Single-molecule mechanics and kinetics of cardiac myosin interacting with regulated thin filaments.

The cardiac cycle is a tightly regulated process wherein the heart generates force to pump blood to the body during systole and then relaxes during diastole. Disruption of this finely tuned cycle can lead to a range of diseases including cardiomyopathies and heart failure. Cardiac contraction is driven by the molecular motor myosin, which pulls regulated thin filaments in a calcium-dependent manner. In some muscle and nonmuscle myosins, regulatory proteins on actin tune the kinetics, mechanics, and load dependence of the myosin working stroke; however, it is not well understood whether or how thin-filament regulatory proteins tune the mechanics of the cardiac myosin motