound domain, a supersonic swirling flow issued from a nozzle into a uniform supersonic flow of lower Mach number is considered for quasi-axisymmetric and three-dimensional flows. The results show several modes of breakdown; e.g., no-breakdown, transient single-bubble breakdown, transient multi-bubble breakdown, periodic multi-bubble multi-frequency breakdown and helical breakdown.

The effect of surface tension on steadily translating bubbles in an unbounded Hele-Shaw cell

PubMed Central

2017-01-01

New numerical solutions to the so-called selection problem for one and two steadily translating bubbles in an unbounded Hele-Shaw cell are presented. Our approach relies on conformal mapping which, for the two-bubble problem, involves the Schottky-Klein prime function associated with an annulus. We show that a countably infinite number of solutions exist for each fixed value of dimensionless surface tension, with the bubble shapes becoming more exotic as the solution branch number increases. Our numerical results suggest that a single solution is selected in the limit that surface tension vanishes, with the scaling between the bubble velocity and surface tension being different to the well-studied problems for a bubble or a finger propagating in a channel geometry. PMID:28588410

Global stabilization analysis of inertial memristive recurrent neural networks with discrete and distributed delays.

PubMed

Wang, Leimin; Zeng, Zhigang; Ge, Ming-Feng; Hu, Junhao

2018-05-02

This paper deals with the stabilization problem of memristive recurrent neural networks with inertial items, discrete delays, bounded and unbounded distributed delays. First, for inertial memristive recurrent neural networks (IMRNNs) with second-order derivatives of states, an appropriate variable substitution method is invoked to transfer IMRNNs into a first-order differential form. Then, based on nonsmooth analysis theory, several algebraic criteria are established for the global stabilizability of IMRNNs under proposed feedback control, where the cases with both bounded and unbounded distributed delays are successfully addressed. Finally, the theoretical results are illustrated via the numerical simulations. Copyright © 2018 Elsevier Ltd. All rights reserved.

Approximation methods for control of acoustic/structure models with piezoceramic actuators

NASA Technical Reports Server (NTRS)

Banks, H. T.; Fang, W.; Silcox, R. J.; Smith, R. C.

1991-01-01

The active control of acoustic pressure in a 2-D cavity with a flexible boundary (a beam) is considered. Specifically, this control is implemented via piezoceramic patches on the beam which produces pure bending moments. The incorporation of the feedback control in this manner leads to a system with an unbounded input term. Approximation methods in this manner leads to a system with an unbounded input term. Approximation methods in the context of linear quadratic regulator (LQR) state space control formulation are discussed and numerical results demonstrating the effectiveness of this approach in computing feedback controls for noise reduction are presented.

γ-ray decay from neutron-bound and unbound states in 95Mo and a novel technique for spin determination

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

Wiedeking, M.; Krticka, M.; Bernstein, L. A.

2016-02-01

The emission of γ rays from neutron-bound and neutron-unbound states in 95Mo, populated in the 94Mo(d,p) reaction, has been investigated. Charged particles and γ radiation were detected with arrays of annular silicon and Clover-type high-purity Germanium detectors, respectively. Utilizing p-γ and p-γ-γ coincidences, the 95Mo level scheme was greatly enhanced with 102 new transitions and 43 new states. It agrees well with shell model calculations for excitation energies below ≈2 MeV. From p-γ coincidence data, a new method for the determination of spins of discrete levels is proposed. The method exploits the suppression of high-angular momentum neutron emission from levelsmore » with high spins populated in the (d,p) reaction above the neutron separation energy. As a result, spins for almost all 95Mo levels below 2 MeV (and for a few levels above) have been determined with this method.« less

A multi-layered active target for the study of neutron-unbound nuclides at NSCL

NASA Astrophysics Data System (ADS)

Freeman, Jessica; Gueye, Paul; Redpath, Thomas; MoNA Collaboration

2017-01-01

The characteristics of neutron-unbound nuclides were investigated using a multi-layered Si/Be active target designed for use with the MoNA/LISA setup at the National Superconducting Cyclotron (NSCL). The setup consists of the MoNA/LISA arrays (for neutron detection) and a superconducting sweeper magnet (for charged separation) to identify products following the decay of neutron unbound states. The segmented target consisted of three 700 mg/cm2 beryllium targets and four 0.14 mm thick 62x62 mm2 silicon detectors. As a commissioning experiment for the target the decay of two-neutron unbound 26O populated in a one-proton removal reaction from a radioactive 27F beam was performed. The 27F secondary radioactive beam from the NSCL's Coupled Cyclotron Facility was produced from the fragmentation of a 140 MeV/u 48Ca beam incident on a thick beryllium target and then cleanly selected by the A1900 fragment separator. The energy loss and position spectra of the incoming beam and reaction products were used to calibrate the Silicon detectors to within 1.5% in both energy and position. A dedicated Geant4 model of the target was developed to simulate the energy loss within the target. A description of the experimental setup, simulation work, and energy and position calibration will be presented. DoE/NNSA - DE-NA0000979.

Fueling the Engine: Smarter, Better Ways to Fund Education Innovators

ERIC Educational Resources Information Center

Hess, Frederick M.

2010-01-01

In "Education Unbound: The Promise and Practice of Greenfield Schooling," this author argued for new education service-delivery organizations that, free from the constricting norms and rules of traditional providers, focused single-mindedly on executing their model. The challenge for reformers is to recognize that enabling such providers is not…

Location-Unbound Color-Shape Binding Representations in Visual Working Memory.

PubMed

Saiki, Jun

2016-02-01

The mechanism by which nonspatial features, such as color and shape, are bound in visual working memory, and the role of those features' location in their binding, remains unknown. In the current study, I modified a redundancy-gain paradigm to investigate these issues. A set of features was presented in a two-object memory display, followed by a single object probe. Participants judged whether the probe contained any features of the memory display, regardless of its location. Response time distributions revealed feature coactivation only when both features of a single object in the memory display appeared together in the probe, regardless of the response time benefit from the probe and memory objects sharing the same location. This finding suggests that a shared location is necessary in the formation of bound representations but unnecessary in their maintenance. Electroencephalography data showed that amplitude modulations reflecting location-unbound feature coactivation were different from those reflecting the location-sharing benefit, consistent with the behavioral finding that feature-location binding is unnecessary in the maintenance of color-shape binding. © The Author(s) 2015.

Scaling from single molecule to macroscopic adhesion at polymer/metal interfaces.

PubMed

Utzig, Thomas; Raman, Sangeetha; Valtiner, Markus

2015-03-10

Understanding the evolution of macroscopic adhesion based on fundamental molecular interactions is crucial to designing strong and smart polymer/metal interfaces that play an important role in many industrial and biomedical applications. Here we show how macroscopic adhesion can be predicted on the basis of single molecular interactions. In particular, we carry out dynamic single molecule-force spectroscopy (SM-AFM) in the framework of Bell-Evans' theory to gain information about the energy barrier between the bound and unbound states of an amine/gold junction. Furthermore, we use Jarzynski's equality to obtain the equilibrium ground-state energy difference of the amine/gold bond from these nonequilibrium force measurements. In addition, we perform surface forces apparatus (SFA) experiments to measure macroscopic adhesion forces at contacts where approximately 10(7) amine/gold bonds are formed simultaneously. The SFA approach provides an amine/gold interaction energy (normalized by the number of interacting molecules) of (36 ± 1)k(B)T, which is in excellent agreement with the interaction free energy of (35 ± 3)k(B)T calculated using Jarzynski's equality and single-molecule AFM experiments. Our results validate Jarzynski's equality for the field of polymer/metal interactions by measuring both sides of the equation. Furthermore, the comparison of SFA and AFM shows how macroscopic interaction energies can be predicted on the basis of single molecular interactions, providing a new strategy to potentially predict adhesive properties of novel glues or coatings as well as bio- and wet adhesion.

Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

PubMed

Vezina, Heather E; Ng, Chee M; Vazquez, Delia M; Barks, John D; Bhatt-Mehta, Varsha

2014-07-01

To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability. Prospective observational cohort study. Level 3 neonatal ICU. Sixty-two critically ill neonates and infants receiving IV hydrocortisone as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23-41), median weight 1.2 kg (range, 0.5-4.4), and 29 females. None. Unbound baseline cortisol and postdose hydrocortisone concentrations measured from blood samples being drawn for routine laboratory tests. A one-compartment model best described the data. Allometric weight and postmenstrual age were significant covariates on unbound hydrocortisone clearance and volume of distribution. Final population estimates for clearance, volume of distribution, and baseline cortisol concentration were 20.2 L/hr, 244 L, and 1.37 ng/mL, respectively. Using the median weight and postmenstrual age of our subjects (i.e., 1.2 kg and 28 wk) in the final model, the typical unbound hydrocortisone clearance and volume of distribution were 1.0 L/hr and 4.2 L, respectively. The typical half-life for unbound hydrocortisone was 2.9 hours. A sharp and continuous increase in unbound hydrocortisone clearance was observed at 35 weeks postmenstrual age. We report the first pharmacokinetic data for unbound hydrocortisone, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound hydrocortisone clearance increased with body weight and was faster in children with an older postmenstrual age. Unbound hydrocortisone clearance increased sharply at 35 weeks postmenstrual age and continued to mature thereafter. This study lays the groundwork for evaluating unbound hydrocortisone exposure-response relationships and drawing definitive conclusions about the dosing of IV hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension

PubMed Central

Vezina, Heather E.; Ng, Chee M.; Vazquez, Delia M.; Barks, John D.; Bhatt-Mehta, Varsha

2014-01-01

Objective To determine the population pharmacokinetics of unbound hydrocortisone (HC) in critically ill neonates and infants receiving intravenous HC for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability. Design Prospective observational cohort study. Setting Level 3 neonatal intensive care unit. Patients Sixty-two critically ill neonates and infants receiving intravenous HC as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23 to 41), median weight 1.2 kg (range, 0.5 to 4.4), 29 females. Interventions None. Measurements Unbound baseline cortisol and post-dose HC concentrations measured from blood samples being drawn for routine laboratory tests. Main Results A one compartment model best described the data. Allometric weight and postmenstrual age (PMA) were significant covariates on unbound HC clearance (CL) and volume of distribution (V). Final population estimates for CL, V, and baseline cortisol concentration were 20.2 L/h, 244 L, and 1.37 ng/mL, respectively. Using the median weight and PMA of our subjects (i.e. 1.2 kg and 28 weeks) in the final model, the typical unbound HC CL and V were 1.0 L/h and 4.2 L, respectively. The typical half-life for unbound HC was 2.9 hours. A sharp and continuous increase in unbound HC CL was observed at 35 weeks PMA. Conclusions We report the first pharmacokinetic data for unbound HC, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound HC CL increased with body weight and was faster in children with an older PMA. Unbound HC CL increased sharply at 35 weeks PMA and continued to mature thereafter. This study lays the groundwork for evaluating unbound HC exposure-response relationships and drawing definitive conclusions about the dosing of intravenous HC in critically-ill neonates and infants with vasopressor-resistant hypotension. PMID:24797719

Altered disposition and effect of lerisetron in rats with elevated alpha 1-acid glycoprotein levels.

PubMed

Jauregizar, N; Calvo, R; Suarez, E; Quintana, A; Raczka, E; Lukas, J C

2001-06-01

To examine the effect of changes in plasma alpha1-acid glycoprotein (AAG) levels on the pharmacokinetics (PK) and pharmacodynamics (PD) of lerisetron, a novel serotonin 5-HT3 receptor antagonist, in the rat. After subcutaneous administration of turpentine oil, AAG was significantly elevated compared with controls. The PK of unchanged lerisetron (UL; high-performance liquid chromatography with radioactivity monitoring) and total lerisetron (TL; unchanged + changed, scintillation counting) was characterized post intravenous (i.v.) 14C lerisetron (50 microg/kg) in control and turpentine oil pretreated rats. The PK (0-180 min) was described by a two-compartmental model. Protein binding of lerisetron in vitro was measured using an ultrafiltration technique. The effect of lerisetron (5 microg/kg, i.v.) over 180 min was measured in anesthetized rats (control and pretreated) with the Bezold-Jarisch reflex (inhibition of bradycardia after 16 microg/kg serotonin i.v.) as the endpoint. PD parameters were estimated by sigmoid Emax models. The unbound fraction was significantly diminished in pretreated rats (mean +/- SEM) (6.60 +/- 1.23% vs. control 14.4 +/- 1.40%, P < 0.05). Volume of distribution (V) and clearance for UL and TL were significantly decreased when compared to the controls (P < 0.0001 for UL and P < 0.05 for TL). Plasma clearance based on unbound concentration for UL did not differ between groups but the unbound V and steady-state unbound V remained decreased (P < 0.05 and P < 0.0001). Pretreated rats showed a significantly diminished drug effect: the area under the E-t curve over 180 min was (mean +/- SEM) 5,189 +/- 657.7 in control animals vs. 3,486 +/- 464.4 in the pretreated group (P < 0.05). The EC50 (concentration at half maximum effect) for UL and TL were increased in pretreated rats and were not compensated when the unbound concentration was used. An increase in AAG causes alterations in the PK and PD of lerisetron, and because this is not compensated with the unbound concentration, we suggest that mechanisms not linked to protein binding may be involved.

Direct Determination of Vibrational Density of States Change on Ligand Binding to a Protein

NASA Astrophysics Data System (ADS)

Balog, Erika; Becker, Torsten; Oettl, Martin; Lechner, Ruep; Daniel, Roy; Finney, John; Smith, Jeremy C.

2004-07-01

The change in the vibrational density of states of a protein (dihydrofolate reductase) on binding a ligand (methotrexate) is determined using inelastic neutron scattering. The vibrations of the complex soften significantly relative to the unbound protein. The resulting free-energy change, which is directly determined by the density of states change, is found to contribute significantly to the binding equilibrium.

Spectroscopy of excited states of unbound nuclei 30Ar and 29Cl

NASA Astrophysics Data System (ADS)

Xu, X.-D.; Mukha, I.; Grigorenko, L. V.; Scheidenberger, C.; Acosta, L.; Casarejos, E.; Chudoba, V.; Ciemny, A. A.; Dominik, W.; Duénas-Díaz, J.; Dunin, V.; Espino, J. M.; Estradé, A.; Farinon, F.; Fomichev, A.; Geissel, H.; Golubkova, T. A.; Gorshkov, A.; Janas, Z.; Kamiński, G.; Kiselev, O.; Knöbel, R.; Krupko, S.; Kuich, M.; Litvinov, Yu. A.; Marquinez-Durán, G.; Martel, I.; Mazzocchi, C.; Nociforo, C.; Ordúz, A. K.; Pfützner, M.; Pietri, S.; Pomorski, M.; Prochazka, A.; Rymzhanova, S.; Sánchez-Benítez, A. M.; Sharov, P.; Simon, H.; Sitar, B.; Slepnev, R.; Stanoiu, M.; Strmen, P.; Szarka, I.; Takechi, M.; Tanaka, Y. K.; Weick, H.; Winkler, M.; Winfield, J. S.

2018-03-01

Several states of proton-unbound isotopes 30Ar and 29Cl were investigated by measuring their in-flight decay products, 28S + proton + proton and 28S + proton, respectively. A refined analysis of 28S-proton angular correlations indicates that the ground state of 30Ar is located at 2 .45-0.10+0.05 MeV above the two-proton emission threshold. The investigation of the decay mechanism of the 30Ar ground state demonstrates that it has the transition dynamics. In the "transitional" region, the correlation patterns of the decay products present a surprisingly strong sensitivity to the two-proton decay energy of the 30Ar ground state and the one-proton decay energy as well as the one-proton decay width of the 29Cl ground state. The comparison of the experimental 28S-proton angular correlations with those resulting from Monte Carlo simulations of the detector response illustrates that other observed 30Ar excited states decay by sequential emission of protons via intermediate resonances in 29Cl. Based on the findings, the decay schemes of the observed states in 30Ar and 29Cl were constructed. For calibration purposes and for checking the performance of the experimental setup, decays of the previously known states of a two-proton emitter 19Mg were remeasured. Evidences for one new excited state in 19Mg and two unknown states in 18Na were found.

Nonlinear diffusion equations as asymptotic limits of Cahn-Hilliard systems on unbounded domains via Cauchy's criterion

NASA Astrophysics Data System (ADS)

Fukao, Takeshi; Kurima, Shunsuke; Yokota, Tomomi

2018-05-01

This paper develops an abstract theory for subdifferential operators to give existence and uniqueness of solutions to the initial-boundary problem (P) for the nonlinear diffusion equation in an unbounded domain $\\Omega\\subset\\mathbb{R}^N$ ($N\\in{\\mathbb N}$), written as \\[ \\frac{\\partial u}{\\partial t} + (-\\Delta+1)\\beta(u) = g \\quad \\mbox{in}\\ \\Omega\\times(0, T), \\] which represents the porous media, the fast diffusion equations, etc., where $\\beta$ is a single-valued maximal monotone function on $\\mathbb{R}$, and $T>0$. Existence and uniqueness for (P) were directly proved under a growth condition for $\\beta$ even though the Stefan problem was excluded from examples of (P). This paper completely removes the growth condition for $\\beta$ by confirming Cauchy's criterion for solutions of the following approximate problem (P)$_{\\varepsilon}$ with approximate parameter $\\varepsilon>0$: \\[ \\frac{\\partial u_{\\varepsilon}}{\\partial t} + (-\\Delta+1)(\\varepsilon(-\\Delta+1)u_{\\varepsilon} + \\beta(u_{\\varepsilon}) + \\pi_{\\varepsilon}(u_{\\varepsilon})) = g \\quad \\mbox{in}\\ \\Omega\\times(0, T), \\] which is called the Cahn--Hilliard system, even if $\\Omega \\subset \\mathbb{R}^N$ ($N \\in \\mathbb{N}$) is an unbounded domain. Moreover, it can be seen that the Stefan problem is covered in the framework of this paper.

Self-adjointness of deformed unbounded operators

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

Much, Albert

2015-09-15

We consider deformations of unbounded operators by using the novel construction tool of warped convolutions. By using the Kato-Rellich theorem, we show that unbounded self-adjoint deformed operators are self-adjoint if they satisfy a certain condition. This condition proves itself to be necessary for the oscillatory integral to be well-defined. Moreover, different proofs are given for self-adjointness of deformed unbounded operators in the context of quantum mechanics and quantum field theory.

Hepatic cyst penetration of cefazolin in patients receiving aspiration sclerotherapy.

PubMed

Lantinga, M A; Wijnands, T F M; Te Morsche, R H M; de Sévaux, R G L; Kuipers, S; Allegaert, K; Burger, D; Drenth, J P H

2016-09-01

Hepatic cyst infection is a potentially severe complication in cystic disease. Treatment demands effective antibiotic concentrations within the infected cyst. The aim of this study was to use elective hepatic cyst drainage as a unique pharmacokinetic model to investigate whether cefazolin, a first-generation cephalosporin, is able to penetrate hepatic cysts. Patients scheduled to undergo percutaneous aspiration sclerotherapy of a symptomatic non-infected, non-neoplastic hepatic cyst were eligible for this study. All participants received a single perioperative prophylactic dose of cefazolin (1000 mg, intravenously). We collected blood and cyst fluid samples to determine total and unbound cefazolin concentrations using HPLC. The primary outcome was hepatic cyst penetration, expressed as the ratio (%) of unbound concentration of cefazolin in cyst fluid to plasma (both in mg/L). We included eight patients [male = 25%, median age = 60 years (IQR 54-75), median estimated glomerular filtration rate = 97 mL/min/1.73 m(2) (IQR 67-102) and median serum albumin = 40 g/L (IQR 37-40)]. We detected low concentrations of unbound cefazolin in cyst fluid (≤1.0 mg/L). The median plasma unbound cefazolin peak level (immediately after cefazolin administration) was 36.6 mg/L (IQR 23.7-54.1) and the level at the time of cyst fluid aspiration was 16.1 mg/L (IQR 13.0-20.1). In total, the hepatic cyst penetration of free cefazolin was only 2.2% (IQR 0.7-5.2). We developed a study model to investigate the penetration of antibiotics into hepatic cysts. Cefazolin did not reach adequate intracystic concentrations. Future studies should explore alternatives. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Conformational Heterogeneity of Unbound Proteins Enhances Recognition in Protein-Protein Encounters.

PubMed

Pallara, Chiara; Rueda, Manuel; Abagyan, Ruben; Fernández-Recio, Juan

2016-07-12

To understand cellular processes at the molecular level we need to improve our knowledge of protein-protein interactions, from a structural, mechanistic, and energetic point of view. Current theoretical studies and computational docking simulations show that protein dynamics plays a key role in protein association and support the need for including protein flexibility in modeling protein interactions. Assuming the conformational selection binding mechanism, in which the unbound state can sample bound conformers, one possible strategy to include flexibility in docking predictions would be the use of conformational ensembles originated from unbound protein structures. Here we present an exhaustive computational study about the use of precomputed unbound ensembles in the context of protein docking, performed on a set of 124 cases of the Protein-Protein Docking Benchmark 3.0. Conformational ensembles were generated by conformational optimization and refinement with MODELLER and by short molecular dynamics trajectories with AMBER. We identified those conformers providing optimal binding and investigated the role of protein conformational heterogeneity in protein-protein recognition. Our results show that a restricted conformational refinement can generate conformers with better binding properties and improve docking encounters in medium-flexible cases. For more flexible cases, a more extended conformational sampling based on Normal Mode Analysis was proven helpful. We found that successful conformers provide better energetic complementarity to the docking partners, which is compatible with recent views of binding association. In addition to the mechanistic considerations, these findings could be exploited for practical docking predictions of improved efficiency.

Approaching the Ultimate Limits of Communication Efficiency with a Photon-Counting Detector

NASA Technical Reports Server (NTRS)

Erkmen, Baris; Moision, Bruce; Dolinar, Samuel J.; Birnbaum, Kevin M.; Divsalar, Dariush

2012-01-01

Coherent states achieve the Holevo capacity of a pure-loss channel when paired with an optimal measurement, but a physical realization of this measurement is as of yet unknown, and it is also likely to be of high complexity. In this paper, we focus on the photon-counting measurement and study the photon and dimensional efficiencies attainable with modulations over classical- and nonclassical-state alphabets. We first review the state-of-the-art coherent on-off-keying (OOK) with a photoncounting measurement, illustrating its asymptotic inefficiency relative to the Holevo limit. We show that a commonly made Poisson approximation in thermal noise leads to unbounded photon information efficiencies, violating the conjectured Holevo limit. We analyze two binary-modulation architectures that improve upon the dimensional versus photon efficiency tradeoff achievable with conventional OOK. We show that at high photon efficiency these architectures achieve an efficiency tradeoff that differs from the best possible tradeoff--determined by the Holevo capacity--by only a constant factor. The first architecture we analyze is a coherent-state transmitter that relies on feedback from the receiver to control the transmitted energy. The second architecture uses a single-photon number-state source.

Ionic effects on the temperature-force phase diagram of DNA.

PubMed

Amnuanpol, Sitichoke

2017-12-01

Double-stranded DNA (dsDNA) undergoes a structural transition to single-stranded DNA (ssDNA) in many biologically important processes such as replication and transcription. This strand separation arises in response either to thermal fluctuations or to external forces. The roles of ions are twofold, shortening the range of the interstrand potential and renormalizing the DNA elastic modulus. The dsDNA-to-ssDNA transition is studied on the basis that dsDNA is regarded as a bound state while ssDNA is regarded as an unbound state. The ground state energy of DNA is obtained by mapping the statistical mechanics problem to the imaginary time quantum mechanics problem. In the temperature-force phase diagram the critical force F c (T) increases logarithmically with the Na + concentration in the range from 32 to 110 mM. Discussing this logarithmic dependence of F c (T) within the framework of polyelectrolyte theory, it inevitably suggests a constraint on the difference between the interstrand separation and the length per unit charge during the dsDNA-to-ssDNA transition.

Is the Kerr black hole a super accelerator?

NASA Astrophysics Data System (ADS)

Krasnikov, S.; Skvortsova, M. V.

2018-02-01

A number of long-standing puzzles, such as the origin of extreme-energy cosmic rays, could perhaps be solved if we found a mechanism for effectively transferring energy from black holes to particles and, correspondingly, accelerating the latter to (unboundedly, as long as we neglect the back reaction) large velocities. As of today the only such candidate mechanism in the case of the nonextreme Kerr black hole is colliding a particle that freely falls from infinity with a particle whose trajectory is subject to some special requirements to fulfil which it has to be suitably corrected by auxiliary collisions. In the present paper we prove that—at least when the relevant particles move in the equatorial plane and experience a single correcting collision—this mechanism does not work too. The energy of the final collision becomes unboundedly high only when the energies of the incoming particles do.

Approximation of discrete-time LQG compensators for distributed systems with boundary input and unbounded measurement

NASA Technical Reports Server (NTRS)

Gibson, J. S.; Rosen, I. G.

1987-01-01

The approximation of optimal discrete-time linear quadratic Gaussian (LQG) compensators for distributed parameter control systems with boundary input and unbounded measurement is considered. The approach applies to a wide range of problems that can be formulated in a state space on which both the discrete-time input and output operators are continuous. Approximating compensators are obtained via application of the LQG theory and associated approximation results for infinite dimensional discrete-time control systems with bounded input and output. Numerical results for spline and modal based approximation schemes used to compute optimal compensators for a one dimensional heat equation with either Neumann or Dirichlet boundary control and pointwise measurement of temperature are presented and discussed.

Continuum Level Density in Complex Scaling Method

NASA Astrophysics Data System (ADS)

Suzuki, R.; Myo, T.; Katō, K.

2005-11-01

A new calculational method of continuum level density (CLD) at unbound energies is studied in the complex scaling method (CSM). It is shown that the CLD can be calculated by employing the discretization of continuum states in the CSM without any smoothing technique.

Dynamical decoupling of unbounded Hamiltonians

NASA Astrophysics Data System (ADS)

Arenz, Christian; Burgarth, Daniel; Facchi, Paolo; Hillier, Robin

2018-03-01

We investigate the possibility to suppress interactions between a finite dimensional system and an infinite dimensional environment through a fast sequence of unitary kicks on the finite dimensional system. This method, called dynamical decoupling, is known to work for bounded interactions, but physical environments such as bosonic heat baths are usually modeled with unbounded interactions; hence, here, we initiate a systematic study of dynamical decoupling for unbounded operators. We develop a sufficient decoupling criterion for arbitrary Hamiltonians and a necessary decoupling criterion for semibounded Hamiltonians. We give examples for unbounded Hamiltonians where decoupling works and the limiting evolution as well as the convergence speed can be explicitly computed. We show that decoupling does not always work for unbounded interactions and we provide both physically and mathematically motivated examples.

Studies of X-ray burst reactions with radioactive ion beams from RESOLUT

NASA Astrophysics Data System (ADS)

Blackmon, J. C.; Wiedenhöver, I.; Belarge, J.; Kuvin, S. A.; Anastasiou, M.; Baby, L. T.; Baker, J.; Colbert, K.; Deibel, C. M.; de Lucio, O.; Gardiner, H. E.; Gay, D. L.; Good, E.; Höflich, P.; Hood, A. A. D.; Keely, N.; Lai, J.; Laminack, A.; Linhardt, L. E.; Lighthall, J.; Macon, K. T.; Need, E.; Quails, N.; Rasco, B. C.; Rijal, N.; Volya, A.

2018-01-01

Reactions on certain proton-rich, radioactive nuclei have been shown to have a significant influence on X-ray bursts. We provide an overview of two recent measurements of important X-ray burst reactions using in-flight radioactive ion beams from the RESOLUT facility at the J. D. Fox Superconducting Accelerator Laboratory at Florida State University. The 17F(d,n)18Ne reaction was measured, and Asymptotic Normalization Coefficients were extracted for bound states in 18Ne that determine the direct-capture cross section dominating the 17F(p,γ)18Ne reaction rate for T≲ 0.45 GK. Unbound resonant states were also studied, and the single-particle strength for the 4.523-MeV (3+) state was found to be consistent with previous results. The 19Ne(d,n)20Na proton transfer reaction was used to study resonances in the 19Ne(p,γ)20Na reaction. The most important 2.65-MeV state in 20Na was observed to decay by proton emission to both the ground and first-excited states in 19Ne, providing strong evidence for a 3+ spin assignment and indicating that proton capture on the thermally-populated first-excited state in 19Ne is an important contributor to the 19Ne(p,γ)20Na reaction rate.

Modeling of Abrasion and Crushing of Unbound Granular Materials During Compaction

NASA Astrophysics Data System (ADS)

Ocampo, Manuel S.; Caicedo, Bernardo

2009-06-01

Unbound compacted granular materials are commonly used in engineering structures as layers in road pavements, railroad beds, highway embankments, and foundations. These structures are generally subjected to dynamic loading by construction operations, traffic and wheel loads. These repeated or cyclic loads cause abrasion and crushing of the granular materials. Abrasion changes a particle's shape, and crushing divides the particle into a mixture of many small particles of varying sizes. Particle breakage is important because the mechanical and hydraulic properties of these materials depend upon their grain size distribution. Therefore, it is important to evaluate the evolution of the grain size distribution of these materials. In this paper an analytical model for unbound granular materials is proposed in order to evaluate particle crushing of gravels and soils subjected to cyclic loads. The model is based on a Markov chain which describes the development of grading changes in the material as a function of stress levels. In the model proposed, each particle size is a state in the system, and the evolution of the material is the movement of particles from one state to another in n steps. Each step is a load cycle, and movement between states is possible with a transition probability. The crushing of particles depends on the mechanical properties of each grain and the packing density of the granular material. The transition probability was calculated using both the survival probability defined by Weibull and the compressible packing model developed by De Larrard. Material mechanical properties are considered using the Weibull probability theory. The size and shape of the grains, as well as the method of processing the packing density are considered using De Larrard's model. Results of the proposed analytical model show a good agreement with the experimental tests carried out using the gyratory compaction test.

Compact solid-state CMOS single-photon detector array for in vivo NIR fluorescence lifetime oncology measurements.

PubMed

Homulle, H A R; Powolny, F; Stegehuis, P L; Dijkstra, J; Li, D-U; Homicsko, K; Rimoldi, D; Muehlethaler, K; Prior, J O; Sinisi, R; Dubikovskaya, E; Charbon, E; Bruschini, C

2016-05-01

In near infrared fluorescence-guided surgical oncology, it is challenging to distinguish healthy from cancerous tissue. One promising research avenue consists in the analysis of the exogenous fluorophores' lifetime, which are however in the (sub-)nanosecond range. We have integrated a single-photon pixel array, based on standard CMOS SPADs (single-photon avalanche diodes), in a compact, time-gated measurement system, named FluoCam. In vivo measurements were carried out with indocyanine green (ICG)-modified derivatives targeting the αvβ 3 integrin, initially on a genetically engineered mouse model of melanoma injected with ICG conjugated with tetrameric cyclic pentapeptide (ICG-E[c(RGD f K)4]), then on mice carrying tumour xenografts of U87-MG (a human primary glioblastoma cell line) injected with monomeric ICG-c(RGD f K). Measurements on tumor, muscle and tail locations allowed us to demonstrate the feasibility of in vivo lifetime measurements with the FluoCam, to determine the characteristic lifetimes (around 500 ps) and subtle lifetime differences between bound and unbound ICG-modified fluorophores (10% level), as well as to estimate the available photon fluxes under realistic conditions.

Population pharmacokinetics of phenytoin in critically ill children.

PubMed

Hennig, Stefanie; Norris, Ross; Tu, Quyen; van Breda, Karin; Riney, Kate; Foster, Kelly; Lister, Bruce; Charles, Bruce

2015-03-01

The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration. © 2014, The American College of Clinical Pharmacology.

Plasma concentrations of fentanyl with subcutaneous infusion in palliative care patients.

PubMed

Miller, R S; Peterson, G M; Abbott, F; Maddocks, I; Parker, D; McLean, S

1995-12-01

1. Plasma concentrations of fentanyl were measured by g.c. in 20 patients (median age: 75 years and range: 54-86 years; eight females) in palliative care receiving the drug by continuous s.c. infusion (median rate: 1200 micrograms day-1 and range: 100-5000 micrograms day-1). 2. The infusion rate was significantly related to the duration of therapy (Spearman rho = 0.56, P < 0.05). The total steady-state plasma concentrations of fentanyl ranged between 0.1 and 9 ng ml-1, with a median of 1 ng ml-1. The unbound fraction of fentanyl in the plasma ranged from 17.8 to 44.4%, with a median value of 33.6%. Infusion rates and both total and unbound plasma concentrations of fentanyl were correlated (Spearman rho = 0.92, P < 0.05 in each case). Even with standardization for dosage, there was an eightfold variation in total plasma concentrations and 3.5-fold variation in unbound plasma concentrations of fentanyl. 3. There is considerable inter-patient variability in the pharmacokinetics of fentanyl with s.c. infusion in the palliative care setting, which necessitates careful titration of dosage according to individual clinical response.

Etravirine in CSF is highly protein bound

PubMed Central

Nguyen, Anh; Rossi, Steven; Croteau, David; Best, Brookie M.; Clifford, David; Collier, Ann C.; Gelman, Benjamin; Marra, Christina; McArthur, Justin; McCutchan, J. Allen; Morgello, Susan; Simpson, David; Ellis, Ronald J.; Grant, Igor; Capparelli, Edmund; Letendre, Scott; Ellis, Ronald J.; Letendre, Scott; Abramson, Ian; Al-Lozi, Muhammad; Atkinson, J. Hampton; Capparelli, Edmund; Clifford, David; Collier, Ann C.; Fennema-Notestine, Christine; Gamst, Anthony C.; Gelman, Benjamin; Heaton, Robert K.; Marcotte, Thomas D.; Marra, Christina; McCutchan, J. Allen; McArthur, Justin; Morgello, Susan; Simpson, David; Smith, Davey M.; Taylor, Michael J.; Theilmann, Rebecca; Vaida, Florin; Paul Woods, Steven; Cushman, Clint; Dawson, Matthew; Franklin, Donald; Jones, Trudy; Lewis, Kristen; Mintz, Letty; Teshome, Mengesha; Toperoff, Will

2013-01-01

Objectives Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL). Methods Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL. Results Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens. Conclusions Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS. PMID:23335197

Quasi-Newton methods for parameter estimation in functional differential equations

NASA Technical Reports Server (NTRS)

Brewer, Dennis W.

1988-01-01

A state-space approach to parameter estimation in linear functional differential equations is developed using the theory of linear evolution equations. A locally convergent quasi-Newton type algorithm is applied to distributed systems with particular emphasis on parameters that induce unbounded perturbations of the state. The algorithm is computationally implemented on several functional differential equations, including coefficient and delay estimation in linear delay-differential equations.

Localized states in an unbounded neural field equation with smooth firing rate function: a multi-parameter analysis.

PubMed

Faye, Grégory; Rankin, James; Chossat, Pascal

2013-05-01

The existence of spatially localized solutions in neural networks is an important topic in neuroscience as these solutions are considered to characterize working (short-term) memory. We work with an unbounded neural network represented by the neural field equation with smooth firing rate function and a wizard hat spatial connectivity. Noting that stationary solutions of our neural field equation are equivalent to homoclinic orbits in a related fourth order ordinary differential equation, we apply normal form theory for a reversible Hopf bifurcation to prove the existence of localized solutions; further, we present results concerning their stability. Numerical continuation is used to compute branches of localized solution that exhibit snaking-type behaviour. We describe in terms of three parameters the exact regions for which localized solutions persist.

Stabilisation of discrete-time polynomial fuzzy systems via a polynomial lyapunov approach

NASA Astrophysics Data System (ADS)

Nasiri, Alireza; Nguang, Sing Kiong; Swain, Akshya; Almakhles, Dhafer

2018-02-01

This paper deals with the problem of designing a controller for a class of discrete-time nonlinear systems which is represented by discrete-time polynomial fuzzy model. Most of the existing control design methods for discrete-time fuzzy polynomial systems cannot guarantee their Lyapunov function to be a radially unbounded polynomial function, hence the global stability cannot be assured. The proposed control design in this paper guarantees a radially unbounded polynomial Lyapunov functions which ensures global stability. In the proposed design, state feedback structure is considered and non-convexity problem is solved by incorporating an integrator into the controller. Sufficient conditions of stability are derived in terms of polynomial matrix inequalities which are solved via SOSTOOLS in MATLAB. A numerical example is presented to illustrate the effectiveness of the proposed controller.

Exploration of Toeplitz-like matrices with unbounded symbols is not a purely academic journey

NASA Astrophysics Data System (ADS)

Böttcher, A.; Garoni, C.; Serra-Capizzano, S.

2017-11-01

It is often asked why Toeplitz-like matrices with unbounded symbols are worth studying. This paper gives an answer by presenting several concrete problems that motivate such studies. It surveys the central results of the theory of Generalized Locally Toeplitz (GLT) sequences in a self-contained tool-kit fashion, and gives a new extension from bounded Riemann integrable functions to unbounded almost everywhere continuous functions. The emergence of unbounded symbols is illustrated by local grid refinements in finite difference and finite element discretizations and also by preconditioning strategies. Bibliography: 40 titles.

Numerical bias in bounded and unbounded number line tasks.

PubMed

Cohen, Dale J; Blanc-Goldhammer, Daryn

2011-04-01

The number line task is often used to assess children's and adults' underlying representations of integers. Traditional bounded number line tasks, however, have limitations that can lead to misinterpretation. Here we present a new task, an unbounded number line task, that overcomes these limitations. In Experiment 1, we show that adults use a biased proportion estimation strategy to complete the traditional bounded number line task. In Experiment 2, we show that adults use a dead-reckoning integer estimation strategy in our unbounded number line task. Participants revealed a positively accelerating numerical bias in both tasks, but showed scalar variance only in the unbounded number line task. We conclude that the unbounded number line task is a more pure measure of integer representation than the bounded number line task, and using these results, we present a preliminary description of adults' underlying representation of integers.

Search for excited states in 25O

NASA Astrophysics Data System (ADS)

Jones, M. D.; Fossez, K.; Baumann, T.; DeYoung, P. A.; Finck, J. E.; Frank, N.; Kuchera, A. N.; Michel, N.; Nazarewicz, W.; Rotureau, J.; Smith, J. K.; Stephenson, S. L.; Stiefel, K.; Thoennessen, M.; Zegers, R. G. T.

2017-11-01

Background: Theoretical calculations suggest the presence of low-lying excited states in 25O. Previous experimental searches by means of proton knockout on 26F produced no evidence for such excitations. Purpose: We search for excited states in 25O using the 24O(d ,p ) 25O reaction. The theoretical analysis of excited states in unbound O,2725 is based on the configuration interaction approach that accounts for couplings to the scattering continuum. Method: We use invariant-mass spectroscopy to measure neutron-unbound states in 25O. For the theoretical approach, we use the complex-energy Gamow Shell Model and Density Matrix Renormalization Group method with a finite-range two-body interaction optimized to the bound states and resonances of O-2623, assuming a core of 22O. We predict energies, decay widths, and asymptotic normalization coefficients. Results: Our calculations in a large s p d f space predict several low-lying excited states in 25O of positive and negative parity, and we obtain an experimental limit on the relative cross section of a possible Jπ=1/2 + state with respect to the ground state of 25O at σ1 /2 +/σg .s .=0 .25-0.25+1.0 . We also discuss how the observation of negative parity states in 25O could guide the search for the low-lying negative parity states in 27O. Conclusion: Previous experiments based on the proton knockout of 26F suffered from the low cross sections for the population of excited states in 25O because of low spectroscopic factors. In this respect, neutron transfer reactions carry more promise.

Bounded energy states in homogeneous turbulent shear flow: An alternative view

NASA Technical Reports Server (NTRS)

Bernard, Peter S.; Speziale, Charles G.

1990-01-01

The equilibrium structure of homogeneous turbulent shear flow is investigated from a theoretical standpoint. Existing turbulence models, in apparent agreement with physical and numerical experiments, predict an unbounded exponential time growth of the turbulent kinetic energy and dissipation rate; only the anisotropy tensor and turbulent time scale reach a structural equilibrium. It is shown that if vortex stretching is accounted for in the dissipation rate transport equation, then there can exist equilibrium solutions, with bounded energy states, where the turbulence production is balanced by its dissipation. Illustrative calculations are present for a k-epsilon model modified to account for vortex stretching. The calculations indicate an initial exponential time growth of the turbulent kinetic energy and dissipation rate for elapsed times that are as large as those considered in any of the previously conducted physical or numerical experiments on homogeneous shear flow. However, vortex stretching eventually takes over and forces a production-equals-dissipation equilibrium with bounded energy states. The validity of this result is further supported by an independent theoretical argument. It is concluded that the generally accepted structural equilibrium for homogeneous shear flow with unbounded component energies is in need of re-examination.

Free-energy landscape of intrinsically disordered proteins investigated by all-atom multicanonical molecular dynamics.

PubMed

Higo, Junichi; Umezawa, Koji

2014-01-01

We introduce computational studies on intrinsically disordered proteins (IDPs). Especially, we present our multicanonical molecular dynamics (McMD) simulations of two IDP-partner systems: NRSF-mSin3 and pKID-KIX. McMD is one of enhanced conformational sampling methods useful for conformational sampling of biomolecular systems. IDP adopts a specific tertiary structure upon binding to its partner molecule, although it is unstructured in the unbound state (i.e. the free state). This IDP-specific property is called "coupled folding and binding". The McMD simulation treats the biomolecules with an all-atom model immersed in an explicit solvent. In the initial configuration of simulation, IDP and its partner molecules are set to be distant from each other, and the IDP conformation is disordered. The computationally obtained free-energy landscape for coupled folding and binding has shown that native- and non-native-complex clusters distribute complicatedly in the conformational space. The all-atom simulation suggests that both of induced-folding and population-selection are coupled complicatedly in the coupled folding and binding. Further analyses have exemplified that the conformational fluctuations (dynamical flexibility) in the bound and unbound states are essentially important to characterize IDP functioning.

Unbound particles in dark matter halos

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

Behroozi, Peter S.; Wechsler, Risa H.; Loeb, Abraham, E-mail: behroozi@stanford.edu, E-mail: aloeb@cfa.harvard.edu, E-mail: rwechsler@stanford.edu

2013-06-01

We investigate unbound dark matter particles in halos by tracing particle trajectories in a simulation run to the far future (a = 100). We find that the traditional sum of kinetic and potential energies is a very poor predictor of which dark matter particles will eventually become unbound from halos. We also study the mass fraction of unbound particles, which increases strongly towards the edges of halos, and decreases significantly at higher redshifts. We discuss implications for dark matter detection experiments, precision calibrations of the halo mass function, the use of baryon fractions to constrain dark energy, and searches formore » intergalactic supernovae.« less

Unbound particles in dark matter halos

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

Behroozi, Peter S.; Loeb, Abraham; Wechsler, Risa H.

2013-06-13

We investigate unbound dark matter particles in halos by tracing particle trajectories in a simulation run to the far future (a = 100). We find that the traditional sum of kinetic and potential energies is a very poor predictor of which dark matter particles will eventually become unbound from halos. We also study the mass fraction of unbound particles, which increases strongly towards the edges of halos, and decreases significantly at higher redshifts. We discuss implications for dark matter detection experiments, precision calibrations of the halo mass function, the use of baryon fractions to constrain dark energy, and searches formore » intergalactic supernovae.« less

MMT HYPERVELOCITY STAR SURVEY. II. FIVE NEW UNBOUND STARS

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

Brown, Warren R.; Geller, Margaret J.; Kenyon, Scott J., E-mail: wbrown@cfa.harvard.edu, E-mail: mgeller@cfa.harvard.edu, E-mail: skenyon@cfa.harvard.edu

2012-05-20

We present the discovery of five new unbound hypervelocity stars (HVSs) in the outer Milky Way halo. Using a conservative estimate of Galactic escape velocity, our targeted spectroscopic survey has now identified 16 unbound HVSs as well as a comparable number of HVSs ejected on bound trajectories. A Galactic center origin for the HVSs is supported by their unbound velocities, the observed number of unbound stars, their stellar nature, their ejection time distribution, and their Galactic latitude and longitude distribution. Other proposed origins for the unbound HVSs, such as runaway ejections from the disk or dwarf galaxy tidal debris, cannotmore » be reconciled with the observations. An intriguing result is the spatial anisotropy of HVSs on the sky, which possibly reflects an anisotropic potential in the central 10-100 pc region of the Galaxy. Further progress requires measurement of the spatial distribution of HVSs over the southern sky. Our survey also identifies seven B supergiants associated with known star-forming galaxies; the absence of B supergiants elsewhere in the survey implies there are no new star-forming galaxies in our survey footprint to a depth of 1-2 Mpc.« less

Disappearance kinetics of solutes from synovial fluid after intra-articular injection.

PubMed Central

Owen, S G; Francis, H W; Roberts, M S

1994-01-01

1. Five rheumatoid patients with a knee joint effusion participated in the study. An aqueous solution (0.1 to 0.2 ml) containing paracetamol, salicylate, diclofenac and [125I]-albumin was injected into a given joint to yield target concentrations of approximately 20 micrograms ml-1 for diclofenac, salicylate and paracetamol and 10(8) counts ml-1 for [125I]-albumin. 2. Paracetamol, salicylate and diclofenac were analysed in synovial fluid by h.p.l.c. [125I]-albumin was analysed using gamma counting. 3. The clearances (+/- s.d.) obtained for the solutes were [125I]-albumin (0.0053 +/- 0.0019 l h-1), diclofenac (0.0096 +/- 0.0061 l h-1), salicylate (0.024 +/- 0.022 l h-1) and paracetamol (0.055 +/- 0.041 l h-1). The corresponding fractions unbound of these solutes in synovial fluid were 0.0, < or = 0.01, 0.34 +/- 0.09 and 0.85 +/- 0.10, respectively. 4. Diffusion of unbound solute through the synovium is estimated to account for (+/- s.d.) 0.52 +/- 0.08, 0.87 +/- 0.06 and 0.99 +/- 0.01 of the total clearance of diclofenac, salicylate and paracetamol from the joint space, respectively. The remaining proportion of clearance is accounted for by efflux of solute bound to albumin. 5. An expression for the ratio of synovial fluid to total plasma concentrations after systemic administration was developed to include both diffusion of unbound solute and albumin flux. Most solutes appear to satisfy the conditions in which this expression reduces to the limiting case where the unbound concentration of the solute is identical in the synovial fluid and plasma under steady state conditions. PMID:7833225

Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs.

PubMed

Kuroha, Masanori; Azumano, Akinori; Kuze, Yoji; Shimoda, Minoru; Kokue, Eiichi

2002-01-01

To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.

Revisiting atenolol as a low passive permeability marker.

PubMed

Chen, Xiaomei; Slättengren, Tim; de Lange, Elizabeth C M; Smith, David E; Hammarlund-Udenaes, Margareta

2017-10-31

Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and the intestinal epithelium. However, the extent of S-atenolol (the active enantiomer) distribution in brain has never been evaluated, at equilibrium, to confirm that no transporters are involved in its transport at the BBB. To assess whether S-atenolol, in fact, depicts the characteristics of a low passive permeable drug at the BBB, a microdialysis study was performed in rats to monitor the unbound concentrations of S-atenolol in brain extracellular fluid (ECF) and plasma during and after intravenous infusion. A pharmacokinetic model was developed, based on the microdialysis data, to estimate the permeability clearance of S-atenolol into and out of brain. In addition, the nonspecific binding of S-atenolol in brain homogenate was evaluated using equilibrium dialysis. The steady-state ratio of unbound S-atenolol concentrations in brain ECF to that in plasma (i.e., K p,uu,brain ) was 3.5% ± 0.4%, a value much less than unity. The unbound volume of distribution in brain (V u, brain ) of S-atenolol was also calculated as 0.69 ± 0.10 mL/g brain, indicating that S-atenolol is evenly distributed within brain parenchyma. Lastly, equilibrium dialysis showed limited nonspecific binding of S-atenolol in brain homogenate with an unbound fraction (f u,brain ) of 0.88 ± 0.07. It is concluded, based on K p,uu,brain being much smaller than unity, that S-atenolol is actively effluxed at the BBB, indicating the need to re-consider S-atenolol as a model drug for passive permeability studies of BBB transport or intestinal absorption.

Photodynamics of the small BLUF protein BlrB from Rhodobacter sphaeroides.

PubMed

Zirak, P; Penzkofer, A; Schiereis, T; Hegemann, P; Jung, A; Schlichting, I

2006-06-01

The BLUF protein BlrB from the non-sulphur anoxyphototrophic purple bacterium Rhodobacter sphaeroides is characterized by absorption and emission spectroscopy. BlrB expressed from E. coli binding FAD, FMN, and riboflavin (called BrlB(I)) and recombinant BlrB containing only FAD (called BlrB(II)) are investigated. The dark-adapted proteins exist in two different receptor conformations (receptor states) with different sub-nanosecond fluorescence lifetimes (BLUF(r,f) and BLUF(r,sl)). Some of the flavin-cofactor (ca. 8%) is unbound in thermodynamic equilibrium with the bound cofactor. The two receptor conformations are transformed to putative signalling states (BLUF(s,f) and BLUF(s,sl)) of decreased fluorescence efficiency and shortened fluorescence lifetime by blue-light excitation. In the dark at room temperature both signalling states recover back to the initial receptor states with a time constant of about 2s. Quantum yields of signalling state formation of about 90% for BlrB(II) and about 40% for BlrB(I) were determined by intensity dependent transmission measurements. Extended blue-light excitation causes unbound flavin degradation (formation of lumichrome and lumiflavin-derivatives) and bound cofactor conversion to the semiquinone form. The flavin-semiquinone further reduces and the reduced flavin re-oxidizes back in the dark. A photo-dynamics scheme is presented and relevant quantum efficiencies and time constants are determined.

A Study on Pharmacokinetics of Bosentan with Systems Modeling, Part 1: Translating Systemic Plasma Concentration to Liver Exposure in Healthy Subjects.

PubMed

Li, Rui; Niosi, Mark; Johnson, Nathaniel; Tess, David A; Kimoto, Emi; Lin, Jian; Yang, Xin; Riccardi, Keith A; Ryu, Sangwoo; El-Kattan, Ayman F; Maurer, Tristan S; Tremaine, Larry M; Di, Li

2018-04-01

Understanding liver exposure of hepatic transporter substrates in clinical studies is often critical, as it typically governs pharmacodynamics, drug-drug interactions, and toxicity for certain drugs. However, this is a challenging task since there is currently no easy method to directly measure drug concentration in the human liver. Using bosentan as an example, we demonstrate a new approach to estimate liver exposure based on observed systemic pharmacokinetics from clinical studies using physiologically based pharmacokinetic modeling. The prediction was verified to be both accurate and precise using sensitivity analysis. For bosentan, the predicted pseudo steady-state unbound liver-to-unbound systemic plasma concentration ratio was 34.9 (95% confidence interval: 4.2, 50). Drug-drug interaction (i.e., CYP3A and CYP2B6 induction) and inhibition of hepatic transporters (i.e., bile salt export pump, multidrug resistance-associated proteins, and sodium-taurocholate cotransporting polypeptide) were predicted based on the estimated unbound liver tissue or plasma concentrations. With further validation and refinement, we conclude that this approach may serve to predict human liver exposure and complement other methods involving tissue biopsy and imaging. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Formal Definitions of Unbounded Evolution and Innovation Reveal Universal Mechanisms for Open-Ended Evolution in Dynamical Systems.

PubMed

Adams, Alyssa; Zenil, Hector; Davies, Paul C W; Walker, Sara Imari

2017-04-20

Open-ended evolution (OEE) is relevant to a variety of biological, artificial and technological systems, but has been challenging to reproduce in silico. Most theoretical efforts focus on key aspects of open-ended evolution as it appears in biology. We recast the problem as a more general one in dynamical systems theory, providing simple criteria for open-ended evolution based on two hallmark features: unbounded evolution and innovation. We define unbounded evolution as patterns that are non-repeating within the expected Poincare recurrence time of an isolated system, and innovation as trajectories not observed in isolated systems. As a case study, we implement novel variants of cellular automata (CA) where the update rules are allowed to vary with time in three alternative ways. Each is capable of generating conditions for open-ended evolution, but vary in their ability to do so. We find that state-dependent dynamics, regarded as a hallmark of life, statistically out-performs other candidate mechanisms, and is the only mechanism to produce open-ended evolution in a scalable manner, essential to the notion of ongoing evolution. This analysis suggests a new framework for unifying mechanisms for generating OEE with features distinctive to life and its artifacts, with broad applicability to biological and artificial systems.

The Relationship between Children's Familiarity with Numbers and Their Performance in Bounded and Unbounded Number Line Estimations

ERIC Educational Resources Information Center

Ebersbach, Mirjam; Luwel, Koen; Verschaffel, Lieven

2015-01-01

Children's estimation skills on a bounded and unbounded number line task were assessed in the light of their familiarity with numbers. Kindergartners, first graders, and second graders (N = 120) estimated the position of numbers on a 1--100 number line, marked with either two reference points (i.e., 1 and 10: unbounded condition) or three…

The Gamow-state description of the decay energy spectrum of neutron-unbound 25O

NASA Astrophysics Data System (ADS)

Id Betan, R. M.; de la Madrid, R.

2018-02-01

We show the feasibility of calculating the decay energy spectrum of neutron emitting nuclei within the Gamow-state description of resonances by obtaining the decay energy spectrum of 25O. We model this nucleus as a valence neutron interacting with an 24O inert core, and we obtain the resulting resonant energies, widths and decay energy spectra for the ground and first excited states. We also discuss the similarities and differences between the decay energy spectrum of a Gamow state and the Breit-Wigner distribution with energy-dependent width.

Search for unbound nuclides and beam/fragment optics with the MoNA/LISA segmented target at NSCL

NASA Astrophysics Data System (ADS)

Gueye, Paul; Frank, Nathan; Thoennessen, Michael; Redpath, Thomas; MoNA Collaboration

2017-09-01

A multi-layered Si/Be segmented target consisting of three 700 mg/cm2 thick Be9 slabs and four 140 microns Si detectors was used by the MoNA Collaboration at the National Superconducting Cyclotron Laboratory of Michigan State University to study the O26 lifetime. This target provides unprecedented information on the incident beams and fragments (energy loss and position), thus allowing for better determination of the incident and outgoing energies and momenta of the detected particles compare to previous experiments conducted at this facility. With the availability of a newly developed Geant4 Monte Carlo simulation of the full N2 vault, we will present and discuss the performances of this target. Search for unbound nuclides and beam/fragment optics with the MoNA/LISA segmented target at NSCL.

Effects of type 1 and type 2 diabetes on the pharmacokinetics of tramadol enantiomers in patients with neuropathic pain phenotyped as cytochrome P450 2D6 extensive metabolizers.

PubMed

de Moraes, Natália Valadares; Lauretti, Gabriela Rocha; Lanchote, Vera Lucia

2014-09-01

The aim of this study was to evaluate the influence of poorly controlled type 1 (T1DM) and type 2 diabetes mellitus (T2DM) on the pharmacokinetics and metabolism of tramadol enantiomers in patients with neuropathic pain. Nondiabetic patients (control group, n = 12), patients with T1DM (n = 9) or T2DM (n = 9), all with neuropathic pain and phenotyped as cytochrome P450 2D6 extensive metabolizers, received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected over a 24-h period. Patients with T1DM showed reduced Cmax of both tramadol enantiomers. The plasma concentrations of the active (+)-M1 were significantly reduced in T1DM (area under the curve plasma concentration versus time (AUC∞ ): 313.1 ng·h/ml) when compared with nondiabetic patients (AUC∞ : 1246.6 ng·h/ml). The fraction unbound of (+)-M1 was increased in patients with T1DM. Patients with T1DM and T2DM showed reduced AUC and increased fraction unbound of (-)-M1. The reduced total plasma concentrations of the active (+)-M1 in patients with T1DM may not be of clinical relevance because they are counterbalanced by the increased fraction unbound. © 2014 Royal Pharmaceutical Society.

The quantitative effect of serum albumin, serum urea, and valproic acid on unbound phenytoin concentrations in children.

PubMed

ter Heine, Rob; van Maarseveen, Erik M; van der Westerlaken, Monique M L; Braun, Kees P J; Koudijs, Suzanne M; Berg, Maarten J Ten; Malingré, Mirte M

2014-06-01

Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity. © The Author(s) 2013.

The spectral theorem for quaternionic unbounded normal operators based on the S-spectrum

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

Alpay, Daniel, E-mail: dany@math.bgu.ac.il; Kimsey, David P., E-mail: dpkimsey@gmail.com; Colombo, Fabrizio, E-mail: fabrizio.colombo@polimi.it

In this paper we prove the spectral theorem for quaternionic unbounded normal operators using the notion of S-spectrum. The proof technique consists of first establishing a spectral theorem for quaternionic bounded normal operators and then using a transformation which maps a quaternionic unbounded normal operator to a quaternionic bounded normal operator. With this paper we complete the foundation of spectral analysis of quaternionic operators. The S-spectrum has been introduced to define the quaternionic functional calculus but it turns out to be the correct object also for the spectral theorem for quaternionic normal operators. The lack of a suitable notion ofmore » spectrum was a major obstruction to fully understand the spectral theorem for quaternionic normal operators. A prime motivation for studying the spectral theorem for quaternionic unbounded normal operators is given by the subclass of unbounded anti-self adjoint quaternionic operators which play a crucial role in the quaternionic quantum mechanics.« less

Development of a Simple and Rapid Method to Measure the Free Fraction of Tacrolimus in Plasma Using Ultrafiltration and LC-MS/MS.

PubMed

Stienstra, Nicolaas A; Sikma, Maaike A; van Dapperen, Anouk L; de Lange, Dylan W; van Maarseveen, Erik M

2016-12-01

Tacrolimus is an immunosuppressant mainly used in the prophylaxis of solid organ transplant rejection. Therapeutic drug monitoring of tacrolimus is essential for avoiding toxicity related to overexposure and transplant rejection from underexposure. Previous studies suggest that unbound tacrolimus concentrations in the plasma may serve as a better predictor of tacrolimus-associated nephrotoxicity and neurotoxicity compared to tacrolimus concentration in whole blood. Monitoring the plasma concentrations of unbound tacrolimus might be of interest in preventing tacrolimus-related toxicity. Therefore, the aim was to develop a method for the measurement of total and unbound tacrolimus concentrations in plasma. The sample preparation for the determination of the plasma concentrations of unbound tacrolimus consisted of an easy-to-use ultrafiltration method followed by solid-phase extraction. To determine the total concentration of tacrolimus in plasma, a simple method based on protein precipitation was developed. The extracts were injected into a Thermo Scientific HyPurity C18 column using gradient elution. The analytes were detected by liquid chromatography-tandem mass spectrometry with positive ionization. The method was validated over a linear range of 1.00-200 ng/L for unbound tacrolimus concentrations in plasma and 100-3200 ng/L for total plasma concentrations. The lower limit of quantification was 1.00 ng/L in ultrafiltrate and 100 ng/L in plasma. The inaccuracy and imprecision for the determination of unbound tacrolimus concentrations in ultrafiltrate and plasma showed a maximum coefficients of variation (CV) of 11.7% and a maximum bias of 3.8%. A rapid and easy method based on ultrafiltration and liquid chromatography-tandem mass spectrometry was established to measure the total and unbound tacrolimus concentrations in plasma. This method can facilitate further investigations on the relationship between plasma concentrations of unbound tacrolimus and clinical outcomes in transplant recipients.

