Associations of β2‐adrenergic receptor genotypes and haplotypes with wheezing illness in Taiwanese schoolchildren

Background: Increasing attention was focused on the β2‐adrenergic receptor gene (ADRB2), whose genetic variability has been implicated as a risk factor for asthma‐related phenotypes. However, only a few studies reported the associations by utilizing haplotypic approaches. We therefore examined the relationship of childhood wheezing illness with polymorphisms at codons 16 and 27, and evaluated the influence of polymorphisms individually and in combination as haplotypes. Methods: We conducted a genetic case–control study comprising 215 wheezing children and 183 nonwheezing controls, all of whom were selected from 2524 fourth‐ to ninth‐grade schoolchildren in southern Taiwan. Results: All participants were homozygous at the ADRB2 Thr164 locus. After controlling for possible confounders, ADRB2 Glu27 allele was significantly associated with wheezing illness in all genetic models, but the risks on Arg16Gly genotypes were inconclusive. Estimated frequencies for the three main hyplotypes were Arg16/Gln27 57.2%, Gly16/Gln27 35.3%, Gly16/Glu27 7.4% in wheezing children, and Arg16/Gln27 56.3%, Gly16/Gln27 32.2%, Gly16/Glu27 10.4% in controls. The protective effect of Gly16/Glu27 haplotype remained relative to all other ADRB2 haplotypes [adjusted relative risk (aRR) = 0.58; 95% confidence interval (CI) 0.35–0.97]. As compared with children without Gly16/Glu27 haplotype, those with Gly16/Glu27 haplotype had a significantly lower risk for wheezing illness (aRR = 0.56; 95% CI 0.33–0.99). The copy numbers of Gly16/Glu27 haplotype also showed a clear dose‐response relationship on the decreased risks. No significant association was found with the prevalence of wheezing illness for other haplotypes. Conclusion: We concluded that ADRB2 Glu27 allele and Gly16/Glu27 haplotype were significantly protective factors for wheezing illness in Taiwanese schoolchildren.     

Linkage study of the α2A adrenergic receptor in attention‐deficit hyperactivity disorder families

Attention‐deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder, characterized by marked and pervasive inattention, hyperactivity, and impulsiveness. An alteration in the expression or function of the adrenergic system has been suggested to be involved in ADHD based on animal models, pharmacological interventions, and the neural circuitry of attentional processes. The efficacy of clonidine in reducing disruptive behaviors in some children with ADHD argues for a causal role of the adrenergic system and more specifically for the α2A receptors as clonidine is an α2A agonist that inhibits release of noradrenaline into the synapse. In animal studies, α2A receptor agonists have also been shown to improve performance on working memory tasks under distracting conditions, indicating that these receptors function in the regulation of attention. We examined the possibility that the gene for the α2A adrenergic receptor (ADRA2A) is linked to ADHD by testing a polymorphism located in the promoter region of the ADRA2A gene in a sample of 94 nuclear families with an ADHD proband. We found no evidence for linkage of the ADRA2A gene with ADHD, using the transmission disequilibrium test in this set of families. © Wiley‐Liss. Inc.     

Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre‐metastatic niche through activating β‐adrenergic signaling

