Activity-Directed Synthesis: A Flexible Approach for Lead Generation

Activity-directed synthesis (ADS) is a structure-blind, functional-driven molecular discovery approach. In this Concept, four case studies highlight the general applicability of ADS and showcase its flexibility to support different medicinal chemistry strategies. ADS deliberately harnesses reactions with multiple possible outcomes, and allows many chemotypes to be evaluated in parallel. Resources are focused on bioactive molecules, which emerge in tandem with associated synthetic routes. Some of the future challenges for ADS are highlighted, including the realisation of an autonomous molecular discovery platform. The prospects for ADS to become a mainstream lead generation approach are discussed.     

Improving narrow bandgap a-SiGe:H alloys grown by hot-wire chemical vapor deposition

We have improved the electronic properties of narrow-bandgap (Tauc gap below 1.5 eV) amorphous-silicon germanium alloys (a-SiGe:H) grown by hot-wire chemical vapor deposition (HWCVD) by lowering the substrate temperature and deposition rate. Prior to this work, we were unable to grow a-SiGe:H alloys with bandgaps below 1.5 eV that had photo-to-dark conductivity ratios comparable with our plasma-enhanced CVD (PECVD) grown materials [B.P. Nelson et al., Mater. Res. Soc. Symp. 507 (1998) 447]. Decreasing the filament diameter from our standard configuration of 0.5 mm to 0.38 or 0.25 mm provides first big improvements in the photoresponse of these alloys. Lowering the substrate temperature from our previous optimal temperatures (T_sub starting at 435 °C) to at 250 °C provides additional photo-to-dark conductivity ratio increasing by two orders of magnitude for growth conditions containing 20–30% GeH₄ in the gas phase (relative to the total GeH₄+SiH₄ flow).     

Predicting Forest Age Classes from High Spatial Resolution Remotely Sensed Imagery Using Voronoi Polygon Aggregation

Efficient identification of forest age is useful for forest management and ecological applications. Here we propose a user-assisted method for determining forest age using high spatial resolution remotely sensed imagery. This method requires individual trees to be extracted from imagery and represented as points. We use a local maximum filter to generate points that are converted to Voronoi polygons. Properties of the Voronoi polygons are correlated with forest age and used to aggregate points (trees) into areas (stands) based on three forest age classes. Accuracy of the aggregation ranges from approximately 68% to 78% and identification of the mature class is more consistent and accurate than the younger classes.     

High dynamic range InP HBT delta-sigma analog-to-digital converters

To date, the development of multifunction multicarrier digital receivers for cellular base station and military communications applications has been limited by the demanding dynamic range requirements for the analog-to-digital converter (ADC). The use of oversampling delta-sigma modulators provides a promising approach to overcoming the dynamic range barriers Nyquist-rate converters face in the same applications. This paper discusses issues involved in the design of high-speed high dynamic range wide-band delta-sigma ADCs for such communications applications. Test results of prototype designs are also presented. The delta-sigma modulators described in this paper operate at sampling frequencies ranging from 1 to 2.5 GHz with center frequencies ranging from dc to 100 MHz, providing between 74 and 84.2 dB signal-to-noise ratio (12 and 13.7 bits) for bandwidths of 25 and 12.5 MHz, respectively. The loop filters are continuous-time low-pass and bandpass implementations of order 6 and 10, and were fabricated in an InP heterojunction bipolar (HBT) technology. A typical tenth-order design consumes 6 W of power and occupies a die area of 23.5 mm/sup 2/.     

Improved RNS FIR filter architectures

A new architecture for implementing finite-impulse response (FIR) filters using the residue number system (RNS) is detailed. The design is based on using a restricted modulus set, with moduli of the form 2/sup n/,2/sup n/-1, and 2/sup n/+1. This does not restrict the modulus set to the common 3 modulus set {2/sup n/-1,2/sup n/,2/sup n/+1}, but any number of pairwise relatively prime moduli of this form, for example, {5,7,17,31,32,33}. Based on a comparison with a 2's complement design, the new RNS design can offer a significant speed improvement. The gain is obtained by using a set of small moduli, selected so as to minimize critical path delay and area. An algorithmic approach is used to obtain full adder based architectures that are optimized for area and delay. The modulus set is optimum based on cost parameters for each modulus. This new architecture presents a practical approach to implementing a fast RNS FIR filter.     

A Revised Methodology for Research on Metamemory: Pre-judgment Recall And Monitoring (PRAM).

A revised methodology is described for research on metacognitive monitoring, especially judgments of learning (JOLs), to investigate psychological processing that previously has been only hypothetical and unobservable. During data collection a new stage of recall occurs just prior to the JOL, so that during data analysis the items can be partitioned into subcategories to measure the degree of JOL accuracy in ways that are more analytic than was previously possible. A weighted-average combinatorial rule allows the component measures of JOL accuracy to be combined into the usual overall measure of metacognitive accuracy. An example using the revised methodology offers a new explanation for the delayed-JOL effect, in which delayed JOLs are more accurate than immediate JOLs for predicting recall. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Risk factors for a medically inappropriate admission to a Department of Internal Medicine

