The Genetic and Environmental Etiology of Shyness Through Childhood.

The objective of this study was to examine the genetic and environmental contributions to shyness throughout the school-age period. Participants were 553 twin pairs from the ongoing prospective longitudinal Quebec Newborn Twin Study. Teacher-rated measures of shyness were collected at five time-points from age 6-12 years. On average, shyness was moderately stable over time (r = 0.23-0.33) and this stability was almost entirely accounted for by genetic factors. Genetic factors at age 6 accounted for 44% of individual differences and these early genetic factors also explained individual differences at all subsequent ages (6-22%). Non-shared environmental factors explained most of individual differences at single time-points (51-63%), and did not account for stability in shyness. Contributions of shared environment were not significant. Our results suggest that the stability in shyness is mostly accounted for by early and persistent genetic contributions.

Early warm-rewarding parenting moderates the genetic contributions to callous-unemotional traits in childhood.

BACKGROUND: Previous gene-environment interaction studies of CU traits have relied on the candidate gene approach, which does not account for the entire genetic load of complex phenotypes. Moreover, these studies have not examined the role of positive environmental factors such as warm/rewarding parenting. The aim of the present study was to determine whether early warm/rewarding parenting moderates the genetic contributions (i.e., heritability) to callous-unemotional (CU) traits at school age. METHODS: Data were collected in a population sample of 662 twin pairs (Quebec Newborn Twin Study - QNTS). Mothers reported on their warm/rewarding parenting. Teachers assessed children's CU traits. These reports were subjected to twin modeling. RESULTS: Callous-unemotional traits were highly heritable, with the remaining variance accounted for by nonshared environmental factors. Warm/rewarding parenting significantly moderated the role of genes in CU traits; heritability was lower when children received high warm/rewarding parenting than when they were exposed to low warm/rewarding parenting. CONCLUSIONS: High warm/rewarding parenting may partly impede the genetic expression of CU traits. Developmental models of CU traits need to account for such gene-environment processes.

Highly Selective Olefin-Assisted PdII -Catalyzed Oxidative Alkynylation of Enallenes.

An olefin-assisted, palladium-catalyzed oxidative alkynylation of enallenes for regio- and stereoselective synthesis of substituted trienynes has been developed. The reaction shows a broad substrate scope and good tolerance for various functional groups on the allene moiety, including carboxylic acid esters, free hydroxyls, imides, and alkyl groups. Also, a wide range of terminal alkynes with electron-donating and electron-withdrawing aryls, heteroaryls, alkyls, trimethylsilyl, and free hydroxyl groups are tolerated.

Defining the sham environment for post-myocardial infarction studies in mice.

The purpose of this study was to evaluate the effect of sham surgery in a minimally invasive surgical model of permanent coronary artery occlusion used to generate myocardial infarction (MI) in mice. Adult male C57BL/6J mice (3-6 mo old) were divided into five groups: day (D) 0 (no surgical operation), D1 Sham, D1 MI, D7 Sham, and D7 MI. A refined MI surgery technique was used to approach the coronary artery without the ribs being cut. Both sham and MI mice had the left ventricle (LV) exposed through a small incision. To test the effects of surgery alone, the suture was passed around the coronary artery but not ligated. The MI mice were subjected to permanent coronary artery ligation. The mice were killed at D1 or D7 postsurgical procedure. Compared with D0 no surgery controls, the D1 and D7 sham groups exhibited no surgical mortality and similar necropsy and echocardiographic variables. Surgery alone did not induce an inflammatory cell response, as evidenced by the lack of leukocyte infiltration in the sham groups. Analysis of 165 inflammatory cytokines and extracellular matrix factors in sham revealed that a minor gene response was initiated but not translated to protein levels. Collagen deposition did not occur in the absence of MI. In contrast, the D1 and D7 MI groups showed the expected robust inflammatory and scar formation responses. When a minimally invasive procedure to generate MI in mice was used, the D0 (no surgical operation) control was an adequate replacement for the use of sham surgery groups.

Linear (-)-Zampanolide: Flexibility in Conformation-Activity Relationships.

Through an understanding of the conformational preferences of the polyketide natural product (-)-zampanolide, and the structural motifs that control these preferences, we developed a linear zampanolide analogue that exhibits potent cytotoxicity against cancer cell lines. This discovery provides a set of three structural handles for further structure-activity relationship (SAR) studies of this potent microtubule-stabilizing agent. Moreover, it provides additional evidence of the complex relationship between ligand preorganization, conformational flexibility, and biological potency. In contrast to medicinal chemistry dogma, these results demonstrate that increased overall conformational flexibility is not necessarily detrimental to protein binding affinity and biological activity.

