The long path towards implementation of clinical proteomics: Exemplified based on CKD273

Clinical proteomics aims at the development and the implementation of novel biomarkers that demonstrate a clear clinical benefit in the management of diseases. However, though the attention in the field is increasing and multiple articles on biomarker research are published, clinical implementation of these biomarkers is scarce. In this paper, we aim towards identifying the hurdles on the path towards implementation, and present one successful approach, based on capillary electrophoresis coupled with mass spectrometry. A panel of biomarkers identified and assessed using this approach, termed CKD273, has recently received a Letter‐of‐Support from the US‐Food and Drug Administration (FDA), and is now implemented in the (early) management of chronic kidney disease. Based on this experience in the process towards implementation of CKD273, issues associated with implementation and suggestions how to meet these challenges are given.     

Stability effects associated with the introduction of a partial and a complete Ca2+-binding site into human lysozyme

Two mutants of human lysozyme were synthesized. Mutant A92D,in which Ala92 was substituted by Asp, contains a partial Ca²⁺-bindingsite and mutant M4, in which Ala83, Gm86, Asn88 and Ala92 werereplaced by Lys, Asp, Asp and Asp respectively, contains thecomplete Ca -binding site of bovine a-lactalbumin. The Ca²⁺-bindingconstants of wild type human lysozyme and of mutants A92D andM4, measured at 25C and pH 7.5, were 2(1) x 102 M"1, 8(2)x l^M"1 and 9(0.5) x 10* M"1 respectively. Information gatheredfrom mkrocalorimetrk and CD spectro-scopic measurements indicatesthat the conformational changes of the M4 mutant lysozyme, inducedby Ca²⁺ binding, are smaller than those observed for bovinea-lactalbumin and for the Ca²⁺-binding equine lysozyme. At pH4.5, the thermostability of both the apo and Ca²⁺ forms of theA92D human was decreased in comparison with that of native humanlysozyme. In particular, within the apo form of this mutantan a-helix-containing sequence was destabilized. In contrast,at the same pH the thermostability of the apo and Ca²⁺ formsof the M4 mutant lysozyme was increased. The e-ammonium groupof the Lys83 side chain is assumed to be responsible for thestabilization of the apo form of this mutant.     

Anionic polymerization of acrylates. XIV. Synthesis of MMA/acrylate block copolymers initiated with ester-enolate/tert-alkoxide complex

Diblock copolymers of methyl methacrylate (MMA) with 2-ethylhexyl, butyl, ethyl or tert-butyl acrylate (EtHA, BuA, EtA, t-BuA) have been prepared by the ligated anionic polymerization initiated with methyl 2-lithioisobutyrate (MIB-Li) in the presence of an excess of Li tert-butoxide (t-BuOLi) in toluene/THF mixture at −60 or −78 °C. The copolymers, prepared at −60 °C, show MWD with a hint of bimodality, indicating partial deactivation of the living PMMA upon addition of acrylic monomer. At −78 °C, the extent of this deactivation is distinctly lower, the formed block copolymers, in particular, poly(MMA-b-EtHA), have unimodal MWD and exhibit tails only in the lower-molecular-weight region. Poly(MMA-b-EtHA)s were extracted with acetonitrile dissolving PMMA; very small parts of the crude products dissolved, whereas prevailing parts remained as solids documenting thus formation of block copolymer in a high yield. Surprisingly, the highest amount of self terminated PMMA was found in block copolymerization of MMA with t-BuA at both the temperatures, the products of which had clearly bimodal MWDs. This finding is shortly discussed on the basis of relatively slow propagation of t-BuA in comparison with EtHA, BuA and EtA.     

(Z,Z)-4,7-tridecadien-(S)-2-yl acetate: sex pheromone of Douglas-fir cone gall midge,Contarinia oregonensis

Our objectives were to identify and field test the sex pheromone of female Douglas-fir cone gall midge, Contarinia oregonensis (Diptera: Cecidomyiidae). Coupled gas chromatographic–electroantennographic detection (GC-EAD) analyses of pheromone extract revealed a single compound (A) that elicited responses from male antennae. Hydrogenation of pheromone extract, followed by renewed GC-EAD analysis, revealed a new EAD-active compound with chromatographic characteristics identical to those of tridecan-2-yl acetate on five fused silica columns (DB-5, DB-210, DB-23, SP-1000, and Cyclodex-B). Syntheses, chromatography, and retention index calculations of all possible tridecen-2-yl acetates suggested that the candidate pheromone A was a tridecadien-2-yl acetate with nonconjugated double bonds. Synthetic candidate pheromone component (Z,Z)-4,7-tridecadien-2-yl acetate (Z4Z7) cochromatographed with A on all analytical columns and elicited comparable antennal activity. In GC-EAD analyses that separated the enantiomers (Z,Z)-4,7-tridecadien-(S)-2-yl acetate (2S-Z4Z7) and (Z,Z)-4,7-tridecadien-(R)-2-yl acetate (2R-Z4Z7) with baseline resolution, only 2S-Z4Z7 as a component in a racemic standard or in pheromone extract elicited antennal responses. In Douglas-fir seed orchards, sticky traps baited with 2S-Z4Z7 captured male C. oregonensis, whereas 2R-Z4Z7 was behaviorally benign. Comparable catches of males in traps baited with racemic Z4Z7 (50 g) or virgin female C. oregonensis suggested that synthetic pheromone baits could be developed for monitoring C. oregonensis populations in commercial Douglas-fir seed orchards.     