Complicated asymptotic behavior of solutions for porous medium equation in unbounded space

NASA Astrophysics Data System (ADS)

Wang, Liangwei; Yin, Jingxue; Zhou, Yong

2018-05-01

In this paper, we find that the unbounded spaces Yσ (RN) (0 < σ <2/m-1 ) can provide the work spaces where complicated asymptotic behavior appears in the solutions of the Cauchy problem of the porous medium equation. To overcome the difficulties caused by the nonlinearity of the equation and the unbounded solutions, we establish the propagation estimates, the growth estimates and the weighted L1-L∞ estimates for the solutions.

Metronidazole and hydroxymetronidazole central nervous system distribution: 2. cerebrospinal fluid concentration measurements in patients with external ventricular drain.

PubMed

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William; Marchand, Sandrine

2014-01-01

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0-τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0-τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.

Carprofen pharmacokinetics in plasma and in control and inflamed canine tissue fluid using in vivo ultrafiltration.

PubMed

Messenger, K M; Wofford, J A; Papich, M G

2016-02-01

Measurement of unbound drug concentrations at their sites of action is necessary for accurate PK/PD modeling. The objective of this study was to determine the unbound concentration of carprofen in canine interstitial fluid (ISF) using in vivo ultrafiltration and to compare pharmacokinetic parameters of free carprofen concentrations between inflamed and control tissue sites. We hypothesized that active concentrations of carprofen would exhibit different dispositions in ISF between inflamed vs. normal tissues. Bilateral ultrafiltration probes were placed subcutaneously in six healthy Beagle dogs 12 h prior to induction of inflammation. Two milliliters of either 2% carrageenan or saline control was injected subcutaneously at each probe site, 12 h prior to intravenous carprofen (4 mg/kg) administration. Plasma and ISF samples were collected at regular intervals for 72 h, and carprofen concentrations were determined using HPLC. Prostaglandin E2 (PGE2 ) concentrations were quantified in ISF using ELISA. Unbound carprofen concentrations were higher in ISF compared with predicted unbound plasma drug concentrations. Concentrations were not significantly higher in inflamed ISF compared with control ISF. Compartmental modeling was used to generate pharmacokinetic parameter estimates, which were not significantly different between sites. Terminal half-life (T½) was longer in the ISF compared with plasma. PGE2 in ISF decreased following administration of carprofen. In vivo ultrafiltration is a reliable method to determine unbound carprofen in ISF, and that disposition of unbound drug into tissue is much higher than predicted from unbound drug concentration in plasma. However, concentrations and pharmacokinetic parameter estimates are not significantly different in inflamed vs. un-inflamed tissues. © 2015 John Wiley & Sons Ltd.

Unbounding the mental number line—new evidence on children's spatial representation of numbers

PubMed Central

Link, Tanja; Huber, Stefan; Nuerk, Hans-Christoph; Moeller, Korbinian

2014-01-01

Number line estimation (i.e., indicating the position of a given number on a physical line) is a standard assessment of children's spatial representation of number magnitude. Importantly, there is an ongoing debate on the question in how far the bounded task version with start and endpoint given (e.g., 0 and 100) might induce specific estimation strategies and thus may not allow for unbiased inferences on the underlying representation. Recently, a new unbounded version of the task was suggested with only the start point and a unit fixed (e.g., the distance from 0 to 1). In adults this task provided a less biased index of the spatial representation of number magnitude. Yet, so far there are no children data available for the unbounded number line estimation task. Therefore, we conducted a cross-sectional study on primary school children performing both, the bounded and the unbounded version of the task. We observed clear evidence for systematic strategic influences (i.e., the consideration of reference points) in the bounded number line estimation task for children older than grade two whereas there were no such indications for the unbounded version for any one of the age groups. In summary, the current data corroborate the unbounded number line estimation task to be a valuable tool for assessing children's spatial representation of number magnitude in a systematic and unbiased manner. Yet, similar results for the bounded and the unbounded version of the task for first- and second-graders may indicate that both versions of the task might assess the same underlying representation for relatively younger children—at least in number ranges familiar to the children assessed. This is of particular importance for inferences about the nature and development of children's magnitude representation. PMID:24478734

The Full Story of the Electron Configurations of the Transition Elements

ERIC Educational Resources Information Center

Schwarz, W. H. Eugen

2010-01-01

The dominant electronic valence configurations of atoms in chemical substances of a transition element of group "G" in period "n" is ("n" - 1)d[superscript "G"]"n"s[superscript 0]. Transition-metal chemistry is d orbital chemistry. In contrast, the ground states of free, unbound atoms derive, in most cases, from configurations ("n" -…

Abstraction Techniques for Parameterized Verification

DTIC Science & Technology

2006-11-01

approach for applying model checking to unbounded systems is to extract finite state models from them using conservative abstraction techniques. Prop...36 2.5.1 Multiple Reference Processes . . . . . . . . . . . . . . . . . . . 36 2.5.2 Adding Monitor Processes...model checking to complex pieces of code like device drivers depends on the use of abstraction methods. An abstraction method extracts a small finite

Calculation of Relative Binding Free Energy in the Water-Filled Active Site of Oligopeptide-Binding Protein A.

PubMed

Maurer, Manuela; de Beer, Stephanie B A; Oostenbrink, Chris

2016-04-15

The periplasmic oligopeptide binding protein A (OppA) represents a well-known example of water-mediated protein-ligand interactions. Here, we perform free-energy calculations for three different ligands binding to OppA, using a thermodynamic integration approach. The tripeptide ligands share a high structural similarity (all have the sequence KXK), but their experimentally-determined binding free energies differ remarkably. Thermodynamic cycles were constructed for the ligands, and simulations conducted in the bound and (freely solvated) unbound states. In the unbound state, it was observed that the difference in conformational freedom between alanine and glycine leads to a surprisingly slow convergence, despite their chemical similarity. This could be overcome by increasing the softness parameter during alchemical transformations. Discrepancies remained in the bound state however, when comparing independent simulations of the three ligands. These difficulties could be traced to a slow relaxation of the water network within the active site. Fluctuations in the number of water molecules residing in the binding cavity occur mostly on a timescale larger than the simulation time along the alchemical path. After extensive simulations, relative binding free energies that were converged to within thermal noise could be obtained, which agree well with available experimental data.

Calculation of Relative Binding Free Energy in the Water-Filled Active Site of Oligopeptide-Binding Protein A

PubMed Central

Maurer, Manuela; de Beer, Stephanie B. A.; Oostenbrink, Chris

2018-01-01

The periplasmic oligopeptide binding protein A (OppA) represents a well-known example of water-mediated protein-ligand interactions. Here, we perform free-energy calculations for three different ligands binding to OppA, using a thermodynamic integration approach. The tripeptide ligands share a high structural similarity (all have the sequence KXK), but their experimentally-determined binding free energies differ remarkably. Thermodynamic cycles were constructed for the ligands, and simulations conducted in the bound and (freely solvated) unbound states. In the unbound state, it was observed that the difference in conformational freedom between alanine and glycine leads to a surprisingly slow convergence, despite their chemical similarity. This could be overcome by increasing the softness parameter during alchemical transformations. Discrepancies remained in the bound state however, when comparing independent simulations of the three ligands. These difficulties could be traced to a slow relaxation of the water network within the active site. Fluctuations in the number of water molecules residing in the binding cavity occur mostly on a timescale larger than the simulation time along the alchemical path. After extensive simulations, relative binding free energies that were converged to within thermal noise could be obtained, which agree well with available experimental data. PMID:27092480

Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations.

PubMed

Delille, Cecile A; Pruett, Sarah T; Marconi, Vincent C; Lennox, Jeffrey L; Armstrong, Wendy S; Arrendale, Richard F; Sheth, Anandi N; Easley, Kirk A; Acosta, Edward P; Vunnava, Aswani; Ofotokun, Ighovwerha

2014-09-01

HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06-0.12] than DRV, 0.04 (95%CI 0.03-0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50 ) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation. © 2014, The American College of Clinical Pharmacology.

Effect of Protein Binding on Unbound Atazanavir and Darunavir Cerebrospinal Fluid Concentrations

PubMed Central

Delille, Cecile A.; Pruett, Sarah T.; Marconi, Vincent C.; Lennox, Jeffrey L.; Armstrong, Wendy S.; Arrendale, Richard F.; Sheth, Anandi N.; Easley, Kirk A.; Acosta, Edward P.; Vunnava, Aswani; Ofotokun, Ighovwerha

2015-01-01

HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06–0.12] than DRV, 0.04 (95%CI 0.03–0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation. PMID:24691856

Unbound Bilirubin and Auditory Neuropathy Spectrum Disorder in Late Preterm and Term Infants with Severe Jaundice

PubMed Central

Amin, Sanjiv B; Wang, Hongyue; Laroia, Nirupama; Orlando, Mark

2016-01-01

Objective To evaluate if unbound bilirubin is a better predictor of auditory neuropathy spectrum disorder (ANSD) than total serum bilirubin (TSB) or the bilirubin albumin molar ratio (BAMR) in late preterm and term neonates with severe jaundice (TSB ≥ 20 mg/dL or TSB that met exchange transfusion criteria). Study design Infants ≥ 34 weeks gestational age with severe jaundice during the first two weeks of life were eligible for the prospective observational study. A comprehensive auditory evaluation was performed within 72 hours of peak TSB. ANSD was defined as absent or abnormal auditory brainstem evoked response waveform morphology at 80 decibel click intensity in the presence of normal outer hair cell function. TSB, serum albumin, and unbound bilirubin were measured using the colorimetric, bromocresol green, and modified peroxidase method, respectively. Results Five of 44 infants developed ANSD. By logistic regression, peak unbound bilirubin but not peak TSB or peak BAMR was associated with ANSD (odds ratio 4.6, 95% CI: 1.6-13.5, p = 0.002). On comparing receiver operating characteristic curves, the area under the curve (AUC) for unbound bilirubin (0.92) was significantly greater (p = 0.04) compared with the AUC for TSB (0.50) or BAMR (0.62). Conclusions Unbound bilirubin is a more sensitive and specific predictor of ANSD than TSB or BAMR in late preterm and term infants with severe jaundice. PMID:26952116

Three-dimensional single-mode nonlinear ablative Rayleigh-Taylor instability

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

Yan, R.; Aluie, H.; Laboratory for Laser Energetics, University of Rochester, Rochester, New York 14627

The nonlinear evolution of the single-mode ablative Rayleigh-Taylor instability is studied in three dimensions. As the mode wavelength approaches the cutoff of the linear spectrum (short-wavelength modes), it is found that the three-dimensional (3D) terminal bubble velocity greatly exceeds both the two-dimensional (2D) value and the classical 3D bubble velocity. Unlike in 2D, the 3D short-wavelength bubble velocity does not saturate. The growing 3D bubble acceleration is driven by the unbounded accumulation of vorticity inside the bubble. The vorticity is transferred by mass ablation from the Rayleigh-Taylor spikes to the ablated plasma filling the bubble volume.

Blood collection techniques, heparin and quinidine protein binding.

PubMed

Kessler, K M; Leech, R C; Spann, J F

1979-02-01

With the use of glass syringes without heparin and all glass equipment, the percent of unbound quinidine was measured by ultrafiltration and a double-extraction assay method after addition of 2 microgram/ml of quinidine sulfate. Compared to the all-glass method, collection of blood using Vacutainers resulted in an erroneous and variable decrease in quinidine binding related to blood to rubber-stopper contact. With glass, the unbound quinidine fraction was (mean +/- standard error) 10 +/- 1% in 10 normal volunteers, 8.5 +/- 1.5% in 10 patients with congestive heart failure, and 11 +/- 2% in 11 patients with chronic renal failure (although in 8 of the latter 11 patients the percent of unbound quinidine was 4 or more standard errors from the mean of the normal group). During cardiac catheterization, patients had markedly elevated unbound quinidine fractions: 24 +/- 2% (p less than 0.001). This abnormality coincided with the addition of heparin in vivo and was less apparent after the addition of up to 10 U/ml of heparin in vitro (120% and 29% increase in unbound quinidine fractions, respectively). Quinidine binding should be measured with all glass or equivalent equipment.

Power-rate synchronization of coupled genetic oscillators with unbounded time-varying delay.

PubMed

Alofi, Abdulaziz; Ren, Fengli; Al-Mazrooei, Abdullah; Elaiw, Ahmed; Cao, Jinde

2015-10-01

In this paper, a new synchronization problem for the collective dynamics among genetic oscillators with unbounded time-varying delay is investigated. The dynamical system under consideration consists of an array of linearly coupled identical genetic oscillators with each oscillators having unbounded time-delays. A new concept called power-rate synchronization, which is different from both the asymptotical synchronization and the exponential synchronization, is put forward to facilitate handling the unbounded time-varying delays. By using a combination of the Lyapunov functional method, matrix inequality techniques and properties of Kronecker product, we derive several sufficient conditions that ensure the coupled genetic oscillators to be power-rate synchronized. The criteria obtained in this paper are in the form of matrix inequalities. Illustrative example is presented to show the effectiveness of the obtained results.

Non-Markovian properties and multiscale hidden Markovian network buried in single molecule time series

NASA Astrophysics Data System (ADS)

Sultana, Tahmina; Takagi, Hiroaki; Morimatsu, Miki; Teramoto, Hiroshi; Li, Chun-Biu; Sako, Yasushi; Komatsuzaki, Tamiki

2013-12-01

We present a novel scheme to extract a multiscale state space network (SSN) from single-molecule time series. The multiscale SSN is a type of hidden Markov model that takes into account both multiple states buried in the measurement and memory effects in the process of the observable whenever they exist. Most biological systems function in a nonstationary manner across multiple timescales. Combined with a recently established nonlinear time series analysis based on information theory, a simple scheme is proposed to deal with the properties of multiscale and nonstationarity for a discrete time series. We derived an explicit analytical expression of the autocorrelation function in terms of the SSN. To demonstrate the potential of our scheme, we investigated single-molecule time series of dissociation and association kinetics between epidermal growth factor receptor (EGFR) on the plasma membrane and its adaptor protein Ash/Grb2 (Grb2) in an in vitro reconstituted system. We found that our formula successfully reproduces their autocorrelation function for a wide range of timescales (up to 3 s), and the underlying SSNs change their topographical structure as a function of the timescale; while the corresponding SSN is simple at the short timescale (0.033-0.1 s), the SSN at the longer timescales (0.1 s to ˜3 s) becomes rather complex in order to capture multiscale nonstationary kinetics emerging at longer timescales. It is also found that visiting the unbound form of the EGFR-Grb2 system approximately resets all information of history or memory of the process.

Unbound motion on a Schwarzschild background: Practical approaches to frequency domain computations

NASA Astrophysics Data System (ADS)

Hopper, Seth

2018-03-01

Gravitational perturbations due to a point particle moving on a static black hole background are naturally described in Regge-Wheeler gauge. The first-order field equations reduce to a single master wave equation for each radiative mode. The master function satisfying this wave equation is a linear combination of the metric perturbation amplitudes with a source term arising from the stress-energy tensor of the point particle. The original master functions were found by Regge and Wheeler (odd parity) and Zerilli (even parity). Subsequent work by Moncrief and then Cunningham, Price and Moncrief introduced new master variables which allow time domain reconstruction of the metric perturbation amplitudes. Here, I explore the relationship between these different functions and develop a general procedure for deriving new higher-order master functions from ones already known. The benefit of higher-order functions is that their source terms always converge faster at large distance than their lower-order counterparts. This makes for a dramatic improvement in both the speed and accuracy of frequency domain codes when analyzing unbound motion.

21 CFR 862.1113 - Bilirubin (total and unbound) in the neonate test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1113 Bilirubin (total and unbound) in the neonate test system. (a...

21 CFR 862.1113 - Bilirubin (total and unbound) in the neonate test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1113 Bilirubin (total and unbound) in the neonate test system. (a...

21 CFR 862.1113 - Bilirubin (total and unbound) in the neonate test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1113 Bilirubin (total and unbound) in the neonate test system. (a...

21 CFR 862.1113 - Bilirubin (total and unbound) in the neonate test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1113 Bilirubin (total and unbound) in the neonate test system. (a...

21 CFR 862.1113 - Bilirubin (total and unbound) in the neonate test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1113 Bilirubin (total and unbound) in the neonate test system. (a...

Unbound Bilirubin and Auditory Neuropathy Spectrum Disorder in Late Preterm and Term Infants with Severe Jaundice.

PubMed

Amin, Sanjiv B; Wang, Hongyue; Laroia, Nirupama; Orlando, Mark

2016-06-01

This study evaluates whether unbound bilirubin is a better predictor of auditory neuropathy spectrum disorder (ANSD) than total serum bilirubin (TSB) or the bilirubin:albumin molar ratio (BAMR) in late preterm and term neonates with severe jaundice (TSB ≥20 mg/dL or TSB that met exchange transfusion criteria). Infants ≥34 weeks' gestation with severe jaundice during the first 2 weeks of life were eligible for the prospective observational study. A comprehensive auditory evaluation was performed within 72 hours of peak TSB. ANSD was defined as absent or abnormal auditory brainstem evoked response waveform morphology at 80-decibel click intensity in the presence of normal outer hair cell function. TSB, serum albumin, and unbound bilirubin were measured using the colorimetric, bromocresol green, and modified peroxidase method, respectively. Five of 44 infants developed ANSD. By logistic regression, peak unbound bilirubin but not peak TSB or peak BAMR was associated with ANSD (OR, 4.6; 95% CI, 1.6-13.5; P = .002). On comparing receiver operating characteristic curves, the area under the curve for unbound bilirubin (0.92) was significantly greater (P = .04) compared with the area under the curve for TSB (0.50) or BAMR (0.62). Unbound bilirubin is a more sensitive and specific predictor of ANSD than TSB or BAMR in late preterm and term infants with severe jaundice. Copyright © 2016 Elsevier Inc. All rights reserved.

To Knock Down Barriers for Returning Adult Learners, RI Tries Something New

ERIC Educational Resources Information Center

Money, Tracy; Littky, Dennis; Bush, Adam

2015-01-01

In a historic unanimous vote on May 20, 2015, the Rhode Island Council on Postsecondary Education welcomed College Unbound as a degree-granting postsecondary option in the state, designed to serve the more than 110,000 Rhode Island adults who began but did not complete bachelor's degrees. The college is the adult-learning initiative of Big Picture…

Resonances in a periodically driven bosonic system.

PubMed

Quelle, Anton; Smith, Cristiane Morais

2017-11-01

Periodically driven systems are a common topic in modern physics. In optical lattices specifically, driving is at the origin of many interesting phenomena. However, energy is not conserved in driven systems, and under periodic driving, heating of a system is a real concern. In an effort to better understand this phenomenon, the heating of single-band systems has been studied, with a focus on disorder- and interaction-induced effects, such as many-body localization. Nevertheless, driven systems occur in a much wider context than this, leaving room for further research. Here, we fill this gap by studying a noninteracting model, characterized by discrete, periodically spaced energy levels that are unbounded from above. We couple these energy levels resonantly through a periodic drive, and discuss the heating dynamics of this system as a function of the driving protocol. In this way, we show that a combination of stimulated emission and absorption causes the presence of resonant stable states. This will serve to elucidate the conditions under which resonant driving causes heating in quantum systems.

Resonances in a periodically driven bosonic system

NASA Astrophysics Data System (ADS)

Quelle, Anton; Smith, Cristiane Morais

2017-11-01

Periodically driven systems are a common topic in modern physics. In optical lattices specifically, driving is at the origin of many interesting phenomena. However, energy is not conserved in driven systems, and under periodic driving, heating of a system is a real concern. In an effort to better understand this phenomenon, the heating of single-band systems has been studied, with a focus on disorder- and interaction-induced effects, such as many-body localization. Nevertheless, driven systems occur in a much wider context than this, leaving room for further research. Here, we fill this gap by studying a noninteracting model, characterized by discrete, periodically spaced energy levels that are unbounded from above. We couple these energy levels resonantly through a periodic drive, and discuss the heating dynamics of this system as a function of the driving protocol. In this way, we show that a combination of stimulated emission and absorption causes the presence of resonant stable states. This will serve to elucidate the conditions under which resonant driving causes heating in quantum systems.

Coexistence of bounded and unbounded motions in a bouncing ball model

NASA Astrophysics Data System (ADS)

Marò, Stefano

2013-05-01

We consider the model describing the vertical motion of a ball falling with constant acceleration on a wall and elastically reflected. The wall is supposed to move in the vertical direction according to a given periodic function f. We apply the Aubry-Mather theory to the generating function in order to prove the existence of bounded motions with prescribed mean time between the bounces. As the existence of unbounded motions is known, it is possible to find a class of functions f that allow both bounded and unbounded motions.

Boundary Approximation Methods for Sloving Elliptic Problems on Unbounded Domains

NASA Astrophysics Data System (ADS)

Li, Zi-Cai; Mathon, Rudolf

1990-08-01

Boundary approximation methods with partial solutions are presented for solving a complicated problem on an unbounded domain, with both a crack singularity and a corner singularity. Also an analysis of partial solutions near the singular points is provided. These methods are easy to apply, have good stability properties, and lead to highly accurate solutions. Hence, boundary approximation methods with partial solutions are recommended for the treatment of elliptic problems on unbounded domains provided that piecewise solution expansions, in particular, asymptotic solutions near the singularities and infinity, can be found.

Interactions of NO and CO with Pd and Pt atoms

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

Smith, G.W.; Carter, E.A.

1991-03-21

The authors report ab initio generalized valence bond and correlation-consistent configuration interaction studies of CO and NO interacting with Pd and Pt atoms. They find dramatically different bonding mechanisms for the two ligands, which are easily understood in terms of changes in the electronic structure of the metal and the ligand. CO bonds to both Pd and pt by a {sigma} donor/{pi} back-bonding mechanism, yielding linear geometries. Their calculations predict that the ground ({sup 1}{Sigma}{sup +}) state of PdCO is bound by 27 kcal/mol, while the ground ({sup 1}{Sigma}{sup +}) state of PtCO is bound by only 18.5 kcal/mol. Bymore » contrast, PdNO and PtNO are both bent, with the dominant bonding involving a covalent {sigma} bond between a singly occupied metal d{sigma} orbital and the singly occupied NO 2{pi}* orbital. While the ground ({sup 2}A{prime}) state of PtNO is strongly bound (D{sub e}(Pt-NO) {approximately} 20 kcal/mol), NO binds very weakly to Pd (D{sub e}(Pd-NO) {le} 4 kcal/mol). Linear excited states ({sup 2}{Sigma} and {sup 2}{Pi}) of PtNO and PdNO are predicted to be only weakly bound or unbound. However, corresponding linear cationic states ({sup 1}{Sigma}{sup +} and {sup 3}{Pi}) are strongly bound, but the cationic bent ({sup 1}A{prime}) states are still the ground states of PtNO{sup +} and PdNO{sup +}. These stark contrasts, in which NO binds strongly to Pt but weakly to Pd while CO binds much more strongly to Pd, are due to the preference for closed-shell species to bind strongly to other closed-shell species (e.g., CO to Pd) and for radicals to bind strongly to other radicals (e.g., NO to Pt).« less

Use of Inert Gases and Carbon Monoxide to Study the Possible Influence of Countercurrent Exchange on Passive Absorption from the Small Bowel

PubMed Central

Bond, John H.; Levitt, David G.; Levitt, Michael D.

1974-01-01

The purpose of the present study was to quantitate the influence of countercurrent exchange on passive absorption of highly diffusible substances from the small intestine of the rabbit. The absorption of carbon monoxide, which is tightly bound to hemoglobin and therefore cannot exchange, was compared to the absorption of four unbound gases (H2, He, CH4, and 133Xe), which should exchange freely. The degree to which the observed absorption of the unbound gases falls below that predicted from CO absorption should provide a quantitative measure of countercurrent exchange. CO uptake at high luminal Pco is flow-limited and, assuming that villus and central hemoglobin concentrations are equal, the flow that equilibrates with CO (Fco) was calculated to equal 7.24 ml/min/100 g. The observed absorption rate of the unbound gases was from two to four times greater than would have been predicted had their entire uptake been accounted for by equilibration with Fco. This is the opposite of what would occur if countercurrent exchange retarded absorption of the unbound gases. The unbound gases have both flow- and diffusion-limited components, and Fco should account for only the fraction of absorption that is flow limited. A simple model of perfusion and diffusion made it possible to calculate the fraction of the total uptake of unbound gases that was flow limited. This fraction of the total observed absorption rate was still about 1.8 times greater than predicted by CO absorption. A possible explanation for this discrepancy is that plasma skimming reduces the hemoglobin of villus blood to about 60% of that of central blood. Thus, Fco is actually about 1.7 times greater than initially calculated, and with this correction, there is close agreement between the predicted and observed rates of absorption of each of the unbound gases. We conclude that countercurrent exchange does not influence passive absorption under the conditions of this study. PMID:4436431

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

PubMed Central

Abd Rahman, Azrin N; Tett, Susan E; Abdul Gafor, Halim A; McWhinney, Brett C; Staatz, Christine E

2015-01-01

Aims The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis. Methods Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0), maximum concentration (Cmax) and area under the concentration–time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events. Results Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l–1 h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l–1, P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l–1 h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l–1 h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l–1 h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023). Conclusions This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis. PMID:25959850

Exposure-effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis.

PubMed

Abd Rahman, Azrin N; Tett, Susan E; Abdul Gafor, Halim A; McWhinney, Brett C; Staatz, Christine E

2015-11-01

The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis. Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events. Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023). This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis. © 2015 The British Pharmacological Society.

Optical nonlinearities of excitonic states in atomically thin 2D transition metal dichalcogenides

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

Soh, Daniel Beom Soo

We calculated the optical nonlinearities of the atomically thin monolayer transition metal dichalcogenide material (particularly MoS 2), particularly for those linear and nonlinear transition processes that utilize the bound exciton states. We adopted the bound and the unbound exciton states as the basis for the Hilbert space, and derived all the dynamical density matrices that provides the induced current density, from which the nonlinear susceptibilities can be drawn order-by-order via perturbative calculations. We provide the nonlinear susceptibilities for the linear, the second-harmonic, the third-harmonic, and the kerr-type two-photon processes.

Molecular Remodeling of Photosystem II during State Transitions in Chlamydomonas reinhardtii[W

PubMed Central

Iwai, Masakazu; Takahashi, Yuichiro; Minagawa, Jun

2008-01-01

State transitions, or the redistribution of light-harvesting complex II (LHCII) proteins between photosystem I (PSI) and photosystem II (PSII), balance the light-harvesting capacity of the two photosystems to optimize the efficiency of photosynthesis. Studies on the migration of LHCII proteins have focused primarily on their reassociation with PSI, but the molecular details on their dissociation from PSII have not been clear. Here, we compare the polypeptide composition, supramolecular organization, and phosphorylation of PSII complexes under PSI- and PSII-favoring conditions (State 1 and State 2, respectively). Three PSII fractions, a PSII core complex, a PSII supercomplex, and a multimer of PSII supercomplex or PSII megacomplex, were obtained from a transformant of the green alga Chlamydomonas reinhardtii carrying a His-tagged CP47. Gel filtration and single particles on electron micrographs showed that the megacomplex was predominant in State 1, whereas the core complex was predominant in State 2, indicating that LHCIIs are dissociated from PSII upon state transition. Moreover, in State 2, strongly phosphorylated LHCII type I was found in the supercomplex but not in the megacomplex. Phosphorylated minor LHCIIs (CP26 and CP29) were found only in the unbound form. The PSII subunits were most phosphorylated in the core complex. Based on these observations, we propose a model for PSII remodeling during state transitions, which involves division of the megacomplex into supercomplexes, triggered by phosphorylation of LHCII type I, followed by LHCII undocking from the supercomplex, triggered by phosphorylation of minor LHCIIs and PSII core subunits. PMID:18757554

Three-dimensional single-mode nonlinear ablative Rayleigh-Taylor instability

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

Yan, R.; Betti, R.; Sanz, J.

The nonlinear evolution of the single-mode ablative Rayleigh-Taylor instability is studied in three dimensions. As the mode wavelength approaches the cutoff of the linear spectrum (short-wavelength modes), it is found that the three-dimensional (3D) terminal bubble velocity greatly exceeds both the two-dimensional (2D) value and the classical 3D bubble velocity. Unlike in 2D, the 3D short-wavelength bubble velocity does not saturate. The growing 3D bubble acceleration is driven by the unbounded accumulation of vorticity inside the bubble. As a result, the vorticity is transferred by mass ablation from the Rayleigh-Taylor spikes to the ablated plasma filling the bubble volume.

Determination of total and unbound concentrations of lopinavir in plasma using liquid chromatography-tandem mass spectrometry and ultrafiltration methods.

PubMed

Illamola, S M; Labat, L; Benaboud, S; Tubiana, R; Warszawski, J; Tréluyer, J M; Hirt, D

2014-08-15

Lopinavir is an HIV protease inhibitor with high protein binding (98-99%) in human plasma. This study was designed to develop an ultrafiltration method to measure the unbound concentrations of lopinavir overcoming the non-specific binding issue. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of total concentrations of lopinavir in plasma was developed and validated, and an adaptation was also optimized and validated for the determination of unbound concentrations. The chromatographic separation was performed with a C18 column (100 mm × 2.1mm i.d., 5 μm particle size) using a mobile phase containing deionized water with formic acid, and acetonitrile, with gradient elution at a flow-rate of 350 μL min(-1). Identification of the compounds was performed by multiple reaction monitoring, using electrospray ionization in positive ion mode. The method was validated over a clinical range of 0.01-1 μg/mL for human plasma ultrafiltrate and 0.1-15 μg/mL in human plasma. The inter and intra-assay accuracies and precisions were between 0.23% and 11.37% for total lopinavir concentrations, and between 3.50% and 13.30% for plasma ultrafiltrate (unbound concentration). The ultrafiltration method described allows an accurate separation of the unbound fraction of lopinavir, circumscribing the loss of drug by nonspecific binding (NSB), and the validated LC-MS/MS methodology proposed is suitable for the determination of total and unbound concentrations of lopinavir in clinical practice. Copyright © 2014 Elsevier B.V. All rights reserved.

A Feasibility Study of Nonlinear Spectroscopic Measurement of Magnetic Nanoparticles Targeted to Cancer Cells.

PubMed

Ficko, Bradley W; NDong, Christian; Giacometti, Paolo; Griswold, Karl E; Diamond, Solomon G

2017-05-01

Magnetic nanoparticles (MNPs) are an emerging platform for targeted diagnostics in cancer. An important component needed for translation of MNPs is the detection and quantification of targeted MNPs bound to tumor cells. This study explores the feasibility of a multifrequency nonlinear magnetic spectroscopic method that uses excitation and pickup coils and is capable of discriminating between quantities of bound and unbound MNPs in 0.5 ml samples of KB and Igrov human cancer cell lines. The method is tested over a range of five concentrations of MNPs from 0 to 80 μg/ml and five concentrations of cells from 50 to 400 000 count per ml. A linear model applied to the magnetic spectroscopy data was able to simultaneously measure bound and unbound MNPs with agreement between the model-fit and lab assay measurements (p < 0.001). The detectable iron of the presented method to bound and unbound MNPs was < 2 μg in a 0.5 ml sample. The linear model parameters used to determine the quantities of bound and unbound nanoparticles in KB cells were also used to measure the bound and unbound MNP in the Igrov cell line and vice versa. Nonlinear spectroscopic measurement of MNPs may be a useful method for studying targeted MNPs in oncology. Determining the quantity of bound and unbound MNP in an unknown sample using a linear model represents an exciting opportunity to translate multifrequency nonlinear spectroscopy methods to in vivo applications where MNPs could be targeted to cancer cells.

Stationary transport processes with unbounded collision operators

NASA Astrophysics Data System (ADS)

Greenberg, William; van der Mee, C. V. M.

1984-01-01

An abstract Hilbert space equation is studied, which models many of the stationary, one-dimensional transport equations with partial-range boundary conditions. In particular, the collision term may be unbounded and nondissipative. A complete existence and uniqueness theory is presented.

Direct Reactions with Exotic Nuclei

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

Baur, G.; Typel, S.

2005-10-14

We discuss recent work on Coulomb dissociation and an effective-range theory of low-lying electromagnetic strength of halo nuclei. We propose to study Coulomb dissociation of a halo nucleus bound by a zero-range potential as a homework problem. We study the transition from stripping to bound and unbound states and point out in this context that the Trojan-Horse method is a suitable tool to investigate subthreshold resonances.

HIV envelope glycoprotein imaged at high resolution | Center for Cancer Research

Cancer.gov

The outer surface of the human immunodeficiency virus (HIV) is surrounded by an envelope studded with spike-shaped glycoproteins called Env that help the deadly virus identify, bind, and infect cells. When unbound, Env exists in a “closed” conformational state. Upon binding with target cells, such as CD4+ T cells, the protein transitions to an “open” configuration. Given that

Seasonal variations in the moduli of unbound pavement layers.

DOT National Transportation Integrated Search

2006-07-01

The in situ moduli of unbound pavement materials vary on a seasonal basis as a function of temperature and moisture conditions. : Knowledge of these variations is required for accurate prediction of pavement life for pavement design and other pavemen...

Effect of drainage in unbound aggregate bases on flexible pavement performance.

DOT National Transportation Integrated Search

2009-03-01

The main objective of this study is to optimize the gradation of Mexican limestone aggregate for use as an unbound drainable base material that has adequate permeability while staying structurally stable during the construction time and the pavement...

Determination of resilient properties of unbound materials with repeated load triaxial and diametral test systems.

DOT National Transportation Integrated Search

1981-12-01

Repeated load diametral test systems are experiencing increased use to determine resilient properties of asphalt concrete and admixture stabilized materials; they have not been used extensively to determine the resilient properties of unbound materia...

Resilient moduli of typical Missouri soils and unbound granular base materials.

DOT National Transportation Integrated Search

2009-01-01

The objective of this project was to determine the resilient moduli for common Missouri subgrade soils and typical unbound granular base materials in accordance with the AASHTO T 307 test method. The results allow Missouri Department of Transportatio...

Verifying Multi-Agent Systems via Unbounded Model Checking

NASA Technical Reports Server (NTRS)

Kacprzak, M.; Lomuscio, A.; Lasica, T.; Penczek, W.; Szreter, M.

2004-01-01

We present an approach to the problem of verification of epistemic properties in multi-agent systems by means of symbolic model checking. In particular, it is shown how to extend the technique of unbounded model checking from a purely temporal setting to a temporal-epistemic one. In order to achieve this, we base our discussion on interpreted systems semantics, a popular semantics used in multi-agent systems literature. We give details of the technique and show how it can be applied to the well known train, gate and controller problem. Keywords: model checking, unbounded model checking, multi-agent systems

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 2. Cerebrospinal Fluid Concentration Measurements in Patients with External Ventricular Drain

PubMed Central

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William

2014-01-01

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0–τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0–τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF. PMID:24277050

Quantum Steering Inequality with Tolerance for Measurement-Setting Errors: Experimentally Feasible Signature of Unbounded Violation

NASA Astrophysics Data System (ADS)

Rutkowski, Adam; Buraczewski, Adam; Horodecki, Paweł; Stobińska, Magdalena

2017-01-01

Quantum steering is a relatively simple test for proving that the values of quantum-mechanical measurement outcomes come into being only in the act of measurement. By exploiting quantum correlations, Alice can influence—steer—Bob's physical system in a way that is impossible in classical mechanics, as shown by the violation of steering inequalities. Demonstrating this and similar quantum effects for systems of increasing size, approaching even the classical limit, is a long-standing challenging problem. Here, we prove an experimentally feasible unbounded violation of a steering inequality. We derive its universal form where tolerance for measurement-setting errors is explicitly built in by means of the Deutsch-Maassen-Uffink entropic uncertainty relation. Then, generalizing the mutual unbiasedness, we apply the inequality to the multisinglet and multiparticle bipartite Bell state. However, the method is general and opens the possibility of employing multiparticle bipartite steering for randomness certification and development of quantum technologies, e.g., random access codes.

Phenytoin pharmacokinetics and clinical effects in African children following fosphenytoin and chloramphenicol coadministration

PubMed Central

Ogutu, Bernhards R; Newton, Charles R J C; Muchohi, Simon N; Otieno, Godfrey O; Kokwaro, Gilbert O

2002-01-01

Aims Some children with malaria and convulsions also have concurrent bacterial meningitis. Chloramphenicol is used to treat the latter whereas phenytoin is used for convulsions. Since chloramphenicol inhibits the metabolism of phenytoin in vivo, we studied the effects of chloramphenicol on phenytoin pharmacokinetics in children with malaria. Methods Multiple intravenous (i.v.) doses of chloramphenicol succinate (CAP) (25 mg kg−1 6 hourly for 72 h) and a single intramuscular (i.m.) seizure prophylactic dose of fosphenytoin (18 mg kg−1 phenytoin sodium equivalents) were concomitantly administered to 15 African children with malaria. Control children (n= 13) with malaria received a similar dose of fosphenytoin and multiple i.v. doses (25 mg kg−1 8 hourly for 72 h) of cefotaxime (CEF). Blood pressure, heart rate, respiratory rate, oxygen saturation, level of consciousness and convulsion episodes were monitored. Cerebrospinal fluid (CSF) and plasma phenytoin concentrations were determined. Results The area under the plasma unbound phenytoin concentration-time curve (AUC(0,∞); means (CAP, CEF): 58.5, 47.6 µg ml−1 h; 95% CI for difference between means: −35.0, 11.4), the peak unbound phenytoin concentrations (Cmax; medians: 1.12, 1.29 µg ml−1; 95% CI: −0.5, 0.04), the times to Cmax(tmax; medians: 4.0, 4.0 h; 95% CI: −2.0, 3.7), the CSF:plasma phenytoin ratios (means: 0.21, 0.22; 95% CI: −0.8, 0.10), the fraction of phenytoin unbound (means: 0.06, 0.09; 95% CI: −0.01, 0.07) and the cardiovascular parameters were not significantly different between CAP and CEF groups. However, mean terminal elimination half-life (t1/2,z) was significantly longer (23.7, 15.5 h; 95% CI: 1.71, 14.98) in the CAP group compared with the CEF group. Seventy per cent of the children had no convulsions during the study period. Conclusions Concomitant administration of chloramphenicol and a single i.m. dose of fosphenytoin alters the t1/2,z but not the other pharmacokinetic parameters or clinical effects of phenytoin in African children with severe malaria. Moreover, a single i.m. dose of fosphenytoin provides anticonvulsant prophylaxis in the majority of the children over 72 h. However, a larger study would be needed to investigate the effect of concomitant administration of multiple doses of the two drugs in this population of patients. PMID:12492612

Resilient moduli of typical Missouri soils and unbound granular base materials

DOT National Transportation Integrated Search

2008-03-01

The objective of this project is to accurately determine the resilient moduli for common Missouri subgrade soils and unbound granular base materials in accordance with the AASHTO T 307 test method. The test results included moduli data from 27 common...

Measurement of seasonal changes and spatial variations in pavement unbound base and subgrade properties.

DOT National Transportation Integrated Search

2009-01-01

Soils often undergo cyclic wetting/drying, but there is very limited research on unsaturated : soils subjected to variations in moisture content. More specifically, field moisture variation : over time in highway unbound bases and subgrade soils is a...

Structural changes and fluctuations of proteins. I. A statistical thermodynamic model.

PubMed

Ikegami, A

1977-01-01

A general theory of the structural changes and fluctuations of proteins has been proposed based on statistical thermodynamic considerations at the chain level. The "structure" of protein was assumed to be characterized by the state of secondary bonds between unique pairs of specific sites on peptide chains. Every secondary bond changes between the bonded and unbonded states by thermal agitation and the "structure" is continuously fluctuating. The free energy of the "structural state" that is defined by the fraction of secondary bonds in the bonded state has been expressed by the bond energy, the cooperative interaction between bonds, the mixing entropy of bonds, and the entropy of polypeptide chains. The most probable "structural state" can be simply determined by graphical analysis and the effect of temperature or solvent composition on it is discussed. The temperature dependence of the free energy, the probability distribution of structural states and the specific heat have been calculted for two examples of structural change. The theory predicts two different types of structural changes from the ordered to disorderd state, a "structured transition" and a "gradual structural change" with rising temperature. In the "structural transition", the probability distribution has two maxima in the temperature range of transition. In the "gradual structural change", the probabilty distribution has only one maximum during the change. A considerable fraction of secondary bonds is in the unbounded state and is always fluctuating even in the ordered state at room temperature. Such structural flucutations in a single protein molecule have been discussed quantitatively. The theory is extended to include small molecules which bind to the protein molecule and affect the structural state. The changes of structural state caused by specific and non-specific binding and allosteric effects are explained in a unified manner.

Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

PubMed Central

Kumpulainen, Elina; Välitalo, Pyry; Kokki, Merja; Lehtonen, Marko; Hooker, Andrew; Ranta, Veli-Pekka; Kokki, Hannu

2010-01-01

AIMS This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h−1 70 kg−1. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (Vss) was 8.1 l 70 kg−1. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants. PMID:20840447

Unbounded orbits of a swinging Atwood's machine

NASA Astrophysics Data System (ADS)

Tufillaro, N.; Nunes, A.; Casasayas, J.

1988-12-01

The motion of a swinging Atwood's machine is examined when the orbits are unbounded. Expressions for the asymptotic behavior of the orbits are derived that exhibit either an infinite number of oscillations or no oscillations, depending only on a critical value of the mass ratio.

Unbounded and revocable hierarchical identity-based encryption with adaptive security, decryption key exposure resistant, and short public parameters

PubMed Central

Wang, Baosheng; Tao, Jing

2018-01-01

Revocation functionality and hierarchy key delegation are two necessary and crucial requirements to identity-based cryptosystems. Revocable hierarchical identity-based encryption (RHIBE) has attracted a lot of attention in recent years, many RHIBE schemes have been proposed but shown to be either insecure or bounded where they have to fix the maximum hierarchical depth of RHIBE at setup. In this paper, we propose a new unbounded RHIBE scheme with decryption key exposure resilience and with short public system parameters, and prove our RHIBE scheme to be adaptively secure. Our system model is scalable inherently to accommodate more levels of user adaptively with no adding workload or restarting the system. By carefully designing the hybrid games, we overcome the subtle obstacle in applying the dual system encryption methodology for the unbounded and revocable HIBE. To the best of our knowledge, this is the first construction of adaptively secure unbounded RHIBE scheme. PMID:29649326

Plasma protein binding of phenytoin in 100 epileptic patients.

PubMed Central

Peterson, G M; McLean, S; Aldous, S; Von Witt, R J; Millingen, K S

1982-01-01

The plasma protein binding of phenytoin was investigated in 100 epileptic patients, using equilibrium dialysis at 37 degrees C. The unbound fractions of phenytoin in plasma formed a skewed distribution, with a range of 9.7 to 24.7% and a median value of 12.3%. Most (80%) patients appeared to form one group with free phenytoin fractions from 9.7 to 14.5%, while the remainder formed a group with elevated free fractions (greater than 14.5%). Total and unbound plasma concentrations of phenytoin were strongly correlated (r=0.95, P less than 0.0001). There was a weak correlation between increasing age and the unbound phenytoin fraction (r=0.28, P less than 0.01). The results indicate that measurement of the total phenytoin concentration in plasma should usually provide a reliable index of anticonvulsant effect. However, determination of the unbound phenytoin fraction would be beneficial in the management of those patients in whom this fraction may be elevated, due to interacting drugs or biochemical abnormalities. PMID:7104186

Protein Binding of Lopinavir and Ritonavir During Four Phases of Pregnancy: Implications for Treatment Guidelines

PubMed Central

Patterson, Kristine B.; Dumond, Julie B.; Prince, Heather A.; Jenkins, Amanda J.; Scarsi, Kimberly K.; Wang, Ruili; Malone, Stephanie; Hudgens, Michael G.; Kashuba, Angela DM.

2013-01-01

Objective To investigate the intraindividual pharmacokinetics of total (protein bound + unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100mg/25mg) can overcome any pregnancy-associated changes. Design Prospective longitudinal pharmacokinetic (PK) study Methods HIV-infected pregnant antiretroviral therapy-naïve and experienced women receiving LPV/RTV 400mg/100mg tablets twice daily. Intensive PK evaluations were performed at 20–24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100mg/25mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4). Results Twelve women completed pre-specified PK evaluations. Median (range) age was 28 (1–35) years and baseline BMI was 32 (19–41) kg/m2. During pregnancy, total area under the time concentration (AUC0–12hr) for LPV was significantly lower than postpartum [PK1, PK2 or PK3 vs. PK4, p= 0.005]. Protein unbound LPV AUC0–12hr remained unchanged during pregnancy [PK1: 1.6 (1.3–1.9) vs. PK2: 1.6 (1.3–1.9) µg*hr/mL, p=0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3–2.1) µg*hr/mL, p=0.5]. Protein unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08–0.15) vs. PK3: 0.12 (0.10–0.15) µg/mL, p=0.09]. Albumin and LPV AUC0–12h fraction unbound were correlated (rs=0.3, p=0.03). Conclusions Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women. PMID:23221983

Procedural uncertainties of Proctor compaction tests applied on MSWI bottom ash.

PubMed

Izquierdo, Maria; Querol, Xavier; Vazquez, Enric

2011-02-28

MSWI bottom ash is a well-graded highly compactable material that can be used as a road material in unbound pavements. Achieving the compactness assumed in the design of the pavement is of primary concern to ensure long term structural stability. Regulations on road construction in a number of EU countries rely on standard tests originally developed for natural aggregates, which may not be appropriate to accurately assess MSWI bottom ash. This study is intended to assist in consistently assessing MSWI bottom ash compaction by means of the Proctor method. This test is routinely applied to address unbound road materials and suggests two methods. Compaction parameters show a marked procedural dependency due to the particle morphology and weak particle strength of ash. Re-compacting a single batch sample to determine Proctor curves is a common practise that turns out to overvalue optimum moisture contents and maximum dry densities. This could result in wet-side compactions not meeting stiffness requirements. Inaccurate moisture content measurements during testing may also induce erroneous determinations of compaction parameters. The role of a number of physical properties of MSWI bottom ash in compaction is also investigated. Copyright © 2011 Elsevier B.V. All rights reserved.

Two-neutron sequential decay of O 24

DOE PAGES

Jones, M. D.; Frank, N.; Baumann, T.; ...

2015-11-25

In this study, a two-neutron unbound excited state of 24O was populated through a (d,d') reaction at 83.4 MeV/nucleon. A state at E=715±110 (stat) ±45 (sys) keV with a width of Γ<2 MeV was observed above the two-neutron separation energy placing it at 7.65 ± 0.2 MeV with respect to the ground state. Three-body correlations for the decay of 24O → 22O + 2n show clear evidence for a sequential decay through an intermediate state in 23O. Neither a di-neutron nor phase-space model for the three-body breakup were able to describe these correlations.

Two-neutron sequential decay of O 24

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

Jones, M. D.; Frank, N.; Baumann, T.

In this study, a two-neutron unbound excited state of 24O was populated through a (d,d') reaction at 83.4 MeV/nucleon. A state at E=715±110 (stat) ±45 (sys) keV with a width of Γ<2 MeV was observed above the two-neutron separation energy placing it at 7.65 ± 0.2 MeV with respect to the ground state. Three-body correlations for the decay of 24O → 22O + 2n show clear evidence for a sequential decay through an intermediate state in 23O. Neither a di-neutron nor phase-space model for the three-body breakup were able to describe these correlations.

Structure of the exotic He 9 nucleus from the no-core shell model with continuum

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

Vorabbi, Matteo; Calci, Angelo; Navratil, Petr

2018-03-13

Here, the exotic 9He nucleus, which presents one of the most extreme neutron-to-proton ratios, belongs to the N = 7 isotonic chain famous for the phenomenon of ground-state parity inversion with decreasing number of protons. Consequently, it would be expected to have an unnatural (positive) parity ground state similar to 11Be and 10Li. Despite many experimental and theoretical investigations, its structure remains uncertain. Apart from the fact that it is unbound, other properties including the spin and parity of its ground state, and the very existence of additional low-lying resonances are still a matter of debate

Generalized Categorial Grammar for Unbounded Dependencies Recovery

ERIC Educational Resources Information Center

Nguyen, Luan Viet

2014-01-01

Accurate recovery of predicate-argument dependencies is vital for interpretation tasks like information extraction and question answering, and unbounded dependencies may account for a significant portion of the dependencies in any given text. This thesis describes a Generalized Categorial Grammar (GCG) which, like other categorial grammars,…

Structure and decays of nuclear three-body systems: The Gamow coupled-channel method in Jacobi coordinates

NASA Astrophysics Data System (ADS)

Wang, S. M.; Michel, N.; Nazarewicz, W.; Xu, F. R.

2017-10-01

Background: Weakly bound and unbound nuclear states appearing around particle thresholds are prototypical open quantum systems. Theories of such states must take into account configuration mixing effects in the presence of strong coupling to the particle continuum space. Purpose: To describe structure and decays of three-body systems, we developed a Gamow coupled-channel (GCC) approach in Jacobi coordinates by employing the complex-momentum formalism. We benchmarked the complex-energy Gamow shell model (GSM) against the new framework. Methods: The GCC formalism is expressed in Jacobi coordinates, so that the center-of-mass motion is automatically eliminated. To solve the coupled-channel equations, we use hyperspherical harmonics to describe the angular wave functions while the radial wave functions are expanded in the Berggren ensemble, which includes bound, scattering, and Gamow states. Results: We show that the GCC method is both accurate and robust. Its results for energies, decay widths, and nucleon-nucleon angular correlations are in good agreement with the GSM results. Conclusions: We have demonstrated that a three-body GSM formalism explicitly constructed in the cluster-orbital shell model coordinates provides results similar to those with a GCC framework expressed in Jacobi coordinates, provided that a large configuration space is employed. Our calculations for A =6 systems and 26O show that nucleon-nucleon angular correlations are sensitive to the valence-neutron interaction. The new GCC technique has many attractive features when applied to bound and unbound states of three-body systems: it is precise, is efficient, and can be extended by introducing a microscopic model of the core.

Probability Distributions over Cryptographic Protocols

DTIC Science & Technology

2009-06-01

Artificial Immune Algorithm . . . . . . . . . . . . . . . . . . . 9 3 Design Decisions 11 3.1 Common Ground...creation algorithm for unbounded distribution . . . . . . . 24 4.2 Message creation algorithm for unbounded naive distribution . . . . 24 4.3 Protocol...creation algorithm for intended-run distributions . . . . . . 26 4.4 Protocol and message creation algorithm for realistic distribution . . 32 ix THIS

Electron emission from surfaces resulting from low energy positron bombardment

NASA Astrophysics Data System (ADS)

Mukherjee, Saurabh

Measurements of the secondary electron energy spectra resulting from very low energy positron bombardment of a polycrystalline Au and Cu (100) surfaces are presented that provide evidence for a single step transition from an unbound scattering state to an image potential bound state. The primary positron energy threshold for secondary electron emission and energy cutoff of the positron induced secondary electron energy peak are consistent with an Auger like process in which an incident positron make a transition from a scattering state to a surface-image potential bound while transferring all of the energy difference to an outgoing secondary electron. We term this process: the Auger mediated quantum sticking effect (AQSE). The intensities of the positron induced secondary electron peak are used to estimate the probability of this process as a function of incident positron energy. Positron annihilation induced Auger spectra (PAES) of Cu and Au are presented that are free of all primary beam induced secondary electron background. This background was eliminated by setting the positron beam energy below AQSE threshold. The background free PAES spectra obtained include the first measurements of the low energy tail of CVV Auger transitions all the way down to zero kinetic energy. The integrated intensity of this tail is several times larger than Auger peak itself which provides strong evidence for multi-electron Auger processes.

Improving the apo-state detergent stability of NTS1 with CHESS for pharmacological and structural studies.

PubMed

Scott, Daniel J; Kummer, Lutz; Egloff, Pascal; Bathgate, Ross A D; Plückthun, Andreas

2014-11-01

The largest single class of drug targets is the G protein-coupled receptor (GPCR) family. Modern high-throughput methods for drug discovery require working with pure protein, but this has been a challenge for GPCRs, and thus the success of screening campaigns targeting soluble, catalytic protein domains has not yet been realized for GPCRs. Therefore, most GPCR drug screening has been cell-based, whereas the strategy of choice for drug discovery against soluble proteins is HTS using purified proteins coupled to structure-based drug design. While recent developments are increasing the chances of obtaining GPCR crystal structures, the feasibility of screening directly against purified GPCRs in the unbound state (apo-state) remains low. GPCRs exhibit low stability in detergent micelles, especially in the apo-state, over the time periods required for performing large screens. Recent methods for generating detergent-stable GPCRs, however, offer the potential for researchers to manipulate GPCRs almost like soluble enzymes, opening up new avenues for drug discovery. Here we apply cellular high-throughput encapsulation, solubilization and screening (CHESS) to the neurotensin receptor 1 (NTS1) to generate a variant that is stable in the apo-state when solubilized in detergents. This high stability facilitated the crystal structure determination of this receptor and also allowed us to probe the pharmacology of detergent-solubilized, apo-state NTS1 using robotic ligand binding assays. NTS1 is a target for the development of novel antipsychotics, and thus CHESS-stabilized receptors represent exciting tools for drug discovery. Copyright © 2014 Elsevier B.V. All rights reserved.

The damped wave equation with unbounded damping

NASA Astrophysics Data System (ADS)

Freitas, Pedro; Siegl, Petr; Tretter, Christiane

2018-06-01

We analyze new phenomena arising in linear damped wave equations on unbounded domains when the damping is allowed to become unbounded at infinity. We prove the generation of a contraction semigroup, study the relation between the spectra of the semigroup generator and the associated quadratic operator function, the convergence of non-real eigenvalues in the asymptotic regime of diverging damping on a subdomain, and we investigate the appearance of essential spectrum on the negative real axis. We further show that the presence of the latter prevents exponential estimates for the semigroup and turns out to be a robust effect that cannot be easily canceled by adding a positive potential. These analytic results are illustrated by examples.

A new concept in laser-assisted chemistry - The electronic-field representation

NASA Technical Reports Server (NTRS)

George, T. F.; Zimmerman, I. H.; Yuan, J.-M.; Laing, J. R.; Devries, P. L.

1977-01-01

Electronic-field representation is proposed as a technique for laser-assisted chemistry. Specifically, it is shown that several field-assisted chemical processes can be described in terms of mixed matter-field quantum states and their associated energies. The technique may be used to analyze the effects exerted by an intense laser on both bound and unbound molecular systems, and to investigate other field-induced effects including multiphoton processes, emission, and photodissociation.

𝒩 = 2 supersymmetric Pais-Uhlenbeck oscillator

NASA Astrophysics Data System (ADS)

Masterov, Ivan

2015-06-01

We construct an 𝒩 = 2 supersymmetric extension of the Pais-Uhlenbeck oscillator for distinct frequencies of oscillation. A link to a set of decoupled 𝒩 = 2 supersymmetric harmonic oscillators with alternating sign in the Hamiltonian is introduced. Symmetries of the model are discussed in detail. The investigation of a quantum counterpart of the constructed model shows that the corresponding Fock space contains negative norm states and the energy spectrum of the system is unbounded from below.

Mass of the H Dibaryon

NASA Astrophysics Data System (ADS)

Shanahan, P. E.; Thomas, A. W.; Young, R. D.

2011-08-01

Recent lattice QCD calculations have reported evidence for the existence of a bound state with strangeness -2 and baryon number 2 at quark masses somewhat higher than the physical values. By developing a description of the dependence of this binding energy on the up, down and strange quark masses that allows a controlled chiral extrapolation, we explore the hypothesis that this state is to be identified with the H dibaryon. Taking as input the recent results of the HAL and NPLQCD Collaborations, we show that the H dibaryon is likely to be unbound by 13±14MeV at the physical point.

"University Unbound" Rebounds: Can MOOCs "Educate" as Well as Train?

ERIC Educational Resources Information Center

McCully, George

2012-01-01

In the days since NEBHE convened hundreds of educators and opinion leaders in Boston for the "University Unbound" conference, people have received a surge of reactions including the one from George McCully, founder of the "Catalogue for Philanthropy." NEBHE has begun focusing the attention of New England institutions on the…

Stiffening of flexible SUMO1 protein upon peptide-binding: Analysis with anisotropic network model.

PubMed

Sarkar, Ranja

2018-01-01

SUMO (small ubiquitin-like modifier) proteins interact with a large number of target proteins via a key regulatory event called sumoylation that encompasses activation, conjugation and ligation of SUMO proteins through specific E1, E2, and E3-type enzymes respectively. Single-molecule atomic force microscopic (AFM) experiments performed to unravel bound SUMO1 along its NC termini direction reveal that E3-ligases (in the form of small peptides) increase mechanical stability (along the axis) of the flexible protein upon binding. The experimental results are expected to correlate with the intrinsic flexibility of bound SUMO1 protein in the native state i.e., the bound conformation of SUMO1 without the binding peptide. The native protein flexibility/stiffness can be measured as a spring constant by normal mode analysis. In the present study, protein normal modes are computed from the protein structural data (as input from protein databank) via a simple anisotropic network model (ANM). ANM is computationally inexpensive and hence, can be explored to investigate and compare the native conformational dynamics of unbound and bound (without the binding partner) structures, if the corresponding structural data (NMR/X-ray) are available. The paper illustrates that SUMO1 stiffens (native flexibility decreases) along the NC termini (end-to-end) direction of the protein upon binding to small peptides; however, the degree of stiffening is peptide sequence-specific. The theoretical results are demonstrated for NMR structures of unbound SUMO1 and that bound to two peptides having short amino acid motifs and of similar size, one being an M-IR2 peptide derived from RanBP2 protein and the other one derived from PIASX protein. The peptide derived from PIASX stiffens SUMO1 remarkably which is evident from an atomic-level normal mode analysis. Copyright © 2017 Elsevier Inc. All rights reserved.

Unbound free fatty acids from preterm infants treated with intralipid decouples unbound from total bilirubin potentially making phototherapy ineffective.

PubMed

Hegyi, Thomas; Kathiravan, Suganya; Stahl, Gary E; Huber, Andrew H; Kleinfeld, Alan

2013-01-01

Extremely low birth weight (ELBW; <1,000 g) infants have poor outcomes, often compromised by bilirubin neurotoxicity. We measured unbound bilirubin (Bf) and unbound free fatty acid (FFAu) levels in 5 ELBW infants in a trial examining the effects of pharmacologic ductal closure on infants treated with Intralipid infusion (3 g/kg/day). The levels for all infants (mean ± SD) were: total serum bilirubin (TSB) 4.6 ± 1.7 mg/dl, FFAu 376 ± 496 nM, and Bf 42 ± 30 nM. Of the 3 infants who died, 2 had TSB <5.9 mg/dl but FFAu >580 nM and Bf >75 nM. Multiple regression revealed a major effect on Bf levels due to FFAu, indicating that Intralipid elevated levels of FFAu and Bf. Indomethacin or ibuprofen reduced Bf levels, most likely by reducing FFAu levels through lipase inhibition. Because displacement of Bf by FFAu decouples Bf from TSB, phototherapy may not reduce the risk of bilirubin or FFAu toxicity in Intralipid-treated ELBW infants. Copyright © 2013 S. Karger AG, Basel.

Spermatozoa with high mitochondrial membrane potential and low tyrosine phosphorylation preferentially bind to oviduct explants in the water buffalo (Bubalus bubalis).