Nonthrombogenic approaches to cardiovascular bioengineering.

Cardiovascular devices such as vascular grafts, stents, and heart valves have been widely used to treat cardiovascular diseases. The failure of these devices is usually initiated by the formation of thrombus and neointima on the device surfaces. Antithrombogenic surface modifications have been employed to improve the performance of these devices. In addition to biochemical modifications, tissue engineering approaches hold the promise to fabricate nonthrombogenic biological substitutes for cardiovascular tissues and devices. Endothelial cells (ECs) and stem cells have been used to cover blood-contacting surfaces. Furthermore, for tissue-engineered vascularized tissues and organs, a nonthrombogenic vascular network is essential for mass transfer and the integration of functional tissues and organs into the host upon transplantation. This review discusses the advances in antithrombogenic approaches for surface modifications and cardiovascular tissue engineering.

Development of Injectable Amniotic Membrane Matrix for Postmyocardial Infarction Tissue Repair.

Ischemic heart disease represents the leading cause of death worldwide. Heart failure following myocardial infarction (MI) is associated with severe fibrosis formation and cardiac remodeling. Recently, injectable hydrogels have emerged as a promising approach to repair the infarcted heart and improve heart function through minimally invasive administration. Here, a novel injectable human amniotic membrane (hAM) matrix is developed to enhance cardiac regeneration following MI. Human amniotic membrane is isolated from human placenta and engineered to be a thermoresponsive, injectable gel around body temperature. Ultrasound-guided injection of hAM matrix into rat MI hearts significantly improves cardiac contractility, as measured by ejection fraction (EF), and decrease fibrosis. The results of this study demonstrate the feasibility of engineering as an injectable hAM matrix and its efficacy in attenuating degenerative changes in cardiac function following MI, which may have broad applications in tissue regeneration.

Genetic Correlation between Child Callous-Unemotional Behaviors and Fear Recognition Deficit: Evidence for a Neurocognitive Endophenotype.

This study investigates emotion recognition deficits as candidate neurocognitive endophenotypes for callous-unemotional (CU) behaviors. Using a twin design, we tested genetic correlations between child CU behaviors and poor processing of fearful and sad facial expressions. Participants were 504 twin pairs (209 MZ pairs; 295 DZ pairs) from the Quebec Newborn Twin Study, a longitudinal study of a population-based sample of twins. Teachers in kindergarten and first grade rated children's CU behaviors and other behavior problems (attention deficit and hyperactivity symptoms, physical aggression, and depressive symptoms). In first grade (mean age 7 years), the children completed the visual subtest of the Diagnostic Analysis of Nonverbal Accuracy Scale 2 (DANVA-II) to assess emotion recognition from facial stimuli. Using structural equation modeling, we examined the genetic-environmental etiology of the association between fear/sadness recognition and child CU behaviors, controlling for other behavior problems and recognition of other emotions. We found a significant genetic correlation between poor fear recognition and CU behaviors that was independent of other behavior problems. Poor recognition of sadness was not significantly associated with CU behaviors after taking into account other behavior problems. Our results suggest that CU behaviors and fear recognition have a partly shared genetic aetiology. This provides support for poor fear recognition as a key neurocognitive endophenotype for CU behaviors. Future research should test a hypothesized causal chain from specific genes, through amygdala functioning and fear recognition, to CU behaviors, and identify specific environmental factors (including intervention) that may disrupt this chain.

Synthesis, conformational preferences, and biological activity of conformational analogues of the microtubule-stabilizing agents, (-)-zampanolide and (-)-dactylolide.

Zampanolide and dactylolide are microtubule-stabilizing polyketides possessing potent cytotoxicity towards a variety of cancer cell lines. Using our understanding of the conformational preferences of the macrolide core in both natural products, we hypothesized that analogues lacking the C17-methyl group would maintain the necessary conformation for bioactivity while reducing the number of synthetic manipulations necessary for their synthesis. Analogues 3, 4 and 5 were prepared via total synthesis, and their conformational preferences were determined through computational and high-field NMR studies. While no observable activities were present in dactylolide analogues 3 and 4, zampanolide analogue 5 exhibited sub-micromolar cytotoxicity. Herein, we describe these efforts towards understanding the structure- and conformation-activity relationships of dactylolide and zampanolide.

A longitudinal twin study of callous-unemotional traits during childhood.

