Plate-based diversity subset screening: an efficient paradigm for high throughput screening of a large screening file

The screening files of many large companies, including Pfizer, have grown considerably due to internal chemistry efforts, company mergers and acquisitions, external contracted synthesis, or compound purchase schemes. In order to screen the targets of interest in a cost-effective fashion, we devised an easy-to-assemble, plate-based diversity subset (PBDS) that represents almost the entire computed chemical space of the screening file whilst comprising only a fraction of the plates in the collection. In order to create this file, we developed new design principles for the quality assessment of screening plates: the Rule of 40 (Ro40) and a plate selection process that insured excellent coverage of both library chemistry and legacy chemistry space. This paper describes the rationale, design, construction, and performance of the PBDS, that has evolved into the standard paradigm for singleton (one compound per well) high-throughput screening in Pfizer since its introduction in 2006.     

Negative thermal expansion in ZrW2O8: mechanisms, rigid unit modes, and neutron total scattering

The local structure of the low-temperature ordered phase of the negative thermal expansion (NTE) material has been investigated by reverse Monte Carlo (RMC) modeling of neutron total scattering data. We obtain, for the first time, quantitative measurements of the extent to which the and polyhedra move as rigid units, and we show that these values are consistent with the predictions of rigid unit mode theory. We suggest that rigid unit modes are associated with the NTE. Our results do not support a recent interpretation of x-ray-absorption fine structure spectroscopy data in terms of a larger rigid structural component involving the Zr-O-W linkage.     

The relationship between frequency selectivity and pitch discrimination: sensorineural hearing loss

This study tested the relationship between frequency selectivity and the minimum spacing between harmonics necessary for accurate fo discrimination. Fundamental frequency difference limens (fo DLs) were measured for ten listeners with moderate sensorineural hearing loss (SNHL) and three normal-hearing listeners for sine- and random-phase harmonic complexes, bandpass filtered between 1500 and 3500 Hz, with fo's ranging from 75 to 500 Hz (or higher). All listeners showed a transition between small (good) fo DLs at high fo's and large (poor) fo DLs at low fo's, although the fo at which this transition occurred (fo,tr) varied across listeners. Three measures thought to reflect frequency selectivity were significantly correlated to both the fo,tr and the minimum fo DL achieved at high fo's: (1) the maximum fo for which fo DLs were phase dependent, (2) the maximum modulation frequency for which amplitude modulation and quasi-frequency modulation were discriminable, and (3) the equivalent rectangular bandwidth of the auditory filter, estimated using the notched-noise method. These results provide evidence of a relationship between fo discrimination performance and frequency selectivity in listeners with SNHL, supporting "spectral" and "spectro-temporal" theories of pitch perception that rely on sharp tuning in the auditory periphery to accurately extract fo information.     

Explicit inertial range renormalization theory in a model for turbulent diffusion

The inertial range for a statistical turbulent velocity field consists of those scales that are larger than the dissipation scale but smaller than the integral scale. Here the complete scale-invariant explicit inertial range renormalization theory for all the higher-order statistics of a diffusing passive scalar is developed in a model which, despite its simplicity, involves turbulent diffusion by statistical velocity fields with arbitrarily many scales, infrared divergence, long-range spatial correlations, and rapid fluctuations in time-such velocity fields retain several characteristic features of those in fully developed turbulence. The main tool in the development of this explicit renormalization theory for the model is an exact quantum mechanical analogy which relates higher-order statistics of the diffusing scalar to the properties of solutions of a family ofN- body parabolic quantum problems. The canonical inertial range renormalized statistical fixed point is developed explicitly here as a function of the velocity spectral parameter, which measures the strength of the infrared divergence: for<2, mean-field behavior in the inertial range occurs with Gaussian statistical behavior for the scalar and standard diffusive scaling laws; for>2 a phase transition occurs to a fixed point with anomalous inertial range scaling laws and a non-Gaussian renormalized statistical fixed point. Several explicit connections between the renormalization theory in the model and intermediate asymptotics are developed explicitly as well as links between anomalous turbulent decay and explicit spectral properties of Schrödinger operators. The differences between this inertial range renormalization theory and the earlier theories for large-scale eddy diffusivity developed by Avellaneda and the author in such models are also discussed here.     

Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin

Background  

Several investigators have coupled toxins to neuropeptides for the purpose of lesioning specific neurons in the central nervous system. By producing deficits in function these toxin conjugates have yielded valuable information about the role of these cells. In an effort to specifically stimulate cells rather than kill them we have conjugated the neuropeptide substance P to the catalytic subunit of cholera toxin (SP-CTA). This conjugate should be taken up selectively by neurokinin receptor expressing neurons resulting in enhanced adenylate cyclase activity and neuronal firing.     

Minimal Informationally Complete Measurements for Pure States

We consider measurements, described by a positive-operator-valued measure (POVM), whose outcome probabilities determine an arbitrary pure state of a D-dimensional quantum system. We call such a measurement a pure-state informationally complete (PS I-complete) POVM. We show that a measurement with 2D−1 outcomes cannot be PS I-complete, and then we construct a POVM with 2D outcomes that suffices, thus showing that a minimal PS I-complete POVM has 2D outcomes. We also consider PS I-complete POVMs that have only rank-one POVM elements and construct an example with 3D−2 outcomes, which is a generalization of the tetrahedral measurement for a qubit. The question of the minimal number of elements in a rank-one PS I-complete POVM is left open.     

