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Internal modifications of mRNA have emerged as widespread and versatile regulatory mechanism to control gene expression at the post-transcriptional level. Most of these modifications are methyl groups, making S -adenosyl- L -methionine (SAM) a central metabolic hub. Here we show that metabolic labeling with a clickable metabolic precursor of SAM, propargyl-selenohomocysteine (PSH), enables detection and identification of various methylation sites. Propargylated A, C, and G nucleosides form at detectable amounts via intracellular generation of the corresponding SAM analogue. Integration into next generation sequencing enables mapping of N 6 -methyladenosine (m 6 A) and 5-methylcytidine (m 5 C) sites in mRNA with single nucleotide precision (MePMe-seq). Analysis of the termination profiles can be used to distinguish m 6 A from 2′- O -methyladenosine (A m ) and N 1-methyladenosine (m 1 A) sites. MePMe-seq overcomes the problems of antibodies for enrichment and sequence-motifs for evaluation, which was limiting previous methodologies. Metabolic labeling via clickable SAM facilitates the joint evaluation of methylation sites in RNA and potentially DNA and proteins. Methylation is the dominant modification in mRNA and occurs at a variety of sites. Here, Hartstock et al. show that a clickable analogue of the key cosubstrate S -adenosyl- L -methionine (SAM) can be produced in cells, allowing for identification and mapping of different methylated nucleosides in mRNA.

We aimed to investigate the effects of endurance training intensity (1) on systolic blood pressure (SBP) and heart rate (HR) at rest before exercise, and during and after a maximal exercise test; and (2) on measures of HR variability at rest before exercise and during recovery from the exercise test, in at least 55-year-old healthy sedentary men and women. A randomized crossover study comprising three 10-week periods was performed. In the first and third period, participants exercised at lower or higher intensity (33% or 66% of HR reserve) in random order, with a sedentary period in between. Training programmes were identical except for intensity, and were performed under supervision thrice for 1 h per week. The results show that in the three conditions, that is, at rest before exercise, during exercise and during recovery, we found endurance training at lower and higher intensity to reduce SBP significantly ( P <0.05) and to a similar extent. Further, SBP during recovery was, on average, not lower than at rest before exercise, and chronic endurance training did not affect the response of SBP after an acute bout of exercise. The effect of training on HR at rest, during exercise and recovery was more pronounced ( P <0.05) with higher intensity. Finally, endurance training had no significant effect on sympathovagal balance. In conclusion, in participants at higher age, both training programmes exert similar effects on SBP at rest, during exercise and during post-exercise recovery, whereas the effects on HR are more pronounced after higher intensity training.

Worldwide, raised blood pressure (BP) or hypertension is the global leading risk factor for the development of cardiovascular diseases and all-cause mortality, with the highest prevalence found in Asian and African origin populations. Post-exercise hypotension (PEH), defined as a sustained reduction in BP after a single bout of exercise is an important physiological phenomenon in BP management. However, little is known about the hypotensive effect of a single bout of exercise in non-Caucasian populations. We systematically summarized the acute effects of a single bout of aerobic exercise on BP in a population of African or Asian origin. We searched the MEDLINE database identifying randomized controlled trials investigating the effect of a single bout of aerobic exercise on BP in African or Asian populations with optimal BP, high normal BP or hypertension published in a peer reviewed journal up to August 2021. A subsequent meta-analysis was performed using random-effect models fitted to estimate effect sizes. We identified 10 aerobic exercise trials performed in individuals of Asian origin (n = 136; mean age: 29.51 (21.2–69) years: 78% male; baseline systolic BP/diastolic BP: 118.9 ± 9.64/68.9 ± 2.69 mmHg) and 11 aerobic exercise trials involving individuals of African origin (n = 157; mean age: 41.05 (29.9–49) years; 59% male; baseline systolic BP/diastolic BP: 134.5 ± 8.65 mmHg/82.2 ± 3.24 mmHg). Non-significant reductions in office systolic BP and diastolic BP at 30 min post exercise (−2.25 [−6.38, 1.88] mmHg, p = 0.28/−1.02 [−2.51, 0.47] mmHg, p = 0.18) and 60 min post exercise (−2.80 [−7.90, 2.28], p = 0.27/−1.95, [−5.66, 1.75], p = 0.3) were observed compared to the control intervention. No statistically significant differences were found between both ethnic groups (p > 0.05). Ambulatory BP was reported only in a few African groups. No effect was found on 24h-systolic BP post exercise, but 24h-diastolic BP was statistically significantly reduced (−1.89 [−3.47, −0.31] mmHg, p < 0.01) after a bout of aerobic exercise compared to the control intervention. The available evidence is insufficient to recommend a single session of aerobic exercise as an efficient tool to lower BP in African and Asian populations. Though, the paucity of data in non-Caucasian populations underscores the need for additional efforts to establish the efficacy of single bouts of exercise, including isometric and dynamic resistance exercise, as a potential non-pharmacological adjunct to help lowering BP in the daily life of descendants of Asian or African origin.