Previous research indicates that genetic factors largely account for the stability of callous-unemotional (CU) traits in adolescence. However, the genetic-environmental etiology of the development of CU traits has not been extensively investigated in childhood, despite work showing the reliable measurement and stability of CU traits from a young age. The aim of this study was to investigate the temporal pattern of genetic and environmental etiology of CU traits across primary school, from school entry (7 years) to middle (9 and 10 years) and late childhood (12 years). Data were collected in a population sample of twins composed of 662 twin pairs (Quebec Newborn Twin Study). CU traits were reported by teachers and analyzed using a biometric latent growth curve model and a Cholesky decomposition model. Latent growth curve analyses revealed that genetic factors explain most of the variance in the intercept of CU traits. Individual differences in change over time were not significant. The Cholesky model revealed that genetic factors at 7 years had enduring contributions to CU traits at 9, 10, and 12 years. New, modest genetic contributions appeared at 9 and 10 years. Nonshared environmental contributions were generally age-specific. No shared environmental contributions were detected. In sum, both modeling approaches showed that genetic factors underlie CU traits during childhood. Initial and new genetic contributions arise during this period. Environments have substantial contributions, over and above genetic factors. Future research should investigate the source of genetic risk associated with CU traits. (PsycINFO Database Record

Engineering the mechanical and biological properties of nanofibrous vascular grafts for in situ vascular tissue engineering.

Synthetic small diameter vascular grafts have a high failure rate, and endothelialization is critical for preventing thrombosis and graft occlusion. A promising approach is in situ tissue engineering, whereby an acellular scaffold is implanted and provides stimulatory cues to guide the in situ remodeling into a functional blood vessel. An ideal scaffold should have sufficient binding sites for biomolecule immobilization and a mechanical property similar to native tissue. Here we developed a novel method to blend low molecular weight (LMW) elastic polymer during electrospinning process to increase conjugation sites and to improve the mechanical property of vascular grafts. LMW elastic polymer improved the elasticity of the scaffolds, and significantly increased the amount of heparin conjugated to the micro/nanofibrous scaffolds, which in turn increased the loading capacity of vascular endothelial growth factor (VEGF) and prolonged the release of VEGF. Vascular grafts were implanted into the carotid artery of rats to evaluate the in vivo performance. VEGF treatment significantly enhanced endothelium formation and the overall patency of vascular grafts. Heparin coating also increased cell infiltration into the electrospun grafts, thus increasing the production of collagen and elastin within the graft wall. This work demonstrates that LMW elastic polymer blending is an approach to engineer the mechanical and biological property of micro/nanofibrous vascular grafts for in situ vascular tissue engineering.

Carbazole Annulation via Cascade Nucleophilic Addition-Cyclization Involving 2-(Silyloxy)pentadienyl Cation.

We report a new strategy toward the synthesis of highly functionalized carbazoles via 2-(silyloxy)pentadienyl cation intermediates, which were generated upon ionization of vinyl-substituted α-hydroxy silyl enol ethers under Brønsted acid catalysis. These electrophilic species were found to readily undergo cascade reactions with substituted indoles to generate carbazole molecular scaffolds in good yields via a sequence of regioselective nucleophilic addition, followed by intramolecular dehydrative cyclization.

Functionalization of Silyldienol Ethers at the γ-Position via 2-Silyloxypentadienyl Cations.

This report describes Brønsted acid catalyzed de novo synthesis of silyldienol ethers bearing tetrasubstituted double bonds via an intermediacy of 2-silyloxypentadienyl cations. The reactivity of these novel cationic intermediates could be modulated and harnessed toward direct nucleophilic additions regioselectively at the γ-position to produce highly functionalized silyldienol ethers with tunable control of the resulting double bond geometry.

Temporal neutrophil polarization following myocardial infarction.

AIMS: Although macrophage phenotypes have been well studied in the myocardial infarction (MI) setting, this study investigated temporal neutrophil polarization and activation mechanisms. METHODS AND RESULTS: Neutrophils isolated from the infarcted left ventricle (LV) of mice showed high expression of proinflammatory markers at Day 1 and anti-inflammatory markers at Days 5 and 7 post-MI, indicating distinct neutrophil phenotypes along the post-MI time continuum. Flow cytometry analysis revealed that although proinflammatory N1 neutrophils were always predominant (>80% of total neutrophils at each time point), the percentage of N2 neutrophils increased post-MI from 2.4 ± 0.6% at Day 1 to 18.1 ± 3.0% at Day 7. In vitro, peripheral blood neutrophils were polarized to proinflammatory N1 by lipopolysaccharide and interferon-γ or anti-inflammatory N2 by interleukin-4, indicating high plasticity potential. The in vivo post-MI relevant LV damage-associated molecular patterns (DAMPs) polarized neutrophils to a proinflammatory N1 phenotype by activating toll-like receptor-4. Transforming growth factor-ß1 inhibited proinflammatory production in neutrophils. N1 neutrophils positively correlated with infarct wall thinning at Day 7 post-MI, possibly due to high production of matrix metalloproteinases-12 and -25. CONCLUSION: This study is the first to identify the existence of N1 and N2 neutrophils in the infarct region and reveals that N1 polarization could be mediated by DAMPs.

Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body ß-hydroxybutyrate.

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite ß-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of ß-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of ß-hydroxybutyrate. Electrophysiological measurements indicate that ß-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

Residential proximity to major highways - United States, 2010.

Traffic-related air pollution is a main contributor to unhealthy ambient air quality, particularly in urban areas with high traffic volume. Within urban areas, traffic is a major source of local variability in air pollution levels, with the highest concentrations and risk of exposure occurring near roads. Motor vehicle emissions represent a complex mixture of criteria air pollutants, including carbon monoxide (CO), nitrogen oxides (NOx), and particulate matter (PM), as well as hydrocarbons that react with NOx and sunlight to form ground-level ozone. Individually, each of these pollutants is a known or suspected cause of adverse health effects. Taking into consideration the entire body of evidence on primary traffic emissions, a recent review determined that there is sufficient evidence of a causal association between exposure to traffic-related air pollution and asthma exacerbation and suggestive evidence of a causal association for onset of childhood asthma, nonasthma respiratory symptoms, impaired lung function, all-cause mortality, cardiovascular mortality, and cardiovascular morbidity.

Heparin-modified small-diameter nanofibrous vascular grafts.

Due to high incidence of vascular bypass procedures, an unmet need for suitable vessel replacements exists, especially for small-diameter vascular grafts. Here we produced 1-mm diameter vascular grafts with nanofibrous structure via electrospinning, and successfully modified the nanofibers by the conjugation of heparin using di-amino-poly(ethylene glycol) (PEG) as a linker. Antithrombogenic activity of these heparin-modified scaffolds was confirmed in vitro. After 1 month implantation using a rat common carotid artery bypass model, heparin-modified grafts exhibited 85.7% patency, versus 57.1% patency of PEGylated grafts and 42.9% patency of untreated grafts. Post-explant analysis of patent grafts showed complete endothelialization of the lumen and neovascularization around the graft. Smooth muscle cells were found in the surrounding neo-tissue. In addition, greater cell infiltration was observed in heparin-modified grafts. These findings suggest heparin modification may play multiple roles in the function and remodeling of nanofibrous vascular grafts, by preventing thrombosis and maintaining patency, and by promoting cell infiltration into the three-dimensional nanofibrous structure for remodeling.

The effect of stromal cell-derived factor-1α/heparin coating of biodegradable vascular grafts on the recruitment of both endothelial and smooth muscle progenitor cells for accelerated regeneration.

Small-diameter synthetic vascular grafts have high failure rate and tissue-engineered blood vessels are limited by the scalability. Here we engineered bioactive materials for in situ vascular tissue engineering, which recruits two types of endogenous progenitor cells for the regeneration of blood vessels. Heparin was conjugated to microfibrous vascular grafts to suppress thrombogenic responses, and stromal cell-derived factor-1α (SDF-1α) was immobilized onto heparin to recruit endogenous progenitor cells. Heparin-bound SDF-1α was more stable than adsorbed SDF-1α under both static and flow conditions. Microfibrous grafts were implanted in rats by anastomosis to test the functional performance. Heparin coating improved the short-term patency, and immobilized SDF-1α further improved the long-term patency. SDF-1α effectively recruited endothelial progenitor cells (EPCs) to the luminal surface of the grafts, which differentiated into endothelial cells (ECs) and accelerated endothelialization. More interestingly, SDF-1α increased the recruitment of smooth muscle progenitor cells (SMPCs) to the grafts, and SMPCs differentiated into smooth muscle cells (SMCs) in vivo and in vitro. Consistently, SDF-1α-immobilized grafts had significantly higher elastic modulus. This work demonstrates the feasibility of simultaneously recruiting progenitor cells of ECs and SMCs for in situ blood vessel regeneration. This in situ tissue engineering approach will have broad applications in regenerative medicine.