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)     

Comparative study of monoclonal antibody scan in diagnosing orthopaedic infection

When clinical data are insufficient to diagnose infection of bone or joints, nuclear scanning becomes crucial in making an accurate diagnosis. The efficacy of (99m)technetium antigranulocyte monoclonal antibody Fab' fragment (LeukoScan) is prospectively compared with (111)indium white blood cell and (99m)technetium methylene diphosphonate bone scans in 74 patients with suspected musculoskeletal infections. They were grouped according to site of suspected infection: 33 long bones, 23 prosthetic joints, and 18 diabetic feet. Sixty-two of these 74 patients had surgical verification with histopathology or culture. The remaining 12 patients had clinical followup as proof of absence of infection. The overall sensitivity of LeukoScan, (111)indium white blood cell, and (99m)technetium methylene diphosphonate bone scans was 93%, 85% and 92%, respectively. Specificity was 89%, 75% and 52%, and accuracy was 90%, 79% and 74%, respectively. The conclusion from this study is that LeukoScan is more accurate in detecting osteomyelitis, with better sensitivity and specificity in prosthetic joints. Compared with (111)indium white blood cell scans, LeukoScan++ gives superior images, and results are obtained in 1 to 6 hours without biohazard risk from handling blood products.     

Quantal release at a neuronal nicotinic synapse from rat adrenal gland

The neuronal nicotinic synapse in tissue slices of the adrenal medulla was studied with whole-cell patch-clamp. Excitatory postsynaptic currents (EPSCs) were evoked by local field stimulation or occurred spontaneously especially when external [K+] was increased. EPSCs were carried by channels sharing biophysical and pharmacological properties of neuronal-type nicotinic receptors (nAChRs). A single-channel conductance (gamma) of 43-45 pS was found from nonstationary variance analysis of EPSCs. Spontaneous EPSCs were tetrodotoxin-insensitive and Ca(2+)-dependent and occurred in burst-like clusters. Quantal analysis of spontaneous EPSCs gave a quantal size of 20 pA and amplitude histograms were well described by binomial models with low values of quantal content, consistent with a small number of spontaneously active release sites. However, rare large amplitude EPSCs suggest that the total number of sites is higher and that extrajunctional receptors are involved. Our estimates of quantal content and size at the chromaffin cell neuronal nicotinic synapse may be useful in characterizing central neuronal-type nicotinic receptor-mediated cholinergic synaptic transmission.     

Diagnosis of systemic causes of uveitis; a matter of ophthalmologist and internist

OBJECTIVE: To assess how often the aetiology is established in patients with uveitis, what systemic disease are found and what is the contribution of the internist to the diagnostic process. DESIGN: Retrospective study. SETTING: University Hospital Leiden, the Netherlands. METHOD: From January 1987 to April 1992, 342 patients presented with uveitis. All patients underwent a standard ophthalmological examination. Referral to an internist and individualised laboratory screening followed in patients with recurrent, chronic, bilateral or panuveitis. Recorded were: ophthalmological data, results of laboratory screening, results of analysis by the internist, final diagnosis and presence of systemic disease. RESULTS: 149 (44%) patients were examined by the internist, 18 (5.2%) were seen by another specialist. In 169 (49%) patients a specific diagnosis was made. 74 (22%) had a systemic disease, 74 a primary ocular disease. In 28 (8%) a systemic disease was presumed (5% were HLA-B27 positive, 3% had abnormal laboratory results); 5 (1%) patients had endophthalmitis as a complication of a septic process. CONCLUSION: In approximately 1/3 of the patients with uveitis a systemic disease was found. Examination by the internist tailored to the individual patient is essential in the evaluation of uveitis patients.