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The role of the forcefield (FF) is critical in predicting the properties of supramolecular systems. Long time dynamic properties depend mostly on vibrations at low wavenumber : this is especially true for molecules adsorbed in zeolites, where low frequency vibrations partly control site-to-site jumps and hence kinetics. It is therefore essential that a FF devoted to study diffusion in zeolites reproduces this vibrational range, that can also be directly observed using inelastic neutron spectroscopy (INS). In this proceeding we present low frequency (LF) vibrational spectra of benzene adsorbed in NaY, as computed from molecular dynamics simulations, using three different FFs. We assess the variability of the spectra on the type of motion (librations and external vibrations,) temperature, local environment, and coupling to the zeolite phonons. A comparison to the experimental INS spectrum allows us to rank the FFs in their ability to reproduce benzene's kinetics in NaY.

We have studied the convergence properties of embedded and constrained cluster models of proton transfer in zeolites. We applied density functional theory to describe clusters and ONIOM to perform the embedding. We focused on converging the reaction energy and barrier of the O(1) to O(4) jump in H−Y zeolite as well as vibrational and structural aspects of this jump. We found that using successively larger clusters in vacuo gives convergence of this reaction energy to 14 ± 2 kJ mol^-1 and the barrier to 135 ± 5 kJ mol^-1 at a cluster size of 5 Å, which contains 11 tetrahedral (Si or Al) atoms. We embedded quantum clusters of various sizes in larger clusters with total radii in the range 7−20 Å, using the universal force field as the lower level of theory in ONIOM. We found convergence to the same values as the constrained clusters, without the use of reactive force fields or periodic boundary conditions in the embedding procedure. For the reaction energy, embedded cluster calculations required smaller clusters than in vacuo calculations, reaching converged reaction energies for quantum systems containing at least 8 tetrahedral atoms. In addition, optimizations on embedded clusters required many fewer cycles, and hence much less CPU time, than did optimizations on comparable constrained clusters.

We have performed molecular dynamics (MD) simulations of zeolite−guest systems driven by microwaves (MW), to study how energy is distributed in these systems as a function of guest loading. Expanding on a previously published communication [Blanco, C.; Auerbach, S. M. J. Am. Chem. Soc. 2002, 124, 6250.], we have found that MW-driven MD with the Andersen thermostat gives robust steady states, while MW-driven MD with the Nosé−Hoover chain thermostat does not. We studied MW-driven zeolites NaY, DAY and silicalite, as well as benzene and/or methanol in DAY or silicalite. DAY and silicalite exhibit little MW heating, while NaY gives strong MW heating primarily through the Na cations, whose kinetic energy was found to equilibrate on picosecond time scales. Zeolite−benzene systems show minimal MW heating, while zeolite−methanol systems exhibit significant MW heating with steady-state temperatures increasing linearly with methanol loading. MW-driven equimolar mixtures of benzene and methanol at low to medium loadings in DAY or silicalite obey Tmethanol ≫ Tbenzene > Tzeolite, suggesting that MW heating of binary mixtures in zeolites can produce novel effects. However, MW-driven MD at higher loadings shows that Tmethanol ~ Tbenzene > Tzeolite, suggesting that closely related MW sorption studies can produce markedly different results viz. athermal effects.

We have developed and applied a new force field for simultaneously modeling the dynamics of hydrofluorocarbons (HFCs) and exchangeable Na cations in faujasite-type zeolites. Our aim is to account for (i) the zeolite's capacity of separating HFC isomers, (ii) the experimentally observed unusual cation migration in Na−Y from the β-cages into the supercages upon the adsorption of HFCs, and (iii) the abnormal trans/gauche ratio in these systems. Energy minimizations and molecular dynamics simulations performed with this force field give excellent agreement with experimental data on heats of adsorption, guest−host distances, infrared spectra, and conformer ratios for different coverages of HFC-134 (CF2H−CF2H) and HFC-134a (CH2F−CF3) in Na−X (Si:Al = 1.2) and Na−Y (Si:Al = 2.4). The force field also accounts partially for the observed cation migration at intermediate loadings and fully at high loadings. The extent of migration is found to be influenced by the competition among Na−O, Na−F, and Na−Na interactions. The Na−O interaction disfavors migration because Na(I‘) sites are found to be energetically more favorable than Na(III‘) sites; the Na−F attraction obviously favors migration; and surprisingly, the Na−Na repulsion also favors migration because moving Na cations into supercages leads to better cation dispersion. This migration occurs in a two-step mechanism that involves first a concerted two-cation jump, S I‘ → SII‘/S II → (SIII or S III‘), followed by a S II‘ → SII jump, leading to a net process S I‘ → (SIII or S III‘). The preferred binding site in both Na−X and Na−Y involves HFCs anchored by both site II and site III‘ cations. The loading dependence of the heat of HFC adsorption in zeolite Na−X is predicted to be different from that in Na−Y, because of the energetics of cation migration in Na−Y. HFC-134 is generally more strongly bound to both zeolites, because of its ability to make close Na−F and O−H contacts with the zeolites. The binding energy for the gauche conformer of HFC-134 is larger than that for trans at low loadings, but as loading increases, the difference decreases. The highly correlated small-amplitude motion predicted for cations in bare faujasites is quenched upon adsorption of HFCs. Most of the HFCs are too strongly bound to exhibit diffusive behavior during our molecular dynamics simulations.

Double resonance NMR experiments have been used to study the binding of the asymmetric hydrofluorocarbons (HFCs) CF3CFH2 (HFC-134a), CF3CF2H (HFC-125) and CF2HCFH2 (HFC-143) on zeolites NaX and NaY. By exploiting the very large differences in ¹⁹F chemical shifts for the −CF3-xHx end groups of each molecule, individual ¹⁹F → ²³Na cross-polarization (CP) build-up curves involving polarization transfer from different parts of the molecule have been obtained. CP efficiencies in the order CF3≪CF2H<CFH2 were found, indicating that the hydrogen-containing groups are bound more strongly to the zeolite framework. This effect is most pronounced for the lowest-sodium content zeolite studied (NaY:  Si/Al = 7.6), and increases with HFC loading. Both the ¹H NMR resonances and ¹H → ²⁷Al and ¹H → ¹⁷O CP MAS NMR experiments are consistent with H-bonding interactions with the zeolite framework. Molecular dynamics and docking calculations for HFC-134 and 134a on model NaY and NaX zeolites revealed the importance of both H-bonding and Na−F interactions in determining the low-energy sorption sites. Stable binding sites for HFC-134a in NaY were found by docking to involve only CFH2−Na(SII) contacts, in qualitative agreement with the CP results. The simulations indicate that Na-binding to the groups with more H atoms is favored by the possibility of achieving shorter Na−F distances and maximizing the number of H-bonds with the framework. The higher sodium content zeolite containing both SII and SIII cations gives minimum energy binding sites involving multiple Na−F and H-bonding contacts. For HFC-134 (gauche conformer), the global energy minimum actually involves several H-bonds but no short Na−F contacts.

We have developed and applied an angular sudden approximation for modeling proton transfer in zeolites, using Miller's semiclassical transition state theory. We have parametrized the rate theory by performing B3LYP/6-311G(d,p) density functional theory calculations for paths with fixed O−Al−O angle in a cluster model of H−Y zeolite. We find that both the barrier height and barrier curvature increase with O−Al−O angle. We also find that the classical barrier height increases with angle more rapidly than does the curvature, forcing the tunneling probability to decrease strongly with angle. The range of important angles for proton transfer, the so-called dynamical distribution, involves angles far from the saddle point angle at low temperatures (i.e., large curvature paths), and broadens significantly at higher temperatures, encompassing the saddle point region. The final temperature dependence of the proton jump rate within the sudden approximation shows surprisingly good agreement with that from conventional semiclassical transition state theory, which is based on the minimum energy path. We attribute this in part to a coincidence that occurs in the temperature regime of interest, namely 200−1000 K, a coincidence that we do not expect will occur in other systems.

