Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR 1 or M-1) Antagonist In Vitro and In Vivo Probe

This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M-1). An M-1 functional, cell-based, calcium-mobilization assay identified three distinct chemical series with initial selectivity for M-1 versus M-4. An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC50 = 130 nM) and selective (>75-fold vs. M-2-M-5 and >10 mu M vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M-1 antagonist. Further profiling demonstrated that VU0255035 was centrally penetrant (Brain(AUC)/Plasma(AUC) of 0.48) and active in vivo, rendering it acceptable as both an in vitro and in vivo MLSCN/MLPCN probe molecule for studying and dissecting M-1 function.

A study of DNA fragmentation patterns in cells irradiated with charged particles: evidence for non-random distributions

Many studies have shown that the effectiveness of radiations of varying LET is similar when yields of dsb have been measured, despite large differences in biological response. Recent evidence has suggested however, that current techniques underestimate the yields of dsb. By monitoring the fragmentation of DNA over a wide range of fragment sizes ( 6 Mbp) by pulsed field electrophoresis, RBE values greater than 1.0 for radiations of around 100 keV/mm have been determined. The data provide evidence for the production of correlated breaks produced within cells as particle tracks traverse the nucleus. The highly ordered structure of DNA within mammalian cells may lead to clustering of breaks over distances related to the repeating unit structures of the chromatin. As well as these regionally damaged sites, a major contributor to radiation effectiveness will be the localised clustering of damage in the 1 - 20 bp region. A major effort is required to elucidate the relative importance of these levels of clustering and their importance in biological response.

ELECTRON-ENERGY DISTRIBUTION-FUNCTIONS AND NEGATIVE-ION CONCENTRATIONS IN TANDEM AND HYBRID MULTICUSP NEGATIVE HYDROGEN-ION SOURCES

The second derivative of a Langmuir probe characteristic is used to establish the electron energy distribution function (EEDF) in both a tandem and hybrid multicusp H- ion source. Moveable probes are used to establish the spatial variation of the EEDF. The negative ion density is measured by laser induced photo-detachment. In the case of the hybrid source the EEDF consists of a cold Maxwellian in the central region of the source; the electron temperature increases with increasing discharge current (rising from 0.3 eV at 1 A to 1.2 eV at 50 A when the pressure is 0.4 Pa). A hot-electron tail exists in the EEDF of the driver region adjacent to each filament which is shown to consist of a distinct group of primary electrons at low pressure (0.08 Pa) but becomes degraded mainly through inelastic collisions at higher pressures (0.27 Pa). The tandem source, on the other hand, has a single driver region which extends throughout the central region. The primary electron confinement times are much longer so that even at the lowest pressure considered (0.07 Pa) the primaries are degraded. In both cases the measured EEDF at specific locations and values of discharge operating parameters are used to establish the rate coefficients for the processes of importance in H- production and destruction.

Nonlinear electrostatic excitations of charged dust in degenerate ultra-dense quantum dusty plasmas

The linear and nonlinear properties of low-frequency electrostatic excitations of charged dust particles (or defects) in a dense collisionless, unmagnetized Thomas-Fermi plasma are investigated. A fully ionized three-component model plasma consisting of electrons, ions, and negatively charged massive dust grains is considered. Electrons and ions are assumed to be in a degenerate quantum state, obeying the Thomas-Fermi density distribution, whereas the inertial dust component is described by a set of classical fluid equations. Considering large-amplitude stationary profile travelling-waves in a moving reference frame, the fluid evolution equations are reduced to a pseudo-energy-balance equation, involving a Sagdeev-type potential function. The analysis describes the dynamics of supersonic dust-acoustic solitary waves in Thomas-Fermi plasmas, and provides exact predictions for their dynamical characteristics, whose dependence on relevant parameters (namely, the ion-to-electron Fermi temperature ratio, and the dust concentration) is investigated. An alternative route is also adopted, by assuming weakly varying small-amplitude disturbances off equilibrium, and then adopting a multiscale perturbation technique to derive a Korteweg–de Vries equation for the electrostatic potential, and finally solving in terms for electric potential pulses (electrostatic solitons). A critical comparison between the two methods reveals that they agree exactly in the small-amplitude, weakly superacoustic limit. The dust concentration (Havnes) parameter h = Zd0nd0/ne0 affects the propagation characteristics by modifying the phase speed, as well as the electron/ion Fermi temperatures. Our results aim at elucidating the characteristics of electrostatic excitations in dust-contaminated dense plasmas, e.g., in metallic electronic devices, and also arguably in supernova environments, where charged dust defects may occur in the quantum plasma regime.

Nonlinear wavepackets in pair-ion and electron-positron-ion plasmas

The occurrence of amplitude-modulated electrostatic and electromagnetic
wavepackets in pair plasmas is investigated. A static additional charged background species is considered, accounting for dust defects or for heavy ion
presence in the background. Relying on a two-fluid description, a nonlinear
Schrodinger type evolution equation is obtained and analyzed, in terms of the
slow dynamics of the wave amplitude. Exact envelope excitations are obtained,
modelling envelope pulses or holes, and their characteristics are discussed.