PubMed

Saraf, Kaustubh Kishor; Kumaresan, Arumugam; Chhillar, Shivani; Nayak, Samiksha; Lathika, Sreela; Datta, Tirtha Kumar; Gahlot, Subhash Chand; Karan, Prabha; Verma, Kiran; Mohanty, Tushar Kumar

2017-05-01

Although it is understood that spermatozoa are subjected to selection processes to form a functional sperm reservoir in the oviduct, the mechanism remains obscure. With the aim to understand the sperm selection process in the oviduct, in the present in vitro study, we analyzed mitochondrial membrane potential and tyrosine phosphorylation status in oviduct-explants bound and unbound spermatozoa. Frozen semen from Murrah buffalo bulls (n=10) used under progeny testing programme were utilized for the study. Oviduct explants were prepared by overnight culture of epithelial cells in TCM- 199 and washed spermatozoa were added to the oviduct explants and incubated for 4h. Mitochondrial membrane potential (MMP) and tyrosine phosphorylation status of bound and unbound spermatozoa were assessed at 1h and 4h of incubation. The proportion of spermatozoa with high MMP was significantly higher (P<0.001) among the bound spermatozoa (range 84.67-96.56%) compared to unbound (range 8.70-21.03%) spermatozoa. The proportion of tyrosine phosphorylated spermatozoa was significantly higher (P<0.001) among unbound population as compared to bound population. The proportion of spermatozoa displaying tyrosine phosphorylation at acrosomal area was significantly (P<0.05) lower in bound sperm population compared to unbound population. It was inferred that spermatozoa with high MMP and low tyrosine phosphorylation were preferred for oviduct-explants binding in the buffalo. Copyright © 2017 Elsevier B.V. All rights reserved.

Population approach to analyze the pharmacokinetics of free and total lopinavir in HIV-infected pregnant women and consequences for dose adjustment.

PubMed

Fauchet, Floris; Treluyer, Jean-Marc; Illamola, Silvia M; Pressiat, Claire; Lui, Gabrielle; Valade, Elodie; Mandelbrot, Laurent; Lechedanec, Jerome; Delmas, Sandrine; Blanche, Stéphane; Warszawski, Josiane; Urien, Saik; Tubiana, Roland; Hirt, Déborah

2015-09-01

The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

PubMed Central

Treluyer, Jean-Marc; Illamola, Silvia M.; Pressiat, Claire; Lui, Gabrielle; Valade, Elodie; Mandelbrot, Laurent; Lechedanec, Jerome; Delmas, Sandrine; Blanche, Stéphane; Warszawski, Josiane; Urien, Saik; Tubiana, Roland; Hirt, Déborah

2015-01-01

The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy. PMID:26149996

Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis

PubMed Central

Hurtado, Felipe K.; Weber, Benjamin; Derendorf, Hartmut; Hochhaus, Guenther

2014-01-01

Levofloxacin is a broad-spectrum fluoroquinolone used in the treatment of both acute and chronic bacterial prostatitis. Currently, the treatment of bacterial prostatitis is still difficult, especially due to the poor distribution of many antimicrobials into the prostate, thus preventing the drug to reach effective interstitial concentrations at the infection site. Newer fluoroquinolones show a greater penetration into the prostate. In the present study, we compared the unbound levofloxacin prostate concentrations measured by microdialysis to those in plasma after a 7-mg/kg intravenous bolus dose to Wistar rats. Plasma and dialysate samples were analyzed using a validated high-pressure liquid chromatography-fluorescence method. Both noncompartmental analysis (NCA) and population-based compartmental modeling (NONMEM 6) were performed. Unbound prostate tissue concentrations represented 78% of unbound plasma levels over a period of 12 h by comparing the extent of exposure (unbound AUC0–∞) of 6.4 and 4.8 h·μg/ml in plasma and tissue, respectively. A three-compartment model with simultaneous passive diffusion and saturable distribution kinetics from the prostate to the central compartment gave the best results in terms of curve fitting, precision of parameter estimates, and model stability. The following parameter values were estimated by the population model: V1 (0.38 liter; where V1 represents the volume of the central compartment), CL (0.22 liter/h), k12 (2.27 h−1), k21 (1.44 h−1), k13 (0.69 h−1), Vmax (7.19 μg/h), kM (0.35 μg/ml), V3/fuprostate (0.05 liter; where fuprostate represents the fraction unbound in the prostate), and k31 (3.67 h−1). The interindividual variability values for V1, CL, Vmax, and kM were 21, 37, 42, and 76%, respectively. Our results suggest that levofloxacin is likely to be substrate for efflux transporters in the prostate. PMID:24217697

Identification of p53 unbound to T-antigen in human cells transformed by simian virus 40 T-antigen.

PubMed

O'Neill, F J; Hu, Y; Chen, T; Carney, H

1997-02-27

In several clones of SV40-transformed human cells, we investigated the relative amounts of large T-Antigen (T-Ag) and p53 proteins, both unbound and associated within complexes, with the goal of identifying changes associated with transformation and immortalization. Cells were transformed by wild type (wt) T-Ag, a functionally temperature sensitive T-Ag (tsA58) and other T-Ag variants. Western analysis showed that while most of the T-Ag was ultimately bound by p53, most of the p53 remained unbound to T-Ag. Unbound p53 remained in the supernatant after a T-Ag immunoprecipitation and p53 was present in two to fourfold excess of T-Ag. In one transformant there was five to tenfold more p53 than T-Ag. p53 was present in transformants in amounts at least 200-fold greater than in untransformed human cells. In wt and variant T-Ag transformants, including those generated with tsA58 T-Ag, large amounts of unbound p53 were present in both pre-crisis and immortal cells and when the cells were grown at permissive or non-permissive temperatures. We also found that in transformants produced by tsA58, an SV40/JCV chimeric T-Ag and other variants, T-Ag appeared to form a complex with p53 slowly perhaps because one or both proteins matured slowly. The presence in transformed human cells of large amounts of unbound p53 and in excess of T-Ag suggests that sequestration of p53 by T-Ag, resulting from complex formation, is required neither for morphological transformation nor immortalization of human cells. Rather, these results support the proposal that high levels of p53, the T-Ag/p53 complexes, or other biochemical event(s), lead to transformation and immortalization of human cells by T-Ag.

Spectroscopy at the two-proton drip line: Excited states in 158W

NASA Astrophysics Data System (ADS)

Joss, D. T.; Page, R. D.; Herzán, A.; Donosa, L.; Uusitalo, J.; Carroll, R. J.; Darby, I. G.; Andgren, K.; Cederwall, B.; Eeckhaudt, S.; Grahn, T.; Greenlees, P. T.; Hadinia, B.; Jakobsson, U.; Jones, P. M.; Julin, R.; Juutinen, S.; Leino, M.; Leppanen, A.-P.; Nyman, M.; O'Donnell, D.; Pakarinen, J.; Rahkila, P.; Sandzelius, M.; Sarén, J.; Scholey, C.; Seweryniak, D.; Simpson, J.; Sorri, J.

2017-09-01

Excited states have been identified in the heaviest known even-Z N = 84 isotone 158W, which lies in a region of one-proton emitters and the two-proton drip line. The observation of γ-ray transitions feeding the ground state establishes the excitation energy of the yrast 6+ state confirming the spin-gap nature of the α-decaying 8+ isomer. The 8+ isomer is also expected to be unbound to two-proton emission but no evidence for this decay mode was observed. An upper limit for the two-proton decay branch has been deduced as b2p ≤ 0.17% at the 90% confidence level. The possibility of observing two-proton emission from multiparticle isomers in nearby nuclides is considered.

Level Density in the Complex Scaling Method

NASA Astrophysics Data System (ADS)

Suzuki, R.; Myo, T.; Katō, K.

2005-06-01

It is shown that the continuum level density (CLD) at unbound energies can be calculated with the complex scaling method (CSM), in which the energy spectra of bound states, resonances and continuum states are obtained in terms of L(2) basis functions. In this method, the extended completeness relation is applied to the calculation of the Green functions, and the continuum-state part is approximately expressed in terms of discretized complex scaled continuum solutions. The obtained result is compared with the CLD calculated exactly from the scattering phase shift. The discretization in the CSM is shown to give a very good description of continuum states. We discuss how the scattering phase shifts can inversely be calculated from the discretized CLD using a basis function technique in the CSM.

Critical screening in the one- and two-electron Yukawa atoms

NASA Astrophysics Data System (ADS)

Montgomery, H. E.; Sen, K. D.; Katriel, Jacob

2018-02-01

The one- and two-electron Yukawa atoms, also referred to as the Debye-Hückel or screened Coulomb atoms, have been topics of considerable interest both for intrinsic reasons and because of their relevance to terrestrial and astrophysical plasmas. At sufficiently high screening the one-electron Yukawa atom ceases to be bound. Some calculations appeared to suggest that as the screening increases in the ground state of the two-electron Yukawa atom (in which both the one-particle attraction and the interparticle repulsion are screened) the two electrons are detached simultaneously, at the same screening constant at which the one-electron atom becomes unbound. Our results rule this scenario out, offering an alternative that is not less interesting. In particular, it is found that for Z <1 a mild amount of screening actually increases the binding energy of the second electron. At the nuclear charge Zc≈0.911028 ... , at which the bare Coulomb two-electron atom becomes unbound, and even over a range of lower nuclear charges, an appropriate amount of screening gives rise to a bound two-electron system.

Random Walk Particle Tracking For Multiphase Heat Transfer

NASA Astrophysics Data System (ADS)

Lattanzi, Aaron; Yin, Xiaolong; Hrenya, Christine

2017-11-01

As computing capabilities have advanced, direct numerical simulation (DNS) has become a highly effective tool for quantitatively predicting the heat transfer within multiphase flows. Here we utilize a hybrid DNS framework that couples the lattice Boltzmann method (LBM) to the random walk particle tracking (RWPT) algorithm. The main challenge of such a hybrid is that discontinuous fields pose a significant challenge to the RWPT framework and special attention must be given to the handling of interfaces. We derive a method for addressing discontinuities in the diffusivity field, arising at the interface between two phases. Analytical means are utilized to develop an interfacial tracer balance and modify the RWPT algorithm. By expanding the modulus of the stochastic (diffusive) step and only allowing a subset of the tracers within the high diffusivity medium to undergo a diffusive step, the correct equilibrium state can be restored (globally homogeneous tracer distribution). The new RWPT algorithm is implemented within the SUSP3D code and verified against a variety of systems: effective diffusivity of a static gas-solids mixture, hot sphere in unbounded diffusion, cooling sphere in unbounded diffusion, and uniform flow past a hot sphere.

A Floating Cylinder on an Unbounded Bath

NASA Astrophysics Data System (ADS)

Chen, Hanzhe; Siegel, David

2018-03-01

In this paper, we reconsider a circular cylinder horizontally floating on an unbounded reservoir in a gravitational field directed downwards, which was studied by Bhatnagar and Finn (Phys Fluids 18(4):047103, 2006). We follow their approach but with some modifications. We establish the relation between the total energy E_T relative to the undisturbed state and the total force F_T , that is, F_T = -dE_T/dh , where h is the height of the center of the cylinder relative to the undisturbed fluid level. There is a monotone relation between h and the wetting angle φ _0 . We study the number of equilibria, the floating configurations and their stability for all parameter values. We find that the system admits at most two equilibrium points for arbitrary contact angle γ , the one with smaller φ _0 is stable and the one with larger φ _0 is unstable. Since the one-sided solution can be translated horizontally, the fluid interfaces may intersect. We show that the stable equilibrium point never lies in the intersection region, while the unstable equilibrium point may lie in the intersection region.

Kinetic rate constant prediction supports the conformational selection mechanism of protein binding.

PubMed

Moal, Iain H; Bates, Paul A

2012-01-01

The prediction of protein-protein kinetic rate constants provides a fundamental test of our understanding of molecular recognition, and will play an important role in the modeling of complex biological systems. In this paper, a feature selection and regression algorithm is applied to mine a large set of molecular descriptors and construct simple models for association and dissociation rate constants using empirical data. Using separate test data for validation, the predicted rate constants can be combined to calculate binding affinity with accuracy matching that of state of the art empirical free energy functions. The models show that the rate of association is linearly related to the proportion of unbound proteins in the bound conformational ensemble relative to the unbound conformational ensemble, indicating that the binding partners must adopt a geometry near to that of the bound prior to binding. Mirroring the conformational selection and population shift mechanism of protein binding, the models provide a strong separate line of evidence for the preponderance of this mechanism in protein-protein binding, complementing structural and theoretical studies.

A Unified Framework for Bounded and Unbounded Numerical Estimation

ERIC Educational Resources Information Center

Kim, Dan; Opfer, John E.

2017-01-01

Representations of numerical value have been assessed by using bounded (e.g., 0-1,000) and unbounded (e.g., 0-?) number-line tasks, with considerable debate regarding whether 1 or both tasks elicit unique cognitive strategies (e.g., addition or subtraction) and require unique cognitive models. To test this, we examined how well a mixed log-linear…

Repulsive Effect for Unbound High Energy Particles Along Rotation Axis in Kerr-Taub-NUT Spacetime

NASA Astrophysics Data System (ADS)

Zhang, Lu; Chen, Song-Bai

2018-04-01

We have investigated the acceleration of the unbound high energy particles moving along the rotation axis in the Kerr-Taub-NUT spacetime, and then study the dependence of the repulsive effects on the NUT charge for the particles in the spacetime. Whether the repulsive effects with the NUT charge become stronger depends on the Carter constant, the position and velocity of the particles themselves. We also present numerically the changes of the observable velocity and acceleration with the NUT charge for the unbound particles in the Kerr-Taub-NUT spacetime. Supported by the Scientific Research Fund of Hunan Provincial Education Department under Grant No. 17A124, and the Construct Program of Key Disciplines in Hunan Province

Coupled-cluster computations of atomic nuclei

NASA Astrophysics Data System (ADS)

Hagen, G.; Papenbrock, T.; Hjorth-Jensen, M.; Dean, D. J.

2014-09-01

In the past decade, coupled-cluster theory has seen a renaissance in nuclear physics, with computations of neutron-rich and medium-mass nuclei. The method is efficient for nuclei with product-state references, and it describes many aspects of weakly bound and unbound nuclei. This report reviews the technical and conceptual developments of this method in nuclear physics, and the results of coupled-cluster calculations for nucleonic matter, and for exotic isotopes of helium, oxygen, calcium, and some of their neighbors.

Nonlinear dynamics of an elliptic vortex embedded in an oscillatory shear flow.

PubMed

Ryzhov, Eugene A

2017-11-01

The nonlinear dynamics of an elliptic vortex subjected to a time-periodic linear external shear flow is studied numerically. Making use of the ideas from the theory of nonlinear resonance overlaps, the study focuses on the appearance of chaotic regimes in the ellipse dynamics. When the superimposed flow is stationary, two general types of the steady-state phase portrait are considered: one that features a homoclinic separatrix delineating bounded and unbounded phase trajectories and one without a separatrix (all the phase trajectories are bounded in a periodic domain). When the external flow is time-periodic, the ensuing nonlinear dynamics differs significantly in both cases. For the case with a separatrix and two distinct types of phase trajectories: bounded and unbounded, the effect of the most influential nonlinear resonance with the winding number of 1:1 is analyzed in detail. Namely, the process of occupying the central stability region associated with the steady-state elliptic critical point by the stability region associated with the nonlinear resonance of 1:1 as the perturbation frequency gradually varies is investigated. A stark increase in the persistence of the central regular dynamics region against perturbation when the resonance of 1:1 associated stability region occupies the region associated with the steady-state elliptic critical point is observed. An analogous persistence of the regular motion occurs for higher perturbation frequencies when the corresponding stability islands reach the central stability region associated with the steady-state elliptic point. An analysis for the case with the resonance of 1:2 is presented. For the second case with only bounded phase trajectories and, therefore, no separatrix, the appearance of much bigger stability islands associated with nonlinear resonances compared with the case with a separatrix is reported.

Adaptive estimation of a time-varying phase with coherent states: Smoothing can give an unbounded improvement over filtering

NASA Astrophysics Data System (ADS)

Laverick, Kiarn T.; Wiseman, Howard M.; Dinani, Hossein T.; Berry, Dominic W.

2018-04-01

The problem of measuring a time-varying phase, even when the statistics of the variation is known, is considerably harder than that of measuring a constant phase. In particular, the usual bounds on accuracy, such as the 1 /(4 n ¯) standard quantum limit with coherent states, do not apply. Here, by restricting to coherent states, we are able to analytically obtain the achievable accuracy, the equivalent of the standard quantum limit, for a wide class of phase variation. In particular, we consider the case where the phase has Gaussian statistics and a power-law spectrum equal to κp -1/|ω| p for large ω , for some p >1 . For coherent states with mean photon flux N , we give the quantum Cramér-Rao bound on the mean-square phase error as [psin(π /p ) ] -1(4N /κ ) -(p -1 )/p . Next, we consider whether the bound can be achieved by an adaptive homodyne measurement in the limit N /κ ≫1 , which allows the photocurrent to be linearized. Applying the optimal filtering for the resultant linear Gaussian system, we find the same scaling with N , but with a prefactor larger by a factor of p . By contrast, if we employ optimal smoothing we can exactly obtain the quantum Cramér-Rao bound. That is, contrary to previously considered (p =2 ) cases of phase estimation, here the improvement offered by smoothing over filtering is not limited to a factor of 2 but rather can be unbounded by a factor of p . We also study numerically the performance of these estimators for an adaptive measurement in the limit where N /κ is not large and find a more complicated picture.

Quasi-steady state conditions in heterogeneous aquifers during pumping tests

NASA Astrophysics Data System (ADS)

Zha, Yuanyuan; Yeh, Tian-Chyi J.; Shi, Liangsheng; Huang, Shao-Yang; Wang, Wenke; Wen, Jet-Chau

2017-08-01

Classical Thiem's well hydraulic theory, other aquifer test analyses, and flow modeling efforts often assume the existence of ;quasi-steady; state conditions. That is, while drawdowns due to pumping continue to grow, the hydraulic gradient in the vicinity of the pumping well does not change significantly. These conditions have built upon two-dimensional and equivalent homogeneous conceptual models, but few field data have been available to affirm the existence of these conditions. Moreover, effects of heterogeneity and three-dimensional flow on this quasi-steady state concept have not been thoroughly investigated and discussed before. In this study, we first present a quantitative definition of quasi-steady state (or steady-shape conditions) and steady state conditions based on the analytical solution of two- or three-dimensional flow induced by pumping in unbounded, homogeneous aquifers. Afterward, we use a stochastic analysis to investigate the influence of heterogeneity on the quasi-steady state concept in heterogeneous aquifers. The results of the analysis indicate that the time to reach an approximate quasi-steady state in a heterogeneous aquifer could be quite different from that estimated based on a homogeneous model. We find that heterogeneity of aquifer properties, especially hydraulic conductivity, impedes the development of the quasi-steady state condition before the flow reaching steady state. Finally, 280 drawdown-time data from the hydraulic tomographic survey conducted at a field site corroborate our finding that the quasi-steady state condition likely would not take place in heterogeneous aquifers unless pumping tests last a long period. Research significance (1) Approximate quasi-steady and steady state conditions are defined for two- or three-dimensional flow induced by pumping in unbounded, equivalent homogeneous aquifers. (2) Analysis demonstrates effects of boundary condition, well screen interval, and heterogeneity of parameters on the existence of the quasi-steady, and validity of approximate quasi-steady concept. (3) Temporal evaluation of information content about heterogeneity in head observations are analyzed in heterogeneous aquifer. (4) 280 observed drawdown-time data corroborate the stochastic analysis that quasi-steady is difficult to reach in highly heterogeneous aquifers.

Protein binding and its potential for eliciting minimal systemic side effects with a novel inhaled corticosteroid, ciclesonide.

PubMed

Rohatagi, Shashank; Luo, Yongyi; Shen, Liduo; Guo, Zuyu; Schemm, Christina; Huang, Yongqing; Chen, Kelly; David, Michael; Nave, Ruediger; King, S Peter

2005-01-01

Freely circulating, protein unbound, active inhaled corticosteroid (ICS) can cause systemic adverse effects. Desisobutyryl-ciclesonide (des-CIC) is the active metabolite of ciclesonide, an effective, novel ICS for persistent asthma. This study examines the free fraction of ciclesonide and des-CIC and determines whether the presence of other agents or disease states affects protein binding. Protein binding of des-CIC (0.5, 5.0, 25, 100, and 500 ng/mL) was determined, using both equilibrium dialysis and ultrafiltration, in plasma from humans (healthy and either renally or hepatically impaired) and several animal species and in the presence of either salicylates or warfarin. Dialyzed samples were analyzed by liquid chromatography with tandem mass spectroscopy to determine both free and bound concentrations of des-CIC. After ultrafiltration, spiked plasma plus H-des-CIC was separated into free and bound fractions by centrifugation and quantified by scintillation counting. Additionally, in another study, protein binding of ciclesonide was determined by equilibrium dialysis. For equilibrium dialysis, the mean percentages of des-CIC (0.5-500 ng/mL) plasma protein binding across species were high, approximately 99%, and no apparent saturation of protein binding was observed. Results were similar for ultrafiltration analysis. Protein binding of des-CIC did not change in the presence of warfarin or salicylates or in the plasma of renally or hepatically impaired patients. The protein binding of ciclesonide was 99.4% in human serum. The very low fraction of unbound des-CIC in the systemic circulation suggests minimal systemic exposure of unbound des-CIC, thus suggesting a low potential for systemic adverse effects after administration of inhaled ciclesonide.

Helicon modes in uniform plasmas. I. Low m modes

NASA Astrophysics Data System (ADS)

Urrutia, J. M.; Stenzel, R. L.

2015-09-01

Helicons are whistler modes with azimuthal wave numbers. They arise in bounded gaseous and solid state plasmas, but the present work shows that very similar modes also exist in unbounded uniform plasmas. The antenna properties determine the mode structure. A simple antenna is a magnetic loop with dipole moment aligned either along or across the ambient background magnetic field B0. For such configurations, the wave magnetic field has been measured in space and time in a large and uniform laboratory plasma. The observed wave topology for a dipole along B0 is similar to that of an m = 0 helicon mode. It consists of a sequence of alternating whistler vortices. For a dipole across B0, an m = 1 mode is excited which can be considered as a transverse vortex which rotates around B0. In m = 0 modes, the field lines are confined to each half-wavelength vortex while for m = 1 modes they pass through the entire wave train. A subset of m = 1 field lines forms two nested helices which rotate in space and time like corkscrews. Depending on the type of the antenna, both m = + 1 and m = -1 modes can be excited. Helicons in unbounded plasmas also propagate transverse to B0. The transverse and parallel wave numbers are about equal and form oblique phase fronts as in whistler Gendrin modes. By superimposing small amplitude fields of several loop antennas, various antenna combinations have been created. These include rotating field antennas, helical antennas, and directional antennas. The radiation efficiency is quantified by the radiation resistance. Since helicons exist in unbounded laboratory plasmas, they can also arise in space plasmas.

Effects of atmospheric relative humidity on Stratum Corneum structure at the molecular level: ex vivo Raman spectroscopy analysis.

PubMed

Vyumvuhore, Raoul; Tfayli, Ali; Duplan, Hélène; Delalleau, Alexandre; Manfait, Michel; Baillet-Guffroy, Arlette

2013-07-21

Skin hydration plays an important role in the optimal physical properties and physiological functions of the skin. Despite the advancements in the last decade, dry skin remains the most common characteristic of human skin disorders. Thus, it is important to understand the effect of hydration on Stratum Corneum (SC) components. In this respect, our interest consists in correlating the variations of unbound and bound water content in the SC with structural and organizational changes in lipids and proteins using a non-invasive technique: Raman spectroscopy. Raman spectra were acquired on human SC at different relative humidity (RH) levels (4-75%). The content of different types of water, bound and free, was measured using the second derivative and curve fitting of the Raman bands in the range of 3100-3700 cm(-1). Changes in lipidic order were evaluated using νC-C and νC-H. To analyze the effect of RH on the protein structure, we examined in the Amide I region, the Fermi doublet of tyrosine, and the νasymCH3 vibration. The contributions of totally bound water were found not to vary with humidity, while partially bound water varied with three different rates. Unbound water increased greatly when all sites for bound water were saturated. Lipid organization as well as protein deployment was found to be optimal at intermediate RH values (around 60%), which correspond to the maximum of SC water binding capacity. This analysis highlights the relationship between bound water, the SC barrier state and the protein structure and elucidates the optimal conditions. Moreover, our results showed that increased content of unbound water in the SC induces disorder in the structures of lipids and proteins.

Melanin targeting for intracellular drug delivery: Quantification of bound and free drug in retinal pigment epithelial cells.

PubMed

Rimpelä, Anna-Kaisa; Hagström, Marja; Kidron, Heidi; Urtti, Arto

2018-05-31

Melanin binding affects drug distribution and retention in pigmented ocular tissues, thereby affecting drug response, duration of activity and toxicity. Therefore, it is a promising possibility for drug targeting and controlled release in the pigmented cells and tissues. Intracellular unbound drug concentrations determine pharmacological and toxicological actions, but analyses of unbound vs. total drug concentrations in pigmented cells are lacking. We studied intracellular binding and cellular drug uptake in pigmented retinal pigment epithelial cells and in non-pigmented ARPE-19 cells with five model drugs (chloroquine, propranolol, timolol, diclofenac, methotrexate). The unbound drug fractions in pigmented cells were 0.00016-0.73 and in non-pigmented cells 0.017-1.0. Cellular uptake (i.e. distribution ratio Kp), ranged from 1.3 to 6300 in pigmented cells and from 1.0 to 25 in non-pigmented cells. Values for intracellular bioavailability, F ic , were similar in both cells types (although larger variation in pigmented cells). In vitro melanin binding parameters were used to predict intracellular unbound drug fraction and cell uptake. Comparison of predictions with experimental data indicates that other factors (e.g. ion-trapping, lipophilicity-related binding to other cell components) also play a role. Melanin binding is a major factor that leads to cellular uptake and unbound drug fractions of a range of 3-4 orders of magnitude indicating that large reservoirs of melanin bound drug can be generated in the cells. Understanding melanin binding has important implications on retinal drug targeting, efficacy and toxicity. Copyright © 2017. Published by Elsevier B.V.

Dual Role of Protein Phosphorylation in DNA Activator/Coactivator Binding

PubMed Central

Dadarlat, Voichita M.; Skeel, Robert D.

2011-01-01

Binding free energies are calculated for the phosphorylated and unphosphorylated complexes between the kinase inducible domain (KID) of the DNA transcriptional activator cAMP response element binding (CREB) protein and the KIX domain of its coactivator, CREB-binding protein (CBP). To our knowledge, this is the first application of a method based on a potential of mean force (PMF) with restraining potentials to compute the binding free energy of protein-protein complexes. The KID:KIX complexes are chosen here because of their biological relevance to the DNA transcription process and their relatively small size (81 residues for the KIX domain of CBP, and 28 residues for KID). The results for pKID:KIX and KID:KIX are −9.55 and −4.96 kcal/mol, respectively, in good agreement with experimental estimates (−8.8 and −5.8 kcal/mol, respectively). A comparison between specific contributions to protein-protein binding for the phosphorylated and unphosphorylated complexes reveals a dual role for the phosphorylation of KID at Ser-133 in effecting a more favorable free energy of the bound system: 1), stabilization of the unbound conformation of phosphorylated KID due to favorable intramolecular interactions of the phosphate group of Ser-133 with the charged groups of an arginine-rich region spanning both α-helices, which lowers the configurational entropy; and 2), more favorable intermolecular electrostatic interactions between pSer-133 and Arg-131 of KID, and Lys-662, Tyr-658, and Glu-666 of KIX. Charge reduction through ligand phosphorylation emerges as a possible mechanism for controlling the unbound state conformation of KID and, ultimately, gene expression. This work also demonstrates that the PMF-based method with restraining potentials provides an added benefit in that important elements of the binding pathway are evidenced. Furthermore, the practicality of the PMF-based method for larger systems is validated by agreement with experiment. In addition, we provide a somewhat differently structured exposition of the PMF-based method with restraining potentials and outline its generalization to systems in which both protein and ligand may adopt unbound conformations that are different from those of the bound state. PMID:21244843

Aerodynamic stiffness of an unbound eccentric whirling centrifugal impeller with an infinite number of blades

NASA Technical Reports Server (NTRS)

Allaire, P. E.; Branagan, L. A.; Kocur, J. A.

1982-01-01

An unbounded eccentric centrifugal impeller with an infinite number of log spiral blades undergoing synchronous whirling in an incompressible fluid is considered. The forces acting on it due to coriolis forces, centripetal forces, changes in linear momentum, changes in pressure due to rotating and changes in pressure due to changes in linear momentum are evaluated.

Different Formulations of the Orthogonal Array Problem and Their Symmetries

DTIC Science & Technology

2014-06-19

t). Note that OAP(k, s, t, λ) is a polytope not an unbounded polyhedron because it can be embedded inside the hypercube [0, λ]m. Theorem 5. The OAP(k...3.1) is a facet since otherwise OAP(k, s, t, λ) would be an unbounded polyhedron . Then there exists Ny ∈ Rm satisfying all but the 28 facet defining

Weak Compactness and Control Measures in the Space of Unbounded Measures

PubMed Central

Brooks, James K.; Dinculeanu, Nicolae

1972-01-01

We present a synthesis theorem for a family of locally equivalent measures defined on a ring of sets. This theorem is then used to exhibit a control measure for weakly compact sets of unbounded measures. In addition, the existence of a local control measure for locally strongly bounded vector measures is proved by means of the synthesis theorem. PMID:16591980

Analysis of Unbound Aggregate Layer Deformation Behavior from Full Scale Aircraft Gear Loading with Wander

ERIC Educational Resources Information Center

Donovan, Phillip Raymond

2009-01-01

This study focuses on the analysis of the behavior of unbound aggregates to offset wheel loads. Test data from full-scale aircraft gear loading conducted at the National Airport Pavement Test Facility (NAPTF) by the Federal Aviation Administration (FAA) are used to investigate the effects of wander (offset loads) on the deformation behavior of…

Alkali Halide Opacity in Brown Dwarf and Cool Stellar Atmospheres: A Study of Lithium Chloride

NASA Astrophysics Data System (ADS)

Kirby, K.; Weck, P. F.; Schweitzer, A.; Stancil, P. C.; Hauschildt, P. H.

2003-12-01

Recent thermochemical equilibrium calculations have revealed the important role played by lithium chloride in the lithium chemistry of cool dwarf atmospheres (K. Lodders 1999, ApJ 519, 793). Indeed, LiCl appears to be the dominant Li-bearing gas over an extended domain of the (P,T) diagram, typically for temperatures below 1500 K. LiCl has a large dipole moment in its ground electronic state which can give rise to intense rovibrational line spectra. In addition, LiCl can make dipole transitions to several low-lying unbound excited states, causing dissociation of the molecule. For these reasons, LiCl may be a significant source of line and continuum opacity in brown dwarf and cool stellar atmospheres. In this work, we report calculations of complete lists of line oscillator strengths and photodissociation cross sections for the low-lying electronic states of LiCl. We have performed single- and double-excitation configuration interaction calculations using the ALCHEMY ab initio package (Mc Lean et al. 1991, MOTECC 91, Elsevier, Leiden) and obtained the potential curves and the corresponding dipole transition moment functions between the X 1Σ ^+ ground state and the B 1Σ ^+ and A 1Π excited states. The resulting line oscillator strengths and molecular photodissociation cross sections have been included in the PHOENIX stellar atmosphere code (Hauschildt & Baron 1999, J. Comput. App. Math. 102, 41). The new models, calculated using spherical geometry for all gravities considered, also incorporate our latest database of nearly 670 million molecular lines, and updated equations of state (EOS). This work was supported in part by NSF grants AST-9720704 and AST-0086246, NASA grants NAG5-8425, NAG5-9222, and NAG5-10551 as well as NASA/JPL grant 961582.

Bounded energy states in homogeneous turbulent shear flow - An alternative view

NASA Technical Reports Server (NTRS)

Bernard, P. S.; Speziale, C. G.

1992-01-01

The equilibrium structure of homogeneous turbulent shear flow is investigated from a theoretical standpoint. Existing turbulence models, in apparent agreement with physical and numerical experiments, predict an unbounded exponential time growth of the turbulent kinetic energy and dissipation rate; only the anisotropy tensor and turbulent time scale reach a structural equilibrium. It is shown that if a residual vortex stretching term is maintained in the dissipation rate transport equation, then there can exist equilibrium solutions, with bounded energy states, where the turbulence production is balanced by its dissipation. Illustrative calculations are presented for a k-epsilon model modified to account for net vortex stretching.

Optical Rogue Waves in Vortex Turbulence.

PubMed

Gibson, Christopher J; Yao, Alison M; Oppo, Gian-Luca

2016-01-29

We present a spatiotemporal mechanism for producing 2D optical rogue waves in the presence of a turbulent state with creation, interaction, and annihilation of optical vortices. Spatially periodic structures with bound phase lose stability to phase unbound turbulent states in complex Ginzburg-Landau and Swift-Hohenberg models with external driving. When the pumping is high and the external driving is low, synchronized oscillations are unstable and lead to spatiotemporal vortex-mediated turbulence with high excursions in amplitude. Nonlinear amplification leads to rogue waves close to turbulent optical vortices, where the amplitude tends to zero, and to probability density functions (PDFs) with long tails typical of extreme optical events.

Observation of the particle-unstable nucleus 10N

NASA Astrophysics Data System (ADS)

Lépine-Szily, A.; Oliveira, J. M.; Vanin, V. R.; Ostrowski, A. N.; Lichtenthäler, R.; di Pietro, A.; Guimarães, V.; Laird, A. M.; Maunoury, L.; Lima, G. F.; de Oliveira Santos, F.; Roussel-Chomaz, P.; Savajols, H.; Trinder, W.; Villari, A. C.; de Vismes, A.

2002-05-01

For the first time evidence of the ground state of the proton-rich, unbound nucleus 10N has been found in the multinucleon transfer reaction 10B(14N,14B)10N. The observed resonance of 10N has a mass excess of 38.8(4) MeV and a width of Γ=2.3(16) MeV, close to the Audi-Wapstra estimation of 38.5(4) MeV. 10N is the last missing A=10 multiplet partner.

Confining potential in momentum space

NASA Technical Reports Server (NTRS)

Norbury, John W.; Kahana, David E.; Maung, Khin Maung

1992-01-01

A method is presented for the solution in momentum space of the bound state problem with a linear potential in r space. The potential is unbounded at large r leading to a singularity at small q. The singularity is integrable, when regulated by exponentially screening the r-space potential, and is removed by a subtraction technique. The limit of zero screening is taken analytically, and the numerical solution of the subtracted integral equation gives eigenvalues and wave functions in good agreement with position space calculations.

Ion Correlation Effects in Salt-Doped Block Copolymers

NASA Astrophysics Data System (ADS)

Brown, Jonathan R.; Seo, Youngmi; Hall, Lisa M.

2018-03-01

We apply classical density functional theory to study how salt changes the microphase morphology of diblock copolymers. Polymers are freely jointed and one monomer type favorably interacts with ions, to account for the selective solvation that arises from different dielectric constants of the microphases. By including correlations from liquid state theory of an unbound reference fluid, the theory can treat chain behavior, microphase separation, ion correlations, and preferential solvation, at the same coarse-grained level. We show good agreement with molecular dynamics simulations.

Radiative decay of neutron-unbound intruder states in 19O

NASA Astrophysics Data System (ADS)

Dungan, R.; Tabor, S. L.; Tripathi, Vandana; Volya, A.; Kravvaris, K.; Abromeit, B.; Caussyn, D. D.; Morrow, S.; Parker, J. J.; Tai, P.-L.; VonMoss, J. M.

2016-02-01

The 9Be(14C, α γ ) reaction at EL a b=30 and 35 MeV was used to study excited states of 19O. The Florida State University (FSU) γ detector array was used to detect γ radiation in coincidence with charged particles detected and identified with a silicon Δ E -E particle telescope. γ decays have been observed for the first time from six states ranging from 368 to 2147 keV above the neutron separation energy (Sn=3962 keV) in 19O. The γ -decaying states are interspersed among states previously observed to decay by neutron emission. The ability of electromagnetic decay to compete successfully with neutron decay is explained in terms of neutron angular momentum barriers and small spectroscopic factors implying higher spin and complex structure for these intruder states. These results illustrate the need for complementary experimental approaches to best illuminate the complete nuclear structure.

Accelerated testing for studying pavement design and performance (FY 2001) : evaluation of the performance of permeable and semi-permeable unbound granular bases under Portland Cement Concrete Pavement (PCCP) slabs and alternate load transfer devices for

DOT National Transportation Integrated Search

2003-11-01

The objectives of this research are to determine the effect of unbound drainable base types on the performance of PCCP and the efficiency of fiber-reinforced polymer (FRP) dowels, compared to epoxy coated steel dowels, when retrofitted to re-establis...

Unbalanced Nature, Unbounded Bodies, and Unlimited Technology: Ecocriticism and Karen Traviss' Wess'har Series

ERIC Educational Resources Information Center

Sullivan, Heather I.

2010-01-01

While nature is often claimed to be a space of harmonized balance or an antidote to the chaos of the modern world, we need a more grounded assessment of nature as endlessly changing and much less predictable than we like to assume. In this essay, I explore Karen Traviss' provocative exploration of unbalanced nature and unbounded bodies in her…

Differential levels of metabolic activity in isolated versus confluent/partially confluent HeLa cells are analyzed by autofluorescent NAD(P)H using multi-photon FLIM microscopy

NASA Astrophysics Data System (ADS)

Chandler, Andrea; Chandler, Aaron; Wallrabe, Horst; Periasamy, Ammasi

2017-02-01

NAD(P)H is a known biomarker for cellular metabolism; a higher ratio of enzyme-bound NAD(P)H to free/unbound NAD(P)H indicates an increase in metabolic activity. Free NADH has a shorter fluorescence lifetime (τ1), the bound version (τ2) a longer lifetime. FLIM's unique capability to establish inter alia the relative fractions of τ1 (a1%) and τ2 (a2%) in each pixel, determines the level of metabolic activity. The relative abundances of bound NAD(P)H were analyzed for single cells, confluent and partially confluent cells within 3 Fields-of-View (FoVs). A gradient of increasing a 2% levels of bound NAD(P)H from single, partially confluent to confluent cells was observed.

[Purification of arsenic-binding proteins in hamster plasma after oral administration of arsenite].

PubMed

Wang, Wenwen; Zhang, Min; Li, Chunhui; Qin, Yingjie; Hua, Naranmandura

2013-01-01

To purify the arsenic-binding proteins (As-BP) in hamster plasma after a single oral administration of arsenite (iAs(III)). Arsenite was given to hamsters in a single dose. Three types of HPLC columns, size exclusion, gel filtration and anion exchange columns, combined with an inductively coupled argon plasma mass spectrometer (ICP MS) were used to purify the As-BP in hamster plasma. SDS-PAGE was used to confirm the arsenic-binding proteins at each purification step. The three-step purification process successfully separated As-BP from other proteins (ie, arsenic unbound proteins) in hamster plasma. The molecular mass of purified As-BP in plasma was approximately 40-50 kD on SDS-PAGE. The three-step purification method is a simple and fast approach to purify the As-BP in plasma samples.

BP-Dock: A Flexible Docking Scheme for Exploring Protein–Ligand Interactions Based on Unbound Structures

PubMed Central

Bolia, Ashini; Gerek, Z. Nevin; Ozkan, S. Banu

2016-01-01

Molecular docking serves as an important tool in modeling protein–ligand interactions. However, it is still challenging to incorporate overall receptor flexibility, especially backbone flexibility, in docking due to the large conformational space that needs to be sampled. To overcome this problem, we developed a novel flexible docking approach, BP-Dock (Backbone Perturbation-Dock) that can integrate both backbone and side chain conformational changes induced by ligand binding through a multi-scale approach. In the BP-Dock method, we mimic the nature of binding-induced events as a first-order approximation by perturbing the residues along the protein chain with a small Brownian kick one at a time. The response fluctuation profile of the chain upon these perturbations is computed using the perturbation response scanning method. These response fluctuation profiles are then used to generate binding-induced multiple receptor conformations for ensemble docking. To evaluate the performance of BP-Dock, we applied our approach on a large and diverse data set using unbound structures as receptors. We also compared the BP-Dock results with bound and unbound docking, where overall receptor flexibility was not taken into account. Our results highlight the importance of modeling backbone flexibility in docking for recapitulating the experimental binding affinities, especially when an unbound structure is used. With BP-Dock, we can generate a wide range of binding site conformations realized in nature even in the absence of a ligand that can help us to improve the accuracy of unbound docking. We expect that our fast and efficient flexible docking approach may further aid in our understanding of protein–ligand interactions as well as virtual screening of novel targets for rational drug design. PMID:24380381

Distribution of lacosamide in the rat brain assessed by in vitro slice technique.

PubMed

Gáll, Zsolt; Vancea, Szende

2018-01-01

Lacosamide is a newer anticonvulsant and is the only one that enhances the slow inactivation of voltage gated sodium channels. It is also claimed to have disease-modifying potential, but its pharmacokinetic properties have been much less discussed in the literature. In rats, lacosamide shows restricted distribution to tissues, and the brain-to-plasma partition coefficient (K p ) is only 0.553. In this study, the brain disposition of lacosamide was evaluated in rat brains, and its neuropharmacokinetic parameters (i.e., protein binding and intracellular accumulation) were assessed using in vitro methods. Brain slice experiments and brain homogenate binding studies were performed for several drugs acting on the central nervous system, and drugs were assayed by using a liquid chromatography-mass spectrometry system. By applying a combined approach, it was found that (1) the unbound volume of distribution in the brain for lacosamide (V u,brain  = 1.37) was lower than that of other classical anticonvulsants; (2) the unbound fraction of lacosamide in the brain (0.899) was slightly lower than its unbound fraction in plasma (0.96); (3) the unbound intracellular-to-extracellular concentration ratio of lacosamide was 1.233, meaning that lacosamide was accumulated in the intracellular space because of its physicochemical properties and zwitterionic structure; and (4) the unbound brain-to-plasma concentration ratio of lacosamide was lower than the total brain-to-plasma concentration ratio (K p,uu,brain  = 0.42 vs. K p  = 0.553). In conclusion, the limited brain distribution of lacosamide is not related to its nonspecific protein-binding capacity; rather, an active transport mechanism across the blood-brain barrier may be involved, which reduces the anticonvulsant and/or antiepileptogenic actions of this drug.

Time to stabilization in single leg drop jump landings: an examination of calculation methods and assessment of differences in sample rate, filter settings and trial length on outcome values.

PubMed

Fransz, Duncan P; Huurnink, Arnold; de Boode, Vosse A; Kingma, Idsart; van Dieën, Jaap H

2015-01-01

Time to stabilization (TTS) is the time it takes for an individual to return to a baseline or stable state following a jump or hop landing. A large variety exists in methods to calculate the TTS. These methods can be described based on four aspects: (1) the input signal used (vertical, anteroposterior, or mediolateral ground reaction force) (2) signal processing (smoothed by sequential averaging, a moving root-mean-square window, or fitting an unbounded third order polynomial), (3) the stable state (threshold), and (4) the definition of when the (processed) signal is considered stable. Furthermore, differences exist with regard to the sample rate, filter settings and trial length. Twenty-five healthy volunteers performed ten 'single leg drop jump landing' trials. For each trial, TTS was calculated according to 18 previously reported methods. Additionally, the effects of sample rate (1000, 500, 200 and 100 samples/s), filter settings (no filter, 40, 15 and 10 Hz), and trial length (20, 14, 10, 7, 5 and 3s) were assessed. The TTS values varied considerably across the calculation methods. The maximum effect of alterations in the processing settings, averaged over calculation methods, were 2.8% (SD 3.3%) for sample rate, 8.8% (SD 7.7%) for filter settings, and 100.5% (SD 100.9%) for trial length. Differences in TTS calculation methods are affected differently by sample rate, filter settings and trial length. The effects of differences in sample rate and filter settings are generally small, while trial length has a large effect on TTS values. Copyright © 2014 Elsevier B.V. All rights reserved.

Quenching methods for background reduction in luminescence-based probe-target binding assays

DOEpatents

Cai, Hong [Los Alamos, NM; Goodwin, Peter M [Los Alamos, NM; Keller, Richard A [Los Alamos, NM; Nolan, Rhiannon L [Santa Fe, NM

2007-04-10

Background luminescence is reduced from a solution containing unbound luminescent probes, each having a first molecule that attaches to a target molecule and having an attached luminescent moiety, and luminescent probe/target adducts. Quenching capture reagent molecules are formed that are capable of forming an adduct with the unbound luminescent probes and having an attached quencher material effective to quench luminescence of the luminescent moiety. The quencher material of the capture reagent molecules is added to a solution of the luminescent probe/target adducts and binds in a proximity to the luminescent moiety of the unbound luminescent probes to quench luminescence from the luminescent moiety when the luminescent moiety is exposed to exciting illumination. The quencher capture reagent does not bind to probe molecules that are bound to target molecules and the probe/target adduct emission is not quenched.

Chandrasekhar equations for infinite dimensional systems. Part 2: Unbounded input and output case

NASA Technical Reports Server (NTRS)

Ito, Kazufumi; Powers, Robert K.

1987-01-01

A set of equations known as Chandrasekhar equations arising in the linear quadratic optimal control problem is considered. In this paper, we consider the linear time-invariant system defined in Hilbert spaces involving unbounded input and output operators. For a general class of such systems, the Chandrasekhar equations are derived and the existence, uniqueness, and regularity of the results of their solutions established.

On the Composition of Public-Coin Zero-Knowledge Protocols

DTIC Science & Technology

2011-05-31

only languages in BPP have public-coin black-box zero-knowledge protocols that are secure under an unbounded (polynomial) number of parallel...only languages in BPP have public-coin black-box zero-knowledge protocols that are secure under an unbounded (polynomial) number of parallel repetitions...and Krawczyk [GK96b] show that only languages in BPP have constant-round public-coin (stand-alone) black-box ZK protocols with negligible soundness

Convergence of the flow of a chemically reacting gaseous mixture to incompressible Euler equations in a unbounded domain

NASA Astrophysics Data System (ADS)

Kwon, Young-Sam

2017-12-01

The flow of chemically reacting gaseous mixture is associated with a variety of phenomena and processes. We study the combined quasineutral and inviscid limit from the flow of chemically reacting gaseous mixture governed by Poisson equation to incompressible Euler equations with the ill-prepared initial data in the unbounded domain R^2× T. Furthermore, the convergence rates are obtained.

Ubiquitin dynamics in complexes reveal molecular recognition mechanisms beyond induced fit and conformational selection.

PubMed

Peters, Jan H; de Groot, Bert L

2012-01-01

Protein-protein interactions play an important role in all biological processes. However, the principles underlying these interactions are only beginning to be understood. Ubiquitin is a small signalling protein that is covalently attached to different proteins to mark them for degradation, regulate transport and other functions. As such, it interacts with and is recognised by a multitude of other proteins. We have conducted molecular dynamics simulations of ubiquitin in complex with 11 different binding partners on a microsecond timescale and compared them with ensembles of unbound ubiquitin to investigate the principles of their interaction and determine the influence of complex formation on the dynamic properties of this protein. Along the main mode of fluctuation of ubiquitin, binding in most cases reduces the conformational space available to ubiquitin to a subspace of that covered by unbound ubiquitin. This behaviour can be well explained using the model of conformational selection. For lower amplitude collective modes, a spectrum of zero to almost complete coverage of bound by unbound ensembles was observed. The significant differences between bound and unbound structures are exclusively situated at the binding interface. Overall, the findings correspond neither to a complete conformational selection nor induced fit scenario. Instead, we introduce a model of conformational restriction, extension and shift, which describes the full range of observed effects.

Structure, stability, and properties of the trans peroxo nitrate radical: the importance of nondynamic correlation.

PubMed

Dutta, Achintya Kumar; Dar, Manzoor; Vaval, Nayana; Pal, Sourav

2014-02-27

We report a comparative single-reference and multireference coupled-cluster investigation on the structure, potential energy surface, and IR spectroscopic properties of the trans peroxo nitrate radical, one of the key intermediates in stratospheric NOX chemistry. The previous single-reference ab initio studies predicted an unbound structure for the trans peroxo nitrate radical. However, our Fock space multireference coupled-cluster calculation confirms a bound structure for the trans peroxo nitrate radical, in accordance with the experimental results reported earlier. Further, the analysis of the potential energy surface in FSMRCC method indicates a well-behaved minima, contrary to the shallow minima predicted by the single-reference coupled-cluster method. The harmonic force field analysis, of various possible isomers of peroxo nitrate also reveals that only the trans structure leads to the experimentally observed IR peak at 1840 cm(-1). The present study highlights the critical importance of nondynamic correlation in predicting the structure and properties of high-energy stratospheric NOx radicals.

A Financial Market Model Incorporating Herd Behaviour.

PubMed

Wray, Christopher M; Bishop, Steven R

2016-01-01

Herd behaviour in financial markets is a recurring phenomenon that exacerbates asset price volatility, and is considered a possible contributor to market fragility. While numerous studies investigate herd behaviour in financial markets, it is often considered without reference to the pricing of financial instruments or other market dynamics. Here, a trader interaction model based upon informational cascades in the presence of information thresholds is used to construct a new model of asset price returns that allows for both quiescent and herd-like regimes. Agent interaction is modelled using a stochastic pulse-coupled network, parametrised by information thresholds and a network coupling probability. Agents may possess either one or two information thresholds that, in each case, determine the number of distinct states an agent may occupy before trading takes place. In the case where agents possess two thresholds (labelled as the finite state-space model, corresponding to agents' accumulating information over a bounded state-space), and where coupling strength is maximal, an asymptotic expression for the cascade-size probability is derived and shown to follow a power law when a critical value of network coupling probability is attained. For a range of model parameters, a mixture of negative binomial distributions is used to approximate the cascade-size distribution. This approximation is subsequently used to express the volatility of model price returns in terms of the model parameter which controls the network coupling probability. In the case where agents possess a single pulse-coupling threshold (labelled as the semi-infinite state-space model corresponding to agents' accumulating information over an unbounded state-space), numerical evidence is presented that demonstrates volatility clustering and long-memory patterns in the volatility of asset returns. Finally, output from the model is compared to both the distribution of historical stock returns and the market price of an equity index option.

Exclusive measurements of quasi-free proton scattering reactions in inverse and complete kinematics

DOE PAGES

Panin, V.; Taylor, J. T.; Paschalis, S.; ...

2016-02-01

Quasi-free scattering reactions of the type (p, 2p)were measured for the first time exclusively in com-plete and inverse kinematics, using a 12C beam at an energy of ~400MeV/uas a benchmark. This new technique has been developed to study the single-particle structure of exotic nuclei in experiments with radioactive-ion beams. The outgoing pair of protons and the fragments were measured simultaneously, enabling an unambiguous identification of the reaction channels and a redundant measurement of the kinematic observables. Both valence and deeply-bound nucleon orbits are probed, including those leading to unbound states of the daughter nucleus. Exclusive (p, 2p)cross sections of 15.8(18)mb,more » 1.9(2)mb and 1.5(2)mb to the low-lying 0p-hole states overlapping with the ground state (3/2 –) and with the bound excited states of 11B at 2.125MeV (1/2 –) and 5.02MeV (3/2 –), respectively, were determined via γ-ray spectroscopy. Particle-unstable deep-hole states, corresponding to proton removal from the 0s-orbital, were studied via the invariant-mass technique. Cross sections and momentum distributions were extracted and compared to theoretical calculations employing the eikonal formalism. The obtained results are in a good agreement with this theory and with direct-kinematics experiments. Furthermore, the dependence of the proton–proton scattering kinematics on the internal momentum of the struck proton and on its separation energy was investigated for the first time in inverse kinematics employing a large-acceptance measurement.« less

Knockout beyond the dripline

NASA Astrophysics Data System (ADS)

Bonaccorso, A.; Charity, R. J.; Kumar, R.; Salvioni, G.

2015-02-01

In this contribution, we will describe neutron and proton removal from 9C and 7Be which are two particularly interesting nuclei entering the nucleo-synthesis pp-chain [1, 2]. Neutron and proton removal reactions have been used in the past twenty years to probe the single-particle structure of exotic nuclei. The core parallel-momentum distribution can give information on the angular momentum and spin of the nucleon initial state while the total removal cross section is sensitive to the asymptotic part of the initial wave function and also to the reaction mechanism. Because knockout is a peripheral reaction from which the Asymptotic Normalization Constant (ANC) of the single-particle wave function can be extracted, it has been used as an indirect method to obtain the rate of reactions like 8B ( p ,γ)9C or 7Be ( p ,γ)8B . Nucleon removal has recently been applied by the HiRA collaboration [3] to situations in which the remaining "core" is beyond the drip line, such as 8C and 6Be , unbound by one or more protons, and whose excitation-energy spectrum can be obtained by the invariant-mass method. By gating on the ground-state peak, "core" parallel-momentum distributions and total knockout cross sections have been obtained similar to previous studies with well-bound "cores". In addition for each projectile, knock out to final bound states has also been obtained in several cases. We will report on the theoretical description and comparison to this experimental data for a few cases for which advances in the accuracy of the transfer-to-the continuum model [4, 5] have been made [6]. These include the use, when available, of "ab-initio" overlaps for the initial state [7] and in particular their ANC values [8]. Also, the construction of a nucleus-target folding potential for the treatment of the core-target S-matrix [9] using for the cores "ab-initio" densities [10] and state-of-the-art n-9Be optical potentials [11]. Preliminary results and open problems will be discussed.

A fast numerical method for the valuation of American lookback put options

NASA Astrophysics Data System (ADS)

Song, Haiming; Zhang, Qi; Zhang, Ran

2015-10-01

A fast and efficient numerical method is proposed and analyzed for the valuation of American lookback options. American lookback option pricing problem is essentially a two-dimensional unbounded nonlinear parabolic problem. We reformulate it into a two-dimensional parabolic linear complementary problem (LCP) on an unbounded domain. The numeraire transformation and domain truncation technique are employed to convert the two-dimensional unbounded LCP into a one-dimensional bounded one. Furthermore, the variational inequality (VI) form corresponding to the one-dimensional bounded LCP is obtained skillfully by some discussions. The resulting bounded VI is discretized by a finite element method. Meanwhile, the stability of the semi-discrete solution and the symmetric positive definiteness of the full-discrete matrix are established for the bounded VI. The discretized VI related to options is solved by a projection and contraction method. Numerical experiments are conducted to test the performance of the proposed method.

Breakout reactions from the CNO-cycle

NASA Astrophysics Data System (ADS)

Jisonna, Louis Joseph, Jr.

Breakout reactions from the CNO cycles leading into the rp -process in explosive stellar hydrogen burning environments have been studied using the Argonne Tandem Linac Accelerator System (ATLAS). Earlier work is reported and summarized with an introduction to the beam, target and detector development in the nuclear astrophysics group at Argonne National Laboratory. The 18 Ne(a,p) 21 Na reaction has been studied via the time inverse reaction p( 21 Na,a) 18 Ne. A 5 × 10^-5 particle nanoamp 21 Na beam was produced at the ATLAS in-flight facility via the p( 21 Ne,n) 21 Na reaction. Cross sections were obtained at five energies covering the region between 9.4 <= E x <= 9.9 MeV in the compound nucleus 22 Mg, and compared with previous measurements. The 19 Ne(p,g) 20 Na reaction was also studied by populating proton unbound states via the 3 He(20 Ne,t) 20 Na* reaction. We have observed for the first time evidence for the g- decay of the astrophysically important 2.645 MeV state in 20 Na. Branching ratios obtained for the first two proton unbound states in 20 Na were G p /G g (2.645 MeV) = [Special characters omitted.] and a lower limit of G p /G g (2.849 MeV) >= 26.0 (1-s CL). The experimental branching ratios were compared with theoretical predictions based on shell-model calculations and on the properties of mirror states in 20 F. Our results favor a J p = 1 + assignment for the 2.645 MeV state and a J p = 3 + for the 2.849 MeV at the 1-s confidence level. Our result also suggests that the resonance strength for radiative capture through the 2.645 MeV state is close to the value og[approximate] 6 meV, in agreement with the value calculated assuming it to be the mirror of the 3.172 MeV intruder state in 20 F with a 6 p2h configuration.

Effects of friction dampers on aerodynamically unstable rotor stages

NASA Technical Reports Server (NTRS)

Griffin, J. H.; Sinha, A.

1983-01-01

Attention is given to the physical concepts and mathematical techniques useful in the analysis of the stabilizing effect of friction on aerodynamically unstable rotor stages. Results are presented for three-, four-, and five-bladed disks. In the present multidegree-of-freedom model of an aerodynamically unstable rotor stage, a harmonic steady state solution due to the friction dampers may be either a stability limit, a stable cycle limit, or neither. A criterion is established in the form of an energy function which determines whether the solution is a stability limit. In the event that the initial displacement and velocity exeed those associated with the steady state solution corresponding to a stability limit, the reponse becomes unbounded.

On the Rayleigh-Taylor Instability in Presence of a Background Shear

NASA Astrophysics Data System (ADS)

Shvydkoy, Roman

2018-01-01

In this note we revisit the classical subject of the Rayleigh-Taylor instability in presence of an incompressible background shear flow. We derive a formula for the essential spectral radius of the evolution group generated by the linearization near the steady state and reveal that the velocity variations neutralize shortwave instabilities. The formula is a direct generalization of the result of Hwang and Guo (Arch Ration Mech Anal 167(3):235-253, (2003). Furthermore, we construct a class of steady states which posses unstable discrete spectrum with neutral essential spectrum. The technique involves the WKB analysis of the evolution equation and contains novel compactness criterion for pseudo-differential operators on unbounded domains.

Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals With Renal Impairment.

PubMed

Heinig, Roland; Kimmeskamp-Kirschbaum, Nina; Halabi, Atef; Lentini, Silvia

2016-11-01

Finerenone (BAY 94-8862) is a nonsteroidal mineralocorticoid receptor antagonist in development for the treatment of diabetic kidney disease. This observational trial compared the pharmacokinetics of a single oral dose of finerenone 10 mg (immediate-release tablet) in adults with mild (creatinine clearance [CL CR ] 50-80 mL/min; n = 8), moderate (CL CR 30 to < 50 mL/min; n = 8), or severe (CL CR < 30 mL/min; n  =  9) renal impairment with those in adults with normal renal function (CL CR > 80 mL/min; n  = 8) over 96 hours postdose. Exposure to finerenone was not affected by mild renal impairment. In participants with moderate or severe renal impairment, exposure to finerenone was increased compared with those with normal renal function (increase in area under the curve for unbound finerenone, 57.1% [outlier excluded] and 46.5%, respectively), with moderate to high interindividual variability. Renal impairment had no consistent effect on the maximum plasma concentration, C max (differences in C max for unbound finerenone of +12% and -7% with moderate [outlier excluded] and severe impairment vs normal renal function, respectively). Renal elimination of finerenone is minimal. However, changes in exposure may occur because of the effects of renal impairment on nonrenal routes of elimination. © 2016, The American College of Clinical Pharmacology.

Nonequilibrium spin transport in integrable spin chains: Persistent currents and emergence of magnetic domains

NASA Astrophysics Data System (ADS)

De Luca, Andrea; Collura, Mario; De Nardis, Jacopo

2017-07-01

We construct exact steady states of unitary nonequilibrium time evolution in the gapless XXZ spin-1/2 chain where integrability preserves ballistic spin transport at long times. We characterize the quasilocal conserved quantities responsible for this feature and introduce a computationally effective way to evaluate their expectation values on generic matrix product initial states. We employ this approach to reproduce the long-time limit of local observables in all quantum quenches which explicitly break particle-hole or time-reversal symmetry. We focus on a class of initial states supporting persistent spin currents and our predictions remarkably agree with numerical simulations at long times. Furthermore, we propose a protocol for this model where interactions, even when antiferromagnetic, are responsible for the unbounded growth of a macroscopic magnetic domain.

Unbound Young Stellar Systems: Star Formation on the Loose

NASA Astrophysics Data System (ADS)

Gouliermis, Dimitrios A.