OBJECTIVE: To identify patient- and admission-related risk factors for a medically inappropriate admission to a department of internal medicine. METHODS: Cross-sectional study of a systematic sample of 500 admissions to the department of internal medicine of an urban teaching hospital. The appropriateness of each admission and reasons for inappropriate admissions were assessed using the Appropriateness Evaluation Protocol. Risk factors included the time (day of week and holidays) and manner (through emergency department or direct admission) of admission, patient age and sex, health status of patient and spouse, living arrangements, formal home care services, and informal support from family or friends. RESULTS: Overall, 76 (15.2%) hospital admissions were rated as medically inappropriate by the Appropriateness Evaluation Protocol. In multivariate analysis, the likelihood of an inappropriate admission was increased by better physical functioning of the patient (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1-2.1 [for 1 SD in Physical Functioning scores]), lower mental health status of the patient's spouse (OR, 2.6; 95% CI, 1.3-5.6), receipt of informal help from family or friends (OR, 3.3; 95% CI, 1.5-7.2), and hospitalization by one's physician (OR, 3.6; 95% CI, 1.7-7.5). Receiving formal adult home care was not associated with inappropriateness of hospitalization. CONCLUSIONS: Inappropriate admissions to internal medicine wards are determined by a mix of factors, including the patient's health and social environment. In addition, the private practitioners' discretionary ability to hospitalize their patients directly may also favor medically inappropriate admissions.     

The ability of the rat to metabolize myristoyl-methionine: an acylamino acid with potentially useful antibacterial properties

Two experiments with Sprague Dawley rats tested their ability to hydrolyse myristoyl-methionine (M-M) into myristic acid and L-methionine (M). In the first experiment, lasting for 3 days. male rats were orally administered [9,10-3H]myristoyl-L-[35S]methionine. The recovery of radioactivity was approximately 90% for both isotopes; 19% of the administered 3H was recovered in the urine and 16% in the faeces, while the recovered 35S activity was 13 and 12%, respectively. The balance of the radioactivity was found among the tissues, organs and blood. In the second experiment, male and female rats received soybean-based diets which were supplemented with either 0.305% M-M or 0.2% M (both diets contained equal amounts of M) for periods up to 4 weeks. The growth rate of the rats receiving the 0.305% M-M diets was slightly slower than that for the rats on the 0.2% M diet, but the difference was not statistically significant (P > 0.05). The M-M rats had a transitory decrease in feed consumption, suggesting that palatability may have contributed to the growth difference and that a somewhat greater amount of M-M was necessary for the rat to attain the same growth rate as that produced by 0.2% M. When the amount of dietary M-M was increased to 3.05% M-M, a greater reduction in feed consumption and body weight gain was observed. This latter diet was an initial attempt to study the potential toxicity of M-M. None of the haematological, clinical chemistry or organ weight data suggested that M-M was overtly toxic per se, but longer-term feeding studies are needed to evaluate the potential toxicity of M-M more fully.     

Kinetic analysis of the coding properties of O6-methylguanine in DNA: the crucial role of the conformation of the phosphodiester bond

Production by N-nitroso compounds of O6-alkylguanine (O6-alkylG) in DNA directs the misincorporation of thymine during DNA replication, leading to G:C to A:T transition mutations, despite the fact that DNA containing O6-alkylG:T base pairs is less stable than that containing O6-alkylG:C pairs. We have examined the kinetics of incorporation by Klenow fragment (KF) of Escherichia coli DNA polymerase I of thymine (T) and of cytosine (C) opposite O6-MeG in the template DNA strand. Both T and C were incorporated opposite O6-MeG much slower than nucleotides forming regular A:T or G:C base pairs. Using various concentrations of dTTP, dCTP, or their phosphorothioate (Sp)-dNTP alpha S analogues, or a mixture of dTTP and dCTP, the progress of incorporation of a single nucleotide in a single catalytic cycle of a preformed KF-DNA complex was measured (pre-steady-state kinetics). The results were consistent with the kinetic scheme (Kuchta, R. D., Benkovic, P., & Benkovic, S. J. (1988) Biochemistry 27, 6716-6725): (1) binding of dNTP to polymerase-DNA; (2) conformational change in polymerase; (3) formation of phosphodiester between the dNTP and the 3'-OH of the primer; (4) conformational change of polymerase; (5) release of pyrophosphate. The results were analyzed mathematically to identify the steps at which the rate constants differ significantly between the incorporation of T and C. The only significant difference was the 5-fold difference in the rates of formation of the phosphodiester bond (for dTTP, kforward = 3.9 s-1 and kback = 1.9 s-1; for dCTP, kforward = 0.7 s-1 and kback = 0.9 s-1). These pre-steady-state progress curves were biphasic with a rapid initial burst followed by an apparently steady-state rise. Deconvolution of these curves gave direct evidence for the importance of the conformational change after polymerization by showing that the curves represented the sum of the rapid accumulation of the product of step 3 followed by the slow conversion of that to the product of step 5 (because of the rapidity of the release of pyrophosphate there was no significant accumulation of the product of step 4). The equilibrium constants for each step suggest that the greatest change in the Gibbs free energy occurs at the conformational change after polymerization and that while the formation of the phosphodiester bond to T is slightly exothermic, that to C is slightly endothermic.(ABSTRACT TRUNCATED AT 400 WORDS)