Site-specific modification of RNA in cells is crucial for analysis and functional investigations. Natural enzymes that promote RNA methylation using S-adenosyl-l-methionine (SAM) exist, but leveraging these proteins for RNA modification is limited by cell permeability, stability and specificity of their substrates. Now, a de novo ribozyme that acts on a stabilized and cell-permeable SAM analogue enables site-specific RNA modification with a click handle in living cells.

Objective: To investigate the effect of oral creatine supplementation in conjunction with an exercise programme on physical fitness in patients with coronary artery disease or chronic heart failure. Design: Single centre double-blind randomized placebo controlled trial. Setting: Cardiac rehabilitation centre. Subjects and intervention: 70 (4 women) cardiac patients (age 57.5 (8.4) years) were randomized to a placebo (n = 37) or creatine (n = 33) treatment for three months. Combined aerobic endurance and resistance training (three sessions/ week) was performed during supplementation. Main Measures: Aerobic power was determined during graded bicycle testing, knee extensor peak isometric and isokinetic strength, endurance and recovery were assessed by an isokinetic dynamometer, and health related quality of life was evaluated with the SF-36 and MacNew Heart Disease questionnaires. In addition, blood samples were taken after an overnight fast and 24 hour urinary collection was performed. Results: At baseline there were no significant differences between both groups. We observed main time effects for aerobic power, muscle performance, health related quality of life, high density lipoprotein cholesterol and triglycerides (pre vs post; P<0.05 for all). However, changes after training were similar between placebo group and creatine group (P>0.05). Further, no detrimental effect on renal or liver function was observed nor were there any reports of side effects. Conclusion: Oral creatine supplementation in combination with exercise training does not exert any additional effect on the improvement in physical performance, health related quality of life, lipid profile in patients with coronary artery disease or chronic heart failure than exercise training alone.

Cardiac rehabilitation (CR) is an essential part of contemporary coronary heart disease management. However, patients exiting a center-based CR program have difficulty retaining its benefits. We aimed to evaluate the added benefit of a home-based CR program with telemonitoring guidance on physical fitness in patients with coronary artery disease (CAD) completing a phase II ambulatory CR program and to compare the effectiveness of this program in a prolonged center-based CR intervention by means of a randomized controlled trial. Between February 2014 and August 2016, 90 CAD patients (unblinded, mean age 61.2 years, SD 7.6; 80/90, 89.0% males; mean height 1.73 m, SD 0.7; mean weight 82.9 kg, SD 13; mean body mass index 27.5 kg/m , SD 3.4) who successfully completed a 3-month ambulatory CR program were randomly allocated to one of three groups: home-based (30), center-based (30), or control group (30) on a 1:1:1 basis. Home-based patients received a home-based exercise intervention with telemonitoring guidance consisting of weekly emails or phone calls; center-based patients continued the standard in-hospital CR, and control group patients received the usual care including the advice to remain physically active. All the patients underwent cardiopulmonary exercise testing for assessment of their peak oxygen uptake (VO P) at baseline and after a 12-week intervention period. Secondary outcomes included physical activity behavior, anthropometric characteristics, traditional cardiovascular risk factors, and quality of life. Following 12 weeks of intervention, the increase in VO P was larger in the center-based (P=.03) and home-based (P=.04) groups than in the control group. In addition, oxygen uptake at the first (P-interaction=.03) and second (P-interaction=.03) ventilatory thresholds increased significantly more in the home-based group than in the center-based group. No significant changes were observed in the secondary outcomes. Adding a home-based exercise program with telemonitoring guidance following completion of a phase II ambulatory CR program results in further improvement of physical fitness and is equally as effective as prolonging a center-based CR in patients with CAD. ClinicalTrials.gov NCT02047942; https://clinicaltrials.gov/ct2/show/NCT02047942 (Archived by WebCite at http://www.webcitation.org/70CBkSURj).

