Development of selective agonists and antagonists of P2Y receptors

Although elucidation of the medicinal chemistry of agonists and antagonists of the P2Y receptors has lagged behind that of many other members of group A G protein-coupled receptors, detailed qualitative and quantitative structure–activity relationships (SARs) were recently constructed for several of the subtypes. Agonists selective for P2Y1, P2Y2, and P2Y6 receptors and nucleotide antagonists selective for P2Y1 and P2Y12 receptors are now known. Selective nonnucleotide antagonists were reported for P2Y1, P2Y2, P2Y6, P2Y11, P2Y12, and P2Y13 receptors. At the P2Y1 and P2Y12 receptors, nucleotide agonists (5′-diphosphate derivatives) were converted into antagonists of nanomolar affinity by altering the phosphate moieties, with a focus particularly on the ribose conformation and substitution pattern. Nucleotide analogues with conformationally constrained ribose-like rings were introduced as selective receptor probes for P2Y1 and P2Y6 receptors. Screening chemically diverse compound libraries has begun to yield new lead compounds for the development of P2Y receptor antagonists, such as competitive P2Y12 receptor antagonists with antithrombotic activity. Selective agonists for the P2Y4, P2Y11, and P2Y13 receptors and selective antagonists for P2Y4 and P2Y14 receptors have not yet been identified. The P2Y14 receptor appears to be the most restrictive of the class with respect to modification of the nucleobase, ribose, and phosphate moieties. The continuing process of ligand design for the P2Y receptors will aid in the identification of new clinical targets

Multi-omic based production strain improvement (MOBpsi) for bio-manufacturing of toxic chemicals

Robust systematic approaches for the metabolic engineering of cell factories remain elusive. The available models for predicting phenotypical responses and mechanisms are incomplete, particularly within the context of compound toxicity that can be a significant impediment to achieving high yields of a target product. This study describes a Multi-Omic Based Production Strain Improvement (MOBpsi) strategy that is distinguished by integrated time-resolved systems analyses of fed-batch fermentations. As a case study, MOBpsi was applied to improve the performance of an Escherichia coli cell factory producing the commodity chemical styrene. Styrene can be bio-manufactured from phenylalanine via an engineered pathway comprised of the enzymes phenylalanine ammonia lyase and ferulic acid decarboxylase. The toxicity, hydrophobicity, and volatility of styrene combine to make bio-production challenging. Previous attempts to create styrene tolerant E. coli strains by targeted genetic interventions have met with modest success. Application of MOBpsi identified new potential targets for improving performance, resulting in two host strains (E. coli NST74ΔaaeA and NST74ΔaaeA cpxPo) with increased styrene production. The best performing re-engineered chassis, NST74ΔaaeA cpxPo, produced ∼3 × more styrene and exhibited increased viability in fed-batch fermentations. Thus, this case study demonstrates the utility of MOBpsi as a systematic tool for improving the bio-manufacturing of toxic chemicals

Metalorganic chemical-vapour-deposition growth and characterization of GaAs

GaAs epitaxial layers have been grown on semi-insulating GaAs substrates using the technique of metalorganic chemical-vapour deposition. The organometallic compounds trimethylgallium and trimethylgallium–trimethylarsenic adduct were used as source reagents for gallium, whereas arsine and trimethylarsenic were used as sources for arsenic. Photoluminescence measurements at 8 K indicated that carbon was present in the layers as the dominant background acceptor, in most cases, and to a lesser extent copper (Cu) and manganese (Mn) acceptors were also present. Secondary-ion mass spectroscopy (SIMS) analysis confirmed the presence of these acceptors. Silicon was also identified by SIMS in most layers. The concentration of Cu and Mn was correlated with the starting substrate and with the deposition parameters (growth rate, deposition temperature). It was also found that their concentration in the epitaxial layers could be reduced by a careful heat-treatment and chemical etch prior to epitaxial growth. </jats:p

All-optical switching in a GaAs-based multiple quantum well directional coupler

The nonlinear, all-optical switching characteristics of a GaAs-based directional coupler are investigated. The structure consists of two Al0.18Ga0.82As planar waveguides coupled through a GaAs–AlGaAs multiple quantum well (MQW) layer. Changing the refractive index of the MQW layer, through a Kerr-type nonlinearity, varies the coupling length of the element, which in turn determines the distribution of optical power at the output of the sample. Our theoretical analysis of the element predicted that a strong nonlinear switching effect should be observed near the critical power, Pc, for samples cleaved to the appropriate length. This has been verified experimentally, for the first time with such a structure, and reveals a full-transfer coupling length of approximately 160 μm and a critical launched power of approximately 750 μW. </jats:p

Theoretical and Experimental Results for Strongly Guiding Semiconductor Rib Waveguide S-Bends

We have fabricated a series of S-bends in MBE-grown epilayers on (100) n+ GaAs substrates. The epilayer structure is a 1.1µm thick GaAs guiding layer above a 3.0µm Al.16Ga.84As cladding layer. The 2.3µm wide rib waveguides are reactive ion etched to a depth of 0.85µm into the guiding layer. The centers of our rib waveguide S-bends follow the equation x(z) = h{z/L − sin(27πz/L)/2π} with h = 10µm and 25µm ≤ L ≤ 400µm. The optical loss was determined experimentally to within ±0.1dB by measuring the Fabry-Perot fringe contrast of the cleaved waveguide sample with TE polarized light from a temperature tuned λ ≈ 1.3µm semiconductor diode laser.</jats:p