Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent,selective, and orally active human dopamine D4 receptor antagonists

A new class of potent dopamine D(4) antagonists was discovered with selectivity over dopamine D(2) and the alpha-1 adrenoceptor. The lead compound was discovered by screening our compound collection. The structure-activity relationships of substituted isoindoline rings and the chirality about the hydroxymethyl side chain were explored. The isoindoline analogues showed modest differences in potency and selectivity. The S enantiomer proved to be the more potent enantiomer at the D(4) receptor. Several analogues with greater than 100-fold selectivity for D(4) over D(2) and the alpha-1 adrenoreceptor were discovered. Several selective analogues were active in vivo upon oral or intraperitoneal administration. A chiral synthesis starting from either D- or L-O-benzylserine is also described.     

A Fast XPS Study of Propene Decomposition over Clean and Sulphated Pt{111}

The thermal decomposition of propene over clean and sulphate precovered Pt{111} has been followed by Fast XPS. The saturation propene coverage over the clean surface is 0.21 mL at 90 K. Propene is stable up to 200 K, above which molecular desorption and dehydrogenation result in the formation of a stable propylidyne intermediate adlayer at 300 K. Propylidyne decomposes above 400 K eventually forming graphitic carbon above 800 K. Preadsorbed surface sulphate promotes room temperature propene combustion associated with the decomposition of a thermally unstable alkyl--sulphate complex. Propylidyne also forms as on clean Pt{111}, but is less reactive, its decomposition above 450 K triggering partial oxidation with residual surface oxygen to liberate gas phase CO.     

An improved accelerated weathering protocol to anticipate Florida exposure behavior of coatings

A new accelerated weathering protocol has been developed which closely replicates the performance of automotive and aerospace coating systems exposed in South Florida. IR spectroscopy was used to verify that the chemical composition changes that occurred during accelerated weathering in devices with a glass filter that produced a high fidelity reproduction of sunlight’s UV spectrum matched those that occurred during natural weathering. Gravimetric water absorption measurements were used to tune the volume of water absorption during accelerated weathering to match that which occurred during natural weathering in South Florida. The frequency of water exposure was then scaled to the appropriate UV dose. A variety of coating systems were used to verify the correlation between the physical failures observed in the accelerated weathering protocol and natural weathering in South Florida. The new accelerated weathering protocol correctly reproduced gloss loss, delamination, cracking, blistering, and good performance in a variety of diverse coating systems. For automotive basecoat/clearcoat paint systems, the new weathering protocol shows significant acceleration over both Florida and previous accelerated weathering tests. For monocoat aerospace systems, the new weathering protocol showed less acceleration than for automotive coatings, but was still an improvement over previous accelerated tests and was faster than Florida exposure.     

Dietary Intake and Food Sources of EPA, DPA and DHA in Australian Children

Secondary analysis of the 2007 Australian National Children’s Nutrition and Physical Activity survey was undertaken to assess the intake and food sources of EPA, DPA and DHA (excluding supplements) in 4,487 children aged 2–16 years. An average of two 24-h dietary recalls was analysed for each child and food sources of EPA, DPA and DHA were assessed using the Australian nutrient composition database called AUSNUT 2007. Median (inter quartile range, IQR) for EPA, DPA and DHA intakes (mg/day) for 2–3, 4–8, 9–13, 14–16 year were: EPA 5.3 (1.5–14), 6.7 (1.8–18), 8.7 (2.6–23), 9.8 (2.7–28) respectively; DPA 6.2 (2.2–14), 8.2 (3.3–18), 10.8 (4.3–24), 12.2 (5–29) respectively; and DHA 3.9 (0.6–24), 5.1 (0.9–26), 6.8 (1.1–27), 7.8 (1.5–33) respectively. Energy-adjusted intakes of EPA, DPA and DHA in children who ate fish were 7.5, 2 and 16-fold higher, respectively (P < 0.001) compared to those who did not eat fish during the 2 days of the survey. Intake of total long chain n-3 PUFA was compared to the energy adjusted suggested dietary target (SDT) for Australian children and 20 % of children who ate fish during the 2 days of the survey met the SDT. Fish and seafood products were the largest contributors to DHA (76 %) and EPA (59 %) intake, while meat, poultry and game contributed to 56 % DPA. Meat consumption was 8.5 times greater than that for fish/seafood. Australian children do not consume the recommended amounts of long chain omega-3 fatty acids, especially DHA, which could be explained by low fish consumption.     

Reactions of glycerol with poly(ethylene ether carbonate) polyols

Poly(ethylene ether carbonate) polyols can be modified by chemical reactions with polyglycol modifiers under conditions of elevated temperatures and reduced pressures. The modifier becomes chemically incorporated into the modified polyol and is used to control properties such as moisture sensitivity, CO₂ content, T_g, density, etc. in the resultant polyol. However, glycerol cannot be used as a modifier for poly(ethylene ether carbonate) polyols under the same conditions since it reacts with poly(ethylene ether carbonate) polyols by a transesterification reaction sequence to form glyceryl carbonate. As the temperature is increased, the glyceryl carbonate decomposes to yield glycidol and carbon dioxide. These reactions are conveniently followed by ¹³C-NMR. The preparation of glyceryl carbonate by this process has not been previously reported.     