Time-dependent density functional theory study of charge transfer in collisions

We study the charge transfer between colliding ions, atoms, or molecules, within time-dependent density functional theory. Two particular cases are presented, the collision between a proton and a Helium atom, and between a gold atom and a butane molecule. In the first case, proton kinetic energies between 16 keV and 1.2 MeV are considered, with impact parameters between 0.31 and 1.9 angstrom. The partial transfer of charge is monitored with time. The total cross-section is obtained as a function of the proton kinetic energy. In the second case, we analyze one trajectory and discuss spin-dependent charge transfer between the different fragments.

Preparation of Highly Stable OEG derivatives-functionalized AuNPs and Its Application in LSPR-based Detection of PSA/ACT Complex

The zero-length crosslinker EDC has been widely used to make amide bonds between carboxylic acid and amine groups for bioconjugation because no residues remain in the crosslinked protein. During the conjugation process, EDC activates the carboxyl groups (negatively charged) and forms an unstable amine-reactive intermediate (positively charged). However, the process turns to be a problematic issue if it is applied to modify carboxyl-functionalized and –stabilized Au nanoparticles (AuNPs) due to the fact that the negatively repulsive forces which help to stabilize the AuNPs were disrupted leading to the colloid aggregation. Therefore, to modify the negatively carboxyl-terminated AuNPs while their stability can be maintained yet, we assume that functionalization of the AuNPs using 02 kinds of negatively charged groups which one serves as a linking agent, and the other one plays a role of negative charge maintainer could overcome the impediment.

In this study, the colloidal gold nanoparticles were synthesized by Turkevitch’s method, and then their surface was rationally functionalized with different molar ratios of HS(CH2)11(OCH2CH2)6OCH2COOH and HS(CH2)11(OCH2CH2)3OH (OEG6-COOH/OEG3-OH) by self assembling technique. As a result, the most appropriate molar ratio was found to be 1:10, and the AuNP aggregation was prevented not only in the activation process by EDC but also in the present of high concentration of NaCl as well as over in a wide pH range. This is the first time that extremely stable OEG derivatives-functionalized Au nanoparticles for protein bioconjugation using EDC chemistry is reported, and the results open the door for covalent bioconjugation of AuNPs in biological applications.

Irradiation of oxygen and water ices at by 4 keV singly and doubly charged ions; sputtering and molecular synthesis

The icy surfaces of dust grains in the Interstellar Medium and those of comets, satellites and Kuiper Belt Objects are continuously exposed tophoton and charged particle irradiation. These energetic particles maysputter and induce chemical changes in the ices and the underlyingsurfaces.In the present work 258 nm thick O2 and H2O ices were deposited at 10 K with the thickness measured by a laser interferometer method. Asimple model fit to the reflected laser intensity as measured by aphotodiode detector enabled the refractive index of the ices to bedetermined. The ices were then irradiated with various singly and doublycharged ions such as He+, 13C+, N+, O+ , Ar+, 13C2+, N2+ and O2+ at 4keV. The decrease in ice thickness as a function of ion dose wasmonitored by a laser interferometer and the model used to determine thesputtering yield as shown in Figure 1.In the case of O2 ice thesputtering yields increased with increasing ion mass in good agreementwith a model calculation [Fama, J, Shi, R.A Baragiola, Surface Sci.,602, 156 (2007)]. In the case of O2 ice, O2+ has a significant lowersputtering yield when compared to O+. The sputtering yields for O2 icewere found to be at least 9 times larger compared to those for H2O ice.For H2O ice the sputter yields for C, N and O ions were found todecrease with increasing mass. Doubly charged C, N and O ions which werefound to have the same sputtering yield as the singly charged ionswithin the experimental errors. A preliminary TPD study was carried outusing a QMS to detect the desorbed species from water ice afterirradiation by 6 × 10^15 ions of 13C+ and 13C2+. The formation of13CO and 13CO2 was observed with the yield of 13CO almost of a factor of100 larger than of 13CO2. This is in contrast to our earlier work whereonly CO¬2 was observed.

Diagnostics for studies of novel laser ion acceleration mechanisms

Diagnostic for investigating and distinguishing different laser ion acceleration mechanisms has been developed and successfully tested. An ion separation wide angle spectrometer can simultaneously investigate three important aspects of the laser plasma interaction: (1) acquire angularly resolved energy spectra for two ion species, (2) obtain ion energy spectra for multiple species, separated according to their charge to mass ratio, along selected axes, and (3) collect laser radiation reflected from and transmitted through the target and propagating in the same direction as the ion beam. Thus, the presented diagnostic constitutes a highly adaptable tool for accurately studying novel acceleration mechanisms in terms of their angular energy distribution, conversion efficiency, and plasma density evolution.

Similarity between Positronium-Atom and Electron-Atom Scattering

We employ the impulse approximation for a description of positronium-atom scattering. Our analysis and calculations of Ps-Kr and Ps-Ar collisions provide a theoretical explanation of the similarity between the cross sections for positronium scattering and electron scattering for a range of atomic and molecular targets observed by S. J. Brawley et al. [Science 330, 789 (2010)].