2018-07-01

Unbound young stellar systems, the loose ensembles of physically related young bright stars, trace the typical regions of recent star formation in galaxies. Their morphologies vary from small few pc-size associations of newly formed stars to enormous few kpc-size complexes composed of stars few 100 Myr old. These stellar conglomerations are located within the disks and along the spiral arms and rings of star-forming disk galaxies, and they are the active star-forming centers of dwarf and starburst galaxies. Being associated with star-forming regions of various sizes, these stellar structures trace the regions where stars form at various length- and timescales, from compact clusters to whole galactic disks. Stellar associations, the prototypical unbound young systems, and their larger counterparts, stellar aggregates, and stellar complexes, have been the focus of several studies for quite a few decades, with special interest on their demographics, classification, and structural morphology. The compiled surveys of these loose young stellar systems demonstrate that the clear distinction of these systems into well-defined classes is not as straightforward as for stellar clusters, due to their low densities, asymmetric shapes and variety in structural parameters. These surveys also illustrate that unbound stellar structures follow a clear hierarchical pattern in the clustering of their stars across various scales. Stellar associations are characterized by significant sub-structure with bound stellar clusters being their most compact parts, while associations themselves are the brighter denser parts of larger stellar aggregates and stellar complexes, which are members of larger super-structures up to the scale of a whole star-forming galaxy. This structural pattern, which is usually characterized as self-similar or fractal, appears to be identical to that of star-forming giant molecular clouds and interstellar gas, driven mainly by turbulence cascade. In this short review, I make a concise compilation of our understanding of unbound young stellar systems across various environments in the local universe, as it is developed during the last 60 years. I present a factual assessment of the clustering behavior of star formation, as revealed from the assembling pattern of stars across loose stellar structures and its relation to the interstellar medium and the environmental conditions. I also provide a consistent account of the processes that possibly play important role in the formation of unbound stellar systems, compiled from both theoretical and observational investigations on the field.

Ultrasensitive protein detection in blood serum using gold nanoparticle probes by single molecule spectroscopy

NASA Astrophysics Data System (ADS)

Chen, Jiji; Wang, Chungang; Irudayaraj, Joseph

2009-07-01

A one-step rapid and ultrasensitive immunoassay capable of detecting proteins in blood serum is developed using gold nanoprobes and fluorescence correlation spectroscopy (FCS). In this approach we take advantage of the inherent photoluminescence property of gold nanoparticles (GNPs) to develop a fluorophore-free assay to observe binding entities by monitoring the diffusion of bound versus unbound molecules in a limited confocal volume. 40-nm GNPs conjugated separately with rabbit anti-IgG (Fc) and goat anti-IgG (Fab) when incubated in blood serum containing IgG forms a sandwich structure constituting dimers and oligomers that can be differentiated by to detect IgG in blood serum at a limit of detection (LOD) of 5 pg/ml. The novelty of integrating GNPs with FCS to develop a sensitive blood immunoassay brings single molecule methods one step closer to the clinic.

Terahertz-infrared electrodynamics of single-wall carbon nanotube films

NASA Astrophysics Data System (ADS)

Zhukova, E. S.; Grebenko, A. K.; Bubis, A. V.; Prokhorov, A. S.; Belyanchikov, M. A.; Tsapenko, A. P.; Gilshteyn, E. P.; Kopylova, D. S.; Gladush, Yu G.; Anisimov, A. S.; Anzin, V. B.; Nasibulin, A. G.; Gorshunov, B. P.

2017-11-01

Broad-band (4-20 000 cm-1) spectra of real and imaginary conductance of a set of high-quality pristine and AuCl3-doped single-walled carbon nanotube (SWCNT) films with different transparency are systematically measured. It is shown that while the high-energy (≥1 eV) response is determined by well-known interband transitions, the lower-energy electrodynamic properties of the films are fully dominated by unbound charge carriers. Their main spectral effect is seen as the free-carrier Drude-type contribution. Partial localization of these carriers leads to a weak plasmon resonance around 100 cm-1. At the lowest frequencies, below 10 cm-1, a gap-like feature is detected whose origin is associated with the energy barrier experienced by the carriers at the intersections between SWCNTs. It is assumed that these three mechanisms are universal and determine the low-frequency terahertz-infrared electrodynamics of SWCNT wafer-scale films.

Energy Landscape and Transition State of Protein-Protein Association

NASA Astrophysics Data System (ADS)

Alsallaq, Ramzi; Zhou, Huan-Xiang

2006-11-01

Formation of a stereospecific protein complex is favored by specific interactions between two proteins but disfavored by the loss of translational and rotational freedom. Echoing the protein folding process, we have previously proposed a transition state for protein-protein association. Here we clarify the specification of the transition state by working with two toy models for protein association. The models demonstrate that a sharp transition between the bound state with numerous short-range interactions but restricted translation and rotational freedom and the unbound state with at most a small number of interactions but expanded configurational freedom. This transition sets the outer boundary of the bound state as well as the transition state for association. The energy landscape is funnel-like, with the deep well of the bound state surrounded by a broad shallow basin. This formalism of protein-protein association is applied to four protein-protein complexes, and is found to give accurate predictions for the effects of charge mutations and ionic strength on the association rates.

The Linear Quadratic Optimal Control Problem for Infinite Dimensional Systems with Unbounded Input and Output Operators.

DTIC Science & Technology

1984-01-01

5.5) respectively (5.3) and (5.8) which means that u(t) - 0 respectively v(t) - 0 for t > o. The evolution of the systems (5.1) and (5.3) in terms ...input/output delays; and b) the general theory is presented in such a way that it applies to both . . ... ..- Lr parabolic and hyperbolic I P9es as...particular emphasis is placed on the development of the duality theory by means of two different state concepts. The resulting evolution equations

Unbounded Violations of Bipartite Bell Inequalities via Operator Space Theory

NASA Astrophysics Data System (ADS)

Junge, M.; Palazuelos, C.; Pérez-García, D.; Villanueva, I.; Wolf, M. M.

2010-12-01

In this work we show that bipartite quantum states with local Hilbert space dimension n can violate a Bell inequality by a factor of order {Ω left(sqrt{n}/log^2n right)} when observables with n possible outcomes are used. A central tool in the analysis is a close relation between this problem and operator space theory and, in particular, the very recent noncommutative L p embedding theory. As a consequence of this result, we obtain better Hilbert space dimension witnesses and quantum violations of Bell inequalities with better resistance to noise.

Super-Penrose process due to collisions inside ergosphere

NASA Astrophysics Data System (ADS)

Zaslavskii, O. B.

If two particles collide inside the ergosphere, the energy in the center of mass frame can be made unbound provided at least one of particles has a large negative angular momentum [A. A. Grib and Yu. V. Pavlov, Europhys. Lett. 101 (2013) 20004]. We show that the same condition can give rise to unbounded Killing energy of debris at infinity, i.e. super-Penrose process. Proximity of the point of collision to the black hole horizon is not required.

The Incidence of Sixteenth Century Cosmic Models in Modern Texts

NASA Astrophysics Data System (ADS)

Maene, S. A.; Best, J. S.; Usher, P. D.

1999-12-01

In the sixteenth century, the bounded cosmological models of Copernicus (1543) and Tycho Brahe (1588), and the unbounded model of Thomas Digges (1576), vied with the bounded geocentric model of Ptolemy (c. 140 AD). The work of the philosopher Giordano Bruno in 1584 lent further support to the Digges model. Despite the eventual acceptance of the unbounded universe, analysis of over 100 modern introductory astronomy texts reveals that these early unbounded models are mentioned infrequently. The ratio of mentions of Digges' model to Copernicus' model has the surprisingly low value of R = 0.08. The philosophical speculation of Bruno receives mention more than twice as often (R = 0.17). The expectation that these early unbounded models warrant inclusion in astronomy texts is supported both by modern hindsight and by the literature of the time. In Shakespeare's "Hamlet" of c. 1601, Prince Hamlet suffers from two transformations. According to the cosmic allegorical model, one transformation changes the bounded geocentricism of Ptolemy to the bounded heliocentricism of Copernicus, while the other completes the change to Digges' model of the infinite universe of suns. This interpretation and the modern world view suggest that both transformations should receive equal mention and thus that the ratio R in introductory texts should be close to unity. This work was supported in part by the NASA West Virginia Space Grant Consortium.

On one-dimensional compressible Navier-Stokes equations for a reacting mixture in unbounded domains

NASA Astrophysics Data System (ADS)

Li, Siran

2017-10-01

In this paper we consider the one-dimensional Navier-Stokes system for a heat-conducting, compressible reacting mixture which describes the dynamic combustion of fluids of mixed kinds on unbounded domains. This model has been discussed on bounded domains by Chen (SIAM J Math Anal 23:609-634, 1992) and Chen-Hoff-Trivisa (Arch Ration Mech Anal 166:321-358, 2003), among others, in which the reaction rate function is a discontinuous function obeying the Arrhenius' law of thermodynamics. We prove the global existence of weak solutions to this model on one-dimensional unbounded domains with large initial data in H^1. Moreover, the large-time behaviour of the weak solution is identified. In particular, the uniform-in-time bounds for the temperature and specific volume have been established via energy estimates. For this purpose we utilise techniques developed by Kazhikhov-Shelukhin (cf. Kazhikhov in Siber Math J 23:44-49, 1982; Solonnikov and Kazhikhov in Annu Rev Fluid Mech 13:79-95, 1981) and refined by Jiang (Commun Math Phys 200:181-193, 1999, Proc R Soc Edinb Sect A 132:627-638, 2002), as well as a crucial estimate in the recent work by Li-Liang (Arch Ration Mech Anal 220:1195-1208, 2016). Several new estimates are also established, in order to treat the unbounded domain and the reacting terms.

Influence of Clinical Status on the Association Between Plasma Total and Unbound Bilirubin and Death or Adverse Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants

PubMed Central

Oh, William; Stevenson, David K.; Tyson, Jon E.; Morris, Brenda H.; Ahlfors, Charles E.; Bender, G. Jesse; Wong, Ronald J.; Perritt, Rebecca; Vohr, Betty R.; Van Meurs, Krista P.; Vreman, Hendrik J.; Das, Abhik; Phelps, Dale L.; O’Shea, T. Michael; Higgins, Rosemary D.

2010-01-01

Objectives To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants. Method Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants. PMID:20105142

Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)-ibuprofen.

PubMed

Evans, A M; Nation, R L; Sansom, L N; Bochner, F; Somogyi, A A

1991-02-01

1. Four healthy male subjects received racemic ibuprofen (200, 400, 800 and 1200 mg), orally, on four occasions, 2 weeks apart, according to a four-way Latin-square design, in order to investigate the influence of increasing dose of ibuprofen on the magnitude and duration of its antiplatelet effect as well as on the relationship between such effect and drug concentration. 2. The antiplatelet effect of ibuprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood. The plasma unbound concentration of S(+)-ibuprofen, the enantiomer shown in an in vitro study to be responsible for the inhibitory effect of platelet TXB2 generation, was measured using an enantioselective method. 3. The maximum percentage inhibition of TXB2 generation increased significantly with dose from a mean +/- s.d. of 93.4 +/- 1.2% after the 200 mg dose to 98.8 +/- 0.3% after the 1200 mg dose, and there was an increase with dose in the duration of inhibition of TXB2 generation. The effect of ibuprofen on platelet TXB2 generation was transient and mirrored the time-course of unbound S(+)-ibuprofen in plasma; on all but one of the 16 occasions, serum TXB2 concentrations returned to at least within 10% of the pretreatment concentrations within 24 h of ibuprofen administration. 4. For each subject, the relationship between the percentage inhibition of TXB2 generation and the unbound concentration of S(+)-ibuprofen in plasma was modelled according to a sigmoidal Emax equation. The mean plasma unbound concentration of S(+)-ibuprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 9.8 +/- 1.0 micrograms l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Physical-depth architectural requirements for generating universal photonic cluster states

NASA Astrophysics Data System (ADS)

Morley-Short, Sam; Bartolucci, Sara; Gimeno-Segovia, Mercedes; Shadbolt, Pete; Cable, Hugo; Rudolph, Terry

2018-01-01

Most leading proposals for linear-optical quantum computing (LOQC) use cluster states, which act as a universal resource for measurement-based (one-way) quantum computation. In ballistic approaches to LOQC, cluster states are generated passively from small entangled resource states using so-called fusion operations. Results from percolation theory have previously been used to argue that universal cluster states can be generated in the ballistic approach using schemes which exceed the critical threshold for percolation, but these results consider cluster states with unbounded size. Here we consider how successful percolation can be maintained using a physical architecture with fixed physical depth, assuming that the cluster state is continuously generated and measured, and therefore that only a finite portion of it is visible at any one point in time. We show that universal LOQC can be implemented using a constant-size device with modest physical depth, and that percolation can be exploited using simple pathfinding strategies without the need for high-complexity algorithms.

Green’s Functions for an Anisotropic Medium: Part 1. Unbounded Case

DTIC Science & Technology

1993-12-01

AA 2 - x • , - a or b (41a) td A -2 A-- ’ -L x " " - , -a or b (41b) 13 4. DISCUSSION Having now derived the DGF of the unbounded biaxially...B 2 A3 121/3 b s- - + (_ + )A + [ (_ L_1/ + - (A13) A - 1 (3q - b) (Al4a) (3q B - -L (-2b 3 + 9bq + 27r) (Al4b) q - Ac - 4d (Al5a) r - - Ad 2 + 4bd - C

Polyhedral sweeping processes with unbounded nonconvex-valued perturbation

NASA Astrophysics Data System (ADS)

Tolstonogov, A. A.

2017-12-01

A polyhedral sweeping process with a multivalued perturbation whose values are nonconvex unbounded sets is studied in a separable Hilbert space. Polyhedral sweeping processes do not satisfy the traditional assumptions used to prove existence theorems for convex sweeping processes. We consider the polyhedral sweeping process as an evolution inclusion with subdifferential operators depending on time. The widely used assumption of Lipschitz continuity for the multivalued perturbation term is replaced by a weaker notion of (ρ - H) Lipschitzness. The existence of solutions is proved for this sweeping process.

Localized basis sets for unbound electrons in nanoelectronics.

PubMed

Soriano, D; Jacob, D; Palacios, J J

2008-02-21

It is shown how unbound electron wave functions can be expanded in a suitably chosen localized basis sets for any desired range of energies. In particular, we focus on the use of Gaussian basis sets, commonly used in first-principles codes. The possible usefulness of these basis sets in a first-principles description of field emission or scanning tunneling microscopy at large bias is illustrated by studying a simpler related phenomenon: The lifetime of an electron in a H atom subjected to a strong electric field.

Shape Complementarity of Protein-Protein Complexes at Multiple Resolutions

PubMed Central

Zhang, Qing; Sanner, Michel; Olson, Arthur J.

2010-01-01

Biological complexes typically exhibit intermolecular interfaces of high shape complementarity. Many computational docking approaches use this surface complementarity as a guide in the search for predicting the structures of protein-protein complexes. Proteins often undergo conformational changes in order to create a highly complementary interface when associating. These conformational changes are a major cause of failure for automated docking procedures when predicting binding modes between proteins using their unbound conformations. Low resolution surfaces in which high frequency geometric details are omitted have been used to address this problem. These smoothed, or blurred, surfaces are expected to minimize the differences between free and bound structures, especially those that are due to side chain conformations or small backbone deviations. In spite of the fact that this approach has been used in many docking protocols, there has yet to be a systematic study of the effects of such surface smoothing on the shape complementarity of the resulting interfaces. Here we investigate this question by computing shape complementarity of a set of 66 protein-protein complexes represented by multi-resolution blurred surfaces. Complexed and unbound structures are available for these protein-protein complexes. They are a subset of complexes from a non-redundant docking benchmark selected for rigidity (i.e. the proteins undergo limited conformational changes between their bound and unbound states). In this work we construct the surfaces by isocontouring a density map obtained by accumulating the densities of Gaussian functions placed at all atom centers of the molecule. The smoothness or resolution is specified by a Gaussian fall-off coefficient, termed “blobbyness”. Shape complementarity is quantified using a histogram of the shortest distances between two proteins' surface mesh vertices for both the crystallographic complexes and the complexes built using the protein structures in their unbound conformation. The histograms calculated for the bound complex structures demonstrate that medium resolution smoothing (blobbyness=−0.9) can reproduce about 88% of the shape complementarity of atomic resolution surfaces. Complexes formed from the free component structures show a partial loss of shape complementarity (more overlaps and gaps) with the atomic resolution surfaces. For surfaces smoothed to low resolution (blobbyness=−0.3), we find more consistency of shape complementarity between the complexed and free cases. To further reduce bad contacts without significantly impacting the good contacts we introduce another blurred surface, in which the Gaussian densities of flexible atoms are reduced. From these results we discuss the use of shape complementarity in protein-protein docking. PMID:18837463

AMP-Activated Protein Kinase β-Subunit Requires Internal Motion for Optimal Carbohydrate Binding

PubMed Central

Bieri, Michael; Mobbs, Jesse I.; Koay, Ann; Louey, Gavin; Mok, Yee-Foong; Hatters, Danny M.; Park, Jong-Tae; Park, Kwan-Hwa; Neumann, Dietbert; Stapleton, David; Gooley, Paul R.

2012-01-01

AMP-activated protein kinase interacts with oligosaccharides and glycogen through the carbohydrate-binding module (CBM) containing the β-subunit, for which there are two isoforms (β1 and β2). Muscle-specific β2-CBM, either as an isolated domain or in the intact enzyme, binds carbohydrates more tightly than the ubiquitous β1-CBM. Although residues that contact carbohydrate are strictly conserved, an additional threonine in a loop of β2-CBM is concurrent with an increase in flexibility in β2-CBM, which may account for the affinity differences between the two isoforms. In contrast to β1-CBM, unbound β2-CBM showed microsecond-to-millisecond motion at the base of a β-hairpin that contains residues that make critical contacts with carbohydrate. Upon binding to carbohydrate, similar microsecond-to-millisecond motion was observed in this β-hairpin and the loop that contains the threonine insertion. Deletion of the threonine from β2-CBM resulted in reduced carbohydrate affinity. Although motion was retained in the unbound state, a significant loss of motion was observed in the bound state of the β2-CBM mutant. Insertion of a threonine into the background of β1-CBM resulted in increased ligand affinity and flexibility in these loops when bound to carbohydrate. However, these mutations indicate that the additional threonine is not solely responsible for the differences in carbohydrate affinity and protein dynamics. Nevertheless, these results suggest that altered protein dynamics may contribute to differences in the ligand affinity of the two naturally occurring CBM isoforms. PMID:22339867

Dynamics of the BH3-Only Protein Binding Interface of Bcl-xL.

PubMed

Liu, Xiaorong; Beugelsdijk, Alex; Chen, Jianhan

2015-09-01

The balance and interplay between pro-death and pro-survival members of the B-cell lymphoma-2 (Bcl-2) family proteins play key roles in regulation of the mitochondrial pathway of programmed cell death. Recent NMR and biochemical studies have revealed that binding of the proapoptotic BH3-only protein PUMA induces significant unfolding of antiapoptotic Bcl-xL at the interface, which in turn disrupts the Bcl-xL/p53 interaction to activate apoptosis. However, the molecular mechanism of such regulated unfolding of Bcl-xL is not fully understood. Analysis of the existing Protein Data Bank structures of Bcl-xL in both bound and unbound states reveal substantial intrinsic heterogeneity at its BH3-only protein binding interface. Large-scale atomistic simulations were performed in explicit solvent for six representative structures to further investigate the intrinsic conformational dynamics of Bcl-xL. The results support that the BH3-only protein binding interface of Bcl-xL is much more dynamic compared to the rest of the protein, both unbound and when bound to various BH3-only proteins. Such intrinsic interfacial conformational dynamics likely provides a physical basis that allows Bcl-xL to respond sensitively to detailed biophysical properties of the ligand. The ability of Bcl-xL to retain or even enhance dynamics at the interface in bound states could further facilitate the regulation of its interactions with various BH3-only proteins such as through posttranslational modifications. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Diphytanyl glycerol ether distributions in sediments of the Orca Basin

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

Pease, T.K.; VanVleet, E.S.; Barre, J.S.

1992-09-01

Archaebacterially produced diphytanyl glycerol ether (DPGE) was examined in core sediments from the Orca Basin, an anoxic hypersaline basin in the northwestern Gulf of Mexico, to observe its spatial variability and potential origin. A differential extraction protocol was employed to quantify the isopranyl glycerol ethers associated with unbound, intermediate-bound, and kerogen-bound lipid fractions. Archaebacterial lipids were evident at all depths for the unbound and intermediate-bound fractions. Concentrations of DPGE ranged from 0.51 to 2.91 [mu]g/g dry sediment at the surface and showed secondary maxima deeper in basin sediments. Intermediate-bound DPGE concentrations exhibited an inverse relationship to unbound DPGE concentrations. Kerogen-boundmore » DPGE concentrations were normally below detection limits. Earlier studies describing the general homogeneity of lipid components within the overlying brine and at the brine/seawater interface suggest that the large-scale sedimentary DPGE variations observed in this study result from spatial and temporal variations in in-situ production by methanogenic or extremely halophilic archaebacteria.« less

Uptake and metabolism of cisplatin by rat kidney.

PubMed

Safirstein, R; Miller, P; Guttenplan, J B

1984-05-01

Cisplatin, an effective antineoplastic agent, is toxic to the kidney. Since the kidney's vulnerability to cisplatin may originate in its ability to accumulate and retain platinum to a greater degree than other organs, we studied the characteristics of the renal accumulation of platinum and investigated the nature of intracellular platinum. Cisplatin and ethylenediamminedichloroplatinum, nephrotoxic and antineoplastic liganded platinum compounds, were concentrated in rat renal cortical slices fivefold above medium concentration. Platinum uptake was energy- and temperature-dependent and could be inhibited by drugs which inhibit base transport. The organic anions para-aminohippurate and pyrazinoate did not reduce renal slice platinum uptake. Unbound platinum in the blood and urine was predominantly cisplatin but unbound platinum in kidney cytosol was not. This latter compound, in contrast to cisplatin, was not active as a mutagen. These studies suggest that the kidney accumulates platinum in part by transport or specific binding to the base transport system in the kidney and biotransforms it intracellularly. Unbound platinum in the cell is not cisplatin and may no longer be toxic.

Platinum nanocatalysts prepared with different surfactants for C1-C3 alcohol oxidations and their surface morphologies by AFM

NASA Astrophysics Data System (ADS)

Ertan, Salih; Şen, Fatih; Şen, Selda; Gökağaç, Gülsün

2012-06-01

In this study, platinum nanoparticle catalysts have been prepared using PtCl4 as a starting material and 1-octanethiol, 1-decanethiol, 1-dodecanethiol, and 1-hexadecanethiol as surfactants for methanol, ethanol, and 2-propanol oxidation reactions. The structure, particle sizes, and surface morphologies of the catalysts were characterized by X-ray diffraction (XRD), atomic force microscopy and transmission electron microscopy (TEM). XRD and TEM results indicate that all prepared catalysts have a face-centered cubic structure and are homogeneously dispersed on the carbon support with a narrow size distribution (2.0-1.3 nm). X-ray photoelectron spectra of the catalysts were examined and it is found that platinum has two different oxidation states, Pt (0) and Pt(IV), oxygen and sulfur compounds are H2Oads and OHads, bound and unbound thiols. The electrochemical and electrocatalytic properties of these catalysts were investigated with respect to C1-C3 alcohol oxidations by cyclic voltammetry and chronoamperometry. The highest electrocatalytic activity was obtained from catalyst I which was prepared with 1-octanethiol. This may be attributed to a decrease in the ratio of bound to unbound thiol species increase in Pt (0)/Pt(IV), H2Oads/OHads ratios, electrochemical surface area, CO tolerance and percent platinum utility.

An integral equation-based numerical solver for Taylor states in toroidal geometries

NASA Astrophysics Data System (ADS)

O'Neil, Michael; Cerfon, Antoine J.

2018-04-01

We present an algorithm for the numerical calculation of Taylor states in toroidal and toroidal-shell geometries using an analytical framework developed for the solution to the time-harmonic Maxwell equations. Taylor states are a special case of what are known as Beltrami fields, or linear force-free fields. The scheme of this work relies on the generalized Debye source representation of Maxwell fields and an integral representation of Beltrami fields which immediately yields a well-conditioned second-kind integral equation. This integral equation has a unique solution whenever the Beltrami parameter λ is not a member of a discrete, countable set of resonances which physically correspond to spontaneous symmetry breaking. Several numerical examples relevant to magnetohydrodynamic equilibria calculations are provided. Lastly, our approach easily generalizes to arbitrary geometries, both bounded and unbounded, and of varying genus.

Exciton fission in monolayer transition metal dichalcogenide semiconductors.

PubMed

Steinhoff, A; Florian, M; Rösner, M; Schönhoff, G; Wehling, T O; Jahnke, F

2017-10-27

When electron-hole pairs are excited in a semiconductor, it is a priori not clear if they form a plasma of unbound fermionic particles or a gas of composite bosons called excitons. Usually, the exciton phase is associated with low temperatures. In atomically thin transition metal dichalcogenide semiconductors, excitons are particularly important even at room temperature due to strong Coulomb interaction and a large exciton density of states. Using state-of-the-art many-body theory, we show that the thermodynamic fission-fusion balance of excitons and electron-hole plasma can be efficiently tuned via the dielectric environment as well as charge carrier doping. We propose the observation of these effects by studying exciton satellites in photoemission and tunneling spectroscopy, which present direct solid-state counterparts of high-energy collider experiments on the induced fission of composite particles.

Quantum-correlated two-photon transitions to excitons in semiconductor quantum wells.

PubMed

Salazar, L J; Guzmán, D A; Rodríguez, F J; Quiroga, L

2012-02-13

The dependence of the excitonic two-photon absorption on the quantum correlations (entanglement) of exciting biphotons by a semiconductor quantum well is studied. We show that entangled photon absorption can display very unusual features depending on space-time-polarization biphoton parameters and absorber density of states for both bound exciton states as well as for unbound electron-hole pairs. We report on the connection between biphoton entanglement, as quantified by the Schmidt number, and absorption by a semiconductor quantum well. Comparison between frequency-anti-correlated, unentangled and frequency-correlated biphoton absorption is addressed. We found that exciton oscillator strengths are highly increased when photons arrive almost simultaneously in an entangled state. Two-photon-absorption becomes a highly sensitive probe of photon quantum correlations when narrow semiconductor quantum wells are used as two-photon absorbers.

Self-consistent quantum kinetic theory of diatomic molecule formation

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

Forrey, Robert C.

2015-07-14

A quantum kinetic theory of molecule formation is presented which includes three-body recombination and radiative association for a thermodynamically closed system which may or may not exchange energy with its surrounding at a constant temperature. The theory uses a Sturmian representation of a two-body continuum to achieve a steady-state solution of a governing master equation which is self-consistent in the sense that detailed balance between all bound and unbound states is rigorously enforced. The role of quasibound states in catalyzing the molecule formation is analyzed in complete detail. The theory is used to make three predictions which differ from conventionalmore » kinetic models. These predictions suggest significant modifications may be needed to phenomenological rate constants which are currently in wide use. Implications for models of low and high density systems are discussed.« less

Interference-free Micro/nanoparticle Cell Engineering by Use of High-Throughput Microfluidic Separation.

PubMed

Yeo, David C; Wiraja, Christian; Zhou, Yingying; Tay, Hui Min; Xu, Chenjie; Hou, Han Wei

2015-09-23

Engineering cells with active-ingredient-loaded micro/nanoparticles is becoming increasingly popular for imaging and therapeutic applications. A critical yet inadequately addressed issue during its implementation concerns the significant number of particles that remain unbound following the engineering process, which inadvertently generate signals and impart transformative effects onto neighboring nontarget cells. Here we demonstrate that those unbound micro/nanoparticles remaining in solution can be efficiently separated from the particle-labeled cells by implementing a fast, continuous, and high-throughput Dean flow fractionation (DFF) microfluidic device. As proof-of-concept, we applied the DFF microfluidic device for buffer exchange to sort labeled suspension cells (THP-1) from unbound fluorescent dye and dye-loaded micro/nanoparticles. Compared to conventional centrifugation, the depletion efficiency of free dyes or particles was improved 20-fold and the mislabeling of nontarget bystander cells by free particles was minimized. The microfluidic device was adapted to further accommodate heterogeneous-sized mesenchymal stem cells (MSCs). Complete removal of unbound nanoparticles using DFF led to the usage of engineered MSCs without exerting off-target transformative effects on the functional properties of neighboring endothelial cells. Apart from its effectiveness in removing free particles, this strategy is also efficient and scalable. It could continuously process cell solutions with concentrations up to 10(7) cells·mL(-1) (cell densities commonly encountered during cell therapy) without observable loss of performance. Successful implementation of this technology is expected to pave the way for interference-free clinical application of micro/nanoparticle engineered cells.

Severe valproic acid intoxication: case study on the unbound fraction and the applicability of extracorporeal elimination.

PubMed

van den Broek, Marcel P H; Sikma, Maaike A; Ververs, Tessa F; Meulenbelt, Jan

2009-12-01

Among anticonvulsants, valproic acid (VPA) is cited as the most frequent cause of unintentional and intentional intoxications. Symptoms of VPA intoxication are diverse and are related to VPA plasma concentration. Although total plasma concentrations of less than 450 mg/l produce limited toxicity, severe intoxications (>850 mg/l) can induce coma and are ultimately life threatening. A 32-year-old comatose woman was admitted to the ICU at our hospital; she suffered from hypotension, respiratory depression, hypoglycaemia, sinus bradycardia, hyperammonaemia, metabolic acidosis, and her core body temperature was 33.7 degrees C. The total VPA plasma concentration was 1244 mg/l with an increased unbound fraction of 85%. After we administered multiple doses of activated charcoal, she underwent continuous veno-venous haemofiltration to reduce the plasma VPA concentration. As the total concentration decreased, the unbound fraction also decreased. Within 20 h of admission, the patient made a full recovery. In cases of VPA intoxication, protein-binding saturation and drug characteristics render extracorporeal elimination, an effective technique for eliminating the unbound drug. Its application should be considered, depending on clinical symptoms, VPA concentration (>300 mg/l), albumin concentration and ammonia concentration (>400 micromol/l). The application of this technique should be weighed against its risks. This case illustrates the clinical significance of applying continuous veno-venous haemofiltration in VPA intoxication because of protein-binding saturation, and suggests when extracorporeal elimination should be considered.

quenched-smFISH: Counting small RNA in Pathogenic Bacteria

NASA Astrophysics Data System (ADS)

Shepherd, Douglas; Li, Nan; Micheva-Viteva, Sofiya; Munsky, Brian; Hong-Geller, Elizabeth; Werner, James

2014-03-01

Here, we present a modification to single-molecule fluorescence in situ hybridization, quenched smFISH (q-smFISH), that enables quantitative detection and analysis of small RNA (sRNA) expressed in bacteria. We show that short nucleic acid targets can be detected when the background of unbound singly dye-labeled DNA oligomers is reduced through hybridization with a set of complementary DNA oligomers labeled with a fluorescence quencher. Exploiting an automated, multi-color wide-field microscope and GPU-accelerated data analysis package, we analyzed the statistics of sRNA expression in thousands of individual Yersinia pseudotuberculosis and Yersinia pestis bacteria before and during a simulated infection. Before infection, we find only a small fraction of either bacteria express the small RNAs YSR35 or YSP8. The copy numbers of these RNA are increased during simulated infection, suggesting a role in pathogenesis. The ability to directly quantify expression level changes of sRNA in single cells as a function of external stimuli provides key information on the role of sRNA in bacterial regulatory networks.

Droplet-based microfluidic washing module for magnetic particle-based assays

PubMed Central

Lee, Hun; Xu, Linfeng; Oh, Kwang W.

2014-01-01

In this paper, we propose a continuous flow droplet-based microfluidic platform for magnetic particle-based assays by employing in-droplet washing. The droplet-based washing was implemented by traversing functionalized magnetic particles across a laterally merged droplet from one side (containing sample and reagent) to the other (containing buffer) by an external magnetic field. Consequently, the magnetic particles were extracted to a parallel-synchronized train of washing buffer droplets, and unbound reagents were left in an original train of sample droplets. To realize the droplet-based washing function, the following four procedures were sequentially carried in a droplet-based microfluidic device: parallel synchronization of two trains of droplets by using a ladder-like channel network; lateral electrocoalescence by an electric field; magnetic particle manipulation by a magnetic field; and asymmetrical splitting of merged droplets. For the stable droplet synchronization and electrocoalescence, we optimized droplet generation conditions by varying the flow rate ratio (or droplet size). Image analysis was carried out to determine the fluorescent intensity of reagents before and after the washing step. As a result, the unbound reagents in sample droplets were significantly removed by more than a factor of 25 in the single washing step, while the magnetic particles were successfully extracted into washing buffer droplets. As a proof-of-principle, we demonstrate a magnetic particle-based immunoassay with streptavidin-coated magnetic particles and fluorescently labelled biotin in the proposed continuous flow droplet-based microfluidic platform. PMID:25379098

The Hierarchical Distribution of the Young Stellar Clusters in Six Local Star-forming Galaxies

NASA Astrophysics Data System (ADS)

Grasha, K.; Calzetti, D.; Adamo, A.; Kim, H.; Elmegreen, B. G.; Gouliermis, D. A.; Dale, D. A.; Fumagalli, M.; Grebel, E. K.; Johnson, K. E.; Kahre, L.; Kennicutt, R. C.; Messa, M.; Pellerin, A.; Ryon, J. E.; Smith, L. J.; Shabani, F.; Thilker, D.; Ubeda, L.

2017-05-01

We present a study of the hierarchical clustering of the young stellar clusters in six local (3-15 Mpc) star-forming galaxies using Hubble Space Telescope broadband WFC3/UVIS UV and optical images from the Treasury Program LEGUS (Legacy ExtraGalactic UV Survey). We identified 3685 likely clusters and associations, each visually classified by their morphology, and we use the angular two-point correlation function to study the clustering of these stellar systems. We find that the spatial distribution of the young clusters and associations are clustered with respect to each other, forming large, unbound hierarchical star-forming complexes that are in general very young. The strength of the clustering decreases with increasing age of the star clusters and stellar associations, becoming more homogeneously distributed after ˜40-60 Myr and on scales larger than a few hundred parsecs. In all galaxies, the associations exhibit a global behavior that is distinct and more strongly correlated from compact clusters. Thus, populations of clusters are more evolved than associations in terms of their spatial distribution, traveling significantly from their birth site within a few tens of Myr, whereas associations show evidence of disruption occurring very quickly after their formation. The clustering of the stellar systems resembles that of a turbulent interstellar medium that drives the star formation process, correlating the components in unbound star-forming complexes in a hierarchical manner, dispersing shortly after formation, suggestive of a single, continuous mode of star formation across all galaxies.

Universal formulation of excitonic linear absorption spectra in all semiconductor microstructures

NASA Astrophysics Data System (ADS)

Lefebvre, Pierre; Christol, Philippe; Mathieu, Henry

1995-01-01

We present a generalization of the well-known exciton absorption calculations of Elliott [Phys. Rev. 108, 1384 (1957)], in the 3-dimensional case, and of Shinada and Sugano [J. Phys. Soc. Japan 21, 1936 (1966)], for 2-dimensional media: We calculate the optical absorption spectra of bound and unbound exciton states, by using a metric space with a noninteger dimension α (1 < α), obtaining almost exactly the same theoretical lineshapes as those resulting from accurate but costly numerical approaches [Chuang et al. Phys. Rev. B, 43, 1500 (1991); Benner and Haug, Phys. Rev. B 47, 15750 (1993)].

Symmetry limit theory for cantilever beam-columns subjected to cyclic reversed bending

NASA Astrophysics Data System (ADS)

Uetani, K.; Nakamura, Tsuneyoshi

THE BEHAVIOR of a linear strain-hardening cantilever beam-column subjected to completely reversed plastic bending of a new idealized program under constant axial compression consists of three stages: a sequence of symmetric steady states, a subsequent sequence of asymmetric steady states and a divergent behavior involving unbounded growth of an anti-symmetric deflection mode. A new concept "symmetry limit" is introduced here as the smallest critical value of the tip-deflection amplitude at which transition from a symmetric steady state to an asymmetric steady state can occur in the response of a beam-column. A new theory is presented for predicting the symmetry limits. Although this transition phenomenon is phenomenologically and conceptually different from the branching phenomenon on an equilibrium path, it is shown that a symmetry limit may theoretically be regarded as a branching point on a "steady-state path" defined anew. The symmetry limit theory and the fundamental hypotheses are verified through numerical analysis of hysteretic responses of discretized beam-column models.

Ultrasensitive detection enabled by nonlinear magnetization of nanomagnetic labels.

PubMed

Nikitin, M P; Orlov, A V; Sokolov, I L; Minakov, A A; Nikitin, P I; Ding, J; Bader, S D; Rozhkova, E A; Novosad, V

2018-06-21

Geometrically confined magnetic particles due to their unique response to external magnetic fields find a variety of applications, including magnetic guidance, heat and drug delivery, magneto-mechanical actuation, and contrast enhancement. Highly sensitive detection and imaging techniques based on the nonlinear properties of nanomagnets were recently proposed as innovative strong-translational potential methods applicable in complex, often opaque, biological systems. Here we report on the significant enhancement of the detection capability using optical-lithography-defined, ferromagnetic iron-nickel alloy disk-shaped particles. We show that an irreversible transition between strongly non-collinear (vortex) and single domain states, driven by an alternating magnetic field, translates into a nonlinear magnetic response that enables ultrasensitive detection of these particles. The record sensitivity of ∼3.5 × 10-9 emu, which is equivalent to ∼39 pg of magnetic material is demonstrated at room temperature for arrays of patterned disks. We also show that unbound disks suspended in the aqueous buffer can be successfully detected and quantified in real-time when administered into a live animal allowing for tracing of their biodistribution. The use of nanoscale ferromagnetic particles with engineered nonlinear properties opens prospects for further enhancing the sensitivity, scalability, and tunability of noise-free magnetic tag detection in high-background environments for various applications spanning from biosensing and medical imaging to anti-counterfeiting technologies.

Linear stiff string vibrations in musical acoustics: Assessment and comparison of models.

PubMed

Ducceschi, Michele; Bilbao, Stefan

2016-10-01

Strings are amongst the most common elements found in musical instruments and an appropriate physical description of string dynamics is essential to modelling, analysis, and simulation. For linear vibration in a single polarisation, the most common model is based on the Euler-Bernoulli beam equation under tension. In spite of its simple form, such a model gives unbounded phase and group velocities at large wavenumbers, and such behaviour may be interpreted as unphysical. The Timoshenko model has, therefore, been employed in more recent works to overcome such shortcoming. This paper presents a third model based on the shear beam equations. The three models are here assessed and compared with regard to the perceptual considerations in musical acoustics.

The nu-process

NASA Technical Reports Server (NTRS)

Woosley, S. E.; Hartmann, D. H.; Hoffman, R. D.; Haxton, W. C.

1990-01-01

As the core of a massive star collapses to form a neutron star, the flux of neutrinos in the overlying shells of heavy elements becomes so great that, despite the small cross section, substantial nuclear transmutation is induced. Neutrinos excite heavy elements and even helium to particle unbound levels. The evaporation of a single neutron or proton, and the back reaction of these nucleons on other species present, significantly alters the outcome of traditional nucleosynthesis calculations leading to a new process: nu-nucleosynthesis. Modifications to traditional hydrostatic and explosive varieties of helium, carbon, neon, oxygen, and silicon burning are considered. The results show that a large number of rare isotopes, including many of the odd-Z nuclei from boron through copper, owe much of their present abundance in nature to this process.

Space-charge-sustained microbunch structure in the Los Alamos Proton Storage Ring

NASA Astrophysics Data System (ADS)

Cousineau, S.; Danilov, V.; Holmes, J.; Macek, R.

2004-09-01

We present experimental data from the Los Alamos Proton Storage Ring (PSR) showing long-lived linac microbunch structure during beam storage with no rf bunching. Analysis of the experimental data and particle-in-cell simulations of the experiments indicate that space charge, coupled with energy spread effects, is responsible for the sustained microbunch structure. The simulated longitudinal phase space of the beam reveals a well-defined separatrix in the phase space between linac microbunches, with particles executing unbounded motion outside of the separatrix. We show that the longitudinal phase space of the beam was near steady state during the PSR experiments, such that the separatrix persisted for long periods of time. Our simulations indicate that the steady state is very sensitive to the experimental conditions. Finally, we solve the steady-state problem in an analytic, self-consistent fashion for a set of periodic longitudinal space-charge potentials.

Exciton absorption of entangled photons in semiconductor quantum wells

NASA Astrophysics Data System (ADS)

Rodriguez, Ferney; Guzman, David; Salazar, Luis; Quiroga, Luis; Condensed Matter Physics Group Team

2013-03-01

The dependence of the excitonic two-photon absorption on the quantum correlations (entanglement) of exciting biphotons by a semiconductor quantum well is studied. We show that entangled photon absorption can display very unusual features depending on space-time-polarization biphoton parameters and absorber density of states for both bound exciton states as well as for unbound electron-hole pairs. We report on the connection between biphoton entanglement, as quantified by the Schmidt number, and absorption by a semiconductor quantum well. Comparison between frequency-anti-correlated, unentangled and frequency-correlated biphoton absorption is addressed. We found that exciton oscillator strengths are highly increased when photons arrive almost simultaneously in an entangled state. Two-photon-absorption becomes a highly sensitive probe of photon quantum correlations when narrow semiconductor quantum wells are used as two-photon absorbers. Research funds from Facultad de Ciencias, Universidad de los Andes

Resistance of Soil-Bound Prions to Rumen Digestion

PubMed Central

Saunders, Samuel E.; Bartelt-Hunt, Shannon L.; Bartz, Jason C.

2012-01-01

Before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. The susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. In this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in PrP levels were measured via western blot. Binding to clay appeared to protect noninfectious hamster PrPc from complete digestion, while both unbound and soil-bound infectious PrPSc proved highly resistant to rumen digestion. In addition, no change in intracerebral incubation period was observed following active rumen digestion of unbound hamster HY TME prions and HY TME prions bound to a silty clay loam soil. These results demonstrate that both unbound and soil-bound prions readily survive rumen digestion without a reduction in infectivity, further supporting the potential for soil-mediated transmission of chronic wasting disease (CWD) and scrapie in the environment. PMID:22937149

From localization to anomalous diffusion in the dynamics of coupled kicked rotors

NASA Astrophysics Data System (ADS)

Notarnicola, Simone; Iemini, Fernando; Rossini, Davide; Fazio, Rosario; Silva, Alessandro; Russomanno, Angelo

2018-02-01

We study the effect of many-body quantum interference on the dynamics of coupled periodically kicked systems whose classical dynamics is chaotic and shows an unbounded energy increase. We specifically focus on an N -coupled kicked rotors model: We find that the interplay of quantumness and interactions dramatically modifies the system dynamics, inducing a transition between energy saturation and unbounded energy increase. We discuss this phenomenon both numerically and analytically through a mapping onto an N -dimensional Anderson model. The thermodynamic limit N →∞ , in particular, always shows unbounded energy growth. This dynamical delocalization is genuinely quantum and very different from the classical one: Using a mean-field approximation, we see that the system self-organizes so that the energy per site increases in time as a power law with exponent smaller than 1. This wealth of phenomena is a genuine effect of quantum interference: The classical system for N ≥2 always behaves ergodically with an energy per site linearly increasing in time. Our results show that quantum mechanics can deeply alter the regularity or ergodicity properties of a many-body-driven system.

Helicon and Trivelpiece-Gould modes in uniform unbounded plasmas

NASA Astrophysics Data System (ADS)

Stenzel, R. L.; Urrutia, J. M.

2016-10-01

Helicon modes are whistler modes with angular orbital momentum caused by phase rotation in addition to the axial phase propagation. Although these modes have been associated with whistler eigenmodes in bounded plasma columns, they do exist in unbounded plasmas. Experiments in a large laboratory plasma show the wave excitation with phased antenna arrays, the wave field topology and the propagation of helicons. Low frequency whistlers can have two modes with different wavelengths at a given frequency, called helicons and Trivelpiece-Gould modes. The latter are whistler modes near the oblique cyclotron resonance. The oblique propagation is due to short radial wavelengths near the boundary. In unbounded plasmas, the oblique propagation arises from short azimuthal wavelengths. This has been observed in high-mode number helicons (e.g., m = 8). It creates wave absorption in the center of the helicon mode. The strong absorption of the wave can heat electrons and create perpendicular wave-particle interactions. These results may be of interest in space plasmas for scattering of energetic electrons and in helicon plasma sources for plasma processing and thruster applications. Work supported by NSF/DOE.

When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

PubMed Central

Stern, Stephan T.; Stevens, David M.

2016-01-01

Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation. PMID:27670412

Analytical formulation of 2-D aeroelastic model in weak ground effect

NASA Astrophysics Data System (ADS)

Dessi, Daniele; Mastroddi, Franco; Mancini, Simone

2013-10-01

This paper deals with the aeroelastic modeling and analysis of a 2-D oscillating airfoil in ground effect, elastically constrained by linear and torsional springs and immersed in an incompressible potential flow (typical section) at a finite distance from the ground. This work aims to extend Theodorsen theory, valid in an unbounded flow domain, to the case of weak ground effect, i.e., for clearances above half the airfoil chord. The key point is the determination of the aerodynamic loads, first in the frequency domain and then in the time domain, accounting for their dependence on the ground distance. The method of images is exploited in order to comply with the impermeability condition on the ground. The new integral equation in the unknown vortex distribution along the chord and the wake is solved using asymptotic expansions in the perturbation parameter defined as the inverse of the non-dimensional ground clearance of the airfoil. The mathematical model describing the aeroelastic system is transformed from the frequency domain into the time domain and then in a pure differential form using a finite-state aerodynamic approximation (augmented states). The typical section, which the developed theory is applied to, is obtained as a reduced model of a wing box finite element representation, thus allowing comparison with the corresponding aeroelastic analysis carried out by a commercial solver based on a 3-D lifting surface aerodynamic model. Stability (flutter margins) and response of the airfoil both in frequency and time domains are then investigated. In particular, within the developed theory, the solution of the Wagner problem can be directly achieved confirming an asymptotic trend of the aerodynamic coefficients toward the steady-state conditions different from that relative to the unbounded domain case. The dependence of flutter speed and the frequency response functions on ground clearance is highlighted, showing the usefulness of this approach in efficiently and robustly accounting for the presence of the ground when unsteady analysis of elastic lifting surfaces in weak ground effect is required.

Probing the structural dynamics of the CRISPR-Cas9 RNA-guided DNA-cleavage system by coarse-grained modeling.

PubMed

Zheng, Wenjun

2017-02-01

In the adaptive immune systems of many bacteria and archaea, the Cas9 endonuclease forms a complex with specific guide/scaffold RNA to identify and cleave complementary target sequences in foreign DNA. This DNA targeting machinery has been exploited in numerous applications of genome editing and transcription control. However, the molecular mechanism of the Cas9 system is still obscure. Recently, high-resolution structures have been solved for Cas9 in different structural forms (e.g., unbound forms, RNA-bound binary complexes, and RNA-DNA-bound tertiary complexes, corresponding to an inactive state, a pre-target-bound state, and a cleavage-competent or product state), which offered key structural insights to the Cas9 mechanism. To further probe the structural dynamics of Cas9 interacting with RNA and DNA at the amino-acid level of details, we have performed systematic coarse-grained modeling using an elastic network model and related analyses. Our normal mode analysis predicted a few key modes of collective motions that capture the observed conformational changes featuring large domain motions triggered by binding of RNA and DNA. Our flexibility analysis identified specific regions with high or low flexibility that coincide with key functional sites (such as DNA/RNA-binding sites, nuclease cleavage sites, and key hinges). We also identified a small set of hotspot residues that control the energetics of functional motions, which overlap with known functional sites and offer promising targets for future mutagenesis efforts to improve the specificity of Cas9. Finally, we modeled the conformational transitions of Cas9 from the unbound form to the binary complex and then the tertiary complex, and predicted a distinct sequence of domain motions. In sum, our findings have offered rich structural and dynamic details relevant to the Cas9 machinery, and will guide future investigation and engineering of the Cas9 systems. Proteins 2017; 85:342-353. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Dynamical stability of a many-body Kapitza pendulum

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

Citro, Roberta, E-mail: citro@sa.infn.it; Dalla Torre, Emanuele G., E-mail: emanuele.dalla-torre@biu.ac.il; Department of Physics, Harvard University, Cambridge, MA 02138

We consider a many-body generalization of the Kapitza pendulum: the periodically-driven sine–Gordon model. We show that this interacting system is dynamically stable to periodic drives with finite frequency and amplitude. This finding is in contrast to the common belief that periodically-driven unbounded interacting systems should always tend to an absorbing infinite-temperature state. The transition to an unstable absorbing state is described by a change in the sign of the kinetic term in the Floquet Hamiltonian and controlled by the short-wavelength degrees of freedom. We investigate the stability phase diagram through an analytic high-frequency expansion, a self-consistent variational approach, and amore » numeric semiclassical calculation. Classical and quantum experiments are proposed to verify the validity of our results.« less

Optical nonlinearities of excitons in monolayer MoS2

NASA Astrophysics Data System (ADS)

Soh, Daniel B. S.; Rogers, Christopher; Gray, Dodd J.; Chatterjee, Eric; Mabuchi, Hideo

2018-04-01

We calculate linear and nonlinear optical susceptibilities arising from the excitonic states of monolayer MoS2 for in-plane light polarizations, using second-quantized bound and unbound exciton operators. Optical selection rules are critical for obtaining the susceptibilities. We derive the valley-chirality rule for the second-order harmonic generation in monolayer MoS2 and find that the third-order harmonic process is efficient only for linearly polarized input light while the third-order two-photon process (optical Kerr effect) is efficient for circularly polarized light using a higher order exciton state. The absence of linear absorption due to the band gap and the unusually strong two-photon third-order nonlinearity make the monolayer MoS2 excitonic structure a promising resource for coherent nonlinear photonics.

Binding mechanism of PicoGreen to DNA characterized by magnetic tweezers and fluorescence spectroscopy.

PubMed

Wang, Ying; Schellenberg, Helene; Walhorn, Volker; Toensing, Katja; Anselmetti, Dario

2017-09-01

Fluorescent dyes are broadly used in many biotechnological applications to detect and visualize DNA molecules. However, their binding to DNA alters the structural and nanomechanical properties of DNA and, thus, interferes with associated biological processes. In this work we employed magnetic tweezers and fluorescence spectroscopy to investigate the binding of PicoGreen to DNA at room temperature in a concentration-dependent manner. PicoGreen is an ultrasensitive quinolinium nucleic acid stain exhibiting hardly any background signal from unbound dye molecules. By means of stretching and overwinding single, torsionally constrained, nick-free double-stranded DNA molecules, we acquired force-extension and supercoiling curves which allow quantifying DNA contour length, persistence length and other thermodynamical binding parameters, respectively. The results of our magnetic tweezers single-molecule binding study were well supported through analyzing the fluorescent spectra of stained DNA. On the basis of our work, we could identify a concentration-dependent bimodal binding behavior, where, apparently, PicoGreen associates to DNA as an intercalator and minor-groove binder simultaneously.

Point-of-care rare cell cancer diagnostics.

PubMed

Issadore, David

2015-01-01

The sparse cells that are shed from tumors into peripheral circulation are an increasingly promising resource for noninvasive monitoring of cancer progression, early diagnosis of disease, and serve as a tool for improving our understanding of cancer metastasis. However, the extremely sparse concentration of circulating tumor cells (CTCs) in blood (~1-100 CTC in 7.5 mL of blood) as well as their heterogeneous biomarker expression has limited their detection using conventional laboratory techniques. To overcome these challenges, we have developed a microfluidic chip-based micro-Hall detector (μHD), which can directly measure single, immunomagnetically tagged cells in whole blood. The μHD can detect individual cells even in the presence of vast numbers of blood cells and unbound reactants, and does not require any washing or purification steps. Furthermore, this cost-effective, single-cell analytical technique is well suited for miniaturization into a mobile platform for low-cost point-of-care use. In this chapter, we describe the methodology used to design, fabricate, and apply these chips to cancer diagnostics.

Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery

PubMed Central

Liu, Jin

2016-01-01

Intra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2) in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Châtelier’s principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery. PMID:27115535

Prednisone Pharmacokinetics During Pregnancy and Lactation.

PubMed

Ryu, Rachel J; Easterling, Thomas R; Caritis, Steve N; Venkataramanan, Raman; Umans, Jason G; Ahmed, Mahmoud S; Clark, Shannon; Kantrowitz-Gordon, Ira; Hays, Karen; Bennett, Brooke; Honaker, Matthew T; Thummel, Kenneth E; Shen, Danny D; Hebert, Mary F

2018-05-07

To evaluate the steady-state pharmacokinetics of prednisone and its metabolite prednisolone in pregnant and lactating female subjects, 19 subjects received prednisone (4-40 mg/day orally) in early (n = 3), mid (n = 9), and late (n = 13) pregnancy as well as postpartum with (n = 2) and without (n = 5) lactation. Serial blood and urine samples were collected over 1 dosing interval. Prednisone and its metabolite, prednisolone, steady-state noncompartmental pharmacokinetic parameters were estimated. During pregnancy, prednisone apparent oral clearance increased with dose (35.1 ± 11.4 L/h with 5 mg, 52.6 ± 5.2 L/h with 10 mg, and 64.3 ± 6.9 L/h with 20 mg, P = .001). Similarly, unbound prednisone apparent oral clearance increased with dose. In addition, prednisolone renal clearance increased with dose (0.3 ± 0.3 L/h with 5 mg, 0.5 ± 0.4 L/h with 10 mg, and 1.3 ± 1.1 L/h with 20 mg, P = .002). Higher prednisone (r = 0.57, P ≤ .05) and prednisolone (r = 0.75, P ≤ .05) concentrations led to a higher percentage of unbound drug. Breast-milk/plasma area under the concentration-time curve ratios were 0.5-0.6 for prednisone and 0.02-0.03 for prednisolone. Relative infant doses were 0.35% to 0.53% and 0.09% to 0.18%, for prednisone and prednisolone, respectively. Prednisone and prednisolone exhibit dose- and concentration-dependent pharmacokinetics during pregnancy, and infant exposure to these agents via breast milk is minimal. © 2018, The American College of Clinical Pharmacology.

A Financial Market Model Incorporating Herd Behaviour

PubMed Central

2016-01-01

Herd behaviour in financial markets is a recurring phenomenon that exacerbates asset price volatility, and is considered a possible contributor to market fragility. While numerous studies investigate herd behaviour in financial markets, it is often considered without reference to the pricing of financial instruments or other market dynamics. Here, a trader interaction model based upon informational cascades in the presence of information thresholds is used to construct a new model of asset price returns that allows for both quiescent and herd-like regimes. Agent interaction is modelled using a stochastic pulse-coupled network, parametrised by information thresholds and a network coupling probability. Agents may possess either one or two information thresholds that, in each case, determine the number of distinct states an agent may occupy before trading takes place. In the case where agents possess two thresholds (labelled as the finite state-space model, corresponding to agents’ accumulating information over a bounded state-space), and where coupling strength is maximal, an asymptotic expression for the cascade-size probability is derived and shown to follow a power law when a critical value of network coupling probability is attained. For a range of model parameters, a mixture of negative binomial distributions is used to approximate the cascade-size distribution. This approximation is subsequently used to express the volatility of model price returns in terms of the model parameter which controls the network coupling probability. In the case where agents possess a single pulse-coupling threshold (labelled as the semi-infinite state-space model corresponding to agents’ accumulating information over an unbounded state-space), numerical evidence is presented that demonstrates volatility clustering and long-memory patterns in the volatility of asset returns. Finally, output from the model is compared to both the distribution of historical stock returns and the market price of an equity index option. PMID:27007236

Erosive Hit-and-Run Impact Events: Debris Unbound

NASA Astrophysics Data System (ADS)

Sarid, Gal; Stewart, Sarah T.; Leinhardt, Zoë M.

2016-01-01

Erosive collisions among planetary embryos in the inner solar system can lead to multiple remnant bodies, varied in mass, composition and residual velocity. Some of the smaller, unbound debris may become available to seed the main asteroid belt. The makeup of these collisionally produced bodies is different from the canonical chondritic composition, in terms of rock/iron ratio and may contain further shock-processed material. Having some of the material in the asteroid belt owe its origin from collisions of larger planetary bodies may help in explaining some of the diversity and oddities in composition of different asteroid groups.

Bubbling in unbounded coflowing liquids.

PubMed

Gañán-Calvo, Alfonso M; Herrada, Miguel A; Garstecki, Piotr

2006-03-31

An investigation of the stability of low density and viscosity fluid jets and spouts in unbounded coflowing liquids is presented. A full parametrical analysis from low to high Weber and Reynolds numbers shows that the presence of any fluid of finite density and viscosity inside the hollow jet elicits a transition from an absolute to a convective instability at a finite value of the Weber number, for any value of the Reynolds number. Below that critical value of the Weber number, the absolute character of the instability leads to local breakup, and consequently to local bubbling. Experimental data support our model.

A Semi-linear Backward Parabolic Cauchy Problem with Unbounded Coefficients of Hamilton–Jacobi–Bellman Type and Applications to Optimal Control

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

Addona, Davide, E-mail: d.addona@campus.unimib.it

2015-08-15

We obtain weighted uniform estimates for the gradient of the solutions to a class of linear parabolic Cauchy problems with unbounded coefficients. Such estimates are then used to prove existence and uniqueness of the mild solution to a semi-linear backward parabolic Cauchy problem, where the differential equation is the Hamilton–Jacobi–Bellman equation of a suitable optimal control problem. Via backward stochastic differential equations, we show that the mild solution is indeed the value function of the controlled equation and that the feedback law is verified.

LQR Control of Shell Vibrations Via Piezoceramic Actuators

NASA Technical Reports Server (NTRS)

delRosario, R. C. H.; Smith, R. C.

1997-01-01

A model-based Linear Quadratic Regulator (LQR) method for controlling vibrations in cylindrical shells is presented. Surface-mounted piezo-ceramic patches are employed as actuators which leads to unbounded control input operators. Modified Donnell-Mushtari shell equations incorporating strong or Kelvin-Voigt damping are used to model the system. The model is then abstractly formulated in terms of sesquilinear forms. This provides a framework amenable for proving model well-posedness and convergence of LQR gains using analytic semigroup results combined with LQR theory for unbounded input operators. Finally, numerical examples demonstrating the effectiveness of the method are presented.

Provably unbounded memory advantage in stochastic simulation using quantum mechanics

NASA Astrophysics Data System (ADS)

Garner, Andrew J. P.; Liu, Qing; Thompson, Jayne; Vedral, Vlatko; Gu, mile

2017-10-01

Simulating the stochastic evolution of real quantities on a digital computer requires a trade-off between the precision to which these quantities are approximated, and the memory required to store them. The statistical accuracy of the simulation is thus generally limited by the internal memory available to the simulator. Here, using tools from computational mechanics, we show that quantum processors with a fixed finite memory can simulate stochastic processes of real variables to arbitrarily high precision. This demonstrates a provable, unbounded memory advantage that a quantum simulator can exhibit over its best possible classical counterpart.

A computational method for the Helmholtz equation in unbounded domains based on the minimization of an integral functional

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

Ciraolo, Giulio, E-mail: g.ciraolo@math.unipa.it; Gargano, Francesco, E-mail: gargano@math.unipa.it; Sciacca, Vincenzo, E-mail: sciacca@math.unipa.it

2013-08-01

We study a new approach to the problem of transparent boundary conditions for the Helmholtz equation in unbounded domains. Our approach is based on the minimization of an integral functional arising from a volume integral formulation of the radiation condition. The index of refraction does not need to be constant at infinity and may have some angular dependency as well as perturbations. We prove analytical results on the convergence of the approximate solution. Numerical examples for different shapes of the artificial boundary and for non-constant indexes of refraction will be presented.