Constrained energy minimization, equilibrium and nonequilibrium molecular dynamics calculations, and constrained Monte Carlo simulations were used to determine the influence of the coupling between benzene adsorbed in a NaY zeolite model (Si/Al = 2) and the framework vibrations on benzene site-to-site dynamics. Benzene at an SII site is strongly coupled to the nearby Na(II) cation, resulting in a decrease of the external vibrational frequency of the center-of-mass of benzene away from this cation by 60 cm^-1. Despite this coupling, framework vibrations have remarkably little influence on the site-to-site rate constants of benzene. Although with a fixed framework no dissipation of the excess kinetic energy of the adsorbed molecule can take place and thus no thermalization to equilibrium, energy redistribution from the translational motion of benzene into the internal degrees of freedom of the flexible molecule is seen to provide a good thermalization.

Systemic administration of selective serotonin reuptake inhibitors (SSRIs) elicits larger increases in serotonin (5-HT) in raphe than in forebrain sites. Because serotonergic neuronal activity is suppressed, the mechanism underlying SSRI-induced increases in extracellular 5-HT is unclear. This study determined whether local infusion of SSRIs also elicited regionally selective increases in extracellular 5-HT, and whether changes depended on serotonergic neuronal depolarization. Conventional microdialysis methods were used to measure 5-HT in dorsal raphe (DRN), median raphe, nucleus accumbens (NAcc), and frontal cortex of unanesthetized rats. During infusion of SSRIs into each site, the maximum response was an approximately 6- to 7-fold increase in 5-HT in NAcc and frontal cortex, and an approximately 20-fold increase in DRN and median raphe. The larger increase in 5-HT in raphe was confirmed using zero-net-flux microdialysis. In NAcc, baseline 5-HT was 0.7 nM, and levels increased to a maximum of 3.1 nM during infusion of the SSRI citalopram. Baseline 5-HT in DRN was greater, 1.3 nM, and increased to 12.4 nM in response to citalopram. Consistent with evidence that autoreceptor activation inhibits serotonergic neuronal discharge, SSRI infusion into DRN produced a moderate decrease in 5-HT in NAcc. However, increases in 5-HT in DRN elicited by SSRI infusion were attenuated by 8-hydroxydipropylaminotetralin and tetrodotoxin. These data indicate that depolarization-dependent 5-HT release was not fully inhibited during SSRI infusion into DRN. In summary, SSRIs produce larger increases in extracellular 5-HT in raphe than in forebrain sites. Increases depend in part on depolarization-induced release, which may be greater in raphe than in forebrain.

It has been suggested in some studies that head injury is a risk factor for AD, and that this risk is heightened among carriers of the APOE-4 allele. We examined the effects of head injury and APOEgenotype on AD risk in a large family study.

A variety of force field based simulations have been used to study the location and diffusion of benzene adsorbed in a model zeolite HY (Si/Al = 2.43), namely:  molecular docking; equilibrium and nonequilibrium molecular dynamics; and Monte Carlo umbrella sampling. Multiple adsorption sites are found, with benzene facially coordinated to one or two H(1) or H(2) protons in the supercage. Some slight adsorption onto the 12-membered ring windows is also observed, in accordance with infrared measurements. The minimum energy path at low temperature proceeds via a creeping of the molecule along the zeolite wall between stable sites, with an activation energy varying between 10 and 20 kJ mol^-1. This type of creeping motion is observed both for intracage and intercage diffusion. Cartwheel jumps between sites are seen to proceed with higher activation energies of approximatively 30 kJ mol^-1. Multiple paths from site to site open as the temperature increases. This results in a strong temperature dependence of the potential of mean force in the zeolite cage, as calculated by umbrella sampling. Nonequilibrium molecular dynamics simulations initialized at the transition state between two states show that the molecules do not relax in a single final state but in a multiplicity of states; only cage-to-cage jumps keep a sense, as a majority of molecules relax in the final cage. Due to the multiplicity of possible cage-to-cage paths, the temperature dependence of the cage-to-cage rate constants is deeply non-Arrhenius.