Modelling the brightness increase signature due to asteroid collisions

We have developed a model to predict the post-collision brightness increase of sub-catastrophic collisions between asteroids and to evaluate the likelihood of a survey detecting these events. It is based on the cratering scaling laws of Holsapple and Housen (2007) and models the ejecta expansion following an impact as occurring in discrete shells each with their own velocity. We estimate the magnitude change between a series of target/impactor pairs, as- suming it is given by the increase in reflecting surface area within a photometric aperture due to the resulting ejecta. As expected the photometric signal increases with impactor size, but we find also that the photometric signature decreases rapidly as the target aster- oid diameter increases, due to gravitational fallback. We have used the model results to make an estimate of the impactor diameter for the (596) Scheila collision of D = 49 − 65m depending on the impactor taxonomy, which is broadly consistent with previous estimates. We varied both the strength regime (highly porous and sand/cohesive soil) and the tax- onomic type (S-, C- and D-type) to examine the effect on the magnitude change, finding that it is significant at early stages but has only a small effect on the overall lifetime of the photometric signal. Combining the results of this model with the collision frequency estimates of Bottke et al. (2005), we find that low-cadence surveys of ∼one visit per luna- tion will be insensitive to impacts on asteroids with D < 20km if relying on photometric detections.

Sputtering of oxygen ice by low energy ions

Naturally occurring ices lie on both interstellar dust grains and on celestial objects, such as those in the outer Solar system. These ices are continuously subjected to irradiation by ions from the solar wind and/or cosmic rays, which modify their surfaces. As a result, new molecular species may form which can be sputtered off into space or planetary atmospheres. We determined the experimental values of sputtering yields for irradiation of oxygen ice at 10 K by singly (He+, C+, N+, O+ and Ar+) and doubly (C2 +, N2 + and O2 +) charged ions with 4 keV kinetic energy. In these laboratory experiments, oxygen ice was deposited and irradiated by ions in an ultra high vacuum chamber at low temperature to simulate the environment of space. The number of molecules removed by sputtering was observed by measurement of the ice thickness using laser interferometry. Preliminary mass spectra were taken of sputtered species and of molecules formed in the ice by temperature programmed desorption (TPD). We find that the experimental sputtering yields increase approximately linearly with the projectile ion mass (or momentum squared) for all ions studied. No difference was found between the sputtering yields for singly and doubly charged ions of the same atom within the experimental uncertainty, as expected for a process dominated by momentum transfer. The experimental sputter yields are in good agreement with values calculated using a theoretical model except in the case of oxygen ions. Preliminary studies have shown molecular oxygen as the dominant species sputtered and TPD measurements indicate ozone formation.

Tailoring the nonlinear frequency coupling between odd harmonics for the optimisation of charged particle dynamics in capacitively coupled oxygen plasmas

The influence of nonlinear frequency coupling in an oxygen plasma excited by two odd harmonics at moderate pressure is investigated using a numerical model. Through variations in the voltage ratio and phase shift between the frequency components changes in ionization dynamics and sheath voltages are demonstrated. Furthermore, a regime in which the voltage drop across the plasma sheath is minimised is identified. This regime provides a significantly higher ion flux than a single frequency discharge driven by the lower of the two frequencies alone. These operating parameters have potential to be exploited for plasma processes requiring low ion bombardment energies but high ion fluxes. 

Simple preparation of positively charged silver nanoparticles for detection of anions by surface-enhanced Raman spectroscopy

Modification of citrate and hydroxylamine reduced Ag colloids with thiocholine bromide, a thiol functionalized quaternary ammonium salt, creates particles where the zeta potential is switched from the normal values of ca. -50 mV to ca. + 50 mV. These colloids are stable but can be aggregated with metal salts in much the same way as the parent colloids. They are excellent SERS substrates for detection of anionic targets since their positive zeta potentials promote adsorption of negatively charged ions. This is important because the vast majority of published SERS studies involve cationic or neutral targets. Moreover, the fact that the modifier is a quaternary ammonium ion means that the negative surface charge is maintained even at alkaline pH. The modified colloids can be used to detect compounds which cannot be detected using conventional negatively-charged citrate or hydroxylamine reduced metal nanoparticles, for example the detection limit was 5.0 x 10(-5) M for perchlorate and

Facile synthesis of nanocrystalline LiFePO4/graphene composite as cathode material for high power lithium ion batteries

We describe a simple strategy, which is based on the idea of space confinement, for the synthesis of carbon coating on LiFePO₄ nanoparticles/graphene nanosheets composites in a water-in-oil emulsion system. The prepared composite displayed high performance as a cathode material for lithium-ion battery, such as high reversible lithium storage capacity (158 mA h g^-1 after 100 cycles), high coulombic efficiency (over 97%), excellent cycling stability and high rate capability (as high as 83 mA h g ^-1 at 60 C). Very significantly, the preparation method employed can be easily adapted and be extended as a general approach to sophisticated compositions and structures for the preparation of highly dispersed nanosized structure on graphene.