A new and highly sensitive method of analyzing metabolic activity using FLIM (Conference Presentation)

NASA Astrophysics Data System (ADS)

Evers, Michael; Salma, Nunciada; Birngruber, Reginald; Evans, Conor L.; Manstein, Dieter

2017-02-01

Traditional assessments of cellular metabolism are often destructive, time consuming and without visual information. Fluorescence lifetime imaging microscopy (FLIM) provides a highly sensitive, non-invasive, and label-free alternative. This study uses FLIM in combination with two-photon microscopy to investigate pharmacological induced metabolic changes of adipocytes via changes in the fluorescence of the metabolic co-factors NADH and FAD. In agreement with recent publications NADH fluorescence suggests the presence of four distinct lifetimes in cell culture and tissue with two unbound and two protein bound states which show different responses to treatment with metabolic modifiers. We evaluated the effects on NADH fluorescence lifetime after systematic manipulations to change the balance between oxidative and glycolytic metabolism using five pharmacological reagents - Oligomycin, 2-DG, FCCP, Rotenone, and Glucose - which interact with different parts of the metabolic pathway. We established several ratios between the four distinct lifetimes of NADH after treatment and compared the results to oxygen consumption rate and extracellular acidification rate. We demonstrated, for the first time, a correlation between the two unbound fluorescence lifetimes components and glycolytic and oxidative metabolic activity with a significant higher sensitivity compared to the commonly used free-to-bound ratio of NADH. Analyzing all four lifetime components of NADH has the potential to become a powerful tool to evaluate metabolic activity of adipocytes with subcellular resolution.

Distribution of ciprofloxacin into the central nervous system in rats with acute renal or hepatic failure.

PubMed

Naora, K; Ichikawa, N; Hirano, H; Iwamoto, K

1999-05-01

Pharmacokinetic changes of various drugs have been reported in renal or hepatic failure. The present study employed ciprofloxacin, a quinolone antibiotic having neurotoxic side effects, to assess the influence of these diseases on distribution of ciprofloxacin into the central nervous system (CNS). After intravenous dosing of ciprofloxacin (10-30 mg kg(-1)), ciprofloxacin levels in plasma and brain were measured in normal rats (Wistar, male, 10-week-old) and those with acute renal and hepatic injuries which were induced by uranyl nitrate and carbon tetrachloride (CCl4), respectively. In the uranyl nitrate-treated rats, the plasma elimination half-life of ciprofloxacin was prolonged and the total body clearance was reduced when compared with those in the normal rats. Similar but smaller changes were observed in the CCl4-treated group. Brain levels of ciprofloxacin were significantly increased by both uranyl nitrate and CCl4 treatments. A proportional correlation between serum unbound levels and brain levels of ciprofloxacin was observed in the normal group. However, brain-to-serum unbound concentration ratios of ciprofloxacin were reduced in the rats with renal or hepatic failure. These results suggest that renal failure as well as hepatic failure retards elimination of ciprofloxacin from the blood, leading to elevation of the CNS level, and also that ciprofloxacin distribution in the brain is reduced in these disease states.

Investigation of arc repressor DNA-binding specificity by comparative molecular dynamics simulations.

PubMed

Song, Wei; Guo, Jun-Tao

2015-01-01

Transcription factors regulate gene expression through binding to specific DNA sequences. How transcription factors achieve high binding specificity is still not well understood. In this paper, we investigated the role of protein flexibility in protein-DNA-binding specificity by comparative molecular dynamics (MD) simulations. Protein flexibility has been considered as a key factor in molecular recognition, which is intrinsically a dynamic process involving fine structural fitting between binding components. In this study, we performed comparative MD simulations on wild-type and F10V mutant P22 Arc repressor in both free and complex conformations. The F10V mutant has lower DNA-binding specificity though both the bound and unbound main-chain structures between the wild-type and F10V mutant Arc are highly similar. We found that the DNA-binding motif of wild-type Arc is structurally more flexible than the F10V mutant in the unbound state, especially for the six DNA base-contacting residues in each dimer. We demonstrated that the flexible side chains of wild-type Arc lead to a higher DNA-binding specificity through forming more hydrogen bonds with DNA bases upon binding. Our simulations also showed a possible conformational selection mechanism for Arc-DNA binding. These results indicate the important roles of protein flexibility and dynamic properties in protein-DNA-binding specificity.

Mapping the Binding Interface of VEGF and a Monoclonal Antibody Fab-1 Fragment with Fast Photochemical Oxidation of Proteins (FPOP) and Mass Spectrometry

NASA Astrophysics Data System (ADS)

Zhang, Ying; Wecksler, Aaron T.; Molina, Patricia; Deperalta, Galahad; Gross, Michael L.

2017-05-01

We previously analyzed the Fab-1:VEGF (vascular endothelial growth factor) system described in this work, with both native top-down mass spectrometry and bottom-up mass spectrometry (carboxyl-group or GEE footprinting) techniques. This work continues bottom-up mass spectrometry analysis using a fast photochemical oxidation of proteins (FPOP) platform to map the solution binding interface of VEGF and a fragment antigen binding region of an antibody (Fab-1). In this study, we use FPOP to compare the changes in solvent accessibility by quantitating the extent of oxidative modification in the unbound versus bound states. Determining the changes in solvent accessibility enables the inference of the protein binding sites (epitope and paratopes) and a comparison to the previously published Fab-1:VEGF crystal structure, adding to the top-down and bottom-up data. Using this method, we investigated peptide-level and residue-level changes in solvent accessibility between the unbound proteins and bound complex. Mapping these data onto the Fab-1:VEGF crystal structure enabled successful characterization of both the binding region and regions of remote conformation changes. These data, coupled with our previous higher order structure (HOS) studies, demonstrate the value of a comprehensive toolbox of methods for identifying the putative epitopes and paratopes for biotherapeutic antibodies.

Accommodating Sensor Bias in MRAC for State Tracking

NASA Technical Reports Server (NTRS)

Patre, Parag; Joshi, Suresh M.

2011-01-01

The problem of accommodating unknown sensor bias is considered in a direct model reference adaptive control (MRAC) setting for state tracking using state feedback. Sensor faults can occur during operation, and if the biased state measurements are directly used with a standard MRAC control law, neither closed-loop signal boundedness, nor asymptotic tracking can be guaranteed and the resulting tracking errors may be unbounded or unacceptably large. A modified MRAC law is proposed, which combines a bias estimator with control gain adaptation, and it is shown that signal boundedness can be accomplished, although the tracking error may not go to zero. Further, for the case wherein an asymptotically stable sensor bias estimator is available, an MRAC control law is proposed to accomplish asymptotic tracking and signal boundedness. Such a sensor bias estimator can be designed if additional sensor measurements are available, as illustrated for the case wherein bias is present in the rate gyro and airspeed measurements. Numerical example results are presented to illustrate each of the schemes.

Nuclear structure beyond the neutron drip line. The lowest energy states in 9He via their T=5/2 isobaric analogs in 9Li

DOE PAGES

Uberseder, E.; Rogachev, G. V.; Goldberg, V. Z.; ...

2016-03-01

The level structure of the very neutron rich and unbound 9He nucleus has been the subject of significant experimental and theoretical study. Many recent works have claimed that the two lowest energy 9He states exist with spins J π=1/2 +and Jπ=1/2 -and widths on the order of 100–200 keV. These find-ings cannot be reconciled with our contemporary understanding of nuclear structure. Our present work is the first high-resolution study with low statistical uncertainty of the relevant excitation energy range in the 8He+n system, performed via a search for the T =5/2 isobaric analog states in 9Li populated through 8He+p elasticmore » scattering. Moreover, the present data show no indication of any narrow structures. Instead, we find evidence for a broad J π=1/2 +state in 9He located approximately 3 MeV above the neutron decay threshold.« less

Ultrafast above-threshold dynamics of the radical anion of a prototypical quinone electron-acceptor.

PubMed

Horke, Daniel A; Li, Quansong; Blancafort, Lluís; Verlet, Jan R R

2013-08-01

Quinones feature prominently as electron acceptors in nature. Their electron-transfer reactions are often highly exergonic, for which Marcus theory predicts reduced electron-transfer rates because of a free-energy barrier that occurs in the inverted region. However, the electron-transfer kinetics that involve quinones can appear barrierless. Here, we consider the intrinsic properties of the para-benzoquinone radical anion, which serves as the prototypical electron-transfer reaction product involving a quinone-based acceptor. Using time-resolved photoelectron spectroscopy and ab initio calculations, we show that excitation at 400 and 480 nm yields excited states that are unbound with respect to electron loss. These excited states are shown to decay on a sub-40 fs timescale through a series of conical intersections with lower-lying excited states, ultimately to form the ground anionic state and avoid autodetachment. From an isolated electron-acceptor perspective, this ultrafast stabilization mechanism accounts for the ability of para-benzoquinone to capture and retain electrons.

Computer simulations reveal changes in the conformational space of the transcriptional regulator MosR upon the formation of a disulphide bond and in the collective motions that regulate its DNA-binding affinity

PubMed Central

Câmara, Amanda Souza

2018-01-01

M. tuberculosis oxidation sense Regulator (MosR) is a transcriptional regulator from Mycobacterium tuberculosis. It senses the environment oxidation and regulates the expression of a secreted oxidoreductase, thus defending the bacilli against oxidative stress from the phagosome. While most of the members of the Multiple antibiotics resistance Regulator (MarR) family are ligand-responsive, MosR may dissociate from its DNA site upon formation of an intrachain disulphide bond. However, the structure of MosR in its oxidized state is not known, and it is not clear how the formation of this disulphide bond would lead to the conformational changes required for dissociation of the DNA. Nonetheless, MosR presents two crystallographically resolved conformations in its reduced state: bound and unbound to DNA. We managed to simulate MosR unbound to the DNA, both in the presence and in the absence of the disulphide bond. Our results indicate that this disulphide bond precludes the N-terminal residues from adopting a conformation that stands in-between the helix α1 and the DNA binding domain (DBD) from the other chain. Once this conformation is achieved in the reduced state, this DBD detaches from the dimerization domain and becomes more flexible, being able to perform motions with higher amplitude and higher degree of collectivity. Only then, MosR may achieve a conformation where its recognition helices fit into the major grooves of its DNA site. The analysis of the collective motions performed by MosR, during the different situations sampled by the molecular dynamics (MDs), was only possible by the method of filtering harmonic modes with specific frequencies. The frequency of the collective motions performed by the DBD of MosR in the reduced state to achieve a DNA-binding conformation is in the range of 20 to 50 MHz, but it may be associated to more sporadic events since it requires the combination of a suitable conformation of the N-terminal residues. PMID:29470546

Quantified Gamow shell model interaction for p s d -shell nuclei

NASA Astrophysics Data System (ADS)

Jaganathen, Y.; Betan, R. M. Id; Michel, N.; Nazarewicz, W.; Płoszajczak, M.

2017-11-01

Background: The structure of weakly bound and unbound nuclei close to particle drip lines is one of the major science drivers of nuclear physics. A comprehensive understanding of these systems goes beyond the traditional configuration interaction approach formulated in the Hilbert space of localized states (nuclear shell model) and requires an open quantum system description. The complex-energy Gamow shell model (GSM) provides such a framework as it is capable of describing resonant and nonresonant many-body states on equal footing. Purpose: To make reliable predictions, quality input is needed that allows for the full uncertainty quantification of theoretical results. In this study, we carry out the optimization of an effective GSM (one-body and two-body) interaction in the p s d f -shell-model space. The resulting interaction is expected to describe nuclei with 5 ≤A ≲12 at the p -s d -shell interface. Method: The one-body potential of the 4He core is modeled by a Woods-Saxon + spin-orbit + Coulomb potential, and the finite-range nucleon-nucleon interaction between the valence nucleons consists of central, spin-orbit, tensor, and Coulomb terms. The GSM is used to compute key fit observables. The χ2 optimization is performed using the Gauss-Newton algorithm augmented by the singular value decomposition technique. The resulting covariance matrix enables quantification of statistical errors within the linear regression approach. Results: The optimized one-body potential reproduces nucleon-4He scattering phase shifts up to an excitation energy of 20 MeV. The two-body interaction built on top of the optimized one-body field is adjusted to the bound and unbound ground-state binding energies and selected excited states of the helium, lithium, and beryllium isotopes up to A =9 . A very good agreement with experimental results was obtained for binding energies. First applications of the optimized interaction include predictions for two-nucleon correlation densities and excitation spectra of light nuclei with quantified uncertainties. Conclusion: The new interaction will enable comprehensive and fully quantified studies of structure and reactions aspects of nuclei from the p s d region of the nuclear chart.

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

Jaganathen, Y.; Betan, R. M. Id; Michel, N.

Background: The structure of weakly bound and unbound nuclei close to particle drip lines is one of the major science drivers of nuclear physics. A comprehensive understanding of these systems goes beyond the traditional configuration interaction approach formulated in the Hilbert space of localized states (nuclear shell model) and requires an open quantum system description. The complex-energy Gamow shell model (GSM) provides such a framework as it is capable of describing resonant and nonresonant many-body states on equal footing. Purpose: To make reliable predictions, quality input is needed that allows for the full uncertainty quantification of theoretical results. In thismore » study, we carry out the optimization of an effective GSM (one-body and two-body) interaction in the psdf-shell-model space. The resulting interaction is expected to describe nuclei with 5 ≤ A ≲ 12 at the p-sd-shell interface. Method: The one-body potential of the 4He core is modeled by a Woods-Saxon + spin-orbit + Coulomb potential, and the finite-range nucleon-nucleon interaction between the valence nucleons consists of central, spin-orbit, tensor, and Coulomb terms. The GSM is used to compute key fit observables. The χ 2 optimization is performed using the Gauss-Newton algorithm augmented by the singular value decomposition technique. The resulting covariance matrix enables quantification of statistical errors within the linear regression approach. Results: The optimized one-body potential reproduces nucleon- 4He scattering phase shifts up to an excitation energy of 20 MeV. The two-body interaction built on top of the optimized one-body field is adjusted to the bound and unbound ground-state binding energies and selected excited states of the helium, lithium, and beryllium isotopes up to A = 9 . A very good agreement with experimental results was obtained for binding energies. First applications of the optimized interaction include predictions for two-nucleon correlation densities and excitation spectra of light nuclei with quantified uncertainties. In conclusion: The new interaction will enable comprehensive and fully quantified studies of structure and reactions aspects of nuclei from the psd region of the nuclear chart.« less

Computer simulations reveal changes in the conformational space of the transcriptional regulator MosR upon the formation of a disulphide bond and in the collective motions that regulate its DNA-binding affinity.

PubMed

Câmara, Amanda Souza; Horjales, Eduardo

2018-01-01

M. tuberculosis oxidation sense Regulator (MosR) is a transcriptional regulator from Mycobacterium tuberculosis. It senses the environment oxidation and regulates the expression of a secreted oxidoreductase, thus defending the bacilli against oxidative stress from the phagosome. While most of the members of the Multiple antibiotics resistance Regulator (MarR) family are ligand-responsive, MosR may dissociate from its DNA site upon formation of an intrachain disulphide bond. However, the structure of MosR in its oxidized state is not known, and it is not clear how the formation of this disulphide bond would lead to the conformational changes required for dissociation of the DNA. Nonetheless, MosR presents two crystallographically resolved conformations in its reduced state: bound and unbound to DNA. We managed to simulate MosR unbound to the DNA, both in the presence and in the absence of the disulphide bond. Our results indicate that this disulphide bond precludes the N-terminal residues from adopting a conformation that stands in-between the helix α1 and the DNA binding domain (DBD) from the other chain. Once this conformation is achieved in the reduced state, this DBD detaches from the dimerization domain and becomes more flexible, being able to perform motions with higher amplitude and higher degree of collectivity. Only then, MosR may achieve a conformation where its recognition helices fit into the major grooves of its DNA site. The analysis of the collective motions performed by MosR, during the different situations sampled by the molecular dynamics (MDs), was only possible by the method of filtering harmonic modes with specific frequencies. The frequency of the collective motions performed by the DBD of MosR in the reduced state to achieve a DNA-binding conformation is in the range of 20 to 50 MHz, but it may be associated to more sporadic events since it requires the combination of a suitable conformation of the N-terminal residues.

Quantified Gamow shell model interaction for p s d -shell nuclei

DOE PAGES

Jaganathen, Y.; Betan, R. M. Id; Michel, N.; ...

2017-11-20

Background: The structure of weakly bound and unbound nuclei close to particle drip lines is one of the major science drivers of nuclear physics. A comprehensive understanding of these systems goes beyond the traditional configuration interaction approach formulated in the Hilbert space of localized states (nuclear shell model) and requires an open quantum system description. The complex-energy Gamow shell model (GSM) provides such a framework as it is capable of describing resonant and nonresonant many-body states on equal footing. Purpose: To make reliable predictions, quality input is needed that allows for the full uncertainty quantification of theoretical results. In thismore » study, we carry out the optimization of an effective GSM (one-body and two-body) interaction in the psdf-shell-model space. The resulting interaction is expected to describe nuclei with 5 ≤ A ≲ 12 at the p-sd-shell interface. Method: The one-body potential of the 4He core is modeled by a Woods-Saxon + spin-orbit + Coulomb potential, and the finite-range nucleon-nucleon interaction between the valence nucleons consists of central, spin-orbit, tensor, and Coulomb terms. The GSM is used to compute key fit observables. The χ 2 optimization is performed using the Gauss-Newton algorithm augmented by the singular value decomposition technique. The resulting covariance matrix enables quantification of statistical errors within the linear regression approach. Results: The optimized one-body potential reproduces nucleon- 4He scattering phase shifts up to an excitation energy of 20 MeV. The two-body interaction built on top of the optimized one-body field is adjusted to the bound and unbound ground-state binding energies and selected excited states of the helium, lithium, and beryllium isotopes up to A = 9 . A very good agreement with experimental results was obtained for binding energies. First applications of the optimized interaction include predictions for two-nucleon correlation densities and excitation spectra of light nuclei with quantified uncertainties. In conclusion: The new interaction will enable comprehensive and fully quantified studies of structure and reactions aspects of nuclei from the psd region of the nuclear chart.« less

Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins.

PubMed

Loos, Walter J; Baker, Sharyn D; Verweij, Jaap; Boonstra, Joke G; Sparreboom, Alex

2003-10-01

Our objectives were to study the extent of docetaxel binding to plasma in the presence and absence of its excipient, polysorbate 80 (Tween 80; Imperial Chemical Industries PLC, London, United Kingdom), in vitro and to evaluate the pharmacokinetics of unbound docetaxel in vivo. Equilibrium dialysis was used for determination of the fraction unbound (f(u)) docetaxel and was applied to study the pharmacokinetic behavior of unbound docetaxel in 23 patients with cancer receiving an intravenous infusion of the drug formulated in polysorbate 80 (Taxotere; Aventis Pharma SA, Vitry-sur-Seine Cedex, France). Polysorbate 80, added at clinically relevant concentrations (up to 1.0 microL/mL), increased f(u) in vitro by 13% (7.84% +/- 0.0752% versus 6.95% +/- 0.0678%, P <.00001). Similarly, f(u) calculated on the basis of the observed area under the plasma concentration-time curve (AUC) values [f(u)(AUC)] in vivo was 12% higher than f(u) in pretreatment samples [f(u)(pre)] (6.00% +/- 1.03% versus 5.49% +/- 1.01%, P =.038). Of various serum proteins evaluated, only alpha(1)-acid glycoprotein was significantly related to f(u) (P <.0018), with higher f(u) in the presence of lower protein levels. Total docetaxel clearance was related to alpha(1)-acid glycoprotein (R(2) = 0.13, P =.058), f(u)(pre) (R(2) = 0.15, P =.039), and f(u)(AUC) (R(2) = 0.29, P =.0048). This study demonstrates that the plasma binding of docetaxel is influenced by both alpha(1)-acid glycoprotein and its formulation vehicle. Further investigation is required to resolve the potential clinical significance of these observations.

Effects of Soybean Lipid Infusion on Unbound Free Fatty Acids and Unbound Bilirubin in Preterm Infants.

PubMed

Hegyi, Thomas; Kleinfeld, Alan; Huber, Andrew; Weinberger, Barry; Memon, Naureen; Shih, Weichung Joe; Carayannopoulos, Mary; Oh, William

2017-05-01

To assess the effects of a soybean lipid emulsion infusions on levels of unbound (free) bilirubin (Bf) and unbound free fatty acids (FFAu) as well as changes in Bf and total serum bilirubin (TSB) during phototherapy in infants born preterm. Ninety-seven infants born preterm (birth weight: 500-2000 g; gestational age: 23-34 weeks) were enrolled to investigate the effect of 0, 1, 2, and 3 g/kg/d of intralipid infusion on Bf and FFAu. Pre- and postphototherapy TSB, FFAu, and Bf also were analyzed in 91 infants to assess the effects of phototherapy. FFAu levels were measured with the fluorescent probe ADIFAB2 and Bf by the fluorescent Bf sensor BL22P1B11-Rh during intralipid infusion and at start and end of phototherapy. TSB and plasma albumin were measured by the diazo and bromcresol green techniques, respectively. Bilirubin-albumin dissociation constants were calculated based on Bf and plasma albumin. Bf and FFAu increased with increasing intralipid dosage across all gestational ages. TSB and Bf were correlated significantly when infants received 0 or 1 g/kg/d of intralipid but not at greater doses of intralipid (2 and 3 g/kg/d). Although phototherapy effectively reduced both TSB and Bf in the total phototherapy group (by 32% and 12%, respectively), it reduced TSB, but not Bf, in infants less than 28 weeks of gestation. Increasing intralipid doses result in increasing FFAu levels, which are associated with increased Bf independent of TSB. In infants born extremely preterm (<28 weeks of gestation), phototherapy effectively reduces TSB but not Bf. Copyright © 2016 Elsevier Inc. All rights reserved.

Posaconazole in Human Serum: a Greater Pharmacodynamic Effect than Predicted by the Non-Protein-Bound Serum Concentration ▿

PubMed Central

Lignell, Anders; Löwdin, Elisabeth; Cars, Otto; Chryssanthou, Erja; Sjölin, Jan

2011-01-01

It is generally accepted that only the unbound fraction of a drug is pharmacologically active. Posaconazole is an antifungal agent with a protein binding of 98 to 99%. Taking into account the degree of protein binding, plasma levels in patients, and MIC levels of susceptible strains, it can be assumed that the free concentration of posaconazole sometimes will be too low to exert the expected antifungal effect. The aim was therefore to test the activity of posaconazole in serum in comparison with that of the calculated unbound concentrations in protein-free media. Significant differences (P < 0.05) from the serum control were found at serum concentrations of posaconazole of 1.0 and 0.10 mg/liter, with calculated free concentrations corresponding to 1× MIC and 0.1× MIC, respectively, against one Candida lusitaniae strain selected for proof of principle. In RPMI 1640, the corresponding calculated unbound concentration of 0.015 mg/liter resulted in a significant effect, whereas that of 0.0015 mg/liter did not. Also, against seven additional Candida strains tested, there was an effect of the low posaconazole concentration in serum, in contrast to the results in RPMI 1640. Fluconazole, a low-grade-protein-bound antifungal, was used for comparison at corresponding concentrations in serum and RPMI 1640. No effect was observed at the serum concentration, resulting in a calculated unbound concentration of 0.1× MIC. In summary, there was a substantially greater pharmacodynamic effect of posaconazole in human serum than could be predicted by the non-protein-bound serum concentration. A flux from serum protein-bound to fungal lanosterol 14α-demethylase-bound posaconazole is suggested. PMID:21502622

Physical basis of destruction of concrete and other building materials

NASA Astrophysics Data System (ADS)

Suleymanova, L. A.; Pogorelova, I. A.; Kirilenko, S. V.; Suleymanov, K. A.

2018-03-01

In the article the scientifically-grounded views of authors on the physical essence of destruction process of concrete and other materials are stated; it is shown that the mechanism of destruction of materials is similar in its essence during the mechanical, thermal, physical-chemical and combined influences, and that in its basis Newton's third law lays. In all cases destruction consists in decompaction of structures, loosening of the internal bonds in materials, in the further integrity damage and their division into separate loosely-bound (full destruction) and unbound with each other (incomplete destruction) elements, which depends on the kind of external influence and perfection of materials structure.

Black hole field theory with a firewall in two spacetime dimensions

NASA Astrophysics Data System (ADS)

Ho, C. T. Marco; Su, Daiqin; Mann, Robert B.; Ralph, Timothy C.

2016-10-01

We propose that the vacuum state of a scalar field around a black hole is a modified Unruh vacuum. In (1 +1 ) dimensions, we show that a free-faller close to such an horizon can be modeled as an inertial observer in a modified Minkowski vacuum. The modification allows for information-leaking correlations at high frequencies. Using a Gaussian detector centered at k0, we find that the expectation value of the number operator for a detector crossing the horizon is proportional to 1 /|k0|, implying that the free-faller will observe unbounded numbers of high-energy photons, i.e. a firewall.

Why Clothes Don't Fall Apart: Tension Transmission in Staple Yarns

NASA Astrophysics Data System (ADS)

Warren, Patrick B.; Ball, Robin C.; Goldstein, Raymond E.

2018-04-01

The problem of how staple yarns transmit tension is addressed within abstract models in which the Amontons-Coulomb friction laws yield a linear programing (LP) problem for the tensions in the fiber elements. We find there is a percolation transition such that above the percolation threshold the transmitted tension is in principle unbounded. We determine that the mean slack in the LP constraints is a suitable order parameter to characterize this supercritical state. We argue the mechanism is generic, and in practical terms, it corresponds to a switch from a ductile to a brittle failure mode accompanied by a significant increase in mechanical strength.

Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters.

PubMed

Yahata, Masahiro; Chiba, Koji; Watanabe, Takao; Sugiyama, Yuichi

2017-09-01

Accurate prediction of target occupancy facilitates central nervous system drug development. In this review, we discuss the predictability of serotonin transporter (SERT) occupancy in human brain estimated from in vitro K i values for human SERT and plasma concentrations of unbound drug (C u,plasma ), as well as the impact of drug transporters in the blood-brain barrier. First, the geometric means of in vitro K i values were compared with the means of in vivo K i values (K i,u,plasma ) which were calculated as C u,plasma values at 50% occupancy of SERT obtained from previous clinical positron emission tomography/single photon emission computed tomography imaging studies for 6 selective serotonin transporter reuptake inhibitors and 3 serotonin norepinephrine reuptake inhibitors. The in vitro K i values for 7 drugs were comparable to their in vivo K i,u,plasma values within 3-fold difference. SERT occupancy was overestimated for 5 drugs (P-glycoprotein substrates) and underestimated for 2 drugs (presumably uptake transporter substrates, although no evidence exists as yet). In conclusion, prediction of human SERT occupancy from in vitro K i values and C u,plasma was successful for drugs that are not transporter substrates and will become possible in future even for transporter substrates, once the transporter activities will be accurately estimated from in vitro experiments. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma.

PubMed

Laramy, Janice K; Kim, Minjee; Gupta, Shiv K; Parrish, Karen E; Zhang, Shuangling; Bakken, Katrina K; Carlson, Brett L; Mladek, Ann C; Ma, Daniel J; Sarkaria, Jann N; Elmquist, William F

2017-11-01

This study investigated how differences in drug distribution and free fraction at different tumor and tissue sites influence the efficacy of the multikinase inhibitor ponatinib in a patient-derived xenograft model of glioblastoma (GBM). Efficacy studies in GBM6 flank (heterotopic) and intracranial (orthotopic) models showed that ponatinib is effective in the flank but not in the intracranial model, despite a relatively high brain-to-plasma ratio. In vitro binding studies indicated that flank tumor had a higher free (unbound) drug fraction than normal brain. The total and free drug concentrations, along with the tissue-to-plasma ratio (Kp) and its unbound derivative (Kp,uu), were consistently higher in the flank tumor than the normal brain at 1 and 6 hours after a single dose in GBM6 flank xenografts. In the orthotopic xenografts, the intracranial tumor core displayed higher Kp and Kp,uu values compared with the brain-around-tumor (BAT). The free fractions and the total drug concentrations, hence free drug concentrations, were consistently higher in the core than in the BAT at 1 and 6 hours postdose. The delivery disadvantages in the brain and BAT were further evidenced by the low total drug concentrations in these areas that did not consistently exceed the in vitro cytotoxic concentration (IC 50 ). Taken together, the regional differences in free drug exposure across the intracranial tumor may be responsible for compromising efficacy of ponatinib in orthotopic GBM6. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

The Hierarchical Distribution of the Young Stellar Clusters in Six Local Star-forming Galaxies

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

Grasha, K.; Calzetti, D.; Adamo, A.

We present a study of the hierarchical clustering of the young stellar clusters in six local (3–15 Mpc) star-forming galaxies using Hubble Space Telescope broadband WFC3/UVIS UV and optical images from the Treasury Program LEGUS (Legacy ExtraGalactic UV Survey). We identified 3685 likely clusters and associations, each visually classified by their morphology, and we use the angular two-point correlation function to study the clustering of these stellar systems. We find that the spatial distribution of the young clusters and associations are clustered with respect to each other, forming large, unbound hierarchical star-forming complexes that are in general very young. Themore » strength of the clustering decreases with increasing age of the star clusters and stellar associations, becoming more homogeneously distributed after ∼40–60 Myr and on scales larger than a few hundred parsecs. In all galaxies, the associations exhibit a global behavior that is distinct and more strongly correlated from compact clusters. Thus, populations of clusters are more evolved than associations in terms of their spatial distribution, traveling significantly from their birth site within a few tens of Myr, whereas associations show evidence of disruption occurring very quickly after their formation. The clustering of the stellar systems resembles that of a turbulent interstellar medium that drives the star formation process, correlating the components in unbound star-forming complexes in a hierarchical manner, dispersing shortly after formation, suggestive of a single, continuous mode of star formation across all galaxies.« less

A Kinetic Study of Accumulation and Elimination of Microcystin-LR in Yellow Perch (Perca Flavescens) Tissue and Implications for Human Fish Consumption

PubMed Central

Dyble, Julianne; Gossiaux, Duane; Landrum, Peter; Kashian, Donna R.; Pothoven, Steven

2011-01-01

Fish consumption is a potential route of human exposure to the hepatotoxic microcystins, especially in lakes and reservoirs that routinely experience significant toxic Microcystis blooms. Understanding the rates of uptake and elimination for microcystins as well as the transfer efficiency into tissues of consumers are important for determining the potential for microcystins to be transferred up the food web and for predicting potential human health impacts. The main objective of this work was to conduct laboratory experiments to investigate the kinetics of toxin accumulation in fish tissue. An oral route of exposure was employed in this study, in which juvenile yellow perch (Perca flavescens) were given a single oral dose of 5 or 20 μg of microcystin-LR (MC-LR) via food and accumulation in the muscle, liver, and tank water were measured over 24 h. Peak concentrations of the water soluble fraction of microcystin were generally observed 8–10 h after dosing in the liver and after 12–16 h in the muscle, with a rapid decline in both tissues by 24 h. Up to 99% of the total recoverable (i.e., unbound) microcystin was measured in the tank water by 16 h after exposure. The relatively rapid uptake and elimination of the unbound fraction of microcystin in the liver and muscle of juvenile yellow perch within 24 h of exposure indicates that fish consumption may not be a major route of human exposure to microcystin, particularly in the Great Lakes. PMID:22363240

Accurate artificial boundary conditions for the semi-discretized linear Schrödinger and heat equations on rectangular domains

NASA Astrophysics Data System (ADS)

Ji, Songsong; Yang, Yibo; Pang, Gang; Antoine, Xavier

2018-01-01

The aim of this paper is to design some accurate artificial boundary conditions for the semi-discretized linear Schrödinger and heat equations in rectangular domains. The Laplace transform in time and discrete Fourier transform in space are applied to get Green's functions of the semi-discretized equations in unbounded domains with single-source. An algorithm is given to compute these Green's functions accurately through some recurrence relations. Furthermore, the finite-difference method is used to discretize the reduced problem with accurate boundary conditions. Numerical simulations are presented to illustrate the accuracy of our method in the case of the linear Schrödinger and heat equations. It is shown that the reflection at the corners is correctly eliminated.

Numerical simulation of high Reynolds number bubble motion

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

McLaughlin, J.B.

This paper presents the results of numerical simulations of bubble motion. All the results are for single bubbles in unbounded fluids. The liquid phase is quiescent except for the motion created by the bubble, which is axisymmetric. The main focus of the paper is on bubbles that are of order 1 mm in diameter in water. Of particular interest is the effect of surfactant molecules on bubble motion. Results for the {open_quotes}insoluble surfactant{close_quotes} model will be presented. These results extend research by other investigators to finite Reynolds numbers. The results indicate that, by assuming complete coverage of the bubble surface,more » one obtains good agreement with experimental observations of bubble motion in tap water. The effect of surfactant concentration on the separation angle is discussed.« less

Dynamical analysis of an n‑H‑T cosmological quintessence real gas model with a general equation of state

NASA Astrophysics Data System (ADS)

Ivanov, Rossen I.; Prodanov, Emil M.

2018-01-01

The cosmological dynamics of a quintessence model based on real gas with general equation of state is presented within the framework of a three-dimensional dynamical system describing the time evolution of the number density, the Hubble parameter and the temperature. Two global first integrals are found and examples for gas with virial expansion and van der Waals gas are presented. The van der Waals system is completely integrable. In addition to the unbounded trajectories, stemming from the presence of the conserved quantities, stable periodic solutions (closed orbits) also exist under certain conditions and these represent models of a cyclic Universe. The cyclic solutions exhibit regions characterized by inflation and deflation, while the open trajectories are characterized by inflation in a “fly-by” near an unstable critical point.

Optimal discrete-time LQR problems for parabolic systems with unbounded input: Approximation and convergence

NASA Technical Reports Server (NTRS)

Rosen, I. G.

1988-01-01

An abstract approximation and convergence theory for the closed-loop solution of discrete-time linear-quadratic regulator problems for parabolic systems with unbounded input is developed. Under relatively mild stabilizability and detectability assumptions, functional analytic, operator techniques are used to demonstrate the norm convergence of Galerkin-based approximations to the optimal feedback control gains. The application of the general theory to a class of abstract boundary control systems is considered. Two examples, one involving the Neumann boundary control of a one-dimensional heat equation, and the other, the vibration control of a cantilevered viscoelastic beam via shear input at the free end, are discussed.

On local strong solutions to the three-dimensional nonhomogeneous incompressible magnetohydrodynamic equations with density-dependent viscosity and vacuum

NASA Astrophysics Data System (ADS)

Song, Sisi

2018-04-01

This paper concerns the three-dimensional nonhomogeneous incompressible magnetohydrodynamic equations with density-dependent viscosity and vacuum on Ω \\subset R^3. The domain Ω \\subset R^3 is a general connected smooth one, either bounded or unbounded. In particular, the initial density can have compact support when Ω is unbounded. First, we obtain the local existence and uniqueness of strong solution to the three-dimensional nonhomogeneous incompressible magnetohydrodynamic equations without any compatibility condition assumed on the initial data. Then, we also prove the continuous dependence of strong solution on the initial data under an additional compatibility condition.

Optimal fixed-finite-dimensional compensator for Burgers' equation with unbounded input/output operators

NASA Technical Reports Server (NTRS)

Burns, John A.; Marrekchi, Hamadi

1993-01-01

The problem of using reduced order dynamic compensators to control a class of nonlinear parabolic distributed parameter systems was considered. Concentration was on a system with unbounded input and output operators governed by Burgers' equation. A linearized model was used to compute low-order-finite-dimensional control laws by minimizing certain energy functionals. Then these laws were applied to the nonlinear model. Standard approaches to this problem employ model/controller reduction techniques in conjunction with linear quadratic Gaussian (LQG) theory. The approach used is based on the finite dimensional Bernstein/Hyland optimal projection theory which yields a fixed-finite-order controller.

Use of recycled aggregates from construction and demolition waste in geotechnical applications: A literature review.

PubMed

Cardoso, Rafaela; Silva, Rui Vasco; Brito, Jorge de; Dhir, Ravindra

2016-03-01

The use of recycled aggregates (RA) in construction constitutes a significant step towards a more sustainable society and also creates a new market opportunity to be exploited. In recent years, several case-studies have emerged in which RA were used in Geotechnical applications, such as filling materials and in unbound pavement layers. This paper presents a review of the most important physical properties of different types of RA and their comparison with natural aggregates (NA), and how these properties affect their hydraulic and mechanical behaviour when compacted. Specifically, the effects of compaction on grading size distribution curves and density are analysed, as well as the consequences of particle crushing on the resilient modulus, CBR and permeability. The paper also contains an analysis of the influence of incorporating different RA types on the performance of unbound road pavement layers as compared with those built with NA by means of the International Roughness Index and deflection values. The results collected from the literature indicate that the performance of most RA is comparable to that of NA and can be used in unbound pavement layers or in other applications requiring compaction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of fat content and homogenization under conventional or ultra-high-pressure conditions on interactions between proteins in rennet curds.

PubMed

Zamora, A; Trujillo, A J; Armaforte, E; Waldron, D S; Kelly, A L

2012-09-01

The objective of this study was to investigate the influence of conventional and ultra-high-pressure homogenization on interactions between proteins within drained rennet curds. The effect of fat content of milk (0.0, 1.8, or 3.6%) and homogenization treatment on dissociation of proteins by different chemical agents was thus studied. Increasing the fat content of raw milk increased levels of unbound whey proteins and calcium-bonded caseins in curds; in contrast, hydrophobic interactions and hydrogen bonds were inhibited. Both homogenization treatments triggered the incorporation of unbound whey proteins in the curd, and of caseins through ionic bonds involving calcium salts. Conventional homogenization-pasteurization enhanced interactions between caseins through hydrogen bonds and hydrophobic interactions. In contrast, ultra-high-pressure homogenization impaired hydrogen bonding, led to the incorporation of both whey proteins and caseins through hydrophobic interactions and increased the amount of unbound caseins. Thus, both homogenization treatments provoked changes in the protein interactions within rennet curds; however, the nature of the changes depended on the homogenization conditions. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Interpreting Tacrolimus Concentrations During Pregnancy and Postpartum

PubMed Central

Hebert, Mary F.; Zheng, Songmao; Hays, Karen; Shen, Danny D.; Davis, Connie L.; Umans, Jason G.; Miodovnik, Menachem; Thummel, Kenneth E.; Easterling, Thomas R.

2012-01-01

Summary Pregnancy following solid organ transplantation, although considered high risk for maternal, fetal and neonatal complications, has been quite successful. Tacrolimus pharmacokinetic changes during pregnancy make interpretation of whole blood trough concentrations particularly challenging. There are multiple factors that can increase the fraction of unbound tacrolimus, including but not limited to low albumin concentration and low RBC count. The clinical titration of dosage to maintain whole blood tacrolimus trough concentrations in the usual therapeutic range can lead to elevated unbound concentrations and possibly toxicity in pregnant women with anemia and hypoalbuminemia. Measurement of plasma or unbound tacrolimus concentrations for pregnant women might better reflect the active form of the drug, though these are technically-challenging and often unavailable in usual clinical practice. Tacrolimus crosses the placenta with in utero exposure being approximately 71% of maternal blood concentrations. The lower fetal blood concentrations are likely due to active efflux transport of tacrolimus from the fetus toward the mother by placental P-glycoprotein. To date, tacrolimus has not been linked to congenital malformations, but can cause reversible nephrotoxicity and hyperkalemia in the newborn. In contrast, very small amounts of tacrolimus are excreted in the breast milk and are unlikely to elicit adverse effects in the nursing infant. PMID:23274970

Unbound or distant planetary mass population detected by gravitational microlensing.

PubMed

2011-05-19

Since 1995, more than 500 exoplanets have been detected using different techniques, of which 12 were detected with gravitational microlensing. Most of these are gravitationally bound to their host stars. There is some evidence of free-floating planetary-mass objects in young star-forming regions, but these objects are limited to massive objects of 3 to 15 Jupiter masses with large uncertainties in photometric mass estimates and their abundance. Here, we report the discovery of a population of unbound or distant Jupiter-mass objects, which are almost twice (1.8(+1.7)(-0.8)) as common as main-sequence stars, based on two years of gravitational microlensing survey observations towards the Galactic Bulge. These planetary-mass objects have no host stars that can be detected within about ten astronomical units by gravitational microlensing. However, a comparison with constraints from direct imaging suggests that most of these planetary-mass objects are not bound to any host star. An abrupt change in the mass function at about one Jupiter mass favours the idea that their formation process is different from that of stars and brown dwarfs. They may have formed in proto-planetary disks and subsequently scattered into unbound or very distant orbits.

Thermodynamics and folding pathway of tetraloop receptor-mediated RNA helical packing

PubMed Central

Vander Meulen, Kirk A.; Davis, Jared H.; Foster, Trenton R.; Record, M. Thomas; Butcher, Samuel E.

2008-01-01

Summary Little is known about the thermodynamic forces that drive the folding pathways of higher order RNA structure. In this study, we employ calorimetric (ITC and DSC) and spectroscopic (NMR and UV) methods to characterize the thermodynamics of the GAAA tetraloop – receptor interaction, utilizing a previously described bivalent construct. ITC studies indicate that the bivalent interaction is enthalpy-driven and highly stable, with a binding constant (Kobs) of 5.5 × 106 M−1 and enthalpy (ΔHobs°) of −33.8 kcal/mol at 45°C in 20 mM KCl and 2 mM MgCl2. Thus we derive the ΔHobs° for a single tetraloop-receptor interaction to be −16.9 kcal/mol at these conditions. UV absorbance data indicate that an increase in base stacking quality contributes to the enthalpy of complex formation. These highly favorable thermodynamics are consistent with the known critical role for the tetraloop-receptor motif in the folding of large RNAs. Additionally, a significant heat capacity change (ΔCp,obs°) of −0.24 kcal·mol−1·K−1 was determined by ITC. DSC and UV monitored thermal denaturation experiments indicate that the bivalent tetraloop-receptor construct follows a minimally 5–state unfolding pathway, and suggest the observed ΔCp,obs° for the interaction results from a temperature-dependent unbound receptor RNA structure. PMID:18845162

Regulation of landslide motion by dilatancy and pore pressure feedback

USGS Publications Warehouse

Iverson, R.M.

2005-01-01

A new mathematical model clarifies how diverse styles and rates of landslide motion can result from regulation of Coulomb friction by dilation or contraction of water-saturated basal shear zones. Normalization of the model equations shows that feedback due to coupling between landslide motion, shear zone volume change, and pore pressure change depends on a single dimensionless parameter ??, which, in turn, depends on the dilatancy angle ?? and the intrinsic timescales for pore pressure generation and dissipation. If shear zone soil contracts during slope failure, then ?? 0, and negative feedback permits slow, steady landslide motion to occur while positive pore pressure is supplied by rain infiltration. Steady state slip velocities v0 obey v0 = -(K/??) p*e, where K is the hydraulic conductivity and p*e is the normalized (dimensionless) negative pore pressure generated by dilation. If rain infiltration and attendant pore pressure growth continue unabated, however, their influence ultimately overwhelms the stabilizing influence of negative p*e. Then, unbounded landslide acceleration occurs, accentuated by an instability that develops if ?? diminishes as landslide motion proceeds. Nonetheless, numerical solutions of the model equations show that slow, nearly steady motion of a clay-rich landslide may persist for many months as a result of negative pore pressure feedback that regulates basal Coulomb friction. Similarly stabilized motion is less likely to occur in sand-rich landslides that are characterized by weaker negative feedback.

Evolutionary Pathways for Asteroid Satellites

NASA Astrophysics Data System (ADS)

Jacobson, Seth Andrew

2015-08-01

The YORP-induced rotational fission hypothesis is a proposed mechanism for the creation of small asteroid binaries, which make up approximately 1/6-th of the near-Earth asteroid and small Main Belt asteroid populations. The YORP effect is a radiative torque that rotationally accelerates asteroids on timescales of thousands to millions of years. As asteroids rotationally accelerate, centrifugal accelerations on material within the body can match gravitational accelerations holding that material in place. When this occurs, that material goes into orbit. Once in orbit that material coalesces into a companion that undergoes continued dynamical evolution.Observations with radar, photometric and direct imaging techniques reveal a diverse array of small asteroid satellites. These systems can be sorted into a number of morphologies according to size, multiplicity of members, dynamical orbit and spin states, and member shapes. For instance, singly synchronous binaries have short separation distances between the two members, rapidly rotating oblate primary members, and tidally locked prolate secondary members. Other confirmed binary morphologies include doubly synchronous, tight asynchronous and wide asynchronous binaries. Related to these binary morphologies are unbound paired asteroid systems and bi-lobate contact binaries.A critical test for the YORP-induced rotational fission hypothesis is whether the binary asteroids produced evolve to the observed binary and related systems. In this talk I will review how this evolution is believed to occur according to gravitational dynamics, mutual body tides and the binary YORP effect.

Time of flight spectrometer for background-free positron annihilation induced Auger electron spectroscopy

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

Mukherjee, S.; Shastry, K.; Anto, C. V.

2016-03-15

We describe a novel spectrometer designed for positron annihilation induced Auger electron spectroscopy employing a time-of-flight spectrometer. The spectrometer’s new configuration enables us to implant monoenergetic positrons with kinetic energies as low as 1.5 eV on the sample while simultaneously allowing for the detection of electrons emitted from the sample surface at kinetic energies ranging from ∼500 eV to 0 eV. The spectrometer’s unique characteristics made it possible to perform (a) first experiments demonstrating the direct transition of a positron from an unbound scattering state to a bound surface state and (b) the first experiments demonstrating that Auger electron spectramore » can be obtained down to 0 eV without the beam induced secondary electron background obscuring the low energy part of the spectra. Data are presented which show alternative means of estimating positron surface state binding energy and background-free Auger spectra.« less

Ultrafast terahertz snapshots of excitonic Rydberg states and electronic coherence in an organometal halide perovskite

DOE PAGES

Luo, Liang; Men, Long; Liu, Zhaoyu; ...

2017-06-01

How photoexcitations evolve into Coulomb-bound electron and hole pairs, called excitons, and unbound charge carriers is a key cross-cutting issue in photovoltaics and optoelectronics. Until now, the initial quantum dynamics following photoexcitation remains elusive in the hybrid perovskite system. Furthermore we reveal excitonic Rydberg states with distinct formation pathways by observing the multiple resonant, internal quantum transitions using ultrafast terahertz quasi-particle transport. Nonequilibrium emergent states evolve with a complex co-existence of excitons, carriers and phonons, where a delayed buildup of excitons under on- and off-resonant pumping conditions allows us to distinguish between the loss of electronic coherence and hot statemore » cooling processes. The nearly ~1 ps dephasing time, efficient electron scattering with discrete terahertz phonons and intermediate binding energy of ~13.5 meV in perovskites are distinct from conventional photovoltaic semiconductors. In addition to providing implications for coherent energy conversion, these are potentially relevant to the development of light-harvesting and electron-transport devices.« less

Measurement of key resonances for the 24Al(p ,γ )25Si reaction rate using in-beam γ -ray spectroscopy

NASA Astrophysics Data System (ADS)

Longfellow, B.; Gade, A.; Brown, B. A.; Richter, W. A.; Bazin, D.; Bender, P. C.; Bowry, M.; Elman, B.; Lunderberg, E.; Weisshaar, D.; Williams, S. J.

2018-05-01

Energy levels and branching ratios for the rp-process nucleus 25Si were determined from the reactions 9Be(26Si,25Si)X and 9Be(25Al,25Si)X using in-beam γ -ray spectroscopy with both high-efficiency and high-resolution detector arrays. Proton-unbound states at 3695(14) and 3802(11) keV were identified and assigned tentative spins and parities based on comparison to theory and the mirror nucleus. The 24Al(p ,γ )25Si reaction rate was calculated using the experimental states and states from charge-dependent USDA and USDB shell-model calculations with downward shifts of the 1 s1 /2 proton orbital to account for the observed Thomas-Ehrman shift, leading to a factor of 10-100 increase in rate for the temperature region of 0.22 GK as compared to a previous calculation. These shifts may be applicable to neighboring nuclei, impacting the proton capture rates in this region of the chart.

Ultrafast terahertz snapshots of excitonic Rydberg states and electronic coherence in an organometal halide perovskite

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

Luo, Liang; Men, Long; Liu, Zhaoyu

How photoexcitations evolve into Coulomb-bound electron and hole pairs, called excitons, and unbound charge carriers is a key cross-cutting issue in photovoltaics and optoelectronics. Until now, the initial quantum dynamics following photoexcitation remains elusive in the hybrid perovskite system. Furthermore we reveal excitonic Rydberg states with distinct formation pathways by observing the multiple resonant, internal quantum transitions using ultrafast terahertz quasi-particle transport. Nonequilibrium emergent states evolve with a complex co-existence of excitons, carriers and phonons, where a delayed buildup of excitons under on- and off-resonant pumping conditions allows us to distinguish between the loss of electronic coherence and hot statemore » cooling processes. The nearly ~1 ps dephasing time, efficient electron scattering with discrete terahertz phonons and intermediate binding energy of ~13.5 meV in perovskites are distinct from conventional photovoltaic semiconductors. In addition to providing implications for coherent energy conversion, these are potentially relevant to the development of light-harvesting and electron-transport devices.« less

Predicting protein complex geometries with a neural network.

PubMed

Chae, Myong-Ho; Krull, Florian; Lorenzen, Stephan; Knapp, Ernst-Walter

2010-03-01

A major challenge of the protein docking problem is to define scoring functions that can distinguish near-native protein complex geometries from a large number of non-native geometries (decoys) generated with noncomplexed protein structures (unbound docking). In this study, we have constructed a neural network that employs the information from atom-pair distance distributions of a large number of decoys to predict protein complex geometries. We found that docking prediction can be significantly improved using two different types of polar hydrogen atoms. To train the neural network, 2000 near-native decoys of even distance distribution were used for each of the 185 considered protein complexes. The neural network normalizes the information from different protein complexes using an additional protein complex identity input neuron for each complex. The parameters of the neural network were determined such that they mimic a scoring funnel in the neighborhood of the native complex structure. The neural network approach avoids the reference state problem, which occurs in deriving knowledge-based energy functions for scoring. We show that a distance-dependent atom pair potential performs much better than a simple atom-pair contact potential. We have compared the performance of our scoring function with other empirical and knowledge-based scoring functions such as ZDOCK 3.0, ZRANK, ITScore-PP, EMPIRE, and RosettaDock. In spite of the simplicity of the method and its functional form, our neural network-based scoring function achieves a reasonable performance in rigid-body unbound docking of proteins. Proteins 2010. (c) 2009 Wiley-Liss, Inc.

Fast immersed interface Poisson solver for 3D unbounded problems around arbitrary geometries

NASA Astrophysics Data System (ADS)

Gillis, T.; Winckelmans, G.; Chatelain, P.

2018-02-01

We present a fast and efficient Fourier-based solver for the Poisson problem around an arbitrary geometry in an unbounded 3D domain. This solver merges two rewarding approaches, the lattice Green's function method and the immersed interface method, using the Sherman-Morrison-Woodbury decomposition formula. The method is intended to be second order up to the boundary. This is verified on two potential flow benchmarks. We also further analyse the iterative process and the convergence behavior of the proposed algorithm. The method is applicable to a wide range of problems involving a Poisson equation around inner bodies, which goes well beyond the present validation on potential flows.

Determination of the absolute binding free energies of HIV-1 protease inhibitors using non-equilibrium molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Ngo, Son Tung; Nguyen, Minh Tung; Nguyen, Minh Tho

2017-05-01

The absolute binding free energy of an inhibitor to HIV-1 Protease (PR) was determined throughout evaluation of the non-bonded interaction energy difference between the two bound and unbound states of the inhibitor and surrounding molecules by the fast pulling of ligand (FPL) process using non-equilibrium molecular dynamics (NEMD) simulations. The calculated free energy difference terms help clarifying the nature of the binding. Theoretical binding affinities are in good correlation with experimental data, with R = 0.89. The paradigm used is able to rank two inhibitors having the maximum difference of ∼1.5 kcal/mol in absolute binding free energies.

The EXPERT project: part of the Super-FRS Experiment Collaboration

NASA Astrophysics Data System (ADS)

Chudoba, V.; "EXPERT project, A nonlocal spatial model for Lyme disease

NASA Astrophysics Data System (ADS)

Yu, Xiao; Zhao, Xiao-Qiang

2016-07-01

This paper is devoted to the study of a nonlocal and time-delayed reaction-diffusion model for Lyme disease with a spatially heterogeneous structure. In the case of a bounded domain, we first prove the existence of the positive steady state and a threshold type result for the disease-free system, and then establish the global dynamics for the model system in terms of the basic reproduction number. In the case of an unbound domain, we obtain the existence of the disease spreading speed and its coincidence with the minimal wave speed. At last, we use numerical simulations to verify our analytic results and investigate the influence of model parameters and spatial heterogeneity on the disease infection risk.

system

NASA Astrophysics Data System (ADS)

Garcilazo, H.; Valcarce, A.; Vijande, J.

2017-07-01

Using local central Yukawa-type Malfliet-Tjon interactions reproducing the low-energy parameters and phase shifts of the nn system, and the latest updates of the nΛ and ΛΛ Nijmegen ESC08c potentials, we study the possible existence of a bound state. Our results indicate that the is unbound, being just above threshold. We discuss the role played by the 1 S 0 nn repulsive term of the Yukawa-type Malfliet-Tjon interaction. Supported by COFAA-IPN (México), Ministerio de Economía, Industria y Competitividad and EU FEDER (FPA2013-47443, FPA2015-69714-REDT, FPA2016-77177), Junta de Castilla y León (SA041U16) and Generalitat Valenciana PrometeoII/2014/066

A single scan skeletonization algorithm: application to medical imaging of trabecular bone

NASA Astrophysics Data System (ADS)

Arlicot, Aurore; Amouriq, Yves; Evenou, Pierre; Normand, Nicolas; Guédon, Jean-Pierre

2010-03-01

Shape description is an important step in image analysis. The skeleton is used as a simple, compact representation of a shape. A skeleton represents the line centered in the shape and must be homotopic and one point wide. Current skeletonization algorithms compute the skeleton over several image scans, using either thinning algorithms or distance transforms. The principle of thinning is to delete points as one goes along, preserving the topology of the shape. On the other hand, the maxima of the local distance transform identifies the skeleton and is an equivalent way to calculate the medial axis. However, with this method, the skeleton obtained is disconnected so it is required to connect all the points of the medial axis to produce the skeleton. In this study we introduce a translated distance transform and adapt an existing distance driven homotopic algorithm to perform skeletonization with a single scan and thus allow the processing of unbounded images. This method is applied, in our study, on micro scanner images of trabecular bones. We wish to characterize the bone micro architecture in order to quantify bone integrity.

Low-lying scalars in an extended linear σ model

NASA Astrophysics Data System (ADS)

Mukherjee, Tamal K.; Huang, Mei; Yan, Qi-Shu

2012-12-01

We formulate an extended linear σ model of a quarkonia nonet and a tetraquark nonet as well as a complex isosinglet (glueball) by virtue of chiral symmetry SUL(3)×SUR(3) and UA(1) symmetry. In the linear realization formalism, we study the mass spectra and components of the low-lying scalars and pseudoscalars in this model. The mass matrices for physical states are obtained and the glueball candidates are examined. We find that the model can accommodate the mass spectra of low-lying states quite well. Our fits indicate that the most glueball-like scalar should be 2 GeV or higher while the glueball pseudoscalar is η(1756). We also examine the parameter region where the lightest isoscalar f0(600) can be the glueball and quarkonia dominant but find such a parameter region may be confronted with the problem of the unbounded vacuum from below.

Unmatter Plasma revisited

NASA Astrophysics Data System (ADS)

Smarandache, Florentin

2017-10-01

Unmmatter Plasma is a novel form of plasma, exclusively made of matter and its antimatter counterpart. The electron-positron beam plasma was generated in the laboratory in the beginning of 2015. This experimental fact shows that unmatter, a new form of matter that is formed by matter and antimatter bind together (mathematically predicted since 2004) really exists. That is the electron-positron plasma experiment of 2015 is the experimentum crucis verifying the mathematically predicted unmatter. Unmatter is formed by combinations of matter and antimatter that bind together, or by long-range mixture of matter and antimatter forming a weakly-coupled phase. Binding and bound state means that the interaction is sufficiently strong to tie together the particles of a system, therefore hindering them from becoming free. For example, a usual liquid is a bound state of molecules, while a gas is an un-bounded where the molecules can move freely in successive collisions.

Phase synchronization in the forced Lorenz system

NASA Astrophysics Data System (ADS)

Park, Eun-Hyoung; Zaks, Michael A.; Kurths, Jürgen

1999-12-01

We demonstrate that the dynamics of phase synchronization in a chaotic system under weak periodic forcing depends crucially on the distribution of intrinsic characteristic times of this system. Under the external periodic action, the frequency of every unstable periodic orbit is locked to the frequency of the force. In systems which in the autonomous case displays nearly isochronous chaotic rotations, the locking ratio is the same for all periodic orbits; since a typical chaotic orbit wanders between the periodic ones, its phase follows the phase of the force. For the Lorenz attractor with its unbounded times of return onto a Poincaré surface, such state of perfect phase synchronization is inaccessible. Analysis with the help of unstable periodic orbits shows that this state is replaced by another one, which we call ``imperfect phase synchronization,'' and in which we observe alternation of temporal segments, corresponding to different rational values of frequency lockings.

A Numerical Approximation Framework for the Stochastic Linear Quadratic Regulator on Hilbert Spaces

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

Levajković, Tijana, E-mail: tijana.levajkovic@uibk.ac.at, E-mail: t.levajkovic@sf.bg.ac.rs; Mena, Hermann, E-mail: hermann.mena@uibk.ac.at; Tuffaha, Amjad, E-mail: atufaha@aus.edu

We present an approximation framework for computing the solution of the stochastic linear quadratic control problem on Hilbert spaces. We focus on the finite horizon case and the related differential Riccati equations (DREs). Our approximation framework is concerned with the so-called “singular estimate control systems” (Lasiecka in Optimal control problems and Riccati equations for systems with unbounded controls and partially analytic generators: applications to boundary and point control problems, 2004) which model certain coupled systems of parabolic/hyperbolic mixed partial differential equations with boundary or point control. We prove that the solutions of the approximate finite-dimensional DREs converge to the solutionmore » of the infinite-dimensional DRE. In addition, we prove that the optimal state and control of the approximate finite-dimensional problem converge to the optimal state and control of the corresponding infinite-dimensional problem.« less

The Resolved Stellar Populations in the LEGUS Galaxies1

NASA Astrophysics Data System (ADS)

Sabbi, E.; Calzetti, D.; Ubeda, L.; Adamo, A.; Cignoni, M.; Thilker, D.; Aloisi, A.; Elmegreen, B. G.; Elmegreen, D. M.; Gouliermis, D. A.; Grebel, E. K.; Messa, M.; Smith, L. J.; Tosi, M.; Dolphin, A.; Andrews, J. E.; Ashworth, G.; Bright, S. N.; Brown, T. M.; Chandar, R.; Christian, C.; Clayton, G. C.; Cook, D. O.; Dale, D. A.; de Mink, S. E.; Dobbs, C.; Evans, A. S.; Fumagalli, M.; Gallagher, J. S., III; Grasha, K.; Herrero, A.; Hunter, D. A.; Johnson, K. E.; Kahre, L.; Kennicutt, R. C.; Kim, H.; Krumholz, M. R.; Lee, J. C.; Lennon, D.; Martin, C.; Nair, P.; Nota, A.; Östlin, G.; Pellerin, A.; Prieto, J.; Regan, M. W.; Ryon, J. E.; Sacchi, E.; Schaerer, D.; Schiminovich, D.; Shabani, F.; Van Dyk, S. D.; Walterbos, R.; Whitmore, B. C.; Wofford, A.