The TATA-binding protein (TBP)-associated factor TAF(II)250 is the largest component of the basal transcription factor IID (TFIID). A missense mutation that maps to the acetyltransferase domain of TAF(II)250 induces the temperature-sensitive (ts) mutant hamster cell lines ts13 and tsBN462 to arrest in late G(1). At the nonpermissive temperature (39.5 degrees C), transcription from only a subset of protein encoding genes, including the G(1) cyclins, is dramatically reduced in the mutant cells. Here we demonstrate that the ability of the ts13 allele of TAF(II)250 to acetylate histones in vitro is temperature sensitive suggesting that this enzymatic activity is compromised at 39.5 degrees C in the mutant cells. Mutagenesis of a putative acetyl coenzyme A binding site produced a TAF(II)250 protein that displayed significantly reduced histone acetyltransferase activity but retained TBP and TAF(II)150 binding. Expression of this mutant in ts13 cells was unable to complement the cell cycle arrest or transcriptional defect observed at 39.5 degrees C. These data suggest that TAF(II)250 acetyltransferase activity is required for cell cycle progression and regulates the expression of essential proliferative control genes.

In airway and renal epithelia, the glucocorticoid-mediated stimulation of amiloride-sensitive Na+ transport is associated with increased expression of the epithelial Na+ channel alpha subunit (alphaENaC). In H441 lung cells, 100 nM dexamethasone increases amiloride-sensitive short-circuit current (3.3 microA/cm2 to 7.5 microA/cm2), correlating with a 5-fold increase in alphaENaC mRNA expression that could be blocked by actinomycin D. To explore transcriptional regulation of alphaENaC, the human alphaENaC 5'-flanking region was cloned and tested in H441 cells. By deletion analysis, a approximately 150-base pair region 5' to the upstream promoter was identified that, when stimulated with 100 nM dexamethasone, increased luciferase expression 15-fold. This region, which contains two imperfect GREs, also functioned when coupled to a heterologous promoter. When individually tested, only the downstream GRE functioned in cis and bound GR in a gel mobility shift assay. In the M-1 collecting duct line Na+ transport, malphaENaC expression and luciferase expression from alphaENaC genomic fragments were also increased by 100 nM dexamethasone. In a colonic cell line, HT29, trans-activation via a heterologously expressed glucocorticoid receptor restored glucocorticoid-stimulated alphaENaC gene transcription. We conclude that glucocorticoids stimulate alphaENaC expression in kidney and lung via activation of a hormone response element in the 5'-flanking region of halphaENaC and this response, in part, is the likely basis for the up-regulation of Na+ transport in these sites.

We have developed and validated a new force field for cations in zeolites, which explicitly distinguishes Si and Al atoms, as well as different types of oxygens in the framework. Our new force field gives excellent agreement with experimental data on cation positions, site occupancies and vibrational frequencies. Energy minimizations show that Na cations in site I are not at the centers of hexagonal prisms, but rather are in one of two symmetric SI sites displaced by about 0.6 Å along the [111] direction. Molecular dynamics (MD) simulations show that most cations are immobile in Na−X and Na−Y on the MD time scale, even at 1000 K. Only Na−X cations in site III‘ exhibit diffusive motion at 1000 K, with a self-diffusivity from MD of 3.6 × 10^-10 m² s^-1. The MD simulations also show that cation movement is highly correlated, composed of jumps involving at least 4 cations or more.