Tailoring Encodable Lanthanide‐Binding Tags as MRI Contrast Agents

Lanthanide‐binding tags (LBTs), peptide‐based coexpression tags with high affinity for lanthanide ions, have previously been applied as luminescent probes to provide phasing for structure determination in X‐ray crystallography and to provide restraints for structural refinement and distance information in NMR. The native affinity of LBTs for Gd³⁺ indicates their potential as the basis for engineering of peptide‐based MRI agents. However, the lanthanide coordination state that enhances luminescence and affords tightest binding would not be ideal for applications of LBTs as contrast agents, due to the exclusion of water from the inner coordination sphere. Herein, we use structurally defined LBTs as the starting point for re‐engineering the first coordination shell of the lanthanide ion to provide for high contrast through direct coordination of water to Gd³⁺ (resulting in the single LBT peptide, m‐sLBT). The effectiveness of LBTs as MRI contrast agents was examined in vitro through measurement of binding affinity and proton relaxivity. For imaging applications that require targeted observation, fusion to specific protein partners is desirable. However, a fusion protein comprising a concatenated double LBT (dLBT) as an N‐terminal tag for the model protein ubiquitin had reduced relaxivity compared with the free dLBT peptide. This limitation was overcome by the use of a construct based on the m‐sLBT sequence (q‐dLBT–ubiquitin). The structural basis for the enhanced contrast was examined by comparison of the X‐ray crystal structure of xq‐dLBT–ubiquitin (wherein two tryptophan residues are replaced with serine), to that of dLBT‐ubiquitin. The structure shows that the backbone conformational dynamics of the MRI variant may allow enhanced water exchange. This engineered LBT represents a first step in expanding the current base of specificity‐targeted agents available.     

Reactive,nonreactive, and flash spark plasma sintering of Al2O3/SiC composites—A comparative study

The influence of different SPS-based methods, that is, conventional spark plasma sintering (SPS), flash SPS (FSPS), and reactive SPS (RSPS) on the properties of Al₂O₃/SiC composite was investigated. It was shown that the application of preliminary high energy ball milling of the powders significantly enhances the sinterability of the ceramics. It was also demonstrated that FSPS provides unique conditions for rapid, that is, less than a minute, consolidation of refractory ceramics. The Al₂O₃-20 wt% SiC composite produced by FSPS possesses the highest relative density (~99%), fracture toughness (7.5 MPa m^1/2), hardness (20.3 GPa) and wear resistance among all ceramics produced by other SPS-based approaches with dwelling time 10 minutes. The RSPS ceramics hold the highest Young's modulus (390 GPa). Substitution of micron-sized Al₂O₃ particles by nano alumina does not lead to measurable enhancement of the mechanical properties.     

Identification of Conserved and Novel MicroRNAs during Tail Regeneration in the Mexican Axolotl

The Mexican axolotl salamander (Ambystoma mexicanum) is one member of a select group of vertebrate animals that have retained the amazing ability to regenerate multiple body parts. In addition to being an important model system for regeneration, the axolotl has also contributed extensively to studies of basic development. While many genes known to play key roles during development have now been implicated in various forms of regeneration, much of the regulatory apparatus controlling the underlying molecular circuitry remains unknown. In recent years, microRNAs have been identified as key regulators of gene expression during development, in many diseases and also, increasingly, in regeneration. Here, we have used deep sequencing combined with qRT-PCR to undertake a comprehensive identification of microRNAs involved in regulating regeneration in the axolotl. Specifically, among the microRNAs that we have found to be expressed in axolotl tissues, we have identified 4564 microRNA families known to be widely conserved among vertebrates, as well as 59,811 reads of putative novel microRNAs. These findings support the hypothesis that microRNAs play key roles in managing the precise spatial and temporal patterns of gene expression that ensures the correct regeneration of missing tissues.     

Direct Chemical Activation of a Rationally Engineered Signaling Enzyme

Few chemical strategies for activating enzymes have been developed. Here we show that a biarsenical compound (FlAsH) can directly activate a rationally engineered protein tyrosine phosphatase (Shp2 PTP) by disrupting autoinhibitory interactions between Shp2's N‐terminal SH2 domain and its PTP domain. We found that introducing a tricysteine motif at a loop of Shp2's N‐SH2 domain confers affinity for FlAsH; binding of FlAsH to the cysteine‐enriched loop relieves Shp2's inhibitory interdomain interaction and substantially increases the enzyme's PTP activity. Activation of engineered Shp2 is substrate independent and is observed in the contexts of both purified enzyme and complex proteomes. A chemical means for activating Shp2 could be useful for investigating its roles in signaling and oncogenesis, and the loop‐targeting strategy described herein could provide a blueprint for the development of target‐specific activators of other autoinhibited enzymes.     

The production of carbon nanotube reinforced poly(vinyl) butyral nanofibers by the Forcespinning® method

Poly(vinyl) butyral (PVB) nanofibers (NFs) and carbon nanotube (CNT) reinforced PVB NF composites were developed by using the Forcespinning® technology. PVB was dissolved in a mixture of ethanol and methanol (7:3 wt/wt) at various concentrations, and the solutions were spun at rotational speeds varying between 3,000 and 9,000 rpm. The CNT/PVB solutions were prepared using the same solvent ratio with varying the concentration of CNTs. The results show that the diameter of the PVB fibers increased with increasing rotational speed; however the standard deviation of the fiber diameter distribution decreased. The morphology and thermal properties of the developed fiber systems were studied by DSC, TGA, Raman, and FTIR. The effect of CNT on the mechanical properties of the developed fibers was investigated by carrying out tensile tests at different strain rates. Raman and FTIR analyses indicate a noncovalent π–π stacking interactions and hydrogen bonding between CNT and the PVB NFs. Adding CNT to the PVB NF matrix resulted in improved tensile strength by 150%. POLYM. ENG. SCI., 55:81–87, 2015. © 2014 Society of Plastics Engineers