Continuous‐scan capability at SSRL and applications to X‐ray diffraction

Typical X‐ray diffraction measurements are made by moving a detector to discrete positions in space and then measuring the signal at each stationary position. This step‐scanning method can be time‐consuming, and may induce vibrations in the measurement system when the motors are accelerated and decelerated at each position. Furthermore, diffraction information between the data points may be missed unless a fine step‐scanning is used, which further increases the total measurement time. To utilize beam time efficiently, the motor acceleration and deceleration time should be minimized, and the signal‐to‐noise ratio should be maximized. To accomplish this, an integrated continuous‐scan system was developed at the Stanford Synchrotron Radiation Lightsource (SSRL). The continuous‐scan system uses an in‐house integrated motor controller system and counter/timer electronics. SPEC software is used to control both the hardware and data acquisition systems. The time efficiency and repeatability of the continuous‐scan system were tested using X‐ray diffraction from a ZnO powder and compared with the step‐scan technique. Advantages and limitations of the continuous‐scan system and a demonstration of variable‐velocity continuous scan are discussed.     

Solvent and pH Effects on the Fluorescence of 7-(Dimethylamino)-2-Fluorenesulfonate

A novel water-soluble solvatochromic molecule, 7-(dimethylamino)-2-fluorenesulfonate (2,7-DAFS), was prepared by a three-step reaction from 2-nitrofluorene in good overall yield. The pH and solvent effects on the UV-VIS absorption and fluorescence spectra of 2,7-DAFS have been studied. Protonation of the dimethylamino group switches the absorption from intramolecular charge-transfer (ICT) to π → π* transition. The ground state pKa value of 2,7-DAFS was determined as 4.51. The fluorescence spectrum of the excited basic form, *(DAFS), shows a structureless single band with a large Stokes shift, whereas that of the acidic form, *(⁺HDAFS), exhibits a structured band with a small Stokes shift. The emission intensities of the basic and acidic forms versus pH/Ho plots show stretched sigmoidal curves and indicate that (1) the rate of deprotonation of *(⁺HDAFS) is comparable to the fluorescence decay of the species, and (2) the efficient proton-induced quenching of *(DAFS) fluorescence occurs. The pKa* was estimated as −1.7 from the fluorescence titration curve. The fluorescence maximum of *(DAFS) is blue-shifted as the polarity of solvent decreases. However, no clear dependency of the emission intensity and spectral half width, and thus fluorescence quantum yield, on the solvent polarity was revealed. It appears that the fluorescence sensitivity of 2,7-DAFS is 15 ∼ 25 times greater than the sensitivity of a widely utilized fluorescent probe, 5-(dimethylamino)-1-naphthalenesulfonate. This higher sensitivity, together with the ease of derivatization, would provide the fluorene-based fluorescent molecules significant advantages for a variety of applications.     

Dynamical arrest in attractive colloids: the effect of long-range repulsion

We study gelation in suspensions of model colloidal particles with short-ranged attractive and long-ranged repulsive interactions by means of three-dimensional fluorescence confocal microscopy. At low packing fractions, particles form stable equilibrium clusters. Upon increasing the packing fraction the clusters grow in size and become increasingly anisotropic until finally associating into a fully connected network at gelation. We find a surprising order in the gel structure. Analysis of spatial and orientational correlations reveals that the gel is composed of dense chains of particles constructed from face-sharing tetrahedral clusters. Our findings imply that dynamical arrest occurs via cluster growth and association.     

Application of 3-D Fluorescence: Characterization of Natural Organic Matter in Natural Water and Water Purification Systems

Natural organic matter (NOM) found in water sources is broadly defined as a mixture of polyfunctional organic molecules, characterized by its complex structure and paramount influence on water quality. Because the inevitable release of pollutants into aquatic environments due to an ineffective control of industrial and agricultural pollution, the evaluation of the interaction of NOM with heavy metals, nanoparticles, organic pollutants and other pollutants in the aquatic environment, has greatly increased. Three-dimensional (3-D) fluorescence has the potential to reveal the interaction mechanisms between NOM and pollutants as well as the source of NOM pollution. In water purification engineering system, the 3-D fluorescence can indicate the variations of NOM composition and gives an effective prediction of water quality as well as the underline water purification mechanisms. Inadequately treated NOM is a cause of precursors of disinfection byproducts (DBPs), posing a potential threat to human health. Effective control and measurement/evaluation of NOM have long been an important factors in the prevention of water pollution. Overall, 3-D fluorescence allows for a rapid identification of organic components thus indicating possible sources of water pollution, mechanisms of pollutant interactions, and possible DBPs formed during conventional treatment of this water. This article reviews the 3-D fluorescence characteristics of NOM in natural water and typical water purification systems. The 3-D fluorescence was effective for indicating the variabilities in NOM composition and chemistry thus providing a better understanding of NOM in natural water system and water engineering system.