Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data

<p>Purpose: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.</p> <p>Methods: The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.</p> <p>Results: The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.</p> <p>Conclusion: This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.</p&gt

Vascular Aging from DNA Damage to Protection

Aging is highly associated with development of cardiovascular disease; however, the underlying mechanisms of these processes are not well understood. Recent advancements in aging research underscore the im

Exploring How Public Libraries Can Build Situational Interest in Science

This project aimed to cultivate library patrons’ interest in earth and space science, using research on how situations can trigger and support interest to deepen across time. The project featured a dynamic but low-tech library display that showcased thematic content to help patrons realize and develop their interest in earth and space science topics. Patrons engaged with and returned regularly to the display, which predicted their participation in additional activities outside of viewing the display, indicating deepening interest. This approach uses a passive program to help libraries build patrons’ interest in accessing science resources and programs

The effect of the thioether-bridged, stabilized angiotensin-(1-7) analogue cyclic Ang-(1-7) on cardiac remodeling and endothelial function in rats with myocardial infarction

Modulation of renin-angiotensin system (RAS) by angiotensin-(17) (Ang-(17)) is an attractive approach to combat the detrimental consequences of myocardial infarction (MI). However Ang-(17) has limited clinical potential due to its unfavorable pharmacokinetic profile. We investigated effects of a stabilized, thioether-bridged analogue of Ang-(17) called cyclic Ang-(17) in rat model of myocardial infarction. Rats underwent coronary ligation or sham surgery. Two weeks thereafter infusion with 0.24 or 2.4 μg/kg/h cAng-(17) or saline was started for 8 weeks. Thereafter, cardiac morphometric and hemodynamic variables as wells as aortic endothelial function were measured. The average infarct size was 13.8 and was not changed by cAng-(17) treatment. MI increased heart weight and myocyte size, which was restored by cAng-(17) to sham levels. In addition, cAng-(17) lowered left ventricular end-diastolic pressure and improved endothelial function. The results suggest that cAng-(17) is a promising new agent in treatment of myocardial infarction and warrant further research.</p

The effect of the thioether-bridged, stabilized angiotensin-(1-7) analogue cyclic Ang-(1-7) on cardiac remodeling and endothelial function in rats with myocardial infarction

Modulation of renin-angiotensin system (RAS) by angiotensin-(17) (Ang-(17)) is an attractive approach to combat the detrimental consequences of myocardial infarction (MI). However Ang-(17) has limited clinical potential due to its unfavorable pharmacokinetic profile. We investigated effects of a stabilized, thioether-bridged analogue of Ang-(17) called cyclic Ang-(17) in rat model of myocardial infarction. Rats underwent coronary ligation or sham surgery. Two weeks thereafter infusion with 0.24 or 2.4 μg/kg/h cAng-(17) or saline was started for 8 weeks. Thereafter, cardiac morphometric and hemodynamic variables as wells as aortic endothelial function were measured. The average infarct size was 13.8 and was not changed by cAng-(17) treatment. MI increased heart weight and myocyte size, which was restored by cAng-(17) to sham levels. In addition, cAng-(17) lowered left ventricular end-diastolic pressure and improved endothelial function. The results suggest that cAng-(17) is a promising new agent in treatment of myocardial infarction and warrant further research.</p

The Effect of the Thioether-Bridged, Stabilized Angiotensin-(1–7) Analogue Cyclic Ang-(1–7) on Cardiac Remodeling and Endothelial Function in Rats with Myocardial Infarction

Modulation of renin-angiotensin system (RAS) by angiotensin-(1–7) (Ang-(1–7)) is an attractive approach to combat the detrimental consequences of myocardial infarction (MI). However Ang-(1–7) has limited clinical potential due to its unfavorable pharmacokinetic profile. We investigated effects of a stabilized, thioether-bridged analogue of Ang-(1–7) called cyclic Ang-(1–7) in rat model of myocardial infarction. Rats underwent coronary ligation or sham surgery. Two weeks thereafter infusion with 0.24 or 2.4 μg/kg/h cAng-(1–7) or saline was started for 8 weeks. Thereafter, cardiac morphometric and hemodynamic variables as wells as aortic endothelial function were measured. The average infarct size was 13.8% and was not changed by cAng-(1–7) treatment. MI increased heart weight and myocyte size, which was restored by cAng-(1–7) to sham levels. In addition, cAng-(1–7) lowered left ventricular end-diastolic pressure and improved endothelial function. The results suggest that cAng-(1–7) is a promising new agent in treatment of myocardial infarction and warrant further research

Phosphodiesterase 1 regulation is a key mechanism in vascular aging

Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d/-) mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1(d/-) to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of PDE1A single nucleotide polymorphisms with diastolic blood pressure (DBP; beta = 0.28, P = 2.47x10(-5)) and carotid intima-media thickness (cIMT; beta = -0.0061, P = 2.89 x 10(-5)). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy

Teacher Use of Loss-Focused, Utility Value Messages, Prior to High-Stakes Examinations, and Their Appraisal by Students

This study set out to assess a new instrument designed to measure the perceived frequency that teachers use fear appeals (communicated value messages that focus on avoiding failure) prior to a high-stakes examination and their appraisal as a challenge or a threat. Data were collected from two samples of students preparing for their high-stakes school exit examinations. Exploratory and confirmatory factor analyses supported a three-factor structure of message frequency, challenge, and threat appraisal. Challenge appraisal positively correlated with value, academic self-efficacy, and engagement. Threat appraisal negatively correlated with academic self-efficacy and engagement. Message frequency was unrelated to value, academic self-efficacy, and engagement. The critical factor in determining relations with antecedents and outcomes is not the message frequency but how it is appraised

Achievement motives and emotional processes in children during problem-solving: Two experimental studies of their relation to performance in different achievement goal conditions

In two studies, the influence of key emotional and motivational factors on performance in different achievement goal-type situations is examined. In study 1, based on 314 sixth-graders, two types of goal situations were induced; performance and mastery. The goals were examined with respect to important antecedents (e.g., motive dispositions) and several consequences (e.g., performance, satisfaction, pleasant affect, worry, and emotionality). The results showed that the motive to achieve success (Ms) produced positive affects, satisfaction, and increased performance, whereas the motive to avoid failure (Mf) produced worries and performance reduction. In study 2, based on 331 sixth-graders, three types of goal situations were induced; performance–approach, performance–avoidance, and mastery goals. The findings revealed that the most important single factors positively related to performance were Ms and mastery–goal situation. In addition, high Ms pupils performed better under mastery condition than under performance condition. Finally, avoidance-goal situation accentuate the negative effects of high Mf on performance