Infima and complements in the lattice of quasi-uniformities

We show that the infimum of any family of proximally symmetric quasi-uniformities is proximally symmetric, while the supremum of two proximally symmetric quasi-uniformities need not be proximally symmetric. On the other hand, the supremum of any family of transitive quasi-uniformities is transitive, while there are transitive quasi-uniformities whose infimum with their conjugate quasi-uniformity is not transitive. Moreover we present two examples that show that neither the supremum topology nor the infimum topology of two transitive topologies need be transitive. Finally, we prove that several operations one can perform on and between quasi-uniformities preserve the property of having a complement.     

Simulating the Kinematic Dynamo Forced by Heteroclinic Convective Velocity Fields

We report on the integration of the kinematic dynamo problem in a spherical domain forced by velocity fields that are convective fluid flows resulting from a bifurcation analysis of the spherical Bénard problem. We derive a code based on generalized spherical harmonics that ensures a divergence-free magnetic field. We determine the growth or decay of a magnetic field in the kinematic dynamo equation for various physically relevant velocity fields which are stationary as well as time-periodic and chaotic. Velocity signals that are produced by heteroclinic cycles are used as an input to an energy-saturated kinematic dynamo equation that limits the growth of the linearly unstable modes. Preliminary calculations indicate the possibility of reversals of the magnetic field for this case of forcing. Received 8 October 1996 and accepted 28 April 1997     

A C-symplectic free -manifold with contractible orbits and

An interesting question in symplectic geometry concerns whether or not a closed symplectic manifold can have a free symplectic circle action with orbits contractible in the manifold. Here we present a c-symplectic example, thus showing that the problem is truly geometric as opposed to topological. Furthermore, we see that our example is the only known example of a c-symplectic manifold having non-trivial fundamental group and Lusternik-Schnirelmann category precisely half its dimension.

     

Nanosensors based on responsive polymer brushes and gold nanoparticle enhanced transmission surface plasmon resonance spectroscopy

Swelling (and shrinking) of poly(2-vinylpyridine), P2VP, polymer brushes, caused by pH changes, could be readily monitored by transmission surface plasmon resonance, T-SPR, spectroscopy. Gold nanoparticles attached to the P2VP polymer brushes dramatically enhanced the pH-induced shift in the T-SPR absorption spectra. (A 50 nm shift of the absorption maximum of the T-SPR spectrum of the supporting gold nanoislands was observed upon changing the pH from 5.0 to 2.0, corresponding to a swelling of the polymer brushes from 8.1 +/- 0.7 to 24.0 +/- 2.0 nm. Same shift in the opposite direction was observed upon changing the pH from 2.0 to 5.0.)     

Is there a difference between leads and drugs? A historical perspective

To be considered for further development, lead structures should display the following properties: (1) simple chemical features, amenable for chemistry optimization; (2) membership to an established SAR series; (3) favorable patent situation; and (4) good absorption, distribution, metabolism, and excretion (ADME) properties. There are two distinct categories of leads: those that lack any therapeutic use (i.e., "pure" leads), and those that are marketed drugs themselves but have been altered to yield novel drugs. We have previously analyzed the design of leadlike combinatorial libraries starting from 18 lead and drug pairs of structures (S. J. Teague et al. Angew. Chem., Int. Ed. Engl. 1999, 38, 3743-3748). Here, we report results based on an extended dataset of 96 lead-drug pairs, of which 62 are lead structures that are not marketed as drugs, and 75 are drugs that are not presumably used as leads. We examined the following properties: MW (molecular weight), CMR (the calculated molecular refractivity), RNG (the number of rings), RTB (the number of rotatable bonds), the number of hydrogen bond donors (HDO) and acceptors (HAC), the calculated logarithm of the n-octanol/water partition (CLogP), the calculated logarithm of the distribution coefficient at pH 7.4 (LogD(74)), the Daylight-fingerprint druglike score (DFPS), and the property and pharmacophore features score (PPFS). The following differences were observed between the medians of drugs and leads: DeltaMW = 69; DeltaCMR = 1.8; DeltaRNG = DeltaHAC =1; DeltaRTB = 2; DeltaCLogP = 0.43; DeltaLogD(74) = 0.97; DeltaHDO = 0; DeltaDFPS = 0.15; DeltaPPFS = 0.12. Lead structures exhibit, on the average, less molecular complexity (less MW, less number of rings and rotatable bonds), are less hydrophobic (lower CLogP and LogD(74)), and less druglike (lower druglike scores). These findings indicate that the process of optimizing a lead into a drug results in more complex structures. This information should be used in the design of novel combinatorial libraries that are aimed at lead discovery.     

Hybridization of oligonucleotide-modified silver and gold nanoparticles in aqueous dispersions and on gold films

Functionalization of silver and gold nanoparticles by 12mer-thiolated homo-oligonucleotides, SA and ST (containing only adenine or thymine, respectively), and their hybridization and dehybridization in aqueous dispersions have been described. In addition, ST and SA were self-assembled onto gold films and hybridized with their complementary pairs, unlabeled or labeled by gold and silver nanoparticles. The base pairing between DNA strands and the types of oligonucleotides (adenine or thymine) attached to the nanoparticles was detected by Polarization Modulated Fourier Transform Infrared Reflection Absorption Spectroscopy (PM-FTIRRAS).     

A fully automated nanoelectrospray tandem mass spectrometric method for analysis of Caco-2 samples

Caco-2 cells offer a means to rapidly screen permeability of drug candidates, allowing pharmaceutical companies to eliminate candidates unable to cross the intestinal barrier early in the discovery process. This screening process is typically performed by conventional liquid chromatography/tandem mass spectrometry (LC/MS/MS), which can require time-consuming method development. An alternative to LC/MS/MS, automated nanoelectrospray tandem mass spectrometry (nanoESI-MS/MS), is introduced. This novel approach requires an off-line ZipTip desalting step followed by automated nanoESI-MS/MS, using the NanoMate 100 and ESI Chip. In addition to reduced method development time, automated nanoESI-MS/MS also offers no carry-over between samples, low sample consumption, and ease-of-use as compared with conventional pulled-capillary nanoelectrospray. Furthermore, the infusion system described has the potential to be high-throughput. A comparison of Caco-2 samples analyzed both by LC/MS/MS and by automated nanoESI-MS/MS is presented. The permeability and recovery data of the two compounds analyzed in this study obtained from conventional LC/MS/MS and by automated nanoESI-MS/MS were in excellent agreement.     

Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

Summary Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/K_i), with an explained variance r² of 0.885, and a cross-validated q² of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q² for one component was 0.62 and 0.61, respectively, while r² was 0.674. We demonstrate that the predictive r² based on the mean activity (Y_m) of the training set is misleading, while the test set Y_m-based predictive r² index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.     

Optimizing the Electricity Consumption with a High Degree of Flexibility Using a Dynamic Tariff and Stackelberg Game

Journal of Optimization Theory and Applications - Recent advancements in the sensor industry, smart metering systems and communication technology have led to interesting electricity consumption...