Regio- and Stereoselective Copper(II)-Catalyzed Hydrosilylation of Activated Allenes in Water: Access to Vinylsilanes

By using catalytic amounts of copper­(II), 4-picoline, and dimethyl­phenylsilyl­pinacol borane, a series of allenoates were silylated on the β carbon in good to excellent yields and high (<i>E</i>)-selectivity. The mild and efficient silylation method is conducted in water under atmospheric conditions to afford vinylsilanes

Phenotypic Heterogeneity of <i>Pseudomonas aeruginosa</i> Populations in a Cystic Fibrosis Patient

<div><p>The opportunistic pathogen <i>Pseudomonas aeruginosa</i> chronically infects the lower airways of patients with cystic fibrosis. Throughout the course of infection this organism undergoes adaptations that contribute to its long-term persistence in the airways. While <i>P. aeruginosa</i> diversity has been documented, it is less clear to what extent within-patient diversity contributes to the overall population structure as most studies have been limited to the analysis of only a few isolates per patient per time point. To examine <i>P. aeruginosa</i> population structure in more detail we collected multiple isolates from individual sputum samples of a patient chronically colonized with <i>P. aeruginosa</i>. This strain collection, comprised of 169 clonal isolates and representing three pulmonary exacerbations as well as clinically stable periods, was assayed for a wide selection of phenotypes. These phenotypes included colony morphology, motility, quorum sensing, protease activity, auxotrophy, siderophore levels, antibiotic resistance, and growth profiles. Each phenotype displayed significant variation even within isolates of the same colony morphotype from the same sample. Isolates demonstrated a large degree of individuality across phenotypes, despite being part of a single clonal lineage, suggesting that the <i>P. aeruginosa</i> population in the cystic fibrosis airways is being significantly under-sampled.</p> </div

Genetic diversity present in collected <i>P. aeruginosa</i> isolates from a single patient.

<p>The Dice coefficient from pulse field gel electrophoresis patterns of each isolate was used to construct a UPGMA tree (unrooted). Isolates from this study were no more than 20% different from each other but were more than 40% different from PA01. Isolates with identical PFGE patterns are grouped into a single node where the size of that node represents the number of isolates. Colouring represents the phenotypic group that the isolate falls into and the colours match the colouring in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060225#pone-0060225-g005" target="_blank">Figure 5</a>. Two PES strains were included in the analysis and are coloured in yellow. The cluster highlighted by purple is a cluster where the phenotypic and genetic groups are similar.</p

Distribution of antibiotic resistance among the analyzed isolates.

<p>Shown are zones of clearing from disc diffusion assays for five commonly used antibiotics in CF clinics and the resistance cutoffs for each antibiotic are given by the dashed lines. Resistance profiles for each colony morphotype are shown individually and coloured according to whether that colony type was initially identified as mucoid or not. Cutoff values for resistant, intermediate and sensitive are indicated by the colour of the background; red, yellow and blue, respectively. Cutoff values for trimethoprim/sulfamethoxazole are not published for <i>P. aeruginosa</i> by the CLSI.</p

Levels of <i>P. aeruginosa</i> during three pulmonary exacerbation periods over the course of one year.

<p>A, Total levels, expressed as colony forming units (CFU) per mL of sputum are shown in green and the numbers of mucoid and non-mucoid isolates are indicated in red and blue, respectively. B, The CFU per ml for each of the 14 colony types are shown.</p

Hierarchical cluster analysis of the phenotype profiles.

<p>Green indicates a value above the mean and red indicates a value below the mean. The three colours on the left side indicate the three main cluster groups. Purple bars on the right side indicate the isolates that group closely in both the phenotypic and genetic analysis. Missing values were removed prior to analysis.</p

Phenotypic diversity of <i>P. aeruginosa</i> isolates from a single sample.

<p>Phenotype profiles were obtained from a total of 88 isolates and were comprised of two different colony morphologies, which are shown as orange and green on the plot.</p

Phenotypic diversity present in collected <i>P. aeruginosa</i> isolates from a single patient.

<p>The data points are coloured according to whether the isolate was classified as mucoid or not. Grey lines indicate the phenotype value measured for the common lab strain, PA01.</p

Synthesis and Pharmacological Characterization of Novel <i>trans</i>-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D₃ Receptor (D₃R)

The development of bitopic ligands directed toward D₂-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D₃ receptor (D₃R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D₃R-selective antagonists SB269,652 (<b>1</b>) and SB277011A (<b>2</b>) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a <i>trans</i>-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D₃R-selective antagonists, <b>18a</b> and <b>25a</b>, which further delineates SAR associated with allosterism at D₃R and provides leads toward novel drug development

Synthesis and Pharmacological Characterization of Novel <i>trans</i>-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D₃ Receptor (D₃R)

The development of bitopic ligands directed toward D₂-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D₃ receptor (D₃R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D₃R-selective antagonists SB269,652 (<b>1</b>) and SB277011A (<b>2</b>) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a <i>trans</i>-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D₃R-selective antagonists, <b>18a</b> and <b>25a</b>, which further delineates SAR associated with allosterism at D₃R and provides leads toward novel drug development