Dielectric spectroscopy on melt processed polycarbonate—multiwalled carbon nanotube composites

Complex permittivity and related AC conductivity measurements in the frequency range between 10⁻⁴ and 10⁷ Hz are presented for composites of polycarbonate (PC) filled with different amounts of multiwalled carbon nanotubes (MWNT) varying in the range between 0.5 and 5 wt%. The composites were obtained by diluting a PC based masterbatch containing 15 wt% MWNT by melt mixing using a Micro Compounder. From DC conductivity measurements it was found that for samples processed at a mixing screw speed of 150 rpm for 5 min, the percolation occurs at a threshold concentration (p_c) between 1.0 and 1.5 wt% MWNT. For concentrations of MWNT near the percolation threshold, the processing conditions (screw speed and mixing time) were varied. The differences in the dispersion of the MWNT in the PC matrix could be detected in the complex permittivity and AC conductivity spectra, and have been explained by changes in p_c. The AC conductivity and permittivity spectra are discussed in terms of charge carrier diffusion on percolation clusters and resistor-capacitor composites.     

‘The older adult’ doesn’t exist: using values to differentiate older adults in the Dutch housing market

Abstract

To date most prognoses of older adults in the housing market have been based on average housing preferences and average housing market behaviour of all persons in a certain age cohort. Due to socialcultural and social-economic dynamics, the relationship between age and housing is expected to change for successive cohorts. This study sets out to improve housing preferences estimates by recognizing the growing differentiation among older adults. This heterogeneity is analysed by differentiating older adults on their lifestyles (operationalized as values), using latent class analysis as a clustering technique. These analyses result in older adults being classified into five segments on the basis of their viewpoints, motivations and attitude. Next, for each lifestyle segment a separate discrete choice model is estimated, offering insight in the relative importance that these segments give to various housing attributes. The findings demonstrate advantages over a traditional, single model approach and can be helpful in formulating contemporary housing policy.     

A simple intrinsic measure for rapid crack propagation in bimodal polyethylene pipe grades validated by elastic–plastic fracture mechanics analysis of data from instrumented Charpy impact test

Conventional test procedures, such as the S4 test to analyze the resistance against rapid crack propagation (RCP) of plastic pipe materials are characterized by usage of a lot of material, are far from saving of time and they are‐in need of special experimental set‐ups. Therefore, in the last decade, small‐scale accelerated reliable tests (SMART) are developed ‐ worldwide to overcome the disadvantage of such conventional tests. In this article, fracture mechanics based analysis of instrumented Charpy impact test data for a set of bimodal high‐density polyethylene pipe grades are compared with data of the conventional Charpy impact test. From this comparison the Charpy impact strength at ?30°C comes forth as a robust reproducible measure of the resistance to RCP and it is therefore proposed as a SMART method to rank materials with respect to RCP resistance. POLYM. ENG. SCI., 57:13–21, 2017. © 2016 Society of Plastics Engineers     

Exploring the Structural Space of the Galectin‐1–Ligand Interaction

Galectin‐1 is a tumor‐associated protein recognizing the Galβ1‐4GlcNAc motif of cell‐surface glycoconjugates. Herein, we report the stepwise expansion of a multifunctional natural scaffold based on N‐acetyllactosamine (LacNAc). We obtained a LacNAc mimetic equipped with an alkynyl function on the 3′‐hydroxy group of the disaccharide facing towards a binding pocket adjacent to the carbohydrate‐recognition domain. It served as an anchor motif for further expansion by the Sharpless–Huisgen–Meldal reaction, which resulted in ligands with a binding mode almost identical to that of the natural carbohydrate template. X‐ray crystallography provided a structural understanding of the galectin‐1–ligand interactions. The results of this study enable the development of bespoke ligands for members of the galectin target family.     

Interference control, working memory, concept shifting, and verbal fluency in adults with attention-deficit/hyperactivity disorder (ADHD).

In this study, the authors aimed to examine 4 domains of executive functioning in adults with attention-deficit/hyperactivity disorder (ADHD)--namely interference control, concept shifting, verbal fluency, and verbal working memory. Four groups of participants were included: (a) adults diagnosed with ADHD (ADHD-; n = 20), (b) adults diagnosed with both ADHD and 1 or more comorbid disorder(s) (ADHD+; n = 22), (c) adults referred for ADHD because of ADHD symptomatology but not diagnosed as such (non-ADHD; n = 34), and (d) healthy controls (n = 136). ADHD-related deficits (independent of comorbidity) were revealed for concept shifting and verbal working memory. In addition, the ADHD+ and non-ADHD groups displayed deficits in terms of general processing speed. Given that these deficits were not found in the ADHD- group, the authors contend that these deficits are likely attributable to comorbidity rather than ADHD itself. Contrary to the authors' expectations, these findings do not correspond with the cognitive subtype hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Greenspace matters: exploring links between greenspace,gender and well-being with conservation volunteers

Abstract

Our study aimed to increase understanding of the effect of gender on mediating engagement with greenspace, currently poorly understood. We engaged with a group of conservation volunteers in a Scottish city to explore how men and women benefit from and interact with greenspace in a deprived area. We found that interactions with the greenspace have multiple health and well-being benefits and that differences in engagement (and therefore potentially in any well-being benefits accrued) can be identified between men and women in terms of: motivations for getting involved with the group (e.g., men got involved for something to do whilst women sought to pursue conservation experience), connections volunteers made being in the group (e.g., men were more likely to value the social connections they made in the group than women) and finally, and potentially most importantly, the greenspace being valued for being a ‘neutral space’ where volunteers (especially men) felt more at ease and equal than in other places. This research enhances understanding of the ways in which benefits from engagement with greenspace are mediated through social factors such as gender and volunteering. Such research is important to planners and policy-makers in understanding how greenspace use can be encouraged for different genders.