2018-03-01

The Legacy ExtraGalactic UV Survey (LEGUS) is a multiwavelength Cycle 21 Treasury program on the Hubble Space Telescope. It studied 50 nearby star-forming galaxies in 5 bands from the near-UV to the I-band, combining new Wide Field Camera 3 observations with archival Advanced Camera for Surveys data. LEGUS was designed to investigate how star formation occurs and develops on both small and large scales, and how it relates to the galactic environments. In this paper we present the photometric catalogs for all the apparently single stars identified in the 50 LEGUS galaxies. Photometric catalogs and mosaicked images for all filters are available for download. We present optical and near-UV color–magnitude diagrams for all the galaxies. For each galaxy we derived the distance from the tip of the red giant branch. We then used the NUV color–magnitude diagrams to identify stars more massive than 14 M ⊙, and compared their number with the number of massive stars expected from the GALEX FUV luminosity. Our analysis shows that the fraction of massive stars forming in star clusters and stellar associations is about constant with the star formation rate. This lack of a relation suggests that the timescale for evaporation of unbound structures is comparable or longer than 10 Myr. At low star formation rates this translates to an excess of mass in clustered environments as compared to model predictions of cluster evolution, suggesting that a significant fraction of stars form in unbound systems. Based on observations with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by AURA Inc., under NASA contract NAS 5-26555.

Purification and biochemical characterization of ionically unbound polyphenol oxidase from Musa paradisiaca leaf.

PubMed

Diwakar, Sanjeev Kumar; Mishra, Sarad Kumar

2011-01-01

An ionically unbound and thermostable polyphenol oxidase (PPO) was extracted from the leaf of Musa paradisiaca. The enzyme was purified 2.54-fold with a total yield of 9.5% by ammonium sulfate precipitation followed by Sephadex G-100 gel filtration chromatography. The purified enzyme exhibited a clear single band on native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate (SDS) PAGE. It was found to be monomeric protein with molecular mass of about 40 kD. The zymographic study using crude extract as enzyme source showed a very clear band around 40 kD and a faint band at around 15 kD, which might be isozymes. The enzyme was optimally active at pH 7.0 and 50°C temperature. The enzyme was active in wide range of pH (4.0-9.0) and temperature (30-90°C). From the thermal inactivation studies in the range 60-75°C, the half-life (t(1/2)) values of the enzyme ranged from 17 to 77 min. The inactivation energy (Ea) value of PPO was estimated to be 91.3 kJ mol(-1). It showed higher specificity with catechol (K(m) = 8 mM) as compared to 4-methylcatechol (K(m) = 10 mM). Among metal ions and reagents tested, Cu(2+), Fe(2+), Hg(2+), Mn(2+), Ni(2+), protocatechuic acid, and ferrulic acid enhanced the enzyme activity, while K(+), Na(+), Co(2+), kojic acid, ascorbic acid, ethylenediamine tetraacetic acid (EDTA), sodium azide, β-mercaptoethanol, and L-cysteine inhibited the activity of the enzyme.

Pharmacokinetics and Pharmacodynamics of Tildipirosin Against Pasteurella multocida in a Murine Lung Infection Model

PubMed Central

Zeng, Dongping; Sun, Meizhen; Lin, Zhoumeng; Li, Miao; Gehring, Ronette; Zeng, Zhenling

2018-01-01

Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound (f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect Imax model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC (fAUC0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log10 kill and 2-log10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle. PMID:29867911

Two related lithium calixarene complexes, [p-tert-butylcalix[4]arene(OMe)(OH)2(OLi)](2).4MeCN and {p-tert-butylcalix[4]arene(OH)2(OLi)[OLi(NCMe)2]}(2).8MeCN, determined using synchrotron radiation.

PubMed

Lee, Darren S; Elsegood, Mark R J; Redshaw, Carl; Zhan, Shuzhong

2009-08-01

The crystal structures of acetonitrile solvates of two related lithium calixarene complexes have been determined by low-temperature single-crystal X-ray diffraction using synchrotron radiation. Bis(mu-5,11,17,23-tetra-tert-butyl-26,28-dihydroxy-25-methoxy-27-oxidocalix[4]arene)dilithium(I) acetonitrile tetrasolvate, [Li2(C45H57O4)2].4C2H3N or [p-tert-butylcalix[4]arene(OMe)(OH)2(OLi)](2).4MeCN, (I), crystallizes with the complex across a centre of symmetry and with four molecules of unbound acetonitrile of crystallization per complex. Tetraacetonitrilebis(mu-5,11,17,23-tetra-tert-butyl-26,28-dihydroxy-25,27-dioxidocalix[4]arene)tetralithium(I) acetonitrile octasolvate, [Li4(C44H54O4)2(C2H3N)4].8C2H3N or {p-tert-butylcalix[4]arene(OH)2(OLi)[OLi(NCMe)2]}(2).8MeCN, (II), also crystallizes with the complex lying across a centre of symmetry and contains eight molecules of unbound acetonitrile per complex plus four more directly bound to two of the lithium ions, two on each ion. The cores of both complexes are partially supported by O-H...O hydrogen bonds. The methoxy methyl groups in (I) prevent the binding of any more than two Li+ ions, while the corresponding two O-atom sites in (II) bind an extra Li(+) ion each, making four in total. The calixarene cone adopts an undistorted cone conformation in (I), but an elliptical one in (II).

Fluorescence sensor for the quantification of unbound bilirubin concentrations.

PubMed

Huber, Andrew H; Zhu, Baolong; Kwan, Thomas; Kampf, J Patrick; Hegyi, Thomas; Kleinfeld, Alan M

2012-05-01

Hyperbilirubinemia in jaundiced neonates is routinely assessed by use of total serum bilirubin. However, the unbound or free form (B(f)), not total bilirubin, crosses the blood-brain barrier and can be neurotoxic. Although the peroxidase-mediated oxidation of bilirubin can be used to measure plasma concentrations of B(f), this measurement is relatively complex and the assay is not routinely used. We describe a fluorescence sensor for quantifying B(f) in plasma. Our method uses a mutated fatty acid binding protein labeled with the fluorescent molecule acrylodan (BL22P1B11), whose fluorescence is quenched upon binding bilirubin. Another configuration (BL22P1B11-Rh) was developed that uses BL22P1B11 together with the fluorophore rhodamine B, which responds by a change in the ratio of its fluorescence. The "B(f) probes" were calibrated with aqueous solutions of bilirubin and yielded similar bilirubin dissociation constants [K(d) = 16 (1.5) nmol/L]. We used the probes to determine B(f) concentrations in equilibrium with human serum albumin (HSA) and in human plasma samples supplemented with bilirubin. We obtained equivalent B(f) values in both systems, and the B(f) probe results were in agreement with the peroxidase assay. B(f) measurements revealed that bilirubin-HSA binding was well described by 2 sites with K(d) values of 15.4 (1) nmol/L and 748 (14) nmol/L. We measured B(f) concentrations in the range expected in jaundiced neonates with a mean CV of approximately 3%. The BL22P1B11-Rh probe provides accurate plasma sample B(f) concentrations with a single measurement, in 1 min with either a handheld B(f) meter or a laboratory fluorometer.

On the role of hydrogel structure and degradation in controlling the transport of cell-secreted matrix molecules for engineered cartilage.

PubMed

Dhote, Valentin; Skaalure, Stacey; Akalp, Umut; Roberts, Justine; Bryant, Stephanie J; Vernerey, Franck J

2013-03-01

Damage to cartilage caused by injury or disease can lead to pain and loss of mobility, diminishing one's quality of life. Because cartilage has a limited capacity for self-repair, tissue engineering strategies, such as cells encapsulated in synthetic hydrogels, are being investigated as a means to restore the damaged cartilage. However, strategies to date are suboptimal in part because designing degradable hydrogels is complicated by structural and temporal complexities of the gel and evolving tissue along multiple length scales. To address this problem, this study proposes a multi-scale mechanical model using a triphasic formulation (solid, fluid, unbound matrix molecules) based on a single chondrocyte releasing extracellular matrix molecules within a degrading hydrogel. This model describes the key players (cells, proteoglycans, collagen) of the biological system within the hydrogel encompassing different length scales. Two mechanisms are included: temporal changes of bulk properties due to hydrogel degradation, and matrix transport. Numerical results demonstrate that the temporal change of bulk properties is a decisive factor in the diffusion of unbound matrix molecules through the hydrogel. Transport of matrix molecules in the hydrogel contributes both to the development of the pericellular matrix and the extracellular matrix and is dependent on the relative size of matrix molecules and the hydrogel mesh. The numerical results also demonstrate that osmotic pressure, which leads to changes in mesh size, is a key parameter for achieving a larger diffusivity for matrix molecules in the hydrogel. The numerical model is confirmed with experimental results of matrix synthesis by chondrocytes in biodegradable poly(ethylene glycol)-based hydrogels. This model may ultimately be used to predict key hydrogel design parameters towards achieving optimal cartilage growth. Copyright © 2012 Elsevier Ltd. All rights reserved.

An Alternative Origin for Hypervelocity Stars

NASA Astrophysics Data System (ADS)

Abadi, Mario G.; Navarro, Julio F.; Steinmetz, Matthias

2009-02-01

Halo stars with unusually high radial velocity (hypervelocity stars, or HVS) are thought to be stars unbound to the Milky Way that originate from the gravitational interaction of stellar systems with the supermassive black hole at the Galactic center. We examine the latest HVS compilation and find peculiarities that are unexpected in this black hole ejection scenario. For example, a large fraction of HVS cluster around the constellation of Leo and share a common travel time of ~100-200 Myr. Furthermore, their velocities are not really extreme if, as suggested by recent galaxy formation models, the Milky Way is embedded within a 2.5 × 1012 h -1 M sun dark halo with virial velocity of ~220 km s-1. In this case, the escape velocity at ~50 kpc would be ~600 km s-1, and very few HVS would be truly unbound. We use numerical simulations to show that disrupting dwarf galaxies may contribute halo stars with velocities up to and sometimes exceeding the nominal escape speed of the system. These stars are arranged in a thinly collimated outgoing "tidal tail" stripped from the dwarf during its latest pericentric passage. We speculate that some HVS may, therefore, be tidal debris from a dwarf recently disrupted near the center of the Galaxy. In this interpretation, the angular clustering of HVS results because, from our perspective, the tail is seen nearly "end on," whereas the common travel time simply reflects the fact that these stars were stripped simultaneously from the dwarf during a single pericentric passage. This proposal is eminently falsifiable, since it makes a number of predictions which are distinct from the black hole ejection mechanism and which should be testable with improved HVS datasets.

On the role of hydrogel structure and degradation in controlling the transport of cell-secreted matrix molecules for engineered cartilage

PubMed Central

Dhote, Valentin; Skaalure, Stacey; Akalp, Umut; Roberts, Justine; Bryant, Stephanie J.; Vernerey, Franck J.

2012-01-01

Damage to cartilage caused by injury or disease can lead to pain and loss of mobility, diminishing one’s quality of life. Because cartilage has a limited capacity for self-repair, tissue engineering strategies, such as cells encapsulated in synthetic hydrogels, are being investigated as a means to restore the damaged cartilage. However, strategies to date are suboptimal in part because designing degradable hydrogels is complicated by structural and temporal complexities of the gel and evolving tissue along multiple length scales. To address this problem, this study proposes a multi-scale mechanical model using a triphasic formulation (solid, fluid, unbound matrix molecules) based on a single chondrocyte releasing extracellular matrix molecules within a degrading hydrogel. This model describes the key players (cells, proteoglycans, collagen) of the biological system within the hydrogel encompassing different length scales. Two mechanisms are included: temporal changes of bulk properties due to hydrogel degradation, and matrix transport. Numerical results demonstrate that the temporal change of bulk properties is a decisive factor in the diffusion of unbound matrix molecules through the hydrogel. Transport of matrix molecules in the hydrogel contributes both to the development of the pericellular matrix and the extracellular matrix and is dependent on the relative size of matrix molecules and the hydrogel mesh. The numerical results also demonstrate that osmotic pressure, which leads to changes in mesh size, is a key parameter for achieving a larger diffusivity for matrix molecules in the hydrogel. The numerical model is confirmed with experimental results of matrix synthesis by chondrocytes in biodegradable poly(ethylene glycol)-based hydrogels. This model may ultimately be used to predict key hydrogel design parameters towards achieving optimal cartilage growth. PMID:23276516

Limited value of the urinary phenytoin metabolic ratio for the assessment of cytochrome P4502C9 activity in vivo

PubMed Central

TASSANEEYAKUL, WICHITTRA; BIRKETT, DONALD J.; PASS, MICHAEL C.; MINERS, JOHN O.

1996-01-01

Relationships between the ratio of p-hydroxyphenytoin (p-HPPH), the major metabolite of phenytoin, to unchanged phenytoin excreted in urine (the urinary metabolic ratio or MR) were compared with a number of indices of the metabolic clearances of phenytoin and tolbutamide published previously for seventeen subjects separately administered these known cytochrome P4502C9 (CYP2C9) substrates. Significant correlations (rs=0.50–0.60, P<0.05) were observed between the phenytoin MR, derived from either 0–24 or 24–48 h urine collections, and inverse areas under the plasma unbound concentration-time curves (measured over various time intervals) of phenytoin and with plasma unbound tolbutamide clearance. Significant correlations (rs =0.59–0.74) were also observed between the phenytoin MRs and metabolic unbound clearances for p-hydroxyphenytoin formation. Despite the significant correlations, variability in tolbutamide and phenytoin metabolic clearance parameters tended to account for <50% of the variability in phenytoin MR. Correlations between the renal clearance of phenytoin and the phenytoin MRs suggest that variability in the renal clearance of unchanged drug limits the usefulness of the phenytoin MR for the investigation of factors influencing CYP2C9 activity in vivo. PMID:8971435

Monte Carlo replica-exchange based ensemble docking of protein conformations.

PubMed

Zhang, Zhe; Ehmann, Uwe; Zacharias, Martin

2017-05-01

A replica-exchange Monte Carlo (REMC) ensemble docking approach has been developed that allows efficient exploration of protein-protein docking geometries. In addition to Monte Carlo steps in translation and orientation of binding partners, possible conformational changes upon binding are included based on Monte Carlo selection of protein conformations stored as ordered pregenerated conformational ensembles. The conformational ensembles of each binding partner protein were generated by three different approaches starting from the unbound partner protein structure with a range spanning a root mean square deviation of 1-2.5 Å with respect to the unbound structure. Because MC sampling is performed to select appropriate partner conformations on the fly the approach is not limited by the number of conformations in the ensemble compared to ensemble docking of each conformer pair in ensemble cross docking. Although only a fraction of generated conformers was in closer agreement with the bound structure the REMC ensemble docking approach achieved improved docking results compared to REMC docking with only the unbound partner structures or using docking energy minimization methods. The approach has significant potential for further improvement in combination with more realistic structural ensembles and better docking scoring functions. Proteins 2017; 85:924-937. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Multiple μ-stability of neural networks with unbounded time-varying delays.

PubMed

Wang, Lili; Chen, Tianping

2014-05-01

In this paper, we are concerned with a class of recurrent neural networks with unbounded time-varying delays. Based on the geometrical configuration of activation functions, the phase space R(n) can be divided into several Φη-type subsets. Accordingly, a new set of regions Ωη are proposed, and rigorous mathematical analysis is provided to derive the existence of equilibrium point and its local μ-stability in each Ωη. It concludes that the n-dimensional neural networks can exhibit at least 3(n) equilibrium points and 2(n) of them are μ-stable. Furthermore, due to the compatible property, a set of new conditions are presented to address the dynamics in the remaining 3(n)-2(n) subset regions. As direct applications of these results, we can get some criteria on the multiple exponential stability, multiple power stability, multiple log-stability, multiple log-log-stability and so on. In addition, the approach and results can also be extended to the neural networks with K-level nonlinear activation functions and unbounded time-varying delays, in which there can store (2K+1)(n) equilibrium points, (K+1)(n) of them are locally μ-stable. Numerical examples are given to illustrate the effectiveness of our results. Copyright © 2014 Elsevier Ltd. All rights reserved.

Note on a modified return period scale for upper-truncated unbounded flood distributions

NASA Astrophysics Data System (ADS)

Bardsley, Earl

2017-01-01

Probability distributions unbounded to the right often give good fits to annual discharge maxima. However, all hydrological processes are in reality constrained by physical upper limits, though not necessarily well defined. A result of this contradiction is that for sufficiently small exceedance probabilities the unbounded distributions anticipate flood magnitudes which are impossibly large. This raises the question of whether displayed return period scales should, as is current practice, have some given number of years, such as 500 years, as the terminating rightmost tick-point. This carries the implication that the scale might be extended indefinitely to the right with a corresponding indefinite increase in flood magnitude. An alternative, suggested here, is to introduce a sufficiently high upper truncation point to the flood distribution and modify the return period scale accordingly. The rightmost tick-mark then becomes infinity, corresponding to the upper truncation point discharge. The truncation point is likely to be set as being above any physical upper bound and the return period scale will change only slightly over all practical return periods of operational interest. The rightmost infinity tick point is therefore proposed, not as an operational measure, but rather to signal in flood plots that the return period scale does not extend indefinitely to the right.

Matrix effect on leaching of Bisphenol A diglycidyl ether (BADGE) from epoxy resin based inner lacquer of aluminium tubes into semi-solid dosage forms.

PubMed

Lipke, Uwe; Haverkamp, Jan Boris; Zapf, Thomas; Lipperheide, Cornelia

2016-04-01

To study the impact of different semi-solid dosage form components on the leaching of Bisphenol A (BPA) and Bisphenol A diglycidyl ether (BADGE) from the epoxy resin-based inner lacquer of aluminium tubes, the tubes were filled with different matrix preparations and stored at an elevated temperature. Despite compliance with the European Standards EN 15348 and EN 15766 on porosity and polymerisation of internal coatings of aluminium tubes, the commercially available tubes used in the study contained an increased amount of polymerisation residues, such as unbound BPA, BADGE and BADGE derivatives in the lacquer, as determined by acetonitrile extraction. Storage of Macrogol ointments in these tubes resulted in an almost quantitative migration of the unbound polymerisation residues from the coating into the ointment. In addition, due to alterations observed in the RP-HPLC chromatograms of the matrix spiked with BADGE and BADGE derivatives it is supposed that the leachates can react with formulation components. The contamination of the medicinal product by BPA, BADGE and BADGE derivatives can be precluded by using aluminium tubes with an internal lacquer with a low degree of unbound polymerisation residues. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Investigational agents for the treatment of growth hormone-insensitivity syndrome.

PubMed

Kemp, Stephen F; Thrailkill, Kathryn M

2006-04-01

Growth hormone-insensitivity syndrome (GHIS) is usually caused by mutations in the growth hormone receptor. Recombinant IGF-I has been used to treat GHIS either alone (mecasermin) or in combination with IGF-binding protein (IGFBP)-3 (mecasermin rinfabate). IGF-I increases the growth velocity of children with IGF deficiency, which is either as a result of GHIS or an IGF-I gene deletion. Hypoglycaemia has been reported with administration of unbound IGF-I and, in addition, the serum half-life of unbound IGF-I is shorter when administered to patients with GHIS (who have low serum concentrations of its binding protein IGFBP-3) than when administered to normal volunteers or to patients with an IGF-I gene deletion (but normal IGFBP-3 levels). The IGF-I-IGFBP-3 combination was developed to prolong the half-life and counteract the acute adverse events (particularly hypoglycaemia) that are associated with administration of IGF-I. It seems that the IGF-I-IGFBP-3 combination has a longer half-life in patients with GHIS than unbound IGF-I, with fewer reports of adverse events (including hypoglycaemia) when administered to patients with diabetes. There are no studies comparing the efficacy of mecasermin with mecasermin rinfabate; both drugs have been shown to be effective but cannot be differentiated in terms of efficacy.

Determination of total and unbound warfarin and warfarin alcohols in human plasma by high performance liquid chromatography with fluorescence detection.

PubMed

Lomonaco, Tommaso; Ghimenti, Silvia; Piga, Isabella; Onor, Massimo; Melai, Bernardo; Fuoco, Roger; Di Francesco, Fabio

2013-11-01

Two analytical procedures are presented for the determination of the total content and unbound fraction of both warfarin and warfarin alcohols in human plasma. Chromatographic separation was carried out in isocratic conditions at 25°C on a C-18 reversed-phase column with a mobile phase consisting of a 70% buffer phosphate 25mM at pH=7, 25% methanol and 5% acetonitrile at a flow rate of 1.2mL/min. Fluorescence detection was performed at 390nm (excitation wavelength 310nm). Neither method showed any detectable interference or matrix effect. Inter-day recovery of the total warfarin and warfarin alcohols at a concentration level of 1000ng/mL was 89±3% and 73±3%, respectively, whereas for their unbound fraction (at a concentration level of 10ng/mL) was 66±8% and 90±7%, respectively. The intra- and inter-day precision (assessed as relative standard deviation) was <10% for both methods. The limits of detection were 0.4 and 0.2ng/mL for warfarin and warfarin alcohols, respectively. The methods were successfully applied to a pooled plasma sample obtained from 69 patients undergoing warfarin therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

PPI4DOCK: large scale assessment of the use of homology models in free docking over more than 1000 realistic targets.

PubMed

Yu, Jinchao; Guerois, Raphaël

2016-12-15

Protein-protein docking methods are of great importance for understanding interactomes at the structural level. It has become increasingly appealing to use not only experimental structures but also homology models of unbound subunits as input for docking simulations. So far we are missing a large scale assessment of the success of rigid-body free docking methods on homology models. We explored how we could benefit from comparative modelling of unbound subunits to expand docking benchmark datasets. Starting from a collection of 3157 non-redundant, high X-ray resolution heterodimers, we developed the PPI4DOCK benchmark containing 1417 docking targets based on unbound homology models. Rigid-body docking by Zdock showed that for 1208 cases (85.2%), at least one correct decoy was generated, emphasizing the efficiency of rigid-body docking in generating correct assemblies. Overall, the PPI4DOCK benchmark contains a large set of realistic cases and provides new ground for assessing docking and scoring methodologies. Benchmark sets can be downloaded from http://biodev.cea.fr/interevol/ppi4dock/ CONTACT: guerois@cea.frSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Analysis of the thermodynamics of binding of an SH3 domain to proline-rich peptides using a chimeric fusion protein.

PubMed

Candel, Adela M; van Nuland, Nico A J; Martin-Sierra, Francisco M; Martinez, Jose C; Conejero-Lara, Francisco

2008-03-14

A complete understanding of the thermodynamic determinants of binding between SH3 domains and proline-rich peptides is crucial to the development of rational strategies for designing ligands for these important domains. Recently we engineered a single-chain chimeric protein by fusing the alpha-spectrin Src homology region 3 (SH3) domain to the decapeptide APSYSPPPPP (p41). This chimera mimics the structural and energetic features of the interaction between SH3 domains and proline-rich peptides. Here we show that analysing the unfolding thermodynamics of single-point mutants of this chimeric fusion protein constitutes a very useful approach to deciphering the thermodynamics of SH3-ligand interactions. To this end, we investigated the contribution of each proline residue of the ligand sequence to the SH3-peptide interaction by producing six single Pro-Ala mutants of the chimeric protein and analysing their unfolding thermodynamics by differential scanning calorimetry (DSC). Structural analyses of the mutant chimeras by circular dichroism, fluorescence and NMR together with NMR-relaxation measurements indicate conformational flexibility at the binding interface, which is strongly affected by the different Pro-Ala mutations. An analysis of the DSC thermograms on the basis of a three-state unfolding model has allowed us to distinguish and separate the thermodynamic magnitudes of the interaction at the binding interface. The model assumes equilibrium between the "unbound" and "bound" states at the SH3-peptide binding interface. The resulting thermodynamic magnitudes classify the different proline residues according to their importance in the interaction as P2 approximately P7 approximately P10>P9 approximately P6>P8, which agrees well with Lim's model for the interaction between SH3 domains and proline-rich peptides. In addition, the thermodynamic signature of the interaction is the same as that usually found for this type of binding, with a strong enthalpy-entropy compensation for all the mutants. This compensation appears to derive from an increase in conformational flexibility concomitant to the weakening of the interactions at the binding interface. We conclude that our approach, based on DSC and site-directed mutagenesis analysis of chimeric fusion proteins, may serve as a suitable tool to analyse the energetics of weak biomolecular interactions such as those involving SH3 domains.

Colloidal gold-labeled insulin complex. Characterization and binding to adipocytes.

PubMed

Moll, U M; Thun, C; Pfeiffer, E F

1986-01-01

Biologically active insulin gold complex was used as an ultrastructural marker to study insulin binding sites, uptake, and internalization in isolated rat adipocytes. The preparation conditions for monodispersed particles, ca. 16 nm in diameter and loaded with approximately 100 insulin molecules, are reported. The complex is stable for at least six weeks. Single particles or small clusters were scattered across the cell membrane. The distribution of unbound receptors seemed to be independent of the extensive system of pre-existing surface connected vesicles in adipocytes. The uptake of particles took place predominantly via non-coated pinocytotic invaginations; clathrin-coated pits did not seem to be important for this process. Lysosome-like structures contained aggregates of 10-15 particles. These data suggest that insulin gold complex is a useful marker for the specific labeling of insulin binding sites.

Wealth condensation in pareto macroeconomies

NASA Astrophysics Data System (ADS)

Burda, Z.; Johnston, D.; Jurkiewicz, J.; Kamiński, M.; Nowak, M. A.; Papp, G.; Zahed, I.

2002-02-01

We discuss a Pareto macroeconomy (a) in a closed system with fixed total wealth and (b) in an open system with average mean wealth, and compare our results to a similar analysis in a super-open system (c) with unbounded wealth [J.-P. Bouchaud and M. Mézard, Physica A 282, 536 (2000)]. Wealth condensation takes place in the social phase for closed and open economies, while it occurs in the liberal phase for super-open economies. In the first two cases, the condensation is related to a mechanism known from the balls-in-boxes model, while in the last case, to the nonintegrable tails of the Pareto distribution. For a closed macroeconomy in the social phase, we point to the emergence of a ``corruption'' phenomenon: a sizeable fraction of the total wealth is always amassed by a single individual.

Stoichiometry of DNA binding by the bacteriophage SP01-encoded type II DNA-binding protein TF1.

PubMed

Schneider, G J; Geiduschek, E P

1990-06-25

The stoichiometry of DNA binding by the bacteriophage SP01-encoded type II DNA-binding protein TF1 has been determined. 3H-Labeled TF1 was allowed to bind to a 32P-labeled DNA fragment containing a TF1 binding site. Multiple TF1-DNA complexes were resolved from each other and from unbound DNA by native gel electrophoresis. DNA-protein complexes were cut from polyacrylamide gels, and the amounts of 3H and 32P contained in each slice were measured. A ratio of 1.12 +/- 0.06 TF1 dimer/DNA molecule was calculated for the fastest-migrating TF1-DNA complex. We conclude that TF1 has a DNA-binding unit of one dimer. More slowly migrating complexes are apparently formed by serial addition of single TF1 dimers.

Exploring Photoinduced Excited State Evolution in Heterobimetallic Ru(II)-Co(III) Complexes.

PubMed

Kuhar, Korina; Fredin, Lisa A; Persson, Petter

2015-06-18

Quantum chemical calculations provide detailed theoretical information concerning key aspects of photoinduced electron and excitation transfer processes in supramolecular donor-acceptor systems, which are particularly relevant to fundamental charge separation in emerging molecular approaches for solar energy conversion. Here we use density functional theory (DFT) calculations to explore the excited state landscape of heterobimetallic Ru-Co systems with varying degrees of interaction between the two metal centers, unbound, weakly bound, and tightly bound systems. The interplay between structural and electronic factors involved in various excited state relaxation processes is examined through full optimizations of multiple charge/spin states of each of the investigated systems. Low-energy relaxed heterobimetallic states of energy transfer and excitation transfer character are characterized in terms of energy, structure, and electronic properties. These findings support the notion of efficient photoinduced charge separation from a Ru(II)-Co(III) ground state, via initial optical excitation of the Ru-center, to low-energy Ru(III)-Co(II) states. The strongly coupled system has significant involvement of the conjugated bridge, qualitatively distinguishing it from the other two weakly coupled systems. Finally, by constructing potential energy surfaces for the three systems where all charge/spin state combinations are projected onto relevant reaction coordinates, excited state decay pathways are explored.

Study of Structure and Small-Scale Fragmentation in TMC-1

NASA Technical Reports Server (NTRS)

Langer, W. D.; Velusamy, T.; Kuiper, T. B.; Levin, S.; Olsen, E.; Migenes, V.

1995-01-01

Large-scale C(sup 18)O maps show that the Taurus molecular cloud 1 (TMC-1) has numerous cores located along a ridge which extends about 12 minutes by at least 35 minutes. The cores traced by C(sup 18)O are about a few arcminutes (0.1-0.2 pc) in extent, typically contain about 0.5-3 solar mass, and are probably gravitationally bound. We present a detailed study of the small-scale fragmentary structure of one of these cores, called core D, within TMC-1 using very high spectral and spatial resolution maps of CCS and CS. The CCS lines are excellent tracers for investigating the density, temperature, and velocity structure in dense cores. The high spectral resolution, 0.008 km /s, data consist mainly of single-dish, Nyquist-sampled maps of CCS at 22 GHz with 45 sec spatial resolution taken with NASA's 70 m DSN antenna at Goldstone. The high spatial resolution spectral line maps were made with the Very Large Array (9 sec resolution) at 22 GHz and with the OVRO millimeter array in CCS and CS at 93 GHz and 98 GHz, respectively, with 6 sec resolution. These maps are supplemented with single-dish observations of CCS and CC(sup 34)S spectra at 33 GHz using a NASA 34 m DSN antenna, CCS 93 GHz, C(sup 34)S (2-1), and C(sup 18)O (1-0) single-dish observations made with the AT&T Bell Laboratories 7 m antenna. Our high spectral and spatial CCS and CS maps show that core D is highly fragmented. The single-dish CCS observations map out several clumps which range in size from approx. 45 sec to 90 sec (0.03-0.06 pc). These clumps have very narrow intrinsic line widths, 0.11-0.25 km/s, slightly larger than the thermal line width for CCS at 10 K, and masses about 0.03-0.2 solar mass. Interferometer observations of some of these clumps show that they have considerable additional internal structure, consisting of several condensations ranging in size from approx. 10 sec- 30 sec (0.007-0.021 pc), also with narrow line widths. The mass of these smallest fragments is of order 0.01 solar mass. These small-scale structures traced by CCS appear to be gravitationally unbound by a large factor. Most of these objects have masses that fall below those of the putative proto-brown dwarfs (approx. less than 0.1 solar mass). The presence of many small gravitationally unbound clumps suggests that fragmentation mechanisms other than a purely Jeans gravitational instability may be important for the dynamics of these cold dense cores.

Underwater sound transmission through arrays of disk cavities in a soft elastic medium.

PubMed

Calvo, David C; Thangawng, Abel L; Layman, Christopher N; Casalini, Riccardo; Othman, Shadi F

2015-10-01

Scattering from a cavity in a soft elastic medium, such as silicone rubber, resembles scattering from an underwater bubble in that low-frequency monopole resonance is obtainable in both cases. Arrays of cavities can therefore be used to reduce underwater sound transmission using thin layers and low void fractions. This article examines the role of cavity shape by microfabricating arrays of disk-shaped air cavities into single and multiple layers of polydimethylsiloxane. Comparison is made with the case of equivalent volume cylinders which approximate spheres. Measurements of ultrasonic underwater sound transmission are compared with finite element modeling predictions. The disks provide a deeper transmission minimum at a lower frequency owing to the drum-type breathing resonance. The resonance of a single disk cavity in an unbounded medium is also calculated and compared with a derived estimate of the natural frequency of the drum mode. Variation of transmission is determined as a function of disk tilt angle, lattice constant, and layer thickness. A modeled transmission loss of 18 dB can be obtained at a wavelength about 20 times the three-layer thickness, and thinner results (wavelength/thickness ∼ 240) are possible for the same loss with a single layer depending on allowable hydrostatic pressure.

Measurement of Isobaric Analogue Resonances of 47Ar with the Active-Target Time Projection Chamber

NASA Astrophysics Data System (ADS)

Bradt, Joshua William

While the nuclear shell model accurately describes the structure of nuclei near stability, the structure of unstable, neutron-rich nuclei is still an area of active research. One region of interest is the set of nuclei near N=28. The shell model suggests that these nuclei should be approximately spherical due to the shell gap predicted by their magic number of neutrons; however, experiments have shown that the nuclei in this region rapidly become deformed as protons are removed from the spherical 48Ca. This makes 46Ar a particularly interesting system as it lies in a transition region between 48Ca and lighter isotones that are known to be deformed. An experiment was performed at the National Superconducting Cyclotron Laboratory (NSCL) to measure resonant proton scattering on 46Ar. The resonances observed in this reaction correspond to unbound levels in the 47K intermediate state nucleus which are isobaric analogues of states in the 47Ar nucleus. By measuring the spectroscopic factors of these states in 47Ar, we gain information about the single-particle structure of this system, which is directly related to the size of the N=28 shell gap. Four resonances were observed: one corresponding to the ground state in 47Ar, one corresponding its first excited 1/2- state, and two corresponding to 1/2+ states in either 47Ar or the intermediate state nucleus. However, only a limited amount of information about these states could be recovered due to the low experimental statistics and limited angular resolution caused by pileup rejection and the inability to accurately reconstruct the beam particle track. In addition to the nuclear physics motivations, this experiment served as the radioactive beam commissioning for the Active-Target Time Projection Chamber (AT-TPC). The AT-TPC is a new gas-filled charged particle detector built at the NSCL to measure low-energy radioactive beams from the ReA3 facility. Since the gas inside the detector serves as both the tracking medium and the scattering target, reactions are measured over a continuous range of energies with near-4π solid angle coverage. This experiment demonstrated that tracks recorded by the AT-TPC can be reconstructed to a good resolution, and it established the feasibility of performing similar experiments with this detector in the future.

An investigation of acetylcholine released in skeletal muscle and protein unbound drug released in blood based on the pyridostigmine bromide (pretreatment drug) sustained-release pellets by microdialysis technique in the rabbit model.

PubMed

Huang, Yuh-Tyng; Cheng, Chun-Jen; Lai, Tsun-Fwu; Tsai, Tong-Rong; Tsai, Tung-Hu; Chuo, Wen-Ho; Cham, Thau-Ming

2007-04-18

Pyridostigmine bromide (PB) is a reversible acetylcholinesterase inhibitor that has been used as a pretreatment drug for "Soman" nerve gas poisoning in combat to increase survival. The once-daily PB-sustained-release (SR) pellets were developed by extrusion-spheronization and fluid-bed methods in our laboratory, which was followed by zero-order release mechanism. The results showed that the released concentration of acetylcholine (ACh) in skeletal muscle and the released concentration of protein unbound drug in blood were determined by microdialysis technique to have significant differences (P<0.05) among the three dosage forms (IV injection, commercial IR tablets and the PB-SR pellet). The released concentrations of ACh and protein unbound drug for PB-SR pellets were slower than IV injection and commercial IR tablets; this phenomenon indicating that the retention period of drug efficacy in vivo for PB-SR pellet was longer than the others, that is to say, the PB-SR pellets provided with SR effect in vivo as well. We believe that once-daily administered PB-SR pellets would improve limitations of post-exposure antidotes, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in wars or terrorist attacks in the future.

Numerical analysis of the angular motion of a neutrally buoyant spheroid in shear flow at small Reynolds numbers.

PubMed

Rosén, T; Einarsson, J; Nordmark, A; Aidun, C K; Lundell, F; Mehlig, B

2015-12-01

We numerically analyze the rotation of a neutrally buoyant spheroid in a shear flow at small shear Reynolds number. Using direct numerical stability analysis of the coupled nonlinear particle-flow problem, we compute the linear stability of the log-rolling orbit at small shear Reynolds number Re(a). As Re(a)→0 and as the box size of the system tends to infinity, we find good agreement between the numerical results and earlier analytical predictions valid to linear order in Re(a) for the case of an unbounded shear. The numerical stability analysis indicates that there are substantial finite-size corrections to the analytical results obtained for the unbounded system. We also compare the analytical results to results of lattice Boltzmann simulations to analyze the stability of the tumbling orbit at shear Reynolds numbers of order unity. Theory for an unbounded system at infinitesimal shear Reynolds number predicts a bifurcation of the tumbling orbit at aspect ratio λ(c)≈0.137 below which tumbling is stable (as well as log rolling). The simulation results show a bifurcation line in the λ-Re(a) plane that reaches λ≈0.1275 at the smallest shear Reynolds number (Re(a)=1) at which we could simulate with the lattice Boltzmann code, in qualitative agreement with the analytical results.

Revisiting hypervelocity stars after Gaia DR2

NASA Astrophysics Data System (ADS)

Boubert, D.; Guillochon, J.; Hawkins, K.; Ginsburg, I.; Evans, N. W.; Strader, J.

2018-06-01

Hypervelocity stars are intriguing rare objects traveling at speeds large enough to be unbound from the Milky Way. Several mechanisms have been proposed for producing them, including the interaction of the Galaxy's super-massive black hole (SMBH) with a binary; rapid mass-loss from a companion to a star in a short-period binary; the tidal disruption of an infalling galaxy and finally ejection from the Large Magellanic Cloud. While previously discovered high-velocity early-type stars are thought to be the result of an interaction with the SMBH, the origin of high-velocity late type stars is ambiguous. The second data release of Gaia (DR2) enables a unique opportunity to resolve this ambiguity and determine whether any late-type candidates are truly unbound from the Milky Way. In this paper, we utilize the new proper motion and velocity information available from DR2 to re-evaluate a collection of historical data compiled on the newly-created Open Fast Stars Catalog. We find that almost all previously-known high-velocity late-type stars are most likely bound to the Milky Way. Only one late-type object (LAMOST J115209.12+120258.0) is unbound from the Galaxy. Performing integrations of orbital histories, we find that this object cannot have been ejected from the Galactic centre and thus may be either debris from the disruption of a satellite galaxy or a disc runaway.

Electromagnetic fields and potentials generated by massless charged particles

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

Azzurli, Francesco, E-mail: francesco.azzurli@gmail.com; Lechner, Kurt, E-mail: lechner@pd.infn.it; INFN, Sezione di Padova, Via F. Marzolo, 8, 35131 Padova

2014-10-15

We provide for the first time the exact solution of Maxwell’s equations for a massless charged particle moving on a generic trajectory at the speed of light. In particular we furnish explicit expressions for the vector potential and the electromagnetic field, which were both previously unknown, finding that they entail different physical features for bounded and unbounded trajectories. With respect to the standard Liénard–Wiechert field the electromagnetic field acquires singular δ-like contributions whose support and dimensionality depend crucially on whether the motion is (a) linear, (b) accelerated unbounded, (c) accelerated bounded. In the first two cases the particle generates amore » planar shock-wave-like electromagnetic field traveling along a straight line. In the second and third cases the field acquires, in addition, a δ-like contribution supported on a physical singularity-string attached to the particle. For generic accelerated motions a genuine radiation field is also present, represented by a regular principal-part type distribution diverging on the same singularity-string. - Highlights: • First exact solution of Maxwell’s equations for massless charges in arbitrary motion. • Explicit expressions of electromagnetic fields and potentials. • Derivations are rigorous and based on distribution theory. • The form of the field depends heavily on whether the motion is bounded or unbounded. • The electromagnetic field contains unexpected Dirac-delta-function contributions.« less

A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human

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

Poulin, Patrick, E-mail: patrick-poulin@videotron.ca; Ekins, Sean; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201

A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V{sub ss}) in humans under in vivo conditions. Thismore » correlation method demonstrated inaccurate predictions of V{sub ss} for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V{sub ss} of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models.« less

Whole-field macro- and micro-deformation characteristic of unbound water-loss in dentin hard tissue.

PubMed

Chen, Zhenning; Nadeau, Bobby; Yu, Kevin; Shao, Xinxing; He, Xiaoyuan; Goh, M Cynthia; Kishen, Anil

2018-04-06

High-resolution deformation measurements in a functionally graded hard tissue such as human dentin are essential to understand the unbound water-loss mediated changes and their role in its mechanical integrity. Yet a whole-field, 3-dimensional (3D) measurement and characterization of fully hydrated dentin in both macro- and micro-scales remain to be a challenge. This study was conducted in 2 stages. In stage-1, a stereo-digital image correlation approach was utilized to determine the water-loss and load-induced 3D deformations of teeth in a sagittal section over consecutively acquired frames, from a fully hydrated state to nonhydrated conditions for a period up to 2 hours. The macroscale analysis revealed concentrated residual deformations at the dentin-enamel-junction and the apical regions of root in the direction perpendicular to the dentinal tubules. Significant difference in the localized deformation characteristics was observed between the inner and outer aspects of the root dentin. During quasi-static loadings, further increase in the residual deformation was observed in the dentin. In stage-2, dentin microstructural variations induced by dynamic water-loss were assessed with environmental scanning electron microscopy and atomic force microscopy (AFM), showing that the dynamic water-loss induced distention of dentinal tubules with concave tubular edges, and concurrent contraction of intertubular dentin with convex profile. The findings from the current macro- and micro-scale analysis provided insight on the free-water-loss induced regional deformations and ultrastructural changes in human dentin. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rosetta FlexPepDock ab-initio: simultaneous folding, docking and refinement of peptides onto their receptors.

PubMed

Raveh, Barak; London, Nir; Zimmerman, Lior; Schueler-Furman, Ora

2011-04-29

Flexible peptides that fold upon binding to another protein molecule mediate a large number of regulatory interactions in the living cell and may provide highly specific recognition modules. We present Rosetta FlexPepDock ab-initio, a protocol for simultaneous docking and de-novo folding of peptides, starting from an approximate specification of the peptide binding site. Using the Rosetta fragments library and a coarse-grained structural representation of the peptide and the receptor, FlexPepDock ab-initio samples efficiently and simultaneously the space of possible peptide backbone conformations and rigid-body orientations over the receptor surface of a given binding site. The subsequent all-atom refinement of the coarse-grained models includes full side-chain modeling of both the receptor and the peptide, resulting in high-resolution models in which key side-chain interactions are recapitulated. The protocol was applied to a benchmark in which peptides were modeled over receptors in either their bound backbone conformations or in their free, unbound form. Near-native peptide conformations were identified in 18/26 of the bound cases and 7/14 of the unbound cases. The protocol performs well on peptides from various classes of secondary structures, including coiled peptides with unusual turns and kinks. The results presented here significantly extend the scope of state-of-the-art methods for high-resolution peptide modeling, which can now be applied to a wide variety of peptide-protein interactions where no prior information about the peptide backbone conformation is available, enabling detailed structure-based studies and manipulation of those interactions. © 2011 Raveh et al.

Rosetta FlexPepDock ab-initio: Simultaneous Folding, Docking and Refinement of Peptides onto Their Receptors

PubMed Central

Raveh, Barak; London, Nir; Zimmerman, Lior; Schueler-Furman, Ora

2011-01-01

Flexible peptides that fold upon binding to another protein molecule mediate a large number of regulatory interactions in the living cell and may provide highly specific recognition modules. We present Rosetta FlexPepDock ab-initio, a protocol for simultaneous docking and de-novo folding of peptides, starting from an approximate specification of the peptide binding site. Using the Rosetta fragments library and a coarse-grained structural representation of the peptide and the receptor, FlexPepDock ab-initio samples efficiently and simultaneously the space of possible peptide backbone conformations and rigid-body orientations over the receptor surface of a given binding site. The subsequent all-atom refinement of the coarse-grained models includes full side-chain modeling of both the receptor and the peptide, resulting in high-resolution models in which key side-chain interactions are recapitulated. The protocol was applied to a benchmark in which peptides were modeled over receptors in either their bound backbone conformations or in their free, unbound form. Near-native peptide conformations were identified in 18/26 of the bound cases and 7/14 of the unbound cases. The protocol performs well on peptides from various classes of secondary structures, including coiled peptides with unusual turns and kinks. The results presented here significantly extend the scope of state-of-the-art methods for high-resolution peptide modeling, which can now be applied to a wide variety of peptide-protein interactions where no prior information about the peptide backbone conformation is available, enabling detailed structure-based studies and manipulation of those interactions. PMID:21572516

Rogue waves and unbounded solutions of the NLSE

NASA Astrophysics Data System (ADS)

Lechuga, Antonio

2017-04-01

Since the pioneering work of Zakharov has been generally admitted that rogue waves can be studied in the framework of the Nonlinear Schrödinger Equation (NLSE). Many researchers, Akhmediev, Peregrine, Matveev among others gave different solutions to this equation that, in some way, could be linked to rogue waves and also to its more important characteristic: its unexpectedness. Janssen (2003, 2004), Onorato (2004, 2006) and Waseda (2006) linked the coefficient of the nonlinear term of the Schrödinger equation with the Benjamin-Feir index (BFI) that, we know, is a measure of the modulational instability of the waves. From this point of view the value of this coefficient of the NLSE could be known from statistics. Thus the relationship between sea states and the mechanism of generation of rogue waves could be found out. Following the well-known Lie group theory researchers have been studying the Lie point symmetries of the NLSE: the scaling transformations, Galilean transformations and phase transformations. Basically these transformations turn the NLSE into a nonlinear ordinary differential equation called Duffing equation (also called eikonal equation). There are different ways to do this, but in most of them the independent variable that could be seen as a space variable is a kind of moving frame with the time incorporated in this way. The main aim of this work is to classify solutions of the Duffing equation (periodic and nonperiodic waves and also bounded and unbounded waves) bearing in mind that the coefficient of the nonlinear term in the NLSE is left unaltered in the process of the transformation.

Computational aspects of pseudospectral Laguerre approximations

NASA Technical Reports Server (NTRS)

Funaro, Daniele

1989-01-01

Pseudospectral approximations in unbounded domains by Laguerre polynomials lead to ill-conditioned algorithms. Introduced are a scaling function and appropriate numerical procedures in order to limit these unpleasant phenomena.

Trailing edge flow conditions as a factor in airfoil design

NASA Technical Reports Server (NTRS)

Ormsbee, A. I.; Maughmer, M. D.

1984-01-01

Some new developments relevant to the design of single-element airfoils using potential flow methods are presented. In particular, the role played by the non-dimensional trailing edge velocity in design is considered and the relationship between the specified value and the resulting airfoil geometry is explored. In addition, the ramifications of the unbounded trailing edge pressure gradients generally present in the potential flow solution of the flow over an airfoil are examined, and the conditions necessary to obtain a class of airfoils having finite trailing edge pressure gradients developed. The incorporation of these conditions into the inverse method of Eppler is presented and the modified scheme employed to generate a number of airfoils for consideration. The detailed viscous analysis of airfoils having finite trailing edge pressure gradients demonstrates a reduction in the strong inviscid-viscid interactions generally present near the trailing edge of an airfoil.

Dual phase multiplex polymerase chain reaction

DOEpatents

Pemov, Alexander [Charlottesville, VA; Bavykin, Sergei [Darien, IL

2008-10-07

Highly specific and sensitive methods were developed for multiplex amplification of nucleic acids on supports such as microarrays. Based on a specific primer design, methods include five types of amplification that proceed in a reaction chamber simultaneously. These relate to four types of multiplex amplification of a target DNA on a solid support, directed by forward and reverse complex primers immobilized to the support and a fifth type--pseudo-monoplex polymerase chain reaction (PCR) of multiple targets in solution, directed by a single pair of unbound universal primers. The addition of the universal primers in the reaction mixture increases the yield over the traditional "bridge" amplification on a solid support by approximately ten times. Methods that provide multitarget amplification and detection of as little as 0.45-4.5.times.10.sup.-12 g (equivalent to 10.sup.2-10.sup.3 genomes) of a bacterial genomic DNA are disclosed.

Nanopolyaniline as immobilization template for signal enhancement of surface plasmon resonance biosensor - A preliminary study

NASA Astrophysics Data System (ADS)

Kamarun, Dzaraini; Abdul Azem, Nor Hazirah Kamel; Sarijo, Siti Halimah; Mohd, Ahmad Faiza; Abdullah @ Mohd Noor, Mashita

2012-07-01

A technique for the enhancement of Surface Plasmon Resonance (SPR) signal for sensing biomolecular interactions is described. Polyaniline (PANI) of particle size in the range of 1 to 15 nm was synthesized and used as the template for the immobilization of protein molecules. Biomolecular interactions of unbound and PANI-bound proteins with antibody molecules were SPR-monitored using a model system comprising of Bovine Serum Albumin (BSA) and anti BSA. A 7-fold increased in the signal was recorded from interactions of the PANI-bound BSA with anti BSA compared to the interactions of its unbound counterpart. This preliminary observation provides new avenue in immunosensor technology for improving the detection sensitivity of SPR biosensor; and thereby increasing the lower detection limit of biomolecules.

Sensors closeness test based on an improved [0, 1] bounded Mahalanobis distance Δ{sup 2}

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

Masnan, Maz Jamilah, E-mail: mazjamilah@unimap.edu.my; Mahat, Nor Idayu, E-mail: noridayu@uum.edu.my; Shakaff, Ali Yeon Md, E-mail: aliyeon@unimap.edu.my

2015-12-11

Mahalanobis distance Δ{sup 2} values are commonly in the range of 0 to +∞ where higher values represent greater distance between class means or points. The increase in Mahalanobis distance is unbounded as the distance multiply. To certain extend, the unbounded distance values pose difficulties in the evaluation and decision for instance in the sensors closeness test. This paper proposes an approach to [0, 1] bounded Mahalanobis distance Δ{sup 2} that enable researcher to easily perform sensors closeness test. The experimental data of four different types of rice based on three different electronic nose sensors namely InSniff, PEN3, and Cyranose320more » were analyzed and sensor closeness test seems successfully performed within the [0, 1] bound.« less

Classical and quantum dynamics in an inverse square potential

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

Guillaumín-España, Elisa, E-mail: ege@correo.azc.uam.mx; Núñez-Yépez, H. N., E-mail: nyhn@xanum.uam.mx; Salas-Brito, A. L., E-mail: asb@correo.azc.uam.mx

2014-10-15

The classical motion of a particle in a 3D inverse square potential with negative energy, E, is shown to be geodesic, i.e., equivalent to the particle's free motion on a non-compact phase space manifold irrespective of the sign of the coupling constant. We thus establish that all its classical orbits with E < 0 are unbounded. To analyse the corresponding quantum problem, the Schrödinger equation is solved in momentum space. No discrete energy levels exist in the unrenormalized case and the system shows a complete “fall-to-the-center” with an energy spectrum unbounded by below. Such behavior corresponds to the non-existence ofmore » bound classical orbits. The symmetry of the problem is SO(3) × SO(2, 1) corroborating previously obtained results.« less

Analytical close-to-source investigation for an isotropic point source in an unbounded, anisotropically scattering medium

NASA Astrophysics Data System (ADS)

Rinzema, Kees; ten Bosch, Jaap J.; Ferwerda, Hedzer A.; Hoenders, Bernhard J.

1995-01-01

The diffusion approximation, which is often used to describe the propagation of light in biological tissues, is only good at a sufficient distance from sources and boundaries. Light- tissue interaction is however most intense in the region close to the source. It would therefore be interesting to study this region more closely. Although scattering in biological tissues is predominantly forward peaked, explicit solutions to the transport equation have only been obtained in the case of isotropic scattering. Particularly, for the case of an isotropic point source in an unbounded, isotropically scattering medium the solution is well known. We show that this problem can also be solved analytically if the scattering is no longer isotropic, while everything else remains the same.

Sources of unbounded priority inversions in real-time systems and a comparative study of possible solutions

NASA Technical Reports Server (NTRS)

Davari, Sadegh; Sha, Lui

1992-01-01

In the design of real-time systems, tasks are often assigned priorities. Preemptive priority driven schedulers are used to schedule tasks to meet the timing requirements. Priority inversion is the term used to describe the situation when a higher priority task's execution is delayed by lower priority tasks. Priority inversion can occur when there is contention for resources among tasks of different priorities. The duration of priority inversion could be long enough to cause tasks to miss their dead lines. Priority inversion cannot be completely eliminated. However, it is important to identify sources of priority inversion and minimize the duration of priority inversion. In this paper, a comprehensive review of the problem of and solutions to unbounded priority inversion is presented.

The range and valence of a real Smirnov function

NASA Astrophysics Data System (ADS)

Ferguson, Timothy; Ross, William T.

2018-02-01

We give a complete description of the possible ranges of real Smirnov functions (quotients of two bounded analytic functions on the open unit disk where the denominator is outer and such that the radial boundary values are real almost everywhere on the unit circle). Our techniques use the theory of unbounded symmetric Toeplitz operators, some general theory of unbounded symmetric operators, classical Hardy spaces, and an application of the uniformization theorem. In addition, we completely characterize the possible valences for these real Smirnov functions when the valence is finite. To do so we construct Riemann surfaces we call disk trees by welding together copies of the unit disk and its complement in the Riemann sphere. We also make use of certain trees we call valence trees that mirror the structure of disk trees.

Measurement of key resonances for the Al 24 ( p , γ ) Si 25 reaction rate using in-beam γ -ray spectroscopy

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

Longfellow, B.; Gade, A.; Brown, B. A.

Energy levels and branching ratios for the rp-process nucleus 25Si were determined from the reactions 9Be ( 26Si, 25Si) X and 9Be ( 25Al, 25Si) X using in-beam γ-ray spectroscopy with both high-efficiency and high-resolution detector arrays. Proton-unbound states at 3695(14) and 3802(11) keV were identified and assigned tentative spins and parities based on comparison to theory and the mirror nucleus. The 24Al (p, γ) 25Si reaction rate was calculated using the experimental states and states from charge-dependent USDA and USDB shell-model calculations with downward shifts of the 1s 1/2 proton orbital to account for the observed Thomas-Ehrman shift, leadingmore » to a factor of 10–100 increase in rate for the temperature region of 0.22 GK as compared to a previous calculation. These shifts may be applicable to neighboring nuclei, impacting the proton capture rates in this region of the chart.« less

Measurement of key resonances for the Al 24 ( p , γ ) Si 25 reaction rate using in-beam γ -ray spectroscopy

DOE PAGES

Longfellow, B.; Gade, A.; Brown, B. A.; ...

2018-05-04

Energy levels and branching ratios for the rp-process nucleus 25Si were determined from the reactions 9Be ( 26Si, 25Si) X and 9Be ( 25Al, 25Si) X using in-beam γ-ray spectroscopy with both high-efficiency and high-resolution detector arrays. Proton-unbound states at 3695(14) and 3802(11) keV were identified and assigned tentative spins and parities based on comparison to theory and the mirror nucleus. The 24Al (p, γ) 25Si reaction rate was calculated using the experimental states and states from charge-dependent USDA and USDB shell-model calculations with downward shifts of the 1s 1/2 proton orbital to account for the observed Thomas-Ehrman shift, leadingmore » to a factor of 10–100 increase in rate for the temperature region of 0.22 GK as compared to a previous calculation. These shifts may be applicable to neighboring nuclei, impacting the proton capture rates in this region of the chart.« less

Understanding the EF-hand closing pathway using non-biased interatomic potentials.

PubMed

Dupuis, L; Mousseau, Normand

2012-01-21

The EF-hand superfamily of proteins is characterized by the presence of calcium binding helix-loop-helix structures. Many of these proteins undergo considerable motion responsible for a wide range of properties upon binding but the exact mechanism at the root of this motion is not fully understood. Here, we use an unbiased accelerated multiscale simulation scheme, coupled with two force fields - CHARMM-EEF1 and the extended OPEP - to explore in details the closing pathway, from the unbound holo state to the closed apo state, of two EF-hand proteins, the Calmodulin and Troponin C N-terminal nodules. Based on a number of closing simulations for these two sequences, we show that the EF-hand β-scaffold, identified as crucial by Grabarek for the EF-hand opening driven by calcium binding, is also important in closing the EF-hand. We also show the crucial importance of the phenylalanine situated at the end of first EF-hand helix, and identify an intermediate state modulating its behavior, providing a detailed picture of the closing mechanism for these two representatives of EF-hand proteins. © 2012 American Institute of Physics

Influence of Sampling on the Determination of Warfarin and Warfarin Alcohols in Oral Fluid

PubMed Central

Lomonaco, Tommaso; Ghimenti, Silvia; Piga, Isabella; Biagini, Denise; Onor, Massimo; Fuoco, Roger; Di Francesco, Fabio

2014-01-01

Background and Objective The determination of warfarin, RS/SR- and RR/SS-warfarin alcohols in oral fluid may offer additional information to the INR assay. This study aimed to establish an optimized sampling technique providing the best correlation between the oral fluid and the unbound plasma concentrations of these compounds. Materials and Methods Samples of non-stimulated and stimulated oral fluid, and blood were collected from 14 patients undergoing warfarin therapy. After acidification, analytes were extracted with a dichloromethane/hexane mixture and determined by HPLC with fluorescence detection. Plasma samples were also ultrafiltered for the determination of the unbound fraction. The chromatographic separation was carried out in isocratic conditions with a phosphate buffer/methanol mobile phase on a C-18 reversed-phase column. The absence of interfering compounds was verified by HPLC-ESI-Q-TOF. Results Stimulation generally increased the oral fluid pH to values close to blood pH in about 6 minutes. The concentration of warfarin and RS/SR-warfarin alcohols in oral fluid followed the same trend, whereas the concentration of RR/SS-warfarin alcohols was not affected. Six minute stimulation with chewing gum followed by collection with a polyester swab was the best sampling procedure, with a good repeatability (RSD <10%) and relatively low inter-subject variability (RSD  = 30%) of the oral fluid to plasma ratio. This procedure provided strong correlations between the measured oral fluid and unbound plasma concentration of warfarin (r  =  0.92, p <0.001) and RS/SR-warfarin alcohols (r  =  0.84, p <0.001), as well as between stimulated oral fluid and total plasma concentration of warfarin (r  =  0.78, p <0.001) and RS/SR-warfarin alcohols (r  =  0.81, p <0.001). Conclusion The very good correlation between oral fluid and unbound plasma concentration of warfarin and RS/SR-warfarin alcohols suggests that oral fluid analysis could provide clinically useful information for the monitoring of anticoagulant therapy, complementary to the INR assay. PMID:25478864

Ground-state properties of H 5 from the He 6 ( d , He 3 ) H 5 reaction

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

Wuosmaa, A. H.; Bedoor, S.; Brown, K. W.

2017-01-01

We have studied the ground state of the unbound, very neutron-rich isotope of hydrogen 5H, using the 6He(d,3He)5H reaction in inverse kinematics at a bombarding energy of E(6He)=55A MeV. The present results suggest a ground-state resonance energy ER=2.4±0.3 MeV above the 3H+2n threshold, with an intrinsic width of Γ=5.3±0.4 MeV in the 5H system. Both the resonance energy and width are higher than those reported in some, but not all previous studies of 5H. The previously unreported 6He(d,t)5Heg.s. reaction is observed in the same measurement, providing a check on the understanding of the response of the apparatus. The data aremore » compared to expectations from direct two-neutron and dineutron decay. The possibility of excited states of 5H populated in this reaction is discussed using different calculations of the 6He→5H+p spectroscopic overlaps from shell-model and ab initio nuclear-structure calculations.« less

DOTAP cationic liposomes prefer relaxed over supercoiled plasmids.