Numerous studies have indicated that primary tumors induce the formation of a pre‐metastatic niche in distant organs by secreting tumor‐derived factors. The present study shows that pre‐exposure to chronic stress enhanced lung colonization efficiency by circulating tumor cells, suggesting that chronic stress critically influences pre‐metastatic lungs before the arrival of disseminated tumor cells. Ablation of the sympathetic nerve function by 6‐OHDA or blockage of the β‐adrenergic signaling by propranolol remarkably suppressed stress‐induced lung metastasis. Depletion of circulating monocytes or lung macrophages strongly abolished stress‐induced lung seeding by tumor cells, whereas treatment of mice with the β‐adrenergic agonist isoproterenol (ISO) during the pre‐metastatic phase promoted the infiltration of macrophages to the lung. Meanwhile, the numbers of monocytes in peripheral blood, spleen, and bone marrow were remarkably increased in response to ISO stimulation. These data indicate that the β‐adrenergic signaling promotes lung metastatic colonization by tumor cells through increased output of monocytes in the pre‐metastatic phase and infiltration of macrophages into the pre‐metastatic lung. Mechanistic studies revealed that ISO stimulation upregulated the expression of CCL2 in pulmonary stromal cells and CCR2 in monocytes/macrophages, leading to the recruitment and infiltration of macrophages into the pre‐metastatic lung. By inducing a response of monocytes/macrophages driven by the CCL2/CCR2 axis, stress‐related catecholamine may act as a crucial factor in regulating the pre‐metastatic niche for and lung colonization by tumor cells. Our data demonstrate that disturbance of host macro‐environmental homeostasis has an influence on future metastatic organs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Evidence for genetic heterogeneity in D‐2‐hydroxyglutaric aciduria

We performed molecular, enzyme, and metabolic studies in 50 patients with D ‐2‐hydroxyglutaric aciduria (D ‐2‐HGA) who accumulated D ‐2‐hydroxyglutarate (D ‐2‐HG) in physiological fluids. Presumed pathogenic mutations were detected in 24 of 50 patients in the D ‐2‐hydroxyglutarate dehydrogenase (D2HGDH) gene, which encodes D ‐2‐hydroxyglutarate dehydrogenase (D ‐2‐HGDH). Enzyme assay of D ‐2‐HGDH confirmed that all patients with mutations had impaired enzyme activity, whereas patients with D ‐2‐HGA whose enzyme activity was normal did not have mutations. Significantly lower D ‐2‐HG concentrations in body fluids were observed in mutation‐positive D ‐2‐HGA patients than in mutation‐negative patients. These results imply that multiple genetic loci may be associated with hyperexcretion of D ‐2‐HG. Accordingly, we suggest a new classification: D ‐2‐HGA Type I associates with D ‐2‐HGDH deficiency, whereas idiopathic D ‐2‐HGA manifests with normal D ‐2‐HGDH activity and higher D ‐2‐HG levels in body fluids compared with Type I patients. It remains possible that several classifications for idiopathic D ‐2‐HGA patients with diverse genetic loci will be revealed in future studies. Hum Mutat 31:1–5, 2010. © 2009 Wiley‐Liss, Inc.     

Direct Insertion Mass Spectrometric Analysis of Thermal Degradation of Poly(2‐alkyl‐2‐oxazoline)

Direct pyrolysis mass spectrometry is applied to investigate the thermal behavior of poly(2‐isopropyl‐2‐oxazoline) (PIPOX, a thermoresponsive polymer) and poly[2‐(3‐butenyl)‐2‐oxazoline] (PBOX, a “clickable” polymer). It is found that the thermal degradation of PIPOX is started by a loss of side chains. At slightly higher temperatures the degradation of the polymer backbone occurs by random chain scission processes. In the case of PBOX, vinyl polymerization of the side chains produces chains with variable thermal stabilities. The number of repeating units of the polymer has almost no effect on the thermal behavior of PIPOX, but significantly affects both thermal stability and degradation product distribution of PBOX.     

Synthesis and Optoelectronic Properties of Benzo[1,2‐b:4,5‐b′]dithiophene‐Based Copolymers with Conjugated 2‐(2‐Ethylhexyl)‐3,4‐dimethoxythiophene Side Chains