Because monoamine reuptake inhibitors and releasing agents both increase extracellular neurotransmitter levels, establishing in vivo experimental criteria for their classification has been difficult. Using microdialysis in the hypothalamus of unanesthetized rats, we provide evidence that serotonin- (5-HT) selective and nonselective reuptake inhibitors can be distinguished from the 5-HT-releasing agent fenfluramine by four criteria: 1) Systemic fenfluramine produces a much greater increase in 5-HT than the reuptake inhibitors. 2) The 5-HT somatodendritic autoreceptor agonist, (+/-)-8-hydroxy-(dipropylamino)tetralin (8-OH-DPAT), attenuates the increase in 5-HT produced by reuptake inhibitors, but not by fenfluramine. 3) The large increase in 5-HT produced by infusion of reuptake inhibitors into the hypothalamus is attenuated by their systemic administration. However, systemic injection of fenfluramine during its local infusion does not attenuate this increase. 4) Reuptake inhibitor pretreatment attenuates fenfluramine-induced increases in 5-HT. According to these criteria, the in vivo effects of the novel antiobesity drug sibutramine are consistent with its characterization as a 5-HT reuptake inhibitor and not a 5-HT releaser. Thus, sibutramine produced increases in hypothalamic 5-HT similar in magnitude to the effects of the known reuptake inhibitors, and the increase was attenuated by 8-OH-DPAT. Also, sibutramine attenuated fenfluramine-induced 5-HT release. Systemic administration of sibutramine failed to attenuate the increase in 5-HT produced by its local infusion, suggesting that this criterion is not applicable to compounds with low affinity for the 5-HT transporter.

In order to study the membrane topology and the possible function of the rat liver 22 kDa integral peroxisomal membrane protein (PMP 22) at a molecular level, we have cloned PMP 22 from a λgt11 expression library and sequenced its cDNA. Hydropathy analysis of the deduced primary structure indicates 4 putative transmembrane segments. The accessibility to exogenous aminopeptidase of PMP 22 in intact peroxisomes suggests that the N‐terminus faces the cytosol. A model of the topology of PMP 22 in the peroxisomal membrane is discussed. Homology studies revealed a striking similarity with the Mpv 17 gene product. Lack of this membrane protein causes nephrotic syndrome in mice.

Without Abstract:

Regulation of serotonin (5-HT) release may be altered during the development of opioid tolerance and dependency. To test this hypothesis, changes in extracellular 5-HT during prolonged administration of morphine were determined by microdialysis in the dorsal raphe nucleus (DRN) of freely behaving rats. Morphine or placebo pellets were implanted s.c. As compared to placebo, morphine pellets induced a sustained, approximately 50% increase in DRN 5-HT and a significant elevation in hot plate latency during the 12-hr period after implantation. One week later DRN 5-HT had returned to control levels, and implanting additional morphine pellets had no effect on 5-HT or hot plate latency. One day after removing the pellets from rats exposed to morphine for 2 wk, acute challenge with morphine (20 mg/kg, s.c.) had a significantly smaller effect on 5-HT in the DRN as compared to the placebo treatment group. Administration of naltrexone to rats implanted with morphine pellets for 2 wk induced signs of withdrawal and a significant decrease in DRN 5-HT. These results suggest that the regulation of 5-HT release is altered during the development of tolerance to morphine. Thus, DRN 5-HT may be one of the factors involved in the changes in physiology and behavioral state during opioid withdrawal.

Phosphorylation of ion channels has been suggested as one molecular mechanism responsible for learning-produced long-term changes in neuronal excitability1. Persistent training-produced changes in two distinct K+currents (IA(ref. 2), IK-Ca(refs 3,4)) and a voltage-dependent calcium current (ICa; refs 3,4) have previously been shown to occur in type B photoreceptors of Hermissenda, as a result of associative learning. But the identity of the phosphorylation pathway(s) responsible for these changes has not as yet been determined. Injections of cyclic AMP-dependent protein kinase5reduce a K+current (IK) in B cells which is different from those changed by training, but fails to reduce IAand IK-Ca· Phosphorylase b kinase (an exogenous calcium/calmodulin-depen-dent kinase) reduces IA6, but whether IK.Caand ICaare changed in the manner of associative training is not yet known. Another protein kinase present in high concentrations in both mammalian brain and molluscan nervous systems is protein kinase C7,8, which is both calcium- and phospholipid-sensitive9,10. We now present evidence that activation of protein kinase C by the tumour promoter phorbol ester (PDB) and intracellular injection of the enzyme induce conductance changes similar to those caused by associative training in Hermissenda B cells (that is a reduction of IAand IK-Ca, and enhancement of ICa). These results represent the first direct demonstration that protein kinase C affects membrane K+ion conductance mechanisms.

