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)     

Failure to cure Mycobacterium gordonae peritonitis associated with continuous ambulatory peritoneal dialysis

Nontuberculous mycobacteria are increasingly recognized as important pathogens in peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). Mycobacterium gordonae rarely causes human infection and is the least likely mycobacterium to produce clinical infection in CAPD patients. We describe a patient with persistent M. gordonae peritonitis acquired while undergoing CAPD. During 18 months of treatment, clinical improvement occurred but a microbiological cure could not be achieved. Principles of therapy for mycobacterial peritonitis developing during CAPD are reviewed, and potential explanations for our patient's failure to respond to therapy are discussed.     

Anti-D in a D-positive renal transplant patient

PURPOSE: We report a case of postoperative reparalysis in the recovery room, following nebulized epinephrine. The patient was pharmacologically reversed with edrophonium after paralysis with rocuronium. CLINICAL FINDINGS: A 12-yr-old girl developed postoperative reparalysis following the intraoperative administration of rocuronium. A total of 0.92 mg.kg-1 rocuronium was administered. After surgery, pharmacological reversal was achieved with 20 mg edrophonium with 0.15 mg atropine sulfate iv 35 min after the last administration of rocuronium. Muscular relaxation was monitored using an ulnar peripheral nerve stimulator (PNS). After reversal, a full train-of-four and sustained tetanus at 50 Hz were present. In the recovery room, following nebulized epinephrine, the patient became apneic. The patient was paralyzed and an ulnar PNS demonstrated only one faint twitch. The paralysis was reversed with 1.5 mg neostigmine with 0.3 mg glycopyrrolate. CONCLUSION: Postoperative reparalysis following rocuronium may be a cause of postoperative respiratory distress. The definitive diagnosis is made using PNS and observing the response to pharmacological reversal. Nebulized epinephrine may have a previously undescribed role in the development of postoperative reparalysis.     

Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus

A side effect of therapy with procainamide and numerous other medications is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We tested the possibility that an effect of lupus-inducing drugs on central T cell tolerance underlies these phenomena. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, resulted in prompt production of IgM antidenatured DNA antibodies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibodies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blocking studies demonstrated that the PAHA-induced antibodies showed remarkable specificity to the (H2A-H2B)-DNA complex. No evidence for polyclonal B cell activation could be detected based on enumeration of Ig-secreting B cells and serum Ig levels, suggesting that a clonally restricted autoimmune response was induced by intrathymic PAHA. The IgG isotype of the antichromatin antibodies indicated involvement of T cell help, and proliferative responses of splenocytes to oligonucleosomes increased up to 100-fold. As little as 5 microM PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neonatal thymi. We suggest that PAHA interferes with self-tolerance mechanisms accompanying T cell maturation in the thymus, resulting in the emergence of chromatin-reactive T cells followed by humoral autoimmunity.     

Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid

Tumor necrosis factor alpha (TNF-alpha) may play a central role in the disease pathogenesis which occurs as a consequence of chlamydial infection. To investigate the importance of TNF-alpha gene promoter polymorphisms and TNF-alpha levels in tear fluid in scarring trachoma, a large matched-pair case-control study was performed in The Gambia. The -308A allele was present in a higher proportion of patients (28.4%) than controls (18.4%), with an increasing association for homozygotes (chi2 for trend, P = 0.032; allele frequency, 0.163 in patients and 0.099 in controls; chi2, P = 0.025). For the -238A allele, the association was similar but not significant. The disease association was highly significant when the number of either -308A or -238A sites in an individual was considered (P = 0.003). TNF-alpha promoter alleles are tightly linked to some HLA class I and II alleles, but multivariate analysis confirmed that the disease associations were independent of HLA, although a class I allele, A*6802, is also associated with disease. TNF-alpha was more frequently detected in tear samples from patients (27.6%) than from controls (15.9%), increasingly so for higher levels of detectable TNF-alpha (P = 0.015). Among patients, detectable TNF-alpha in tears was highly associated with the presence of ocular chlamydial infection (P < 0.001). The results indicate that TNF-alpha plays a major role in the tissue damage and scarring which occurs as a consequence of Chlamydia trachomatis infection.