In order to regulate the electronic ability of benzo[1,2‐b:4,5‐b′]dithiophene (BDT), the new electron‐donating unit (BDTOT) is designed and synthesized which consists of a BDT backbone with conjugated 2‐(2‐ethylhexyl)‐3,4‐dimethoxythiophene side chains. By alternating copolymerization of BDTOT with electron‐accepting units of fluorinated benzothiadiazole (FBT), benzothiadiazole (BT), and pyrrolo[3,4‐c]pyrrole‐1,4‐dione (DPP), three donor–acceptor (D‐A) copolymers (PBDTOT‐FBT, PBDTOT‐BT, and PBDTOT‐DPP) have been developed for PSC applications. The impact of dimethoxythiophene substituent and the electron‐accepting strength of the acceptor units on the absorption, HOMO/LUMO energy levels, and photovoltaic properties of the resultant polymers is investigated in detail. PBDTOT‐BT and PBDTOT‐DPP exhibit relatively narrower bandgaps and PBDTOT‐FBT possesses a down‐shifted HOMO energy level as compared to their corresponding analogs without methoxy groups onto the conjugated thiophene side chains. The screening of the different blend ratio, the processing additive, and polar solvent post‐treatment is conducted to optimize the polymer solar cell (PSC) devices. PSCs with PBDTOT‐FBT as donor deliver a power conversion efficiency (PCE) of 2.55%. By treatment of the active layer with methanol to tailor the morphology, the solar cell based on PBDTOT‐FBT exhibits the remarkably improved PCE of 4.84% with a V _oc of 0.92 V, a J _sc of 8.71 mA cm^?2, and an FF of 60.3%.

     

Click‐Chemistry: An Alternative Way to Functionalize Poly(2‐methyl‐2‐oxazoline)

CROP has been used to synthesize well‐defined POXZ with a monofunctional (iodomethane) or a bifunctional (1,3‐diiodopropane) initiator. POXZ has been functionalized with an azido group at one (α‐azido‐POXZ, = 3.58 × 10³ g · mol^?1) or both ends (α,ω‐azido‐POXZ, = 6.21 × 10³ g · mol^?1) of the macromolecular chain. The Huisgen 1,3‐dipolar cycloaddition has been investigated between azido‐POXZ and a terminal alkyne on a small or larger molecule (PEG). In each case, the click reaction has been successful and quantitative. In this way, different telechelic polymers (polymers bearing different functions such as acrylate, epoxide, or carboxylic acid) and block copolymers of POXZ and PEG have been prepared. The polymers have been characterized by means of FTIR, ¹H NMR, and SEC.

     

Norepinephrine transporter and α2c adrenoceptor allelic variants and personality factors

It has been suggested that reward dependence, as measured by the Tridimensional Personality Questionnaire (TPQ), is related to central noradrenergic activity, a proposition supported by two studies of urinary norepinephrine metabolite. In the current investigation, 190 normal young Han Chinese were examined, with genetic polymorphisms determined for the norepinephrine transporter (1287G/A) and the α_2c‐adrenoceptor (Del322–325) to test the association with TPQ personality traits. No significant association was demonstrated for these two polymorphisms and any of the TPQ personality‐factor scores, including reward dependence and its subscales. Our negative findings suggest that the investigated polymorphisms of the norepinephrine transporter and the α_2c adrenoceptor do not play a major role in the reward‐dependence personality trait as assessed by TPQ. © 2002 Wiley‐Liss, Inc.     

Hydrolyzed Poly(2‐plenyl‐2‐oxazoline)s in Aqueous Media and Biological Fluids

Hydrolyzed poly(2‐phenyl‐2‐oxazoline)s (PPhOx) are synthesized by partial hydrolysis of PPhOx in order to produce self‐assembling copolymers with chargeable and hydrophobic units. The resulting poly(ethylene imine‐co‐2‐phenyl‐2‐oxazoline) [P(EI‐co‐PhOx)] amphiphilic copolymers contain phenyl‐oxazoline and ethylene imine segments in a random sequence and their chemical structure is confirmed by ¹H NMR and attenuated total reflection‐Fourier transform infrared spectroscopy. Static and dynamic light scattering experiments show that in aqueous solutions the random copolymers associate into aggregates of sizes in the range between 50 and 200 nm depending on the solution conditions and hydrophobic content. The positive charge of the nanoaggregates that is caused by protonation of the amine nitrogen is confirmed by zeta potential measurements. Self‐assembly in phosphate buffered saline results in large aggregates. The aggregates are proved to interact with fetal bovine serum proteins. This investigation shows that hydrolyzed phenyl oxazoline‐based copolymers provide stable amphiphilic nanoparticles able to interact with biological macromolecules for biotechnological and pharmaceutical applications.     