The effect of acute uptake inhibition on serotonin (5-HT) in the rat central nervous system was monitored by using in vivo dialysis. Peripheral administration of the selective 5-HT uptake blocker, fluoxetine, caused a dose-dependent increase in extracellular 5-HT in both the diencephalon and the striatum. Administration of fluoxetine or sertraline, another selective 5-HT uptake inhibitor, caused a prolonged (24 hr) increase in 5-HT and decrease in 5-hydroxyindoleacetic acid. In addition, fluoxetine and sertraline attenuated the 5-HT releasing effect of fenfluramine administered 24 hr later. Local infusion of fluoxetine into the diencephalon caused an increase in 5-HT that was twice as large as the effect of peripheral injection. Peripheral fluoxetine, by enhancing extracellular 5-HT in the raphe, probably resulted in activation of somatodendritic autoreceptors and inhibition of 5-HT neuronal discharge. Thus, the increase in 5-HT in the diencephalon after peripheral fluoxetine presumably reflected a balance between decreased release and inhibition of reuptake. In support of this, after first infusing fluoxetine into the diencephalon to maximally block reuptake, peripheral injection of the uptake inhibitor caused a decrease in 5-HT.

Molecular dynamics simulations of the diffusion of trans-2-butene in zeolite type MEL at 623 K have revealed an initial increase of the self-diffusivity with increasing loading, in contrast to simulation data collected for the other butene isomers. This is usually the signature of repulsive guest−guest interactions. At higher loadings, however, the concentration dependence was shown to decrease in a way consistent with attractive guest−guest interactions (Jousse, F.; et al. J. Phys. Chem. B 1997, 101, 4717). The initial rise reaches a maximum of about 25% for a loading of 1.5−2 molecules per unit cell. A jump diffusion model with parameters deduced from the molecular dynamics simulations accurately reproduces the diffusivity simulated at infinite dilution. For higher loadings guest−guest interaction parameters must be included in the jump diffusion model. Two simple models are presented, in order to rationalize the simulation results with a small number of parameters. The simpler model considers spherically symmetric adsorption sites and uses only two parameters; it is shown, however, that this model is unable to account for the simulated concentration dependence of the trans-2-butene self-diffusivity. The second model, with three parameters, includes the channel-like structure of the adsorption site and fits very effectively the concentration dependence of the diffusivity. Repulsive interactions between two molecules in the same site are responsible for the initial increase of the diffusivity. Attractive interactions arise when more than two molecules are in the same site, leading to a steeper decrease of the diffusivities with increasing loading.

By definition radionuclide cycling implies recurrent transfers of radioelements between and within ecosystems of the biosphere. The circulation of elements in ecosystems is an important regulatory process as well as a possible boundary condition for characterizing ecosystems. Because of increased recognition of the importance of cycling there has been a considerable increase in biogeochemical studies of terrestrial environments. That the ecologic processes of biogeochemical cycling govern the movement of and are the determinants affecting long-term behavior of long-lived radionuclides, were not recognized sufficiently to merit serious research attention until the late 1950's. Since then, radionuclide cycling has become a recognized facet of radioecological research. The concept currently appears to include four categories of investigation. They are: (1) deductive analyses derived from studies of fallout nuclides in different trophic levels of varying ecosystems, (2) tracer experiments to elucidate links in a food chain and develop data on rate of movement in the chain, (3) studies of rates of turnover of particular radionuclides within a single trophic level and (4) experiments employing tracers to measure the complete cycle in an ecosystem. Current problems such as interpretation of the significance of 90Sr and 137Cs levels in selected compartments of arctic ecosystems reinforce the need for more experiments of the fourth category emphasizing simple ecosystems.

People with AD have deficient contrast sensitivity and impaired face discrimination. The authors presented photographs of unfamiliar faces of three different sizes to enhance the low, middle, or high facial frequency information (cycles per face). Patients with AD demonstrated normal discrimination of small faces only, indicating that impaired contrast sensitivity at low facial frequencies contributes to their poor face discrimination.