PubMed

Even-Chen, S; Barenholz, Y

2000-12-20

Cationic liposomes and DNA interact electrostatically to form complexes called lipoplexes. The amounts of unbound (free) DNA in a mixture of cationic liposomes and DNA at different cationic lipid:DNA molar ratios can be used to describe DNA binding isotherms; these provide a measure of the binding efficiency of DNA to different cationic lipid formulations at various medium conditions. In order to quantify the ratio between the various forms of naked DNA and supercoiled, relaxed and single-stranded DNA, and the ratio between cationic lipid bound and unbound DNA of various forms we developed a simple, sensitive quantitative assay using agarose gel electrophoresis, followed by staining with the fluorescent cyanine DNA dyes SYBR Green I or SYBR Gold. This assay was compared with that based on the use of ethidium bromide (the most commonly used nucleic acid stain). Unlike ethidium bromide, SYBR Green I DNA sensitivity and concentration-dependent fluorescence intensity were identical for supercoiled and nicked-relaxed forms. DNA detection by SYBR Green I in solution is approximately 40-fold more sensitive than by ethidium bromide for double-stranded DNA and approximately 10-fold for single-stranded DNA, and in agarose gel it is 16-fold more sensitive for double-stranded DNA compared with ethidium bromide. SYBR Gold performs similarly to SYBR Green I. This study shows that: (a) there is no significant difference in DNA binding isotherms to the monocationic DOTAP (DOTAP/DOPE) liposomes and to the polycationic DOSPA (DOSPA/DOPE) liposomes, even when four DOSPA positive charges are involved in the electrostatic interaction with DNA; (b) the helper lipids affect DNA binding, as DOTAP/DOPE liposomes bind more DNA than DOTAP/cholesterol; (c) in the process of lipoplex formation, when the DNA is a mixture of two forms, supercoiled and nicked-relaxed (open circular), there is a preference for the binding to the cationic liposomes of plasmid DNA in the nicked-relaxed over the supercoiled form. This preference is much more pronounced when the cationic liposome formulation is based on the monocationic lipid DOTAP than on the polycationic lipid DOSPA. The preference of DOTAP formulations to bind to the relaxed DNA plasmid suggests that the binding of supercoiled DNA is weaker and easier to dissociate from the complex.

Meso-Beta scale numerical simulation studies of terrain-induced jet streak mass/momentum perturbations

NASA Technical Reports Server (NTRS)

Lin, Yuh-Lang; Kaplan, Michael L.

1993-01-01

The Control-B simulation experiment was designed to improve on the Control-A experiment performed with the GMASS model. This experiment addressed several inadequacies with the first smooth terrain numerical simulation by including: (1) increased nested-grid resolution to better define the simulated gravity waves, (2) increased horizontal diffusion to remove outflow boundary condition noise, and (3) the use of reanalyzed rawinsonde data and surface observations in the initial state to increase the definition of the observed jet streak as well as other low-level features. A smoothed-terrain dry simulation with the nested-grid GMASS model has revealed many important aspects of the processes which resulted in the generation of gravity waves in the region and time when and where they were observed. However, the vertical structure, number, and characteristics of the waves are still quite different from observed waves as diagnosed thus necessitating future improved simulations. However, this control simulation has produced substantial insight into processes which occur on many spatial scales over a 30 hour time period thus allowing one to draw promising inferences as to the mechanisms for the complex process which occurred in nature during the CCOPE case study. The theoretical aspects of the project have focus on understanding the nature of the ageostrophic circulations which are produced in idealized models of the atmosphere in which the troposphere is modeled in one of two ways. The first model assumes that the lower atmosphere can be represented as a single layer of homogeneous fluid whose upper surface is free to exhibit vertical displacement. Two-dimensional internal convergence (divergence) occurring during the adjustment to an asymptotic equilibrium state from an ageostrophic initial state whose momentum structure is representative of a midlatitude localized zonal wind anomaly will cause the free upper surface of the homogeneous atmosphere to rise (fall), and therefore the response can be viewed as being physically three-dimensional. The second model assumes that the troposphere can be represented by an unbounded continuously stratified Boussinesq fluid of constant Brunt-Vaisala frequency N, where the vertical gradient of the basic state potential temperature profile allows for the existence of vertically propagating internal inertia-gravity waves.

Consideration of plant behaviour in optimal servo-compensator design

NASA Astrophysics Data System (ADS)

Moase, W. H.; Manzie, C.

2016-07-01

Where the most prevalent optimal servo-compensator formulations penalise the behaviour of an error system, this paper considers the problem of additionally penalising the actual states and inputs of the plant. Doing so has the advantage of enabling the penalty function to better resemble an economic cost. This is especially true of problems where control effort needs to be sensibly allocated across weakly redundant inputs or where one wishes to use penalties to soft-constrain certain states or inputs. It is shown that, although the resulting cost function grows unbounded as its horizon approaches infinity, it is possible to formulate an equivalent optimisation problem with a bounded cost. The resulting optimisation problem is similar to those in earlier studies but has an additional 'correction term' in the cost function, and a set of equality constraints that arise when there are redundant inputs. A numerical approach to solve the resulting optimisation problem is presented, followed by simulations on a micro-macro positioner that illustrate the benefits of the proposed servo-compensator design approach.

Rigorously modeling self-stabilizing fault-tolerant circuits: An ultra-robust clocking scheme for systems-on-chip.

PubMed

Dolev, Danny; Függer, Matthias; Posch, Markus; Schmid, Ulrich; Steininger, Andreas; Lenzen, Christoph

2014-06-01

We present the first implementation of a distributed clock generation scheme for Systems-on-Chip that recovers from an unbounded number of arbitrary transient faults despite a large number of arbitrary permanent faults. We devise self-stabilizing hardware building blocks and a hybrid synchronous/asynchronous state machine enabling metastability-free transitions of the algorithm's states. We provide a comprehensive modeling approach that permits to prove, given correctness of the constructed low-level building blocks, the high-level properties of the synchronization algorithm (which have been established in a more abstract model). We believe this approach to be of interest in its own right, since this is the first technique permitting to mathematically verify, at manageable complexity, high-level properties of a fault-prone system in terms of its very basic components. We evaluate a prototype implementation, which has been designed in VHDL, using the Petrify tool in conjunction with some extensions, and synthesized for an Altera Cyclone FPGA.

Distribution of chaos and periodic spikes in a three-cell population model of cancer. Auto-organization of oscillatory phases in parameter planes

NASA Astrophysics Data System (ADS)

Gallas, Michelle R.; Gallas, Marcia R.; Gallas, Jason A. C.

2014-10-01

We study complex oscillations generated by the de Pillis-Radunskaya model of cancer growth, a model including interactions between tumor cells, healthy cells, and activated immune system cells. We report a wide-ranging systematic numerical classification of the oscillatory states and of their relative abundance. The dynamical states of the cell populations are characterized here by two independent and complementary types of stability diagrams: Lyapunov and isospike diagrams. The model is found to display stability phases organized regularly in old and new ways: Apart from the familiar spirals of stability, it displays exceptionally long zig-zag networks and intermixed cascades of two- and three-doubling flanked stability islands previously detected only in feedback systems with delay. In addition, we also characterize the interplay between continuous spike-adding and spike-doubling mechanisms responsible for the unbounded complexification of periodic wave patterns. This article is dedicated to Prof. Hans Jürgen Herrmann on the occasion of his 60th birthday.

Dynamics in atomic signaling games.

PubMed

Fox, Michael J; Touri, Behrouz; Shamma, Jeff S

2015-07-07

We study an atomic signaling game under stochastic evolutionary dynamics. There are a finite number of players who repeatedly update from a finite number of available languages/signaling strategies. Players imitate the most fit agents with high probability or mutate with low probability. We analyze the long-run distribution of states and show that, for sufficiently small mutation probability, its support is limited to efficient communication systems. We find that this behavior is insensitive to the particular choice of evolutionary dynamic, a property that is due to the game having a potential structure with a potential function corresponding to average fitness. Consequently, the model supports conclusions similar to those found in the literature on language competition. That is, we show that efficient languages eventually predominate the society while reproducing the empirical phenomenon of linguistic drift. The emergence of efficiency in the atomic case can be contrasted with results for non-atomic signaling games that establish the non-negligible possibility of convergence, under replicator dynamics, to states of unbounded efficiency loss. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rigorously modeling self-stabilizing fault-tolerant circuits: An ultra-robust clocking scheme for systems-on-chip☆

PubMed Central

Dolev, Danny; Függer, Matthias; Posch, Markus; Schmid, Ulrich; Steininger, Andreas; Lenzen, Christoph

2014-01-01

We present the first implementation of a distributed clock generation scheme for Systems-on-Chip that recovers from an unbounded number of arbitrary transient faults despite a large number of arbitrary permanent faults. We devise self-stabilizing hardware building blocks and a hybrid synchronous/asynchronous state machine enabling metastability-free transitions of the algorithm's states. We provide a comprehensive modeling approach that permits to prove, given correctness of the constructed low-level building blocks, the high-level properties of the synchronization algorithm (which have been established in a more abstract model). We believe this approach to be of interest in its own right, since this is the first technique permitting to mathematically verify, at manageable complexity, high-level properties of a fault-prone system in terms of its very basic components. We evaluate a prototype implementation, which has been designed in VHDL, using the Petrify tool in conjunction with some extensions, and synthesized for an Altera Cyclone FPGA. PMID:26516290

Mechanistic insights into Pin1 peptidyl-prolyl cis-trans isomerization from umbrella sampling simulations.

PubMed

Di Martino, Giovanni Paolo; Masetti, Matteo; Cavalli, Andrea; Recanatini, Maurizio

2014-11-01

The peptidyl-proyl isomerase Pin1 plays a key role in the regulation of phospho(p)-Ser/Thr-Pro proteins, acting as a molecular timer of the cell cycle. After recognition of these motifs, Pin1 catalyzes the rapid cis-trans isomerization of proline amide bonds of substrates, contributing to maintain the equilibrium between the two conformations. Although a great interest has arisen on this enzyme, its catalytic mechanism has long been debated. Here, the cis-trans isomerization of a model peptide system was investigated by means of umbrella sampling simulations in the Pin1-bound and unbound states. We obtained free energy barriers consistent with experimental data, and identified several enzymatic features directly linked to the acceleration of the prolyl bond isomerization. In particular, an enhanced autocatalysis, the stabilization of perturbed ground state conformations, and the substrate binding in a procatalytic conformation were found as main contributions to explain the lowering of the isomerization free energy barrier. © 2014 Wiley Periodicals, Inc.

Increase in tiagabine serum concentration with coadministration of gemfibrozil.

PubMed

Burstein, Aaron H; Boudreau, Eilis A; Theodore, William H

2009-02-01

To report a case of possible acute tiagabine toxicity secondary to administration of gemfibrozil. A 39-year-old male was taking tiagabine 16 mg orally 3 times per day and carbamazepine 500 mg orally twice per day for complex partial seizures secondary to mesial temporal sclerosis. He was found to have type IV hypertriglyceridemia and was prescribed gemfibrozil. Because he reported severe confusion and altered consciousness shortly after a single 600-mg dose of gemfibrozil, he was admitted for controlled challenge with that drug. A single 300-mg dose of gemfibrozil resulted in lightheadedness and led to a 59% and 75% increase in total tiagabine serum concentrations at 2 and 5 hours, respectively, without significant change in baseline carbamazepine concentrations. This is the first report of an interaction between the widely used antihyperlipidemic drug gemfibrozil and tiagabine. Since tiagabine, which was originally developed as an antiepileptic medication, is now being used widely for a variety of other indications such as anxiety and depression, there is an increased risk for clinically significant interactions with gemfibrozil. Increased total and unbound tiagabine concentrations following a single 300-mg dose of gemfibrozil and reproduction of clinical symptoms with gemfibrozil rechallenge suggests the toxicity our patient experienced was due to a pharmacokinetic drug interaction. Use of the Horn Drug Interaction Probability Scale showed a probable interaction between gemfibrozil and tiagabine.

Propagation of arbitrary initial wave packets in a quantum parametric oscillator: Instability zones for higher order moments

NASA Astrophysics Data System (ADS)

Biswas, Subhadip; Chattopadhyay, Rohitashwa; Bhattacharjee, Jayanta K.

2018-05-01

We consider the dynamics of a particle in a parametric oscillator with a view to exploring any quantum feature of the initial wave packet that shows divergent (in time) behaviour for parameter values where the classical motion dynamics of the mean position is bounded. We use Ehrenfest's theorem to explore the dynamics of nth order moment which reduces exactly to a linear non autonomous differential equation of order n + 1. It is found that while the width and skewness of the packet is unbounded exactly in the zones where the classical motion is unbounded, the kurtosis of an initially non-gaussian wave packet can become infinitely large in certain additional zones. This implies that the shape of the wave packet can change drastically with time in these zones.

Cryptic binding sites on proteins: definition, detection, and druggability.

PubMed

Vajda, Sandor; Beglov, Dmitri; Wakefield, Amanda E; Egbert, Megan; Whitty, Adrian

2018-05-22

Many proteins in their unbound structures lack surface pockets appropriately sized for drug binding. Hence, a variety of experimental and computational tools have been developed for the identification of cryptic sites that are not evident in the unbound protein but form upon ligand binding, and can provide tractable drug target sites. The goal of this review is to discuss the definition, detection, and druggability of such sites, and their potential value for drug discovery. Novel methods based on molecular dynamics simulations are particularly promising and yield a large number of transient pockets, but it has been shown that only a minority of such sites are generally capable of binding ligands with substantial affinity. Based on recent studies, current methodology can be improved by combining molecular dynamics with fragment docking and machine learning approaches. Copyright © 2018 Elsevier Ltd. All rights reserved.

The lift force on a drop in unbounded plane Poiseuille flow

NASA Technical Reports Server (NTRS)

Wohl, P. R.

1976-01-01

The lift force on a deformable liquid sphere moving in steady, plane Poiseuille-Stokes flow and subjected to an external body force is calculated. The results are obtained by seeking a solution to Stokes' equations for the motion of the liquids inside and outside the slightly perturbed sphere surface, as expansions valid for small values of the ratio of the Weber number to the Reynolds number. When the ratio of the drop and external fluid viscosities is small, the lift exerted on a neutrally buoyant drop is found to be approximately one-tenth of the magnitude of the force reported by Wohl and Rubinow acting on the same drop in unbounded Poiseuille flow in a tube. The resultant trajectory of the drop is calculated and displayed as a function of the external body force.

A rapid procedure for measurement of the free testosterone fraction in human plasma using the centria radioimmunoassay centrifugal analyzer.

PubMed

Schwarz, S; Boyd, J

1981-01-01

Following the incubation of plasma with a tracer amount of tritiated testosterone, the reaction mixture is separated into a sex hormone-binding globulin bound and an unbound fraction of radioligand using DEAE-cellulose columns placed in the incubator-separator module of the Centria radioimmunoassay centrifugal analyzer. Neural Tris-buffer elutes unbound steroid from the matrix, while acidic Tris-buffer can remove the protein-bound fraction in a subsequent step. Complementary and thus qualitatively equal results are obtained when counting either eluate. Comparison of this technique with an ammonium sulfate precipitation method showed high correlation. Free testosterone indices as determined by the Centria modification in a number of prepuberal children, normal men and women, as well as pregnant and hirsute women similar to those previously reported.

Parabolic transformation cloaks for unbounded and bounded cloaking of matter waves

NASA Astrophysics Data System (ADS)

Chang, Yu-Hsuan; Lin, De-Hone

2014-01-01

Parabolic quantum cloaks with unbounded and bounded invisible regions are presented with the method of transformation design. The mass parameters of particles for perfect cloaking are shown to be constant along the parabolic coordinate axes of the cloaking shells. The invisibility performance of the cloaks is inspected from the viewpoints of waves and probability currents. The latter shows the controllable characteristic of a probability current by a quantum cloak. It also provides us with a simpler and more efficient way of exhibiting the performance of a quantum cloak without the solutions of the transformed wave equation. Through quantitative analysis of streamline structures in the cloaking shell, one defines the efficiency of the presented quantum cloak in the situation of oblique incidence. The cloaking models presented here give us more choices for testing and applying quantum cloaking.

Determination of Cefalothin and Cefazolin in Human Plasma, Urine and Peritoneal Dialysate by UHPLC-MS/MS: application to a pilot pharmacokinetic study in humans.

PubMed

Parker, Suzanne L; Guerra Valero, Yarmarly C; Roberts, Darren M; Lipman, Jeffrey; Roberts, Jason A; Wallis, Steven C

2016-06-01

An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the analysis of cefazolin and cefalothin in human plasma (total and unbound), urine and peritoneal dialysate has been developed and validated. Total plasma concentrations are measured following protein precipitation and are suitable for the concentration range of 1-500 µg/mL. Unbound concentrations are measured from ultra-filtered plasma acquired using Centrifree(®) devices and are suitable for the concentration range of 0.1-500 µg/mL for cefazolin and 1-500 µg/mL for cefalothin. The urine method is suitable for a concentration range of 0.1-20 mg/mL for cefazolin and 0.2-20 mg/mL for cefalothin. Peritoneal dialysate concentrations are measured using direct injection, and are suitable for the concentration range of 0.2-100 µg/mL for both cefazolin and cefalothin. The cefazolin and cefalothin plasma (total and unbound), urine and peritoneal dialysate results are reported for recovery, inter-assay precision and accuracy, and the lower limit of quantification, linearity, stability and matrix effects, with all results meeting acceptance criteria. The method was used successfully in a pilot pharmacokinetic study with patients with peritoneal dialysis-associated peritonitis, receiving either intraperitoneal cefazolin or cefalothin. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Measuring in vitro biotransformation rates of super hydrophobic chemicals in rat liver s9 fractions using thin-film sorbent-phase dosing.

PubMed

Lee, Yung-Shan; Otton, S Victoria; Campbell, David A; Moore, Margo M; Kennedy, Chris J; Gobas, Frank A P C

2012-01-03

Methods for rapid and cost-effective assessment of the biotransformation potential of very hydrophobic and potentially bioaccumulative chemicals in mammals are urgently needed for the ongoing global evaluation of the environmental behavior of commercial chemicals. We developed and tested a novel solvent-free, thin-film sorbent-phase in vitro dosing system to measure the in vitro biotransformation rates of very hydrophobic chemicals in male Sprague-Dawley rat liver S9 homogenates and compared the rates to those measured by conventional solvent-delivery dosing. The thin-film sorbent-phase dosing system using ethylene vinyl acetate coated vials was developed to eliminate the incomplete dissolution of very hydrophobic substances in largely aqueous liver homogenates, to determine biotransformation rates at low substrate concentrations, to measure the unbound fraction of substrate in solution, and to simplify chemical analysis by avoiding the difficult extraction of test chemicals from complex biological matrices. Biotransformation rates using sorbent-phase dosing were 2-fold greater than those measured using solvent-delivery dosing. Unbound concentrations of very hydrophobic test chemicals were found to decline with increasing S9 and protein concentrations, causing measured biotransformation rates to be independent of S9 or protein concentrations. The results emphasize the importance of specifying both protein content and unbound substrate fraction in the measurement and reporting of in vitro biotransformation rates of very hydrophobic substances, which can be achieved in a thin-film sorbent-phase dosing system.

Bounded and unbounded boundaries - Untangling mechanisms for estuarine-marine ecological connectivity: Scales of m to 10,000 km - A review

NASA Astrophysics Data System (ADS)

Wolanski, Eric

2017-11-01

Recent advances in our understanding of the self-recruitment and connectivity of estuarine and coastal fauna and flora were made possible by an integration of physical oceanographic observations and modelling with results from studies of the behaviour of the seeds, eggs, larvae, propagules, juveniles and polyps, of population dynamics, microchemical tagging using natural and artificial markers, genetics and direct observations of trajectories. The species studied in those case studies were jellyfish in marine lakes, corals in acidified bays, seagrass, mangrove propagules, mussels and oysters, prawns, some estuarine fish larvae, the copepod Calanus finmarchius in the North Sea, sea turtles in the Coral Sea, and the ornate spiny lobster Panulirus ornatus in the Southeast Asia archipelago. The spatial scales for self-recruitment and connectivity vary with the species from a few m to 10,000 km, and the temporal scales vary from one to three generations. These studies suggest that, with increasing physical openness of a given site for a given species, self-recruiting increasingly relies on the behaviour of the species. Estuarine and coastal systems thus are simultaneously bounded and unbounded depending on the sites and the species considered and, although often ignored, the integration of oceanographic and behavioural understanding is increasingly required. This paper has shown the importance of understanding the hydrological and ecological dynamics with unbounded boundaries in creating the connectivity between parts of the aquatic continuum from the river catchment to the open seas.

Coupling of active motion and advection shapes intracellular cargo transport.

PubMed

Khuc Trong, Philipp; Guck, Jochen; Goldstein, Raymond E

2012-07-13

Intracellular cargo transport can arise from passive diffusion, active motor-driven transport along cytoskeletal filament networks, and passive advection by fluid flows entrained by such cargo-motor motion. Active and advective transport are thus intrinsically coupled as related, yet different representations of the same underlying network structure. A reaction-advection-diffusion system is used here to show that this coupling affects the transport and localization of a passive tracer in a confined geometry. For sufficiently low diffusion, cargo localization to a target zone is optimized either by low reaction kinetics and decoupling of bound and unbound states, or by a mostly disordered cytoskeletal network with only weak directional bias. These generic results may help to rationalize subtle features of cytoskeletal networks, for example as observed for microtubules in fly oocytes.

Electrohydrodynamic Quincke rotation of a prolate ellipsoid

NASA Astrophysics Data System (ADS)

Brosseau, Quentin; Hickey, Gregory; Vlahovska, Petia M.

2017-01-01

We study experimentally the occurrence of spontaneous spinning (Quincke rotation) of an ellipsoid in a uniform direct current (dc) electric field. For an ellipsoid suspended in an unbounded fluid, we find two stable states characterized by the orientation of the ellipsoid long axis relative to the applied electric field: spinless (parallel) and spinning (perpendicular). The phase diagram of ellipsoid behavior as a function of field strength and aspect ratio is in close agreement with the theory of Cēbers et al. [Phys. Rev. E 63, 016301 (2000)], 10.1103/PhysRevE.63.016301. We also investigate the dynamics of the ellipsoidal Quincke rotor resting on a planar surface with normal perpendicular to the field direction. We find behaviors, such as swinging (long axis oscillating around the applied field direction) and tumbling, due to the confinement.

How Many-Body Correlations and α Clustering Shape He 6

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

Romero-Redondo, Carolina; Quaglioni, Sofia; Navrátil, Petr

The Borromean 6He nucleus is an exotic system characterized by two halo neutrons orbiting around a compact 4He (or α) core, in which the binary subsystems are unbound. The simultaneous reproduction of its small binding energy and extended matter and point-proton radii has been a challenge for ab initio theoretical calculations based on traditional bound-state methods. Using soft nucleon-nucleon interactions based on chiral effective field theory potentials, we show that supplementing the model space with 4He + n + n cluster degrees of freedom largely solves this issue. Lastly, we analyze the role played by α clustering and many-body correlations,more » and study the dependence of the energy spectrum on the resolution scale of the interaction.« less

The axisymmetric elasticity problem for a laminated plate containing a circular hole

NASA Technical Reports Server (NTRS)

Delale, F.; Erdogan, F.

1981-01-01

The elasticity problem for a laminated thick plate which consists of two bonded dissimilar layers and which contains a circular hole is considered. The problem is formulated for arbitrary axisymmetric tractions on the hole surface by using the Love strain function. Through the expansion of the boundary conditions into Fourier series the problem is reduced to an infinite system of algebraic equations which is solved by the method of reduction. Of particular interest in the problem are the stresses along the interface as they relate to the question of delamination failure of the composite plate. These stresses are calculated and are observed to become unbounded at the hole boundary. An approximate treatment of the singular behavior of the stress state is presented and the stress intensity factors are calculated.

Borromean Windows for Three-Particle Systems under Screened Coulomb Interactions

NASA Astrophysics Data System (ADS)

Jiang, Zi-Shi; Song, Xiu-Dan; Zhou, Lin; Kar, Sabyasachi

2017-05-01

We have carried out calculations to search Borromean windows (BWs) for 11 different three-body systems interacting with screened Coulomb (Yukawa-type) potentials using Hylleraas-type wave functions within the framework of a variational approach. The critical values of the screening parameters for the ground states of the systems under consideration are reported for which the three-body systems are stable, while all the possible fragments are unbound; that is, it shows windows for Borromean binding. Supported by the National Natural Science Foundation of China under Grant No. 11304086, the University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province of China under Grant No. UNPYSCT-2015019, and the Natural Science Foundation for Distinguished Young Scholars in Heilongjiang University under Grant No. JCL201503

How Many-Body Correlations and α Clustering Shape He 6

DOE PAGES

Romero-Redondo, Carolina; Quaglioni, Sofia; Navrátil, Petr; ...

2016-11-23

The Borromean 6He nucleus is an exotic system characterized by two halo neutrons orbiting around a compact 4He (or α) core, in which the binary subsystems are unbound. The simultaneous reproduction of its small binding energy and extended matter and point-proton radii has been a challenge for ab initio theoretical calculations based on traditional bound-state methods. Using soft nucleon-nucleon interactions based on chiral effective field theory potentials, we show that supplementing the model space with 4He + n + n cluster degrees of freedom largely solves this issue. Lastly, we analyze the role played by α clustering and many-body correlations,more » and study the dependence of the energy spectrum on the resolution scale of the interaction.« less

Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive

PubMed Central

Hofmann, Birte; Reinecke, Isabel; Schuett, Barbara; Merz, Martin; Zurth, Christian

2014-01-01

Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). Materials: Participants were healthy, non-obese women aged 18 – 45 years (study 1) or 18 – 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P–M–E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M–P–E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 – 1.16), indicating average daily delivery similar to oral administration of 0.019 – 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 – 0.885), indicating average daily delivery from the patch of 0.057 – 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0–168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 – 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives. PMID:25295716

Binary-corrected velocity dispersions from single- and multi-epoch radial velocities: massive stars in R136 as a test case

NASA Astrophysics Data System (ADS)

Cottaar, M.; Hénault-Brunet, V.

2014-02-01

Orbital motions from binary stars can broaden the observed line-of-sight velocity distribution of a stellar system and artificially inflate the measured line-of-sight velocity dispersion, which can in turn lead to erroneous conclusions about the dynamical state of the system. Recently, a maximum-likelihood procedure was proposed to recover the intrinsic velocity dispersion of a resolved star cluster from a single epoch of radial velocity data of individual stars, which was achieved by simultaneously fitting the intrinsic velocity distribution of the single stars and the centers of mass of the binaries along with the velocity shifts caused by binary orbital motions. Assuming well-characterized binary properties, this procedure can accurately reproduce intrinsic velocity dispersions below 1 km s-1 for solar-type stars. Here we investigate the systematic offsets induced when the binary properties are uncertain and we show that two epochs of radial velocity data with an appropriate baseline can help to mitigate these systematic effects. We first test the method described above using Monte Carlo simulations, taking into account the large uncertainties in the binary properties of OB stars. We then apply it to radial velocity data in the young massive cluster R136 for which the intrinsic velocity dispersion of O-type stars is known from an intensive multi-epoch approach. For typical velocity dispersions of young massive clusters (≳4 km s-1) and with a single epoch of data, we demonstrate that the method can just about distinguish between a cluster in virial equilibrium and an unbound cluster. This is due to the higher spectroscopic binary fraction and more loosely constrained distributions of orbital parameters of OB stars compared to solar-type stars. By extending the maximum-likelihood method to multi-epoch data, we show that the accuracy on the fitted velocity dispersion can be improved by only a few percent by using only two epochs of radial velocities. This procedure offers a promising method of accurately measuring the intrinsic stellar velocity dispersion in other systems for which the binary properties are poorly constrained, for example, young clusters and associations whose luminosity is dominated by OB stars. Appendix A is available in electronic form at http://www.aanda.org

Glucuronidation and Sulfation Kinetics of Diflunisal in Man.

NASA Astrophysics Data System (ADS)

Loewen, Gordon Rapheal

Diflunisal is a nonsteroidal anti-inflammatory drug used in the treatment of arthritis and musculoskeletal pain. Diflunisal exhibits concentration- and dose-dependent kinetics, the mechanism of which has not been determined. The purpose of this study was to determine the mechanism(s) responsible for non-linear disposition of diflunisal and to examine environmental factors which may affect the elimination of diflunisal. The metabolites of diflunisal, including a new metabolite, the sulphate conjugate, were purified by column and semi-preparative high pressure liquid chromatography. Assays for the quantitation of diflunisal and conjugates in urine and diflunisal in plasma were developed. Plasma protein binding of diflunisal in blank plasma and in plasma obtained following multiple doses of diflunisal was determined by equilibrium dialysis. Total body clearance of diflunisal decreased when dose increased from 100 to 750 mg. Total clearance increased when dose increased from 750 to 1000 mg. The percent of recovered dose eliminated as the acyl glucuronide decreased and the percent eliminated as the sulphate increased with increasing dose of diflunisal. Plasma protein binding of diflunisal was concentration dependent over a range of diflunisal plasma concentrations of 3 to 257 mug/ml. Total clearance, and to a lesser degree, unbound clearance of diflunisal were decreased following multiple dose administration of 250 and 500 mg diflunisal. Percent of recovered dose eliminated as the acyl glucuronide decreased and percent eliminated as the sulphate conjugate increased following multiple dosing. Plasma protein binding of diflunisal was similar in blank plasma and plasma obtained at steady state. Unbound clearance of diflunisal exceeded liver plasma flow. Frequency distributions of the elimination of the conjugates of diflunisal were normally distributed. Sex, smoking, and use of vitamins or oral contraceptives were identified as factors which may affect the elimination of diflunisal.

Three-Dimensional General-Relativistic Magnetohydrodynamic Simulations of Remnant Accretion Disks from Neutron Star Mergers: Outflows and r -Process Nucleosynthesis

NASA Astrophysics Data System (ADS)

Siegel, Daniel M.; Metzger, Brian D.

2017-12-01

The merger of binary neutron stars, or of a neutron star and a stellar-mass black hole, can result in the formation of a massive rotating torus around a spinning black hole. In addition to providing collimating media for γ -ray burst jets, unbound outflows from these disks are an important source of mass ejection and rapid neutron capture (r -process) nucleosynthesis. We present the first three-dimensional general-relativistic magnetohydrodynamic (GRMHD) simulations of neutrino-cooled accretion disks in neutron star mergers, including a realistic equation of state valid at low densities and temperatures, self-consistent evolution of the electron fraction, and neutrino cooling through an approximate leakage scheme. After initial magnetic field amplification by magnetic winding, we witness the vigorous onset of turbulence driven by the magnetorotational instability (MRI). The disk quickly reaches a balance between heating from MRI-driven turbulence and neutrino cooling, which regulates the midplane electron fraction to a low equilibrium value Ye≈0.1 . Over the 380-ms duration of the simulation, we find that a fraction ≈20 % of the initial torus mass is unbound in powerful outflows with asymptotic velocities v ≈0.1 c and electron fractions Ye≈0.1 - 0.25 . Postprocessing the outflows through a nuclear reaction network shows the production of a robust second- and third-peak r process. Though broadly consistent with the results of previous axisymmetric hydrodynamical simulations, extrapolation of our results to late times suggests that the total ejecta mass from GRMHD disks is significantly higher. Our results provide strong evidence that postmerger disk outflows are an important site for the r process.

Dynamics of proteins aggregation. I. Universal scaling in unbounded media

NASA Astrophysics Data System (ADS)

Zheng, Size; Javidpour, Leili; Shing, Katherine S.; Sahimi, Muhammad

2016-10-01

It is well understood that in some cases proteins do not fold correctly and, depending on their environment, even properly-folded proteins change their conformation spontaneously, taking on a misfolded state that leads to protein aggregation and formation of large aggregates. An important factor that contributes to the aggregation is the interactions between the misfolded proteins. Depending on the aggregation environment, the aggregates may take on various shapes forming larger structures, such as protein plaques that are often toxic. Their deposition in tissues is a major contributing factor to many neuro-degenerative diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and prion. This paper represents the first part in a series devoted to molecular simulation of protein aggregation. We use the PRIME, a meso-scale model of proteins, together with extensive discontinuous molecular dynamics simulation to study the aggregation process in an unbounded fluid system, as the first step toward MD simulation of the same phenomenon in crowded cellular environments. Various properties of the aggregates have been computed, including dynamic evolution of aggregate-size distribution, mean aggregate size, number of peptides that contribute to the formation of β sheets, number of various types of hydrogen bonds formed in the system, radius of gyration of the aggregates, and the aggregates' diffusivity. We show that many of such quantities follow dynamic scaling, similar to those for aggregation of colloidal clusters. In particular, at long times the mean aggregate size S(t) grows with time as, S(t) ˜ tz, where z is the dynamic exponent. To our knowledge, this is the first time that the qualitative similarity between aggregation of proteins and colloidal aggregates has been pointed out.

Artificial Boundary Conditions for Computation of Oscillating External Flows

NASA Technical Reports Server (NTRS)

Tsynkov, S. V.

1996-01-01

In this paper, we propose a new technique for the numerical treatment of external flow problems with oscillatory behavior of the solution in time. Specifically, we consider the case of unbounded compressible viscous plane flow past a finite body (airfoil). Oscillations of the flow in time may be caused by the time-periodic injection of fluid into the boundary layer, which in accordance with experimental data, may essentially increase the performance of the airfoil. To conduct the actual computations, we have to somehow restrict the original unbounded domain, that is, to introduce an artificial (external) boundary and to further consider only a finite computational domain. Consequently, we will need to formulate some artificial boundary conditions (ABC's) at the introduced external boundary. The ABC's we are aiming to obtain must meet a fundamental requirement. One should be able to uniquely complement the solution calculated inside the finite computational domain to its infinite exterior so that the original problem is solved within the desired accuracy. Our construction of such ABC's for oscillating flows is based on an essential assumption: the Navier-Stokes equations can be linearized in the far field against the free-stream back- ground. To actually compute the ABC's, we represent the far-field solution as a Fourier series in time and then apply the Difference Potentials Method (DPM) of V. S. Ryaben'kii. This paper contains a general theoretical description of the algorithm for setting the DPM-based ABC's for time-periodic external flows. Based on our experience in implementing analogous ABC's for steady-state problems (a simpler case), we expect that these boundary conditions will become an effective tool for constructing robust numerical methods to calculate oscillatory flows.

Three-Dimensional General-Relativistic Magnetohydrodynamic Simulations of Remnant Accretion Disks from Neutron Star Mergers: Outflows and r-Process Nucleosynthesis.

PubMed

Siegel, Daniel M; Metzger, Brian D

2017-12-08

The merger of binary neutron stars, or of a neutron star and a stellar-mass black hole, can result in the formation of a massive rotating torus around a spinning black hole. In addition to providing collimating media for γ-ray burst jets, unbound outflows from these disks are an important source of mass ejection and rapid neutron capture (r-process) nucleosynthesis. We present the first three-dimensional general-relativistic magnetohydrodynamic (GRMHD) simulations of neutrino-cooled accretion disks in neutron star mergers, including a realistic equation of state valid at low densities and temperatures, self-consistent evolution of the electron fraction, and neutrino cooling through an approximate leakage scheme. After initial magnetic field amplification by magnetic winding, we witness the vigorous onset of turbulence driven by the magnetorotational instability (MRI). The disk quickly reaches a balance between heating from MRI-driven turbulence and neutrino cooling, which regulates the midplane electron fraction to a low equilibrium value Y_{e}≈0.1. Over the 380-ms duration of the simulation, we find that a fraction ≈20% of the initial torus mass is unbound in powerful outflows with asymptotic velocities v≈0.1c and electron fractions Y_{e}≈0.1-0.25. Postprocessing the outflows through a nuclear reaction network shows the production of a robust second- and third-peak r process. Though broadly consistent with the results of previous axisymmetric hydrodynamical simulations, extrapolation of our results to late times suggests that the total ejecta mass from GRMHD disks is significantly higher. Our results provide strong evidence that postmerger disk outflows are an important site for the r process.

Climate Change Impacts on Transportation; Groundwater Elevation, Road Performance, and Robust Adaptation

NASA Astrophysics Data System (ADS)

Kirshen, P. H.; Knott, J. F.; Ray, P.; Elshaer, M.; Daniel, J.; Jacobs, J. M.

2016-12-01

Transportation climate change vulnerability and adaptation studies have primarily focused on surface-water flooding from sea-level rise (SLR); little attention has been given to the effects of climate change and SLR on groundwater and subsequent impacts on the unbound foundation layers of coastal-road infrastructure. The magnitude of service-life reduction depends on the height of the groundwater in the unbound pavement materials, the pavement structure itself, and the loading. Using a steady-state groundwater model, and a multi-layer elastic pavement evaluation model, the strain changes in the layers can be determined as a function of parameter values and the strain changes translated into failure as measured by number of loading cycles to failure. For a section of a major coastal road in New Hampshire, future changes in sea-level, precipitation, temperature, land use, and groundwater pumping are characterized by deep uncertainty. Parameters that describe the groundwater system such as hydraulic conductivity can be probabilistically described while road characteristics are assumed to be deterministic. To understand the vulnerability of this road section, a bottom-up planning approach was employed over time where the combinations of parameter values that cause failure were determined and their plausibility of their occurring was analyzed. To design a robust adaptation strategy that will function reasonably well in the present and the future given the large number of uncertain parameter values, performance of adaptation options were investigated. Adaptation strategies that were considered include raising the road, load restrictions, increasing pavement layer thicknesses, replacing moisture-sensitive materials with materials that are not moisture sensitive, improving drainage systems, and treatment of the underlying materials.

Output Feedback Adaptive Control of Non-Minimum Phase Systems Using Optimal Control Modification

NASA Technical Reports Server (NTRS)

Nguyen, Nhan; Hashemi, Kelley E.; Yucelen, Tansel; Arabi, Ehsan

2018-01-01

This paper describes output feedback adaptive control approaches for non-minimum phase SISO systems with relative degree 1 and non-strictly positive real (SPR) MIMO systems with uniform relative degree 1 using the optimal control modification method. It is well-known that the standard model-reference adaptive control (MRAC) cannot be used to control non-SPR plants to track an ideal SPR reference model. Due to the ideal property of asymptotic tracking, MRAC attempts an unstable pole-zero cancellation which results in unbounded signals for non-minimum phase SISO systems. The optimal control modification can be used to prevent the unstable pole-zero cancellation which results in a stable adaptation of non-minimum phase SISO systems. However, the tracking performance using this approach could suffer if the unstable zero is located far away from the imaginary axis. The tracking performance can be recovered by using an observer-based output feedback adaptive control approach which uses a Luenberger observer design to estimate the state information of the plant. Instead of explicitly specifying an ideal SPR reference model, the reference model is established from the linear quadratic optimal control to account for the non-minimum phase behavior of the plant. With this non-minimum phase reference model, the observer-based output feedback adaptive control can maintain stability as well as tracking performance. However, in the presence of the mismatch between the SPR reference model and the non-minimum phase plant, the standard MRAC results in unbounded signals, whereas a stable adaptation can be achieved with the optimal control modification. An application of output feedback adaptive control for a flexible wing aircraft illustrates the approaches.

The mode of inhibitor binding to peptidyl-tRNA hydrolase: binding studies and structure determination of unbound and bound peptidyl-tRNA hydrolase from Acinetobacter baumannii.

PubMed

Kaushik, Sanket; Singh, Nagendra; Yamini, Shavait; Singh, Avinash; Sinha, Mau; Arora, Ashish; Kaur, Punit; Sharma, Sujata; Singh, Tej P

2013-01-01

The incidences of infections caused by an aerobic Gram-negative bacterium, Acinetobacter baumannii are very common in hospital environments. It usually causes soft tissue infections including urinary tract infections and pneumonia. It is difficult to treat due to acquired resistance to available antibiotics is well known. In order to design specific inhibitors against one of the important enzymes, peptidyl-tRNA hydrolase from Acinetobacter baumannii, we have determined its three-dimensional structure. Peptidyl-tRNA hydrolase (AbPth) is involved in recycling of peptidyl-tRNAs which are produced in the cell as a result of premature termination of translation process. We have also determined the structures of two complexes of AbPth with cytidine and uridine. AbPth was cloned, expressed and crystallized in unbound and in two bound states with cytidine and uridine. The binding studies carried out using fluorescence spectroscopic and surface plasmon resonance techniques revealed that both cytidine and uridine bound to AbPth at nanomolar concentrations. The structure determinations of the complexes revealed that both ligands were located in the active site cleft of AbPth. The introduction of ligands to AbPth caused a significant widening of the entrance gate to the active site region and in the process of binding, it expelled several water molecules from the active site. As a result of interactions with protein atoms, the ligands caused conformational changes in several residues to attain the induced tight fittings. Such a binding capability of this protein makes it a versatile molecule for hydrolysis of peptidyl-tRNAs having variable peptide sequences. These are the first studies that revealed the mode of inhibitor binding in Peptidyl-tRNA hydrolases which will facilitate the structure based ligand design.

General Relativity and Energy

ERIC Educational Resources Information Center

Jackson, A. T.

1973-01-01

Reviews theoretical and experimental fundamentals of Einstein's theory of general relativity. Indicates that recent development of the theory of the continually expanding universe may lead to revision of the space-time continuum of the finite and unbounded universe. (CC)

Behavior of plastic sand confinement grids

DOT National Transportation Integrated Search

1986-01-01

The concept of improving the load carrying ability of unbound aggregates, particularly sand, by lateral confinement has been investigated for some time. Extensive full-scale testing of the trafficability of confined beach sand pavement layers has bee...

Improving accuracy of unbound resilient modulus testing

DOT National Transportation Integrated Search

1997-07-01

The P46 Laboratory Startup and Quality Control Procedure was developed to ensure the accuracy and reliability of the resilient modulus data produced while testing soil and aggregate materials using closed-loop servo-hydraulic systems. It was develope...

Prometheus unbound: A study of the Dallas/Fort Worth Regional Airport. [Socio-economic considerations

NASA Technical Reports Server (NTRS)

Starling, J. D.; Brown, J.; Dominus, M. I.

1975-01-01

The history of the controversies in the development of the Dallas/Fort Worth Regional Airport is detailed. Present technological and organizational management problems are outlined. Maps and illustrations are included.

Standardizing lightweight deflectometer modulus measurements for compaction quality assurance

DOT National Transportation Integrated Search

2017-09-01

To evaluate the compaction of unbound geomaterials under unsaturated conditions and replace the conventional methods with a practical modulus-based specification using LWD, this study examined three different LWDs, the Zorn ZFG 3000 LWD, Dynatest 303...

Low-cost rural surface alternatives : literature review and recommendations.

DOT National Transportation Integrated Search

2013-12-01

Freezing and thawing action induces damage to unbound gravel roads in Iowa resulting in maintenance costs for secondary road departments. Some approaches currently used by County Engineers to deal with this problem include temporarily spreading rock ...

Operator algebra as an application of logarithmic representation of infinitesimal generators

NASA Astrophysics Data System (ADS)

Iwata, Yoritaka

2018-02-01

The operator algebra is introduced based on the framework of logarithmic representation of infinitesimal generators. In conclusion a set of generally-unbounded infinitesimal generators is characterized as a module over the Banach algebra.

Constraining gluon distributions in nuclei using dijets in proton-proton and proton-lead collisions at $$\\sqrt{s_{_\\mathrm{NN}}} =$$ 5.02 TeV

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

Sirunyan, Albert M; et al.

2018-05-12

The pseudorapidity distributions of dijets as a function of their average transverse momentum (more » $$p_\\mathrm{T}^\\text{ave}$$) are measured in proton-lead (pPb) and proton-proton (pp) collisions. The data samples were collected by the CMS experiment at the CERN LHC, at a nucleon-nucleon center-of-mass energy of 5.02 TeV. A significant modification of the pPb spectra with respect to the pp spectra is observed in all $$p_\\mathrm{T}^\\text{ave}$$ intervals investigated. The ratios of the pPb and pp distributions are compared to next-to-leading order perturbative quantum chromodynamics calculations with unbound nucleon and nuclear parton distribution functions (PDFs). These results give the first evidence that the gluon PDF at large Bjorken $x$ in lead ions is strongly suppressed with respect to the PDF in unbound nucleons.« less

The control gain region for synchronization in non-diffusively coupled complex networks

NASA Astrophysics Data System (ADS)

Gequn, Liu; Wenhui, Li; Huijie, Yang; Knowles, Gareth

2014-07-01

The control gain region for synchronization of non-diffusively coupled networks was studied with respect to three conditions: synchronization, synchronization in finite time, and synchronization in the minimum time. Based on cancellation control methodology and master stability function formalism, we found that a complete feasible control gain region may be bounded, unbounded, empty or a union of several bounded and unbounded regions, with a similar shape to the synchronized region. An interesting possibility emerged that a network could be synchronized by both negative and positive feedback control simultaneously. By bridging synchronizability and synchronizing response speeds with a settling time index, we have developed timed synchronized region (TSR) as a substitute for the classical synchronized region to study finite time synchronization. As for the last condition, a graphical method was developed to estimate control gain with the minimum synchronization time (CGMST). Each condition has examples provided for illustration and verification.

In vivo excitation of nanoparticles using luminescent bacteria

PubMed Central

Dragavon, Joe; Blazquez, Samantha; Rekiki, Abdessalem; Samson, Chelsea; Theodorou, Ioanna; Rogers, Kelly L.; Tournebize, Régis; Shorte, Spencer L.

2012-01-01

The lux operon derived from Photorhabdus luminescens incorporated into bacterial genomes, elicits the production of biological chemiluminescence typically centered on 490 nm. The light-producing bacteria are widely used for in vivo bioluminescence imaging. However, in living samples, a common difficulty is the presence of blue-green absorbers such as hemoglobin. Here we report a characterization of fluorescence by unbound excitation from luminescence, a phenomenon that exploits radiating luminescence to excite nearby fluorophores by epifluorescence. We show that photons from bioluminescent bacteria radiate over mesoscopic distances and induce a red-shifted fluorescent emission from appropriate fluorophores in a manner distinct from bioluminescence resonance energy transfer. Our results characterizing fluorescence by unbound excitation from luminescence, both in vitro and in vivo, demonstrate how the resulting blue-to-red wavelength shift is both necessary and sufficient to yield contrast enhancement revealing mesoscopic proximity of luminescent and fluorescent probes in the context of living biological tissues. PMID:22615349

Modeling and Managing Risk in Billing Infrastructures

NASA Astrophysics Data System (ADS)

Baiardi, Fabrizio; Telmon, Claudio; Sgandurra, Daniele

This paper discusses risk modeling and risk management in information and communications technology (ICT) systems for which the attack impact distribution is heavy tailed (e.g., power law distribution) and the average risk is unbounded. Systems with these properties include billing infrastructures used to charge customers for services they access. Attacks against billing infrastructures can be classified as peripheral attacks and backbone attacks. The goal of a peripheral attack is to tamper with user bills; a backbone attack seeks to seize control of the billing infrastructure. The probability distribution of the overall impact of an attack on a billing infrastructure also has a heavy-tailed curve. This implies that the probability of a massive impact cannot be ignored and that the average impact may be unbounded - thus, even the most expensive countermeasures would be cost effective. Consequently, the only strategy for managing risk is to increase the resilience of the infrastructure by employing redundant components.

Superior memory efficiency of quantum devices for the simulation of continuous-time stochastic processes

NASA Astrophysics Data System (ADS)

Elliott, Thomas J.; Gu, Mile

2018-03-01

Continuous-time stochastic processes pervade everyday experience, and the simulation of models of these processes is of great utility. Classical models of systems operating in continuous-time must typically track an unbounded amount of information about past behaviour, even for relatively simple models, enforcing limits on precision due to the finite memory of the machine. However, quantum machines can require less information about the past than even their optimal classical counterparts to simulate the future of discrete-time processes, and we demonstrate that this advantage extends to the continuous-time regime. Moreover, we show that this reduction in the memory requirement can be unboundedly large, allowing for arbitrary precision even with a finite quantum memory. We provide a systematic method for finding superior quantum constructions, and a protocol for analogue simulation of continuous-time renewal processes with a quantum machine.

A computational tool to predict the evolutionarily conserved protein-protein interaction hot-spot residues from the structure of the unbound protein.

PubMed

Agrawal, Neeraj J; Helk, Bernhard; Trout, Bernhardt L

2014-01-21

Identifying hot-spot residues - residues that are critical to protein-protein binding - can help to elucidate a protein's function and assist in designing therapeutic molecules to target those residues. We present a novel computational tool, termed spatial-interaction-map (SIM), to predict the hot-spot residues of an evolutionarily conserved protein-protein interaction from the structure of an unbound protein alone. SIM can predict the protein hot-spot residues with an accuracy of 36-57%. Thus, the SIM tool can be used to predict the yet unknown hot-spot residues for many proteins for which the structure of the protein-protein complexes are not available, thereby providing a clue to their functions and an opportunity to design therapeutic molecules to target these proteins. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Unbounded number of channel uses may be required to detect quantum capacity.

PubMed

Cubitt, Toby; Elkouss, David; Matthews, William; Ozols, Maris; Pérez-García, David; Strelchuk, Sergii

2015-03-31

Transmitting data reliably over noisy communication channels is one of the most important applications of information theory, and is well understood for channels modelled by classical physics. However, when quantum effects are involved, we do not know how to compute channel capacities. This is because the formula for the quantum capacity involves maximizing the coherent information over an unbounded number of channel uses. In fact, entanglement across channel uses can even increase the coherent information from zero to non-zero. Here we study the number of channel uses necessary to detect positive coherent information. In all previous known examples, two channel uses already sufficed. It might be that only a finite number of channel uses is always sufficient. We show that this is not the case: for any number of uses, there are channels for which the coherent information is zero, but which nonetheless have capacity.

On the linear stability of compressible plane Couette flow

NASA Technical Reports Server (NTRS)

Duck, Peter W.; Erlebacher, Gordon; Hussaini, M. Yousuff

1991-01-01

The linear stability of compressible plane Couette flow is investigated. The correct and proper basic velocity and temperature distributions are perturbed by a small amplitude normal mode disturbance. The full small amplitude disturbance equations are solved numerically at finite Reynolds numbers, and the inviscid limit of these equations is then investigated in some detail. It is found that instability can occur, although the stability characteristics of the flow are quite different from unbounded flows. The effects of viscosity are also calculated, asymptotically, and shown to have a stabilizing role in all the cases investigated. Exceptional regimes to the problem occur when the wavespeed of the disturbances approaches the velocity of either of the walls, and these regimes are also analyzed in some detail. Finally, the effect of imposing radiation-type boundary conditions on the upper (moving) wall (in place of impermeability) is investigated, and shown to yield results common to both bounded and unbounded flows.

Predicted space motions for hypervelocity and runaway stars: proper motions and radial velocities for the Gaia Era

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

Kenyon, Scott J.; Brown, Warren R.; Geller, Margaret J.

We predict the distinctive three-dimensional space motions of hypervelocity stars (HVSs) and runaway stars moving in a realistic Galactic potential. For nearby stars with distances less than 10 kpc, unbound stars are rare; proper motions alone rarely isolate bound HVSs and runaways from indigenous halo stars. At large distances of 20-100 kpc, unbound HVSs are much more common than runaways; radial velocities easily distinguish both from indigenous halo stars. Comparisons of the predictions with existing observations are encouraging. Although the models fail to match observations of solar-type HVS candidates from SEGUE, they agree well with data for B-type HVS andmore » runaways from other surveys. Complete samples of g ≲ 20 stars with Gaia should provide clear tests of formation models for HVSs and runaways and will enable accurate probes of the shape of the Galactic potential.« less

Stellar dynamics. The fastest unbound star in our Galaxy ejected by a thermonuclear supernova.

PubMed

Geier, S; Fürst, F; Ziegerer, E; Kupfer, T; Heber, U; Irrgang, A; Wang, B; Liu, Z; Han, Z; Sesar, B; Levitan, D; Kotak, R; Magnier, E; Smith, K; Burgett, W S; Chambers, K; Flewelling, H; Kaiser, N; Wainscoat, R; Waters, C

2015-03-06

Hypervelocity stars (HVSs) travel with velocities so high that they exceed the escape velocity of the Galaxy. Several acceleration mechanisms have been discussed. Only one HVS (US 708, HVS 2) is a compact helium star. Here we present a spectroscopic and kinematic analysis of US 708. Traveling with a velocity of ~1200 kilometers per second, it is the fastest unbound star in our Galaxy. In reconstructing its trajectory, the Galactic center becomes very unlikely as an origin, which is hardly consistent with the most favored ejection mechanism for the other HVSs. Furthermore, we detected that US 708 is a fast rotator. According to our binary evolution model, it was spun-up by tidal interaction in a close binary and is likely to be the ejected donor remnant of a thermonuclear supernova. Copyright © 2015, American Association for the Advancement of Science.

Method and apparatus for shape and end position determination using an optical fiber

NASA Technical Reports Server (NTRS)

Moore, Jason P. (Inventor)

2010-01-01

A method of determining the shape of an unbound optical fiber includes collecting strain data along a length of the fiber, calculating curvature and bending direction data of the fiber using the strain data, curve-fitting the curvature and bending direction data to derive curvature and bending direction functions, calculating a torsion function using the bending direction function, and determining the 3D shape from the curvature, bending direction, and torsion functions. An apparatus for determining the 3D shape of the fiber includes a fiber optic cable unbound with respect to a protective sleeve, strain sensors positioned along the cable, and a controller in communication with the sensors. The controller has an algorithm for determining a 3D shape and end position of the fiber by calculating a set of curvature and bending direction data, deriving curvature, bending, and torsion functions, and solving Frenet-Serret equations using these functions.

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug-drug and drug-herb interaction by LC-ESI/MS/MS.

PubMed

Borkar, Roshan M; Bhandi, Murali Mohan; Dubey, Ajay P; Ganga Reddy, V; Komirishetty, Prashanth; Nandekar, Prajwal P; Sangamwar, Abhay T; Kamal, Ahmed; Banerjee, Sanjay K; Srinivas, R

2016-10-01

The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Strength and Persistence of Energy-Based Vessel Seals Rely on Tissue Water and Glycosaminoglycan Content.

PubMed

Kramer, Eric A; Cezo, James D; Fankell, Douglas P; Taylor, Kenneth D; Rentschler, Mark E; Ferguson, Virginia L

2016-11-01

Vessel ligation using energy-based surgical devices is steadily replacing conventional closure methods during minimally invasive and open procedures. In exploring the molecular nature of thermally-induced tissue bonds, novel applications for surgical resection and repair may be revealed. This work presents an analysis of the influence of unbound water and hydrophilic glycosaminoglycans on the formation and resilience of vascular seals via: (a) changes in pre-fusion tissue hydration, (b) the enzymatic digestion of glycosaminoglycans (GAGs) prior to fusion and (c) the rehydration of vascular seals following fusion. An 11% increase in pre-fusion unbound water led to an 84% rise in vascular seal strength. The digestion of GAGs prior to fusion led to increases of up to 82% in seal strength, while the rehydration of native and GAG-digested vascular seals decreased strengths by 41 and 44%, respectively. The effects of increased unbound water content prior to fusion combined with the effects of seal rehydration after fusion suggest that the heat-induced displacement of tissue water is a major contributor to tissue adhesion during energy-based vessel sealing. The effects of pre-fusion GAG-digestion on seal integrity indicate that GAGs are inhibitory to the bond formation process during thermal ligation. GAG digestion may allow for increased water transport and protein interaction during the fusion process, leading to the formation of stronger bonds. These findings provide insight into the physiochemical nature of the fusion bond, its potential for optimization in vascular closure and its application to novel strategies for vascular resection and repair.

Effect of alpha(1)-acid glycoprotein on the pharmacokinetics of tamsulosin in rats treated with turpentine oil.

PubMed

Matsushima, H; Watanabe, T; Higuchi, S

2000-04-01

The pharmacokinetics of tamsulosin (TAM) was investigated using male Sprague-Dawley rats in which plasma alpha(1)-acid glycoprotein (alpha(1)-AGP) levels were elevated by the subcutaneous injection of 0.2 mL/kg of turpentine oil. alpha(1)-AGP levels increased about eight times after turpentine oil treatment, causing a threefold decrease in plasma unbound fraction (f(u)) of TAM. When 0.3 mg/kg of TAM was dosed intravenously, total and nonrenal clearances (CL(tot) and CL(nr)) in turpentine-treated rats were 47% and 44% lower than those in nontreated controls, respectively. The area under the concentration-time curve of plasma unbound TAM (AUC(inf,u)) was lower than that in the control. When 1 mg/kg of TAM was dosed orally, oral clearance (CL(oral)) in alpha1-AGP-induced rats was 65% lower than in the control. The AUC(inf,u) and unbound oral clearance (CL(oral,u)) were nearly equal in both groups. Moreover, a positive correlation was observed between fu and CL(oral) of TAM (r(2) = 0.603, P < 0.01), whereas no correlation was observed between f(u) and CL(oral,u). The absolute bioavailability (BA) increased from 19.2% to 46.9% by induction of alpha(1)-AGP. These results suggest that decreased f(u) caused by the elevation of plasma alpha(1)-AGP level affects the pharmacokinetics of TAM, but does not affect the CL(oral,u,) which represents the hepatic metabolism of TAM. Copyright 2000 Wiley-Liss, Inc.

Unbound bilirubin measurements by a novel probe in preterm infants.

PubMed

Hegyi, Thomas; Kleinfeld, Alan; Huber, Andrew; Weinberger, Barry; Memon, Naureen; Shih, Weichung; Carayannopoulos, Mary; Oh, William

2018-03-12

Hyperbilirubinemia occurs in over 80% of newborns and severe bilirubin toxicity can lead to neurological dysfunction and death, especially in preterm infants. Currently, the risk of bilirubin toxicity is assessed by measuring the levels of total serum bilirubin (TSB), which are used to direct treatments including immunoglobulin administration, phototherapy, and exchange transfusion. However, free, unbound bilirubin levels (Bf) predict the risk of bilirubin neurotoxicity more accurately than TSB. To examine Bf levels in preterm infants and determine the frequency with which they exceed reported neurotoxic thresholds. One hundred thirty preterm infants (BW 500-2000 g; GA 23-34 weeks) were enrolled and Bf levels measured during the first week of life by the fluorescent Bf sensor BL22P1B11-Rh. TSB and plasma albumin were measured by standard techniques. Bilirubin-albumin dissociation constants (K d ) were calculated based on Bf and plasma albumin. Five hundred eighty samples were measured during the first week of life, with an overall mean Bf of 13.6 ± 9.0 nM. A substantial number of measurements exceeded potential toxic thresholds levels as reported in the literature. The correlation between Bf and TSB was statistically significant (r 2 0.17), but this weak relationship was lost at high Bf levels. Infants <28-week gestations had more hearing screening failures than infants ≥28-week gestation. Unbound (free) bilirubin values are extremely variable during the first week of life in preterm infants. A significant proportion of these values exceeded reported neurotoxic thresholds.

Tacrolimus placental transfer at delivery and neonatal exposure through breast milk.

PubMed

Zheng, Songmao; Easterling, Thomas R; Hays, Karen; Umans, Jason G; Miodovnik, Menachem; Clark, Shannon; Calamia, Justina C; Thummel, Kenneth E; Shen, Danny D; Davis, Connie L; Hebert, Mary F

2013-12-01

The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk. Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. Mean (±SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng ml(-1)) were 71 ± 18% (range 45-99%) of maternal concentrations (9.0 ± 3.4 ng ml(-1)). The mean umbilical cord venous plasma (0.09 ± 0.04 ng ml(-1)) and unbound drug concentrations (0.003 ± 0.001 ng ml(-1)) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant. © 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Effect of drainage in unbound aggregate bases on flexible pavement performance.