Amphiphilic Block Copolymers Containing Regioregular Poly(3‐hexylthiophene) and Poly(2‐ethyl‐2‐oxazoline)

Poly(3‐hexylthiophene)‐block‐poly(2‐ethyl‐2‐oxazoline) amphiphilic rod–coil diblock copolymers have been synthesized by a combination of Grignard metathesis (GRIM) and ring‐opening cationic polymerization. Diblock copolymers containing 5, 15, and 30 mol‐% poly(2‐ethyl‐2‐oxazoline) have been synthesized and characterized. The synthesized rod–coil block copolymers display nanofibrillar morphology where the density of the nanofibrills is dependent on the concentration of the poly(2‐ethyl‐2‐oxazoline) coil segment. The conductivity of the diblock copolymers was lowered from 200 to 35 S · cm^?1 with an increase in the content of the insulating poly(2‐ethyl‐2‐oxazoline) block. By contrast, the field‐effect mobility decreased by 2–3 orders of magnitude upon the incorporation of the poly(2‐ethyl‐2‐oxazoline) insulating segment.

     

A Mechanistic and Characteristic Investigation of Electrooxidation of 2‐Amino‐3‐cyano‐4‐methylthiophene

The electrochemical oligomerization of 2‐amino‐3‐cyano‐4‐methylthiophene (ACMT) has been studied by cyclic voltammetry, potential controlled electrolysis and digital simulation. The product analysis after preparative electrolysis was carried out by UV‐vis‐NIR, ¹H and ¹³C NMR and FT‐IR spectroscopic techniques. The kinetic data were estimated using the results of fitting the digitally simulated voltammograms to the experimentally obtained cyclic voltammograms. The oligomerization proceeds according to an ECE mechanism resulting in the formation of an oligomeric mixture containing dimer and tetramer. UV‐vis‐NIR and fluorescence measurements indicated that the isolated dimer and tetramer showed higher conjugation than the monomer unit and the conjugation increased with an increase in the number of monomer units.

     

ABA and BAB Triblock Copolymers Based on 2‐Methyl‐2‐oxazoline and 2‐n‐Propyl‐2‐oxazoline: Synthesis and Thermoresponsive Behavior in Water

Inspired by the well‐known amphiphilic block copolymer platform known as Pluronics or poloxamers, a small library of ABA and BAB triblock copolymers comprising hydrophilic 2‐methyl‐2‐oxazoline (A) and thermoresponsive 2‐n‐propyl‐2‐oxazoline (B) is synthesized. These novel copolymers exhibit temperature‐induced self‐assembly in aqueous solution. The formation and size of aggregates depend on the polymer structure, temperature, and concentration. The BAB copolymers tend to agglomerate in water, with the cloud point temperature depending on the length of poly(2‐n‐propyl‐2‐oxazoline) chain. On the other hand, ABA copolymers form smaller aggregates with hydrodynamic radius from 25 to 150 nm. The dependence of viscosity and viscoelastic properties on the temperature is also studied. While several Pluronic block copolymers are known to form thermoreversible hydrogels in the concentration range 20–30 wt%, thermogelation is not observed for any of the investigated poly(2‐oxazoline)s at the investigated temperature range from 10 to 50 °C.

     

Acetyl Halide Initiator Screening for the Cationic Ring‐Opening Polymerization of 2‐Ethyl‐2‐Oxazoline

Kinetic investigations on the cationic ring‐opening polymerization of 2‐ethyl‐2‐oxazoline were conducted using acetyl chloride, acetyl bromide, and acetyl iodide as initiators. Various polymerization temperatures ranging from 80 to 220 °C were applied under microwave irradiation. The resulting polymerization mixtures were characterized with GC and GPC for the determination of monomer conversion and molecular weight distribution, respectively. Well defined polymers with narrow molecular weight distributions ( = 6 000 Dalton, PDI ≈ 1.10) were obtained with all three initiators.