Hypertension is recognised as a leading attributable risk factor for cardiovascular disease and premature mortality. Global initiatives towards the prevention and treatment of arterial hypertension are centred around non-pharmacological lifestyle modification. Exercise recommendations differ between professional and scientific organisations, but are generally unanimous on the primary role of traditional aerobic and dynamic resistance exercise. In recent years, isometric exercise training (IET) has emerged as an effective novel exercise intervention with consistent evidence of reductions in blood pressure (BP) superior to that reported from traditional guideline-recommended exercise modes. Despite a wealth of emerging new data and endorsement by select governing bodies, IET remains underutilised and is not widely prescribed in clinical practice. This expert-informed review critically examines the role of IET as a potential adjuvant tool in the future clinical management of BP. We explore the efficacy, prescription protocols, evidence quality and certainty, acute cardiovascular stimulus, and physiological mechanisms underpinning its anti-hypertensive effects. We end the review with take-home suggestions regarding the direction of future IET research.

Cardiac rehabilitation (CR) is highly effective as secondary prevention for cardiovascular diseases (CVDs). Uptake of CR remains suboptimal (30% of eligible patients), and long-term adherence to a physically active lifestyle is even lower. Innovative strategies are needed to counteract this phenomenon. The Physical Activity Toward Health (PATHway) system was developed to provide a comprehensive, remotely monitored, home-based CR program for CVD patients. The PATHway-I study aimed to investigate its feasibility and clinical efficacy during phase III CR. Participants were randomized on a 1:1 basis to the PATHway (PW) intervention group or usual care (UC) control group in a single-blind, multicenter, randomized controlled pilot trial. Outcomes were assessed at completion of phase II CR and 6-month follow-up. The primary outcome was physical activity (PA; Actigraph GT9X link). Secondary outcomes included measures of physical fitness, modifiable cardiovascular risk factors, endothelial function, intima-media thickness of the common carotid artery, and quality of life. System usability and patients' experiences were evaluated only in PW. A mixed-model analysis of variance with Bonferroni adjustment was used to analyze between-group effects over time. Missing values were handled by means of an intention-to-treat analysis. Statistical significance was set at a 2-sided alpha level of .05. Data are reported as mean (SD). A convenience sample of 120 CVD patients (mean 61.4 years, SD 13.5 years; 22 women) was included. The PATHway system was deployed in the homes of 60 participants. System use decreased over time and system usability was average with a score of 65.7 (SD 19.7; range 5-100). Moderate-to-vigorous intensity PA increased in PW (PW: 127 [SD 58] min to 141 [SD 69] min, UC: 146 [SD 66] min to 143 [SD 71] min; P =.04; effect size of 0.42), while diastolic blood pressure (PW: 79 [SD 11] mmHg to 79 [SD 10] mmHg, UC: 78 [SD 9] mmHg to 83 [SD 10] mmHg; P =.004; effect size of -0.49) and cardiovascular risk score (PW: 15.9% [SD 10.4%] to 15.5% [SD 10.5%], UC: 14.5 [SD 9.7%] to 15.7% [SD 10.9%]; P =.004; effect size of -0.36) remained constant, but deteriorated in UC. This pilot study demonstrated the feasibility and acceptability of a technology-enabled, remotely monitored, home-based CR program. Although clinical effectiveness was demonstrated, several challenges were identified that could influence the adoption of PATHway. ClinicalTrials.gov NCT02717806; https://clinicaltrials.gov/ct2/show/NCT02717806. RR2-10.1136/bmjopen-2017-016781.