DOT National Transportation Integrated Search

2008-05-01

It has been well demonstrated that a positive subsurface drainage is beneficial in enhancing pavement performance and thus extending pavement service life. Typical permeable base materials include asphalt/cement-treated, open-graded aggregates and un...

Accelerated characterization of full-scale flexible pavements using a vibroseis.

DOT National Transportation Integrated Search

2010-03-01

Geosynthetic basal reinforcement has been used in flexible pavements and unbound roads to limit the occurrence of rutting, fatigue, and environmental-related cracking, and to permit reduction in base course thickness. However, the lack of a represent...

Tumor-specific detection of an optically targeted antibody combined with a quencher-conjugated neutravidin "quencher-chaser": a dual "quench and chase" strategy to improve target to nontarget ratios for molecular imaging of cancer.

PubMed

Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L; Kobayashi, Hisataka

2009-01-01

In vivo molecular cancer imaging with monoclonal antibodies has great potential not only for cancer detection, but also for cancer characterization. However, the prolonged retention of intravenously injected antibody in the blood causes low target tumor-to-background ratio (TBR). Avidin has been used as a "chase" to clear the unbound, circulating biotinylated antibody and decrease the background signal. Here, we utilize a combined approach of a fluorescence resonance energy transfer (FRET) quenched antibody with an "avidin chase" to increase TBR. Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor type 2 (HER2), was biotinylated and conjugated with the near-infrared (NIR) fluorophore Alexa680 to synthesize Tra-Alexa680-biotin. Next, the FRET quencher, QSY-21, was conjugated to avidin, neutravidin (nAv), or streptavidin (sAv), thus creating Av-QSY21, nAv-QSY21, or sAv-QSY21 as "chasers". The fluorescence was quenched in vitro by binding Tra-Alexa680-biotin to Av-QSY21, nAv-QSY21, or sAv-QSY21. To evaluate if the injection of quencher-conjugated avidin derivatives can improve target TBR by using a dual "quench and chase" strategy, both target (3T3/HER2+) and nontarget (Balb3T3/ZsGreen) tumor-bearing mice were employed. The "FRET quench" effect induced by all the QSY21 avidin-based conjugates reduced but did not totally eliminate background signal from the blood pool. The addition of nAv-QSY21 administration increased target TBR mainly because of the "chase" effect where unbound conjugated antibody was preferentially cleared to the liver. The relatively slow clearance of unbound nAv-QSY21 leads to further reductions in background signal by leaking out of the vascular space and binding to unbound antibodies in the extravascular space of tumors, resulting in decreased nontarget tumor-to-background ratios but increased target TBR due to the "FRET quench" effect, because target-bound antibodies were internalized and could not bind to nAv-QSY21. In conclusion, the proposed "quench-and-chase" system combines two strategies, fluorescent quenching and avidin chasing, to improve target TBR and reduce nontarget TBR, which should result in both improved tumor sensitivity and improved specificity.

Experimental evidence for subshell closure in {sup 8}He and indication of a resonant state in {sup 7}He below 1 MeV

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

Skaza, F.; Lapoux, V.; Keeley, N.

2006-04-15

The spectroscopy of the unstable {sup 8}He and unbound {sup 7}He nuclei is investigated via the p({sup 8}He, d) transfer reaction with a 15.7A MeV {sup 8}He beam from the SPIRAL facility. The emitted deuterons were detected by the telescope array MUST. The results are analyzed within the coupled-channels Born approximation framework, and a spectroscopic factor C{sup 2}S=4.4{+-}1.3 for neutron pickup to the {sup 7}He{sub g.s.} is deduced. This value is consistent with a full p3/2 subshell for {sup 8}He. Tentative evidence for the first excited state of {sup 7}He is found at E{sup *}=0.9{+-}0.5 MeV (width {gamma}=1.0{+-}0.9 MeV). Themore » second one is observed at a position compatible with previous measurements, E{sup *}=2.9{+-}0.1 MeV. Both are in agreement with previous separate measurements. The reproduction of the first excited state below 1 MeV would be a challenge for the most sophisticated nuclear theories.« less

Active and passive transport of cargo in a corrugated channel: A lattice model study

NASA Astrophysics Data System (ADS)

Dey, Supravat; Ching, Kevin; Das, Moumita

2018-04-01

Inside cells, cargos such as vesicles and organelles are transported by molecular motors to their correct locations via active motion on cytoskeletal tracks and passive, Brownian diffusion. During the transportation of cargos, motor-cargo complexes (MCCs) navigate the confining and crowded environment of the cytoskeletal network and other macromolecules. Motivated by this, we study a minimal two-state model of motor-driven cargo transport in confinement and predict transport properties that can be tested in experiments. We assume that the motion of the MCC is directly affected by the entropic barrier due to confinement if it is in the passive, unbound state but not in the active, bound state where it moves with a constant bound velocity. We construct a lattice model based on a Fokker Planck description of the two-state system, study it using a kinetic Monte Carlo method and compare our numerical results with analytical expressions for a mean field limit. We find that the effect of confinement strongly depends on the bound velocity and the binding kinetics of the MCC. Confinement effectively reduces the effective diffusivity and average velocity, except when it results in an enhanced average binding rate and thereby leads to a larger average velocity than when unconfined.

Timing analysis by model checking

NASA Technical Reports Server (NTRS)

Naydich, Dimitri; Guaspari, David

2000-01-01

The safety of modern avionics relies on high integrity software that can be verified to meet hard real-time requirements. The limits of verification technology therefore determine acceptable engineering practice. To simplify verification problems, safety-critical systems are commonly implemented under the severe constraints of a cyclic executive, which make design an expensive trial-and-error process highly intolerant of change. Important advances in analysis techniques, such as rate monotonic analysis (RMA), have provided a theoretical and practical basis for easing these onerous restrictions. But RMA and its kindred have two limitations: they apply only to verifying the requirement of schedulability (that tasks meet their deadlines) and they cannot be applied to many common programming paradigms. We address both these limitations by applying model checking, a technique with successful industrial applications in hardware design. Model checking algorithms analyze finite state machines, either by explicit state enumeration or by symbolic manipulation. Since quantitative timing properties involve a potentially unbounded state variable (a clock), our first problem is to construct a finite approximation that is conservative for the properties being analyzed-if the approximation satisfies the properties of interest, so does the infinite model. To reduce the potential for state space explosion we must further optimize this finite model. Experiments with some simple optimizations have yielded a hundred-fold efficiency improvement over published techniques.

Free Electron coherent sources: From microwave to X-rays

NASA Astrophysics Data System (ADS)

Dattoli, Giuseppe; Di Palma, Emanuele; Pagnutti, Simonetta; Sabia, Elio

2018-04-01

The term Free Electron Laser (FEL) will be used, in this paper, to indicate a wide collection of devices aimed at providing coherent electromagnetic radiation from a beam of "free" electrons, unbound at the atomic or molecular states. This article reviews the similarities that link different sources of coherent radiation across the electromagnetic spectrum from microwaves to X-rays, and compares the analogies with conventional laser sources. We explore developing a point of view that allows a unified analytical treatment of these devices, by the introduction of appropriate global variables (e.g. gain, saturation intensity, inhomogeneous broadening parameters, longitudinal mode coupling strength), yielding a very effective way for the determination of the relevant design parameters. The paper looks also at more speculative aspects of FEL physics, which may address the relevance of quantum effects in the lasing process.

The limit behavior of the evolution of the Tsallis entropy in self-gravitating systems

NASA Astrophysics Data System (ADS)

Zheng, Yahui; Du, Jiulin; Liang, Faku

2017-06-01

In this letter, we study the limit behavior of the evolution of the Tsallis entropy in self-gravitating systems. The study is carried out under two different situations, drawing the same conclusion. No matter in the energy transfer process or in the mass transfer process inside the system, when the nonextensive parameter q is more than unity, the total entropy is bounded; on the contrary, when this parameter is less than unity, the total entropy is unbounded. There are proofs in both theory and observation that the q is always more than unity. So the Tsallis entropy in self-gravitating systems generally exhibits a bounded property. This indicates the existence of a global maximum of the Tsallis entropy. It is possible for self-gravitating systems to evolve to thermodynamically stable states.

Turing patterns in parabolic systems of conservation laws and numerically observed stability of periodic waves

NASA Astrophysics Data System (ADS)

Barker, Blake; Jung, Soyeun; Zumbrun, Kevin

2018-03-01

Turing patterns on unbounded domains have been widely studied in systems of reaction-diffusion equations. However, up to now, they have not been studied for systems of conservation laws. Here, we (i) derive conditions for Turing instability in conservation laws and (ii) use these conditions to find families of periodic solutions bifurcating from uniform states, numerically continuing these families into the large-amplitude regime. For the examples studied, numerical stability analysis suggests that stable periodic waves can emerge either from supercritical Turing bifurcations or, via secondary bifurcation as amplitude is increased, from subcritical Turing bifurcations. This answers in the affirmative a question of Oh-Zumbrun whether stable periodic solutions of conservation laws can occur. Determination of a full small-amplitude stability diagram - specifically, determination of rigorous Eckhaus-type stability conditions - remains an interesting open problem.

Stochastic Games for Continuous-Time Jump Processes Under Finite-Horizon Payoff Criterion

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

Wei, Qingda, E-mail: weiqd@hqu.edu.cn; Chen, Xian, E-mail: chenxian@amss.ac.cn

In this paper we study two-person nonzero-sum games for continuous-time jump processes with the randomized history-dependent strategies under the finite-horizon payoff criterion. The state space is countable, and the transition rates and payoff functions are allowed to be unbounded from above and from below. Under the suitable conditions, we introduce a new topology for the set of all randomized Markov multi-strategies and establish its compactness and metrizability. Then by constructing the approximating sequences of the transition rates and payoff functions, we show that the optimal value function for each player is a unique solution to the corresponding optimality equation andmore » obtain the existence of a randomized Markov Nash equilibrium. Furthermore, we illustrate the applications of our main results with a controlled birth and death system.« less

A necessary and sufficient condition for well-posedness of initial value problems of retarded functional differential equations

NASA Astrophysics Data System (ADS)

Nishiguchi, Junya

2017-09-01

We introduce the retarded functional differential equations (RFDEs) with general delay structure to treat various delay differential equations (DDEs) in a unified way and to clarify the delay structure in those dynamics. We are interested in the question as to which space of histories is suitable for the dynamics of each DDE, and investigate the well-posedness of the initial value problems (IVPs) of the RFDEs. A main theorem is that the IVP is well-posed for any ;admissible; history functional if and only if the semigroup determined by the trivial RFDE x ˙ = 0 is continuous. We clarify the meaning of the Hale-Kato axiom (Hale & Kato [12]) by applying this result to RFDEs with infinite delay. We also apply the result to DDEs with unbounded time- and state-dependent delays.

Ground-state proton decay of 69Br and implications for the 68Se astrophysical rp-process waiting point

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

Rogers, Andrew M; Famiano, Micahel; Lynch, William

2011-01-01

We report on the first direct measurement of the proton separation energy for the proton-unbound nucleus {sup 69}Br. Bypassing the {sup 68}Se waiting point in the rp process is directly related to the 2p-capture rate through {sup 69}Br, which depends exponentially on the proton separation energy. We find a proton separation energy for {sup 69}Br of S{sub p}({sup 69}Br) = -785{sub -40}{sup +34} keV; this is less bound compared to previous predictions which have relied on uncertain theoretical calculations. The influence of the extracted proton separation energy on the rp process occurring in type I x-ray bursts is examined withinmore » the context of a one-zone burst model.« less

Ground-state proton decay of {sup 69}Br and implications for the {sup 68}Se astrophysical rapid proton-capture process waiting point.

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

Rogers, A. M.; Famiano, M. A.; Lynch, W. G.

2011-06-24

We report on the first direct measurement of the proton separation energy for the proton-unbound nucleus {sup 69}Br. Bypassing the {sup 68}Se waiting point in the rp process is directly related to the 2p-capture rate through {sup 69}Br, which depends exponentially on the proton separation energy. We find a proton separation energy for {sup 69}Br of S{sub p}({sup 69}Br) = -785{sub -40}{sup +34} keV; this is less bound compared to previous predictions which have relied on uncertain theoretical calculations. The influence of the extracted proton separation energy on the rp process occurring in type I x-ray bursts is examined withinmore » the context of a one-zone burst model.« less

Measuring the orbital angular momentum spectrum of an electron beam

PubMed Central

Grillo, Vincenzo; Tavabi, Amir H.; Venturi, Federico; Larocque, Hugo; Balboni, Roberto; Gazzadi, Gian Carlo; Frabboni, Stefano; Lu, Peng-Han; Mafakheri, Erfan; Bouchard, Frédéric; Dunin-Borkowski, Rafal E.; Boyd, Robert W.; Lavery, Martin P. J.; Padgett, Miles J.; Karimi, Ebrahim

2017-01-01

Electron waves that carry orbital angular momentum (OAM) are characterized by a quantized and unbounded magnetic dipole moment parallel to their propagation direction. When interacting with magnetic materials, the wavefunctions of such electrons are inherently modified. Such variations therefore motivate the need to analyse electron wavefunctions, especially their wavefronts, to obtain information regarding the material's structure. Here, we propose, design and demonstrate the performance of a device based on nanoscale holograms for measuring an electron's OAM components by spatially separating them. We sort pure and superposed OAM states of electrons with OAM values of between −10 and 10. We employ the device to analyse the OAM spectrum of electrons that have been affected by a micron-scale magnetic dipole, thus establishing that our sorter can be an instrument for nanoscale magnetic spectroscopy. PMID:28537248

Corporate science education: Westinghouse and the value of science in mid-twentieth century America.

PubMed

Terzian, Sevan G; Shapiro, Leigh

2015-02-01

This study examines a largely neglected aspect of the history of science popularization in the United States: corporate depictions of the value of science to society. It delineates the Westinghouse Electric Corporation's portrayals of science to its shareholders, employees and consumers, and schoolchildren and educators during World War Two and the postwar era. Annual reports to shareholders, in-house news publications, publicity records, advertising campaigns, and educational pamphlets distributed to schools reveal the company's distinct, but complementary, messages for different stakeholders about the importance of science to American society. Collectively, Westinghouse encouraged these audiences to rely on scientists' expert leadership for their nation's security and material comforts. In an era of military mobilization, the company was able to claim that industry-led scientific research would fortify the nation and create unbounded prosperity. © The Author(s) 2013.

Lower Current Large Deviations for Zero-Range Processes on a Ring

NASA Astrophysics Data System (ADS)

Chleboun, Paul; Grosskinsky, Stefan; Pizzoferrato, Andrea

2017-04-01

We study lower large deviations for the current of totally asymmetric zero-range processes on a ring with concave current-density relation. We use an approach by Jensen and Varadhan which has previously been applied to exclusion processes, to realize current fluctuations by travelling wave density profiles corresponding to non-entropic weak solutions of the hyperbolic scaling limit of the process. We further establish a dynamic transition, where large deviations of the current below a certain value are no longer typically attained by non-entropic weak solutions, but by condensed profiles, where a non-zero fraction of all the particles accumulates on a single fixed lattice site. This leads to a general characterization of the rate function, which is illustrated by providing detailed results for four generic examples of jump rates, including constant rates, decreasing rates, unbounded sublinear rates and asymptotically linear rates. Our results on the dynamic transition are supported by numerical simulations using a cloning algorithm.

Ergodicity and model quality in template-restrained canonical and temperature/Hamiltonian replica exchange coarse-grained molecular dynamics simulations of proteins.

PubMed

Karczyńska, Agnieszka S; Czaplewski, Cezary; Krupa, Paweł; Mozolewska, Magdalena A; Joo, Keehyoung; Lee, Jooyoung; Liwo, Adam

2017-12-05

Molecular simulations restrained to single or multiple templates are commonly used in protein-structure modeling. However, the restraints introduce additional barriers, thus impairing the ergodicity of simulations, which can affect the quality of the resulting models. In this work, the effect of restraint types and simulation schemes on ergodicity and model quality was investigated by performing template-restrained canonical molecular dynamics (MD), multiplexed replica-exchange molecular dynamics, and Hamiltonian replica exchange molecular dynamics (HREMD) simulations with the coarse-grained UNRES force field on nine selected proteins, with pseudo-harmonic log-Gaussian (unbounded) or Lorentzian (bounded) restraint functions. The best ergodicity was exhibited by HREMD. It has been found that non-ergodicity does not affect model quality if good templates are used to generate restraints. However, when poor-quality restraints not covering the entire protein are used, the improved ergodicity of HREMD can lead to significantly improved protein models. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Far-Field Lorenz-Mie Scattering in an Absorbing Host Medium: Theoretical Formalism and FORTRAN Program

NASA Technical Reports Server (NTRS)

Mishchenko, Michael I.; Yang, Ping

2018-01-01

In this paper we make practical use of the recently developed first-principles approach to electromagnetic scattering by particles immersed in an unbounded absorbing host medium. Specifically, we introduce an actual computational tool for the calculation of pertinent far-field optical observables in the context of the classical Lorenzâ€"Mie theory. The paper summarizes the relevant theoretical formalism, explains various aspects of the corresponding numerical algorithm, specifies the input and output parameters of a FORTRAN program available at https://www.giss.nasa.gov/staff/mmishchenko/Lorenz-Mie.html, and tabulates benchmark results useful for testing purposes. This public-domain FORTRAN program enables one to solve the following two important problems: (i) simulate theoretically the reading of a remote well-collimated radiometer measuring electromagnetic scattering by an individual spherical particle or a small random group of spherical particles; and (ii) compute the single-scattering parameters that enter the vector radiative transfer equation derived directly from the Maxwell equations.

Exact Solution to Stationary Onset of Convection Due to Surface Tension Variation in a Multicomponent Fluid Layer With Interfacial Deformation

NASA Technical Reports Server (NTRS)

Skarda, J. Raymond Lee; McCaughan, Frances E.

1998-01-01

Stationary onset of convection due to surface tension variation in an unbounded multicomponent fluid layer is considered. Surface deformation is included and general flux boundary conditions are imposed on the stratifying agencies (temperature/composition) disturbance equations. Exact solutions are obtained to the general N-component problem for both finite and infinitesimal wavenumbers. Long wavelength instability may coexist with a finite wavelength instability for certain sets of parameter values, often referred to as frontier points. For an impermeable/insulated upper boundary and a permeable/conductive lower boundary, frontier boundaries are computed in the space of Bond number, Bo, versus Crispation number, Cr, over the range 5 x 10(exp -7) less than or equal to Bo less than or equal to 1. The loci of frontier points in (Bo, Cr) space for different values of N, diffusivity ratios, and, Marangoni numbers, collapsed to a single curve in (Bo, D(dimensional variable)Cr) space, where D(dimensional variable) is a Marangoni number weighted diffusivity ratio.

Far-field Lorenz-Mie scattering in an absorbing host medium: Theoretical formalism and FORTRAN program

NASA Astrophysics Data System (ADS)

Mishchenko, Michael I.; Yang, Ping

2018-01-01

In this paper we make practical use of the recently developed first-principles approach to electromagnetic scattering by particles immersed in an unbounded absorbing host medium. Specifically, we introduce an actual computational tool for the calculation of pertinent far-field optical observables in the context of the classical Lorenz-Mie theory. The paper summarizes the relevant theoretical formalism, explains various aspects of the corresponding numerical algorithm, specifies the input and output parameters of a FORTRAN program available at https://www.giss.nasa.gov/staff/mmishchenko/Lorenz-Mie.html, and tabulates benchmark results useful for testing purposes. This public-domain FORTRAN program enables one to solve the following two important problems: (i) simulate theoretically the reading of a remote well-collimated radiometer measuring electromagnetic scattering by an individual spherical particle or a small random group of spherical particles; and (ii) compute the single-scattering parameters that enter the vector radiative transfer equation derived directly from the Maxwell equations.

PCNA appears in two populations of slow and fast diffusion with a constant ratio throughout S-phase in replicating mammalian cells.

PubMed

Zessin, Patrick J M; Sporbert, Anje; Heilemann, Mike

2016-01-13

DNA replication is a fundamental cellular process that precedes cell division. Proliferating cell nuclear antigen (PCNA) is a central scaffold protein that orchestrates DNA replication by recruiting many factors essential for the replication machinery. We studied the mobility of PCNA in live mammalian cells using single-particle tracking in combination with photoactivated-localization microscopy (sptPALM) and found two populations. The first population which is only present in cells with active DNA replication, showed slow diffusion and was found to be located in replication foci. The second population showed fast diffusion, and represents the nucleoplasmic pool of unbound PCNA not involved in DNA replication. The ratio of these two populations remained constant throughout different stages of S-phase. A fraction of molecules in both populations showed spatially constrained mobility. We determined an exploration radius of ~100 nm for 13% of the slow-diffusing PCNA molecules, and of ~600 nm for 46% of the fast-diffusing PCNA molecules.

Discovery of a parsec-scale bipolar nebula around MWC 349A

NASA Astrophysics Data System (ADS)

Gvaramadze, V. V.; Menten, K. M.

2012-05-01

We report the discovery of a bipolar nebula around the peculiar emission-line star MWC 349A using archival Spitzer Space Telescope 24 μm data. The nebula extends over several arcminutes (up to 5 pc) and has the same orientation and geometry as the well-known subarcsecond-scale (~400 times smaller) bipolar radio nebula associated with this star. We discuss the physical relationship between MWC 349A and the nearby B0 III star MWC 349B and propose that both stars were members of a hierarchical triple system, which was ejected from the core of the Cyg OB2 association several Myr ago and recently was dissolved into a binary system (now MWC 349A) and a single unbound star (MWC 349B). Our proposal implies that MWC 349A is an evolved massive star (likely a luminous blue variable) in a binary system with a low-mass star. A possible origin of the bipolar nebula around MWC 349A is discussed.

Axisymmetric capillary-gravity waves at the interface of two viscous, immiscible fluids - Initial value problem

NASA Astrophysics Data System (ADS)

Farsoiya, Palas Kumar; Dasgupta, Ratul

2017-11-01

When the interface between two radially unbounded, viscous fluids lying vertically in a stable configuration (denser fluid below) at rest, is perturbed, radially propagating capillary-gravity waves are formed which damp out with time. We study this process analytically using a recently developed linearised theory. For small amplitude initial perturbations, the analytical solution to the initial value problem, represented as a linear superposition of Bessel modes at time t = 0 , is found to agree very well with results obtained from direct numerical simulations of the Navier-Stokes equations, for a range of initial conditions. Our study extends the earlier work by John W. Miles who studied this initial value problem analytically, taking into account, a single viscous fluid only. Implications of this study for the mechanistic understanding of droplet impact into a deep pool, will be discussed. Some preliminary, qualitative comparison with experiments will also be presented. We thank SERB Dept. Science & Technology, Govt. of India, Grant No. EMR/2016/000830 for financial support.

Highlighting cancer cells with macromolecular probes

NASA Astrophysics Data System (ADS)

Tang, Sicheng; Zhang, Yang; Thapaliya, Ek Raj; Brown, Adrienne S.; Wilson, James N.; Raymo, Françisco M.

2017-02-01

Conventional fluorophore-ligand constructs for the detection of cancer cells generally produce relatively weak signals with modest contrast. The inherently low brightness accessible per biding event with the pairing of a single organic fluorophore to a single ligand as well as the contribution of unbound probes to background fluorescence are mainly responsible for these limitations. Our laboratories identified a viable structural design to improve both brightness and contrast. It is based on the integration of activatable fluorophores and targeting ligands within the same macromolecular construct. The chromophoric components are engineered to emit bright fluorescence exclusively in acidic environments. The targeting agents are designed to bind complementary receptors overexpressed on the surface of cancer cells and allow internalization of the macromolecules into acidic organelles. As a result of these properties, our macromolecular probes switch their intense emission on exclusively in the intracellular space of target cells with minimal background fluorescence from the extracellular matrix. In fact, these operating principles translate into a 170-fold enhancement in brightness, relative to equivalent but isolated chromophoric components, and a 3-fold increase in contrast, relative to model but non-activatable fluorophores. Thus, our macromolecular probes might ultimately evolve into valuable analytical tools to highlight cancer cells with optimal signal-to-noise ratios in a diversity of biomedical applications.

Dancing the night away: Improving the persistence of locomotion on the micron scale

NASA Astrophysics Data System (ADS)

Gehrels, Emily W.; Rogers, W. Benjamin; Zeravcic, Zorana; Manoharan, Vinothan N.

In recent years a range of nano and microscale walkers (motors that are able to move along a preformed track) have been developed. Many of these walkers bind to their tracks using a single binding site at each station along the track. A disadvantage of these systems is that any failure involving a single site becoming unbound leads to the walker falling off of the track and locomotion being prematurely terminated. For this reason, it has been difficult to develop a motor that can reliably take more than a few sequential steps. We present an experimental system of DNA-functionalized colloidal particles which exhibit directed motion along patterned substrates in response to temperature cycling. Many DNA bridges form between each pair of interacting particles, adding redundancy to the binding at each station to realize a system that should be able to consistently take many steps. We take advantage of toehold exchange in the design of the DNA sequences that mediate the colloidal interactions to produce broadened, flat, or even re-entrant binding and unbinding transitions between the particles and substrate. Using this new freedom of design, we devise systems where, by thermal ratcheting, we can externally control the direction of motion and sequence of steps of the colloidal motor.

Nondeterministic self-assembly of two tile types on a lattice.

PubMed

Tesoro, S; Ahnert, S E

2016-04-01

Self-assembly is ubiquitous in nature, particularly in biology, where it underlies the formation of protein quaternary structure and protein aggregation. Quaternary structure assembles deterministically and performs a wide range of important functions in the cell, whereas protein aggregation is the hallmark of a number of diseases and represents a nondeterministic self-assembly process. Here we build on previous work on a lattice model of deterministic self-assembly to investigate nondeterministic self-assembly of single lattice tiles and mixtures of two tiles at varying relative concentrations. Despite limiting the simplicity of the model to two interface types, which results in 13 topologically distinct single tiles and 106 topologically distinct sets of two tiles, we observe a wide variety of concentration-dependent behaviors. Several two-tile sets display critical behaviors in the form of a sharp transition from bound to unbound structures as the relative concentration of one tile to another increases. Other sets exhibit gradual monotonic changes in structural density, or nonmonotonic changes, while again others show no concentration dependence at all. We catalog this extensive range of behaviors and present a model that provides a reasonably good estimate of the critical concentrations for a subset of the critical transitions. In addition, we show that the structures resulting from these tile sets are fractal, with one of two different fractal dimensions.

Greener Protection for Steel Bridges : Testing Nano-Enhanced Corrosion-Resistant Coatings

DOT National Transportation Integrated Search

2013-06-03

Permanent deformation within the unbound granular is a predominant feature that results in the degradation and loss of serviceability to the pavement structure as the passage of traffic wheel loads accumulate. Proper characterization of the multi-lay...

Characterization of unbound materials (soils/aggregates) for mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2009-02-01

The resilient modulus (MR) input parameters in the Mechanistic-Empirical Pavement Design Guide (MEPDG) program have a significant effect on the projected pavement performance. The MEPDG program uses three different levels of inputs depending on the d...

Polygon patterns on Europa

NASA Technical Reports Server (NTRS)

Smalley, I. J.

1981-01-01

The formation of polygon patterns in the development of crack networks in cooling basalt flows and similar contracting systems, and under natural conditions in an essentially unbounded basalt flow, are analyzed, and the characteristics of hexagonal and pentagonal patterns in isotropic stress fields are discussed.

3 CFR 8435 - Proclamation 8435 of October 7, 2009. Leif Erikson Day, 2009

Code of Federal Regulations, 2010 CFR

2010-01-01

... determined not to turn back, in order to learn what lay beyond the setting sun. This same spirit lived within... their pioneering spirit continues to embody our Nation’s unbounded enthusiasm for discovery and learning...

Out of bounds additive manufacturing

DOE PAGES

Holshouser, Chris; Newell, Clint; Palas, Sid; ...

2013-03-01

Lockheed Martin and Oak Ridge National Laboratory are working on an additive manufacturing system capable of manufacturing components measured not in terms of inches or feet, but multiple yards in all dimensions with the potential to manufacture parts that are completely unbounded in size.

Accelerated Characterization of Full-Scale Reinforced Flexible Pavement Models Using Vibroseis

DOT National Transportation Integrated Search

2010-03-01

Geosynthetic basal reinforcement has been used in flexible pavements and unbound roads to limit the occurrence of rutting, fatigue, and environmental-related cracking, and to permit reduction in base course thickness. However, the lack of a represent...

Local infiltration analgesia in knee and hip arthroplasty efficacy and safety.

PubMed

Affas, Fatin

2016-10-01

This is a secondary publication of a PhD thesis. Local infiltration analgesia (LIA) is a new multimodal wound infiltration method for treating postoperative pain after knee and hip arthroplasty. This method is based on systematic infiltration of a mixture of ropivacaine, a long acting local anaesthetic, ketorolac, a cyclooxygenase inhibitor (NSAID), and adrenalin around all structures subject to surgical trauma in knee and hip arthroplasty. Paper I: to assess whether pain relief after LIA in total knee arthroplasty (TKA) is as effective as femoral block. Paper II: to assess whether the plasma concentration of ropivacaine and ketorolac after LIA in TKA reaches levels linked to toxicity. Paper III: to assess whether the plasma concentration of unbound ropivacaine after LIA in THA reaches levels linked to toxicity and if it is higher in THA as compared to TKA. Paper IV: to assess whether the plasma concentration of ketorolac after LIA in THA reaches levels linked to toxicity, and whether administration of ketorolac in LIA is safer as compared to the intramuscular route. Two patient cohorts of 40 patients scheduled for elective total knee arthroplasty (TKA) and 15 patients scheduled for total hip arthroplasty (THA) contributed to this work. In a randomized trial the efficacy of LIA in TKA with regard to pain at rest and upon movement was compared to femoral block. Both methods result in a high quality pain relief and similar morphine consumption during the 24h monitoring period. In the same patient cohort the maximal total plasma concentration of ropivacaine was below the established toxic threshold for most patients. All patients in the THA cohort were subjected to the routine LIA protocol. In these patients both the total and unbound plasma concentration of ropivacaine was determined. The concentration was below the established toxic threshold. As ropivacaine binds to α-1 acid glycoprotein (AAG) we assessed the possibility that increased AAG may decrease the unbound concentration of ropivacaine. A 40% increase in AAG was detected during the first 24h after surgery, however the fraction of unbound ropivacaine remained the same. There was a trend towards increased C max of ropivacaine with increasing age and decreasing creatinine clearance but the statistical power was too low to draw any conclusion. Administration of 30mg ketorolac according to the LIA protocol both in TKA and THA resulted in a similar C max as previously reported after 10mg intramuscular ketorolac. Neither age, nor body weight or BMI, nor creatinine clearance, correlates to maximal ketorolac plasma concentration or total exposure to ketorolac (AUC). LIA provides good postoperative analgesia which is similar to femoral block after total knee arthroplasty. The plasma concentration of ropivacaine seems to be below toxic levels in most TKA patients. The unbound plasma concentration of ropivacaine in THA seems to be below the toxic level. The use of ketorolac in LIA may not be safer than other routes of administration, and similar restrictions should be applied in patients at risk of developing side effects. Copyright © 2016. Published by Elsevier B.V.

Disordered Berezinskii-Kosterlitz-Thouless transition and superinsulation

DOE PAGES

Sankar, S.; Vinokur, V. M.; Tripathi, V.

2018-01-22

Here, we investigate the critical Berezinskii-Kosterlitz-Thouless (BKT) behavior of disordered two-dimensional Josephson-junction arrays (JJA) on the insulating side of the superconductor-insulator transition (SIT) taking into account the effect of hitherto ignored residual random dipole moments of the superconducting grains. We show that for weak Josephson coupling the model is equivalent to a Coulomb gas subjected to a disorder potential with logarithmic correlations. We demonstrate that strong enough disorder transforms the BKT divergence of the correlation length, ξ BKT ∝ exp (const / √T-T BKT), characterizing the average distance between the unbound topological excitations of the opposite signs, into a moremore » singular Vogel-Fulcher-Tamman (VFT) behavior, ξ VFT ∝ exp [const / (T-T VFT)] , which is viewed as a hallmark of glass transitions in glass-forming materials. We further show that the VFT criticality is a precursor of the transition into a nonergodic superinsulating state, while the BKT critical behavior implies freezing into an ergodic confined BKT state. Finally, our finding sheds light on the yet unresolved problem of the origin of the VFT criticality.« less

Twisted photon entanglement through turbulent air across Vienna

PubMed Central

Krenn, Mario; Handsteiner, Johannes; Fink, Matthias; Fickler, Robert; Zeilinger, Anton

2015-01-01

Photons with a twisted phase front can carry a discrete, in principle, unbounded amount of orbital angular momentum (OAM). The large state space allows for complex types of entanglement, interesting both for quantum communication and for fundamental tests of quantum theory. However, the distribution of such entangled states over large distances was thought to be infeasible due to influence of atmospheric turbulence, indicating a serious limitation on their usefulness. Here we show that it is possible to distribute quantum entanglement encoded in OAM over a turbulent intracity link of 3 km. We confirm quantum entanglement of the first two higher-order levels (with OAM=± 1ℏ and ± 2ℏ). They correspond to four additional quantum channels orthogonal to all that have been used in long-distance quantum experiments so far. Therefore, a promising application would be quantum communication with a large alphabet. We also demonstrate that our link allows access to up to 11 quantum channels of OAM. The restrictive factors toward higher numbers are technical limitations that can be circumvented with readily available technologies. PMID:26578763

Twisted photon entanglement through turbulent air across Vienna.

PubMed

Krenn, Mario; Handsteiner, Johannes; Fink, Matthias; Fickler, Robert; Zeilinger, Anton

2015-11-17

Photons with a twisted phase front can carry a discrete, in principle, unbounded amount of orbital angular momentum (OAM). The large state space allows for complex types of entanglement, interesting both for quantum communication and for fundamental tests of quantum theory. However, the distribution of such entangled states over large distances was thought to be infeasible due to influence of atmospheric turbulence, indicating a serious limitation on their usefulness. Here we show that it is possible to distribute quantum entanglement encoded in OAM over a turbulent intracity link of 3 km. We confirm quantum entanglement of the first two higher-order levels (with OAM=± 1ħ and ± 2ħ). They correspond to four additional quantum channels orthogonal to all that have been used in long-distance quantum experiments so far. Therefore, a promising application would be quantum communication with a large alphabet. We also demonstrate that our link allows access to up to 11 quantum channels of OAM. The restrictive factors toward higher numbers are technical limitations that can be circumvented with readily available technologies.

Markov chain aggregation and its applications to combinatorial reaction networks.

PubMed

Ganguly, Arnab; Petrov, Tatjana; Koeppl, Heinz

2014-09-01

We consider a continuous-time Markov chain (CTMC) whose state space is partitioned into aggregates, and each aggregate is assigned a probability measure. A sufficient condition for defining a CTMC over the aggregates is presented as a variant of weak lumpability, which also characterizes that the measure over the original process can be recovered from that of the aggregated one. We show how the applicability of de-aggregation depends on the initial distribution. The application section is devoted to illustrate how the developed theory aids in reducing CTMC models of biochemical systems particularly in connection to protein-protein interactions. We assume that the model is written by a biologist in form of site-graph-rewrite rules. Site-graph-rewrite rules compactly express that, often, only a local context of a protein (instead of a full molecular species) needs to be in a certain configuration in order to trigger a reaction event. This observation leads to suitable aggregate Markov chains with smaller state spaces, thereby providing sufficient reduction in computational complexity. This is further exemplified in two case studies: simple unbounded polymerization and early EGFR/insulin crosstalk.

Live-Cell Imaging of DNA Methylation Based on Synthetic-Molecule/Protein Hybrid Probe.

PubMed

Kumar, Naresh; Hori, Yuichiro; Kikuchi, Kazuya

2018-06-04

The epigenetic modification of DNA involves the conversion of cytosine to 5-methylcytosine, also known as DNA methylation. DNA methylation is important in modulating gene expression and thus, regulating genome and cellular functions. Recent studies have shown that aberrations in DNA methylation are associated with various epigenetic disorders or diseases including cancer. This stimulates great interest in the development of methods that can detect and visualize DNA methylation. For instance, fluorescent proteins (FPs) in conjugation with methyl-CpG-binding domain (MBD) have been employed for live-cell imaging of DNA methylation. However, the FP-based approach showed fluorescence signals for both the DNA-bound and -unbound states and thus differentiation between these states is difficult. Synthetic-molecule/protein hybrid probes can provide an alternative to overcome this restriction. In this article, we discuss the synthetic-molecule/protein hybrid probe that we developed recently for live-cell imaging of DNA methylation, which exhibited fluorescence enhancement only after binding to methylated DNA. © 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Sankar, S.; Vinokur, V. M.; Tripathi, V.

Here, we investigate the critical Berezinskii-Kosterlitz-Thouless (BKT) behavior of disordered two-dimensional Josephson-junction arrays (JJA) on the insulating side of the superconductor-insulator transition (SIT) taking into account the effect of hitherto ignored residual random dipole moments of the superconducting grains. We show that for weak Josephson coupling the model is equivalent to a Coulomb gas subjected to a disorder potential with logarithmic correlations. We demonstrate that strong enough disorder transforms the BKT divergence of the correlation length, ξ BKT ∝ exp (const / √T-T BKT), characterizing the average distance between the unbound topological excitations of the opposite signs, into a moremore » singular Vogel-Fulcher-Tamman (VFT) behavior, ξ VFT ∝ exp [const / (T-T VFT)] , which is viewed as a hallmark of glass transitions in glass-forming materials. We further show that the VFT criticality is a precursor of the transition into a nonergodic superinsulating state, while the BKT critical behavior implies freezing into an ergodic confined BKT state. Finally, our finding sheds light on the yet unresolved problem of the origin of the VFT criticality.« less

The 3H(d,γ)5He Reaction for Ec.m. ≤ 300 keV

NASA Astrophysics Data System (ADS)

Parker, C. E.; Brune, C. R.; Massey, T. N.; O'Donnell, J. E.; Richard, A. L.; Sayre, D. B.

2016-03-01

The 3H(d, γ)5He reaction has been measured using a 500-keV pulsed deuteron beam incident on a stopping titanium tritide target at Ohio University's Edwards Accelerator Laboratory. The time-of-flight (TOF) technique has been used to distinguish the γ-rays from neutrons detected in the bismuth germinate (BGO) γ-ray detector. A stilbene scintillator and an NE-213 scintillator have been used to detect the neutrons from the 3H(d, n)4He reaction using both the pulse-shape discrimination and TOF techniques. A newly-designed target holder with a silicon surface barrier detector to simultaneously measure α-particles to normalize the neutron count was incorporated for subsequent measurements. The γ-rays have been measured at laboratory angles of 0°, 45°, 90°, and 135°. Information about the γ-ray energy distribution for the unbound ground state and first excited state of 5He can be obtained experimentally by comparing the BGO data to Monte Carlo simulations. The 3H(d, γ)/3H(d, n) branching ratio has also been determined.

On effective holographic Mott insulators

NASA Astrophysics Data System (ADS)

Baggioli, Matteo; Pujolàs, Oriol

2016-12-01

We present a class of holographic models that behave effectively as prototypes of Mott insulators — materials where electron-electron interactions dominate transport phenomena. The main ingredient in the gravity dual is that the gauge-field dynamics contains self-interactions by way of a particular type of non-linear electrodynamics. The electrical response in these models exhibits typical features of Mott-like states: i) the low-temperature DC conductivity is unboundedly low; ii) metal-insulator transitions appear by varying various parameters; iii) for large enough self-interaction strength, the conductivity can even decrease with increasing doping (density of carriers) — which appears as a sharp manifestation of `traffic-jam'-like behaviour; iv) the insulating state becomes very unstable towards superconductivity at large enough doping. We exhibit some of the properties of the resulting insulator-superconductor transition, which is sensitive to the momentum dissipation rate in a specific way. These models imply a clear and generic correlation between Mott behaviour and significant effects in the nonlinear electrical response. We compute the nonlinear current-voltage curve in our model and find that indeed at large voltage the conductivity is largely reduced.

Computed parameters : moisture content for unbound materials at seasonal monitoring program sites

DOT National Transportation Integrated Search

2000-01-01

Moisture content plays a significant role in the performance of pavements. Variation in the amount of moisture in the subgrade can change the volume of swelling soil, which may result in detrimental deformation of the pavement structure. An increase ...

Financial impact of fines in the unbound pavement layers.

DOT National Transportation Integrated Search

2014-10-01

This study continued the research effort on evaluating the resilient behavior of D-1 base course materials when there is limited water : access during freezing. D-1 material from the Northern region of Alaska was used, and a closed system was adopted...

Use of Subcutaneous and Intraperitoneal Administration Methods to Facilitate Cassette Dosing in Microdialysis Studies in Rats.

PubMed

Durk, Matthew R; Deshmukh, Gauri; Valle, Nicole; Ding, Xiao; Liederer, Bianca M; Liu, Xingrong

2018-07-01

Microdialysis is a powerful technique allowing for real-time measurement of unbound drug concentrations in brain interstitial fluid in conscious animals. Use of microdialysis in drug discovery is limited by high resource requirement and low throughput, but this may be improved by cassette dosing. Administering multiple compounds intravenously of diverse physiochemical properties, it is often very challenging and time consuming to identify a vehicle that can dissolve all of the compounds. To overcome this limitation, the present study explores the possibility of administering a cassette dose of nine diverse compounds (carbamazepine, citalopram, desmethylclozapine, diphenhydramine, gabapentin, metoclopramide, naltrexone, quinidine, and risperidone) in suspension, rather than in solution, by intraperitoneal and subcutaneous routes, and determining if this is a viable option for assessing blood-brain barrier penetration in microdialysis studies. Repeated hourly subcutaneous dosing during the 6-hour microdialysis study allowed for the best attainment of distributional equilibrium between brain and plasma, resulting in less than a 2-fold difference in the unbound brain to unbound plasma concentration ratio for the cassette dosing method versus discrete dosing. Both subcutaneous and intraperitoneal repeated dosing can provide a more practical substitute for intravenous dosing in determining brain penetration of a cassette of diverse compounds in brain microdialysis studies. The results from the present study demonstrate that dosing compounds in suspension represents a practical approach to eliminating the technical challenge and labor-intensive step of preparation of solutions of a mixture of compounds and will enable the use of the cassette brain microdialysis method in a central nervous system drug discovery setting. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

An Investigation into the Prediction of in Vivo Clearance for a Range of Flavin-containing Monooxygenase Substrates.

PubMed

Jones, Barry C; Srivastava, Abhishek; Colclough, Nicola; Wilson, Joanne; Reddy, Venkatesh Pilla; Amberntsson, Sara; Li, Danxi

2017-10-01

Flavin-containing monooxygenases (FMO) are metabolic enzymes mediating the oxygenation of nucleophilic atoms such as nitrogen, sulfur, phosphorus, and selenium. These enzymes share similar properties to the cytochrome P450 system but can be differentiated through heat inactivation and selective substrate inhibition by methimazole. This study investigated 10 compounds with varying degrees of FMO involvement to determine the nature of the correlation between human in vitro and in vivo unbound intrinsic clearance. To confirm and quantify the extent of FMO involvement six of the compounds were investigated in human liver microsomal (HLM) in vitro assays using heat inactivation and methimazole substrate inhibition. Under these conditions FMO contribution varied from 21% (imipramine) to 96% (itopride). Human hepatocyte and HLM intrinsic clearance (CL int ) data were scaled using standard methods to determine the predicted unbound intrinsic clearance (predicted CL int u ) for each compound. This was compared with observed unbound intrinsic clearance (observed CL int u ) values back calculated from human pharmacokinetic studies. A good correlation was observed between the predicted and observed CL int u using hepatocytes ( R 2 = 0.69), with 8 of the 10 compounds investigated within or close to a factor of 2. For HLM the in vitro-in vivo correlation was maintained ( R 2 = 0.84) but the accuracy was reduced with only 3 out of 10 compounds falling within, or close to, twofold. This study demonstrates that human hepatocytes and HLM can be used with standard scaling approaches to predict the human in vivo clearance for FMO substrates. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

A Unified Conformational Selection and Induced Fit Approach to Protein-Peptide Docking

PubMed Central

Trellet, Mikael; Melquiond, Adrien S. J.; Bonvin, Alexandre M. J. J.

2013-01-01

Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have enabled exhaustive studies on the peptide recognition preferences for a number of peptide-binding domain families. Yet, the paucity of data regarding their molecular binding mechanisms together with their inherent flexibility makes the structural prediction of protein-peptide interactions very challenging. This leaves flexible docking as one of the few amenable computational techniques to model these complexes. We present here an ensemble, flexible protein-peptide docking protocol that combines conformational selection and induced fit mechanisms. Starting from an ensemble of three peptide conformations (extended, a-helix, polyproline-II), flexible docking with HADDOCK generates 79.4% of high quality models for bound/unbound and 69.4% for unbound/unbound docking when tested against the largest protein-peptide complexes benchmark dataset available to date. Conformational selection at the rigid-body docking stage successfully recovers the most relevant conformation for a given protein-peptide complex and the subsequent flexible refinement further improves the interface by up to 4.5 Å interface RMSD. Cluster-based scoring of the models results in a selection of near-native solutions in the top three for ∼75% of the successfully predicted cases. This unified conformational selection and induced fit approach to protein-peptide docking should open the route to the modeling of challenging systems such as disorder-order transitions taking place upon binding, significantly expanding the applicability limit of biomolecular interaction modeling by docking. PMID:23516555

A unified conformational selection and induced fit approach to protein-peptide docking.

PubMed

Trellet, Mikael; Melquiond, Adrien S J; Bonvin, Alexandre M J J

2013-01-01

Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have enabled exhaustive studies on the peptide recognition preferences for a number of peptide-binding domain families. Yet, the paucity of data regarding their molecular binding mechanisms together with their inherent flexibility makes the structural prediction of protein-peptide interactions very challenging. This leaves flexible docking as one of the few amenable computational techniques to model these complexes. We present here an ensemble, flexible protein-peptide docking protocol that combines conformational selection and induced fit mechanisms. Starting from an ensemble of three peptide conformations (extended, a-helix, polyproline-II), flexible docking with HADDOCK generates 79.4% of high quality models for bound/unbound and 69.4% for unbound/unbound docking when tested against the largest protein-peptide complexes benchmark dataset available to date. Conformational selection at the rigid-body docking stage successfully recovers the most relevant conformation for a given protein-peptide complex and the subsequent flexible refinement further improves the interface by up to 4.5 Å interface RMSD. Cluster-based scoring of the models results in a selection of near-native solutions in the top three for ∼75% of the successfully predicted cases. This unified conformational selection and induced fit approach to protein-peptide docking should open the route to the modeling of challenging systems such as disorder-order transitions taking place upon binding, significantly expanding the applicability limit of biomolecular interaction modeling by docking.

A simple and highly sensitive on-line column extraction liquid chromatography-tandem mass spectrometry method for the determination of protein-unbound tacrolimus in human plasma samples.

PubMed

Bittersohl, Heike; Schniedewind, Björn; Christians, Uwe; Luppa, Peter B

2018-04-27

Therapeutic drug monitoring (TDM) of the immunosuppressive drug tacrolimus is essential to avoid side effects and rejection of the allograft after transplantation. In the blood circulation, tacrolimus is largely located inside erythrocytes or bound to plasma proteins and less than 0.1% is protein-unbound (free). One basic principle of clinical pharmacology is that only free drug is pharmacologically active and monitoring this portion has the potential to better reflect the drug effect than conventional measurements of total tacrolimus in whole blood. To address this, a highly sensitive and straightforward on-line liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed, validated and applied to patient plasma samples. The sample preparation included ultracentrifugation and addition of the stable isotope labeled drug analogue D2,13C-tacrolimus, followed by on-line sample extraction and measurement using a Sciex QTRAP ® 6500 in the multiple reaction monitoring mode. Due to very low concentrations of protein-unbound tacrolimus, it was important to develop a highly sensitive, precise and accurate assay. Here, we first report the efficient formation of tacrolimus lithium adduct ions, which greatly increased assay sensitivity. A lower limit of quantification (LLOQ) of 1 pg/mL (10 fg on column) was achieved and the assay was linear between 1 and 200 pg/mL. There was no carry-over detected. The inaccuracy ranged from -9.8 to 7.4% and the greatest imprecision was 7.5%. The matrix factor was found to be smaller than 1.1%. In summary, this method represents a suitable tool to investigate the potential clinical value of free tacrolimus monitoring in organ transplant recipients. Copyright © 2018 Elsevier B.V. All rights reserved.

Oviduct binding and elevated environmental ph induce protein tyrosine phosphorylation in stallion spermatozoa.

PubMed

Leemans, Bart; Gadella, Bart M; Sostaric, Edita; Nelis, Hilde; Stout, Tom A E; Hoogewijs, Maarten; Van Soom, Ann

2014-07-01

Sperm-oviduct binding is an essential step in the capacitation process preparing the sperm for fertilization in several mammalian species. In many species, capacitation can be induced in vitro by exposing spermatozoa to bicarbonate, Ca(2+), and albumin; however, these conditions are insufficient in the horse. We hypothesized that binding to the oviduct epithelium is an essential requirement for the induction of capacitation in stallion spermatozoa. Sperm-oviduct binding was established by coincubating equine oviduct explants for 2 h with stallion spermatozoa (2 × 10(6) spermatozoa/ml), during which it transpired that the highest density (per mm(2)) of oviduct-bound spermatozoa was achieved under noncapacitating conditions. In subsequent experiments, sperm-oviduct incubations were performed for 6 h under noncapacitating versus capacitating conditions. The oviduct-bound spermatozoa showed a time-dependent protein tyrosine phosphorylation response, which was not observed in unbound spermatozoa or spermatozoa incubated in oviduct explant conditioned medium. Both oviduct-bound and unbound sperm remained motile with intact plasma membrane and acrosome. Since protein tyrosine phosphorylation can be induced in equine spermatozoa by media with high pH, the intracellular pH (pHi) of oviduct explant cells and bound spermatozoa was monitored fluorometrically after staining with BCECF-AM dye. The epithelial secretory cells contained large, alkaline vesicles. Moreover, oviduct-bound spermatozoa showed a gradual increase in pHi, presumably due to an alkaline local microenvironment created by the secretory epithelial cells, given that unbound spermatozoa did not show pHi changes. Thus, sperm-oviduct interaction appears to facilitate equine sperm capacitation by creating an alkaline local environment that triggers intracellular protein tyrosine phosphorylation in bound sperm. © 2014 by the Society for the Study of Reproduction, Inc.

Vinorelbine Delivery and Efficacy in the MDA-MB-231BR Preclinical Model of Brain Metastases of Breast Cancer.

PubMed

Samala, Ramakrishna; Thorsheim, Helen R; Goda, Satyanarayana; Taskar, Kunal; Gril, Brunilde; Steeg, Patricia S; Smith, Quentin R

2016-12-01

To evaluate vinorelbine drug exposure and activity in brain metastases of the human MDA-MB-231BR breast cancer model using integrated imaging and analysis. Brain and systemic metastases were created by administration of cancer cells in female NuNu mice. After metastases developed, animals were administered vinorelbine at the maximal tolerated dose (12 mg/kg), and were evaluated thereafter for total and unbound drug pharmacokinetics, biomarker TUNEL staining, and barrier permeability to Texas red. Median brain metastasis drug exposure was 4-fold greater than normal brain, yet only ~8% of non-barrier systemic metastases, which suggests restricted brain exposure. Unbound vinorelbine tissue/plasma partition coefficient, K p,uu , equaled ~1.0 in systemic metastases, but 0.03-0.22 in brain metastases, documenting restricted equilibration. In select sub-regions of highest drug-uptake brain metastases, K p,uu approached 1.0, indicating complete focal barrier breakdown. Most vinorelbine-treated brain metastases exhibited little or no positive early apoptosis TUNEL staining in vivo. The in vivo unbound vinorelbine IC 50 for TUNEL-positive staining (56 nM) was 4-fold higher than that measured in vitro (14 nM). Consistent with this finding, P-glycoprotein expression was observed to be substantially upregulated in brain metastasis cells in vivo. Vinorelbine exposure at maximum tolerated dose was less than one-tenth that in systemic metastases in >70% of brain metastases, and was associated with negligible biomarker effect. In small subregions of the highest uptake brain metastases, compromise of blood-tumor barrier appeared complete. The results suggest that restricted delivery accounts for 80% of the compromise in drug efficacy for vinorelbine against this model.

Factors influencing palmitoyl-CoA oxidation by rat liver peroxisomal fractions. Substrate concentration, organelle integrity and ATP.

PubMed Central

Thomas, J; Debeer, L J; De Schepper, P J; Mannaerts, G P

1980-01-01

1. The first dehydrogenation step of peroxisomal beta-oxidation involves the reduction of O2 to H2O2. Production rates of H2O2 and acetyl units by purified rat liver peroxisomes oxidizing palmitoyl-CoA were equal, indicating that H2O2 production is a reliable index for the release of acetyl units during peroxisomal fatty-acid oxidation. 2. Measurements of H2O2 and acid-soluble oxidation products during [1-14C]palmitoyl-CoA oxidation by purified peroxisomes revealed that the number of acetyl units released per molecule of palmitoyl-CoA oxidized rapidly decreased with increasing unbound palmitoyl-CoA concentrations. Structural damage to the peroxisomes caused by detergents or other treatments also decreased the number of acetyl units released. Under conditions where oxidation proceeded linearly with time the theoretical maximum of 5 acetyl units released per molecule of palmitoyl-CoA oxidized [Lazarow (1978) J. Biol. Chem. 253, 1522--1528] was never reached. 3. Expressed in terms of acetyl units produced and measured at low unbound-palmitoyl-CoA concentrations, mitochondrial oxidation was 10--20-fold higher than peroxisomal oxidation. 4. ATP stimulated peroxisomal palmitoyl-CoA oxidation approx. 2-fold. The ATP effect required the presence of Mg2+ and was lost when peroxisomal membranes were disrupted by Triton X-100 or high concentrations of unbound palmitoyl-CoA. 5. Disruption of peroxisomes by detergents, freeze--thawing, osmotic or mechanical treatment did not stimulate palmitoyl-CoA oxidation in the presence of ATP, indicating that peroxisomal fatty-acid-CoA oxidation was not latent. In the absence of ATP, Triton X-100 stimulated peroxisomal palmitoyl-CoA oxidation approx. 2-fold. PMID:7470063

Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus

PubMed Central

Ogutu, Bernhards R; Newton, Charles R J C; Muchohi, Simon N; Otieno, Godfrey O; Edwards, Geoffrey; Watkins, William M; Kokwaro, Gilbert O

2003-01-01

Aims Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. Methods Children received intravenous (i.v.) phenytoin as a 18 mg kg−1 loading dose infused over 20 min followed by a 2.5 mg kg−1 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg min−1 phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg kg−1 loading dose followed by 2.5 mg kg−1 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. Results After all routes of administration, a plasma unbound phenytoin concentration of more than 1 µg ml−1 was rapidly (within 5–20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08–0.17), 0.37 (0.33–0.67) and 0.38 (0.17–2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. Conclusions Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation. PMID:12848783

Effect of hepatic impairment on the pharmacokinetics of a single dose of cilostazol.

PubMed

Bramer, S L; Forbes, W P

1999-01-01

The pharmacokinetic profiles of cilostazol and its metabolites following a single oral dose of cilostazol 100 mg were compared between individuals with impaired and normal liver function. The study was conducted as a single-centre, open-label, single dose pharmacokinetic and tolerability trial. 12 patients with impaired and compensated liver function were compared with 12 volunteers with normal liver function. Participants in each group were matched for gender, age and weight. Of the 12 patients with hepatic impairment examined in this study, 10 had mild impairment (Child-Pugh class A) and 2 had moderate impairment (Child-Pugh class B). Blood and urine were collected up to 144 hours after drug administration. Pharmacokinetics were determined by noncompartmental methods. Protein binding did not differ between the groups (95.2% healthy volunteers, 94.6% hepatically impaired patients). Mean +/- SD unbound oral clearance of cilostazol decreased by 8.6% because of hepatic impairment (3380 +/- 1400 ml/min in healthy volunteers, 3260 +/- 2030 ml/min in hepatically impaired patients). Total urinary excretion of metabolites was significantly higher in healthy volunteers (26 vs 17% of dose). Overall, the pharmacokinetics of cilostazol and its metabolites, OPC-13213 and OPC-13015, were not substantially different in those with mild and moderate hepatic disease compared with values in healthy volunteers. Except for terminal-phase disposition half-life and apparent terminal-phase volume of distribution for cilostazol, the ratios of geometric means of pharmacokinetic parameters for plasma cilostazol, OPC-13213 and OPC-13015 in those with hepatic impairment versus healthy volunteers were close to 100%. Based on the results of the pharmacokinetic analysis, dose adjustment in patients with mild hepatic impairment is not necessary. However, caution should be exercised when cilostazol is administered to patients with moderate or severe hepatic impairment.

Pharmacokinetics of a Single Oral Dose of the MEK1/2 Inhibitor Selumetinib in Subjects With End‐Stage Renal Disease or Varying Degrees of Hepatic Impairment Compared With Healthy Subjects

PubMed Central

Dymond, Angela W.; Martin, Paul; Huang, Yifan; Severin, Paul; Holmes, Victoria; Mariani, Gabriella; Marbury, Thomas

2016-01-01

Abstract Two phase I open‐label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of selumetinib in subjects with end‐stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control group comprised of healthy individuals. In the renal impairment study, subjects received single doses of selumetinib 50 mg; those with ESRD received selumetinib before and after dialysis (with a between‐treatment washout period of ≥7 days). In the hepatic impairment study, subjects received varying single doses of selumetinib (20‐50 mg) depending on liver dysfunction (mild, moderate, or severe as per Child‐Pugh classification). PK, safety, and tolerability data were collected from both studies. Overall, 24 subjects were included in the renal impairment study (ESRD, N = 12; healthy subjects, N = 12). Selumetinib exposure (AUC and Cmax) was not increased in the ESRD group vs healthy subjects. Selumetinib exposure was lower when selumetinib was dosed before vs after dialysis, although individual exposure was variable. Overall, 32 subjects were included in the hepatic impairment study (mild, moderate, and severe impairment, N = 8 per group; healthy subjects, N = 8). Generally, dose‐normalized total selumetinib exposure was increased by 25% to 59% in subjects with moderate and severe hepatic impairment compared with healthy subjects. Increasing Child‐Pugh score, decreasing serum albumin, and increasing prothrombin time correlated with increasing unbound selumetinib exposure. In both studies, selumetinib was well tolerated with no new safety concerns. These studies will inform dose adjustment considerations in patients. PMID:28019010

From Continuous Improvement to Organisational Learning: Developmental Theory.

ERIC Educational Resources Information Center

Murray, Peter; Chapman, Ross

2003-01-01

Explores continuous improvement methods, which underlie total quality management, finding barriers to implementation in practice that are related to a one-dimensional approach. Suggests a multiple, unbounded learning cycle, a holistic approach that includes adaptive learning, learning styles, generative learning, and capability development.…

Study of LTPP laboratory resilient modulus test data and response characteristics.

DOT National Transportation Integrated Search

2002-10-01

The resilient modulus of every unbound structural layer of the Long Term Pavement Performance (LTPP) Specific Pavement and : General Pavement Studies Test Sections is being measured in the laboratory using LTPP test protocol P46. A total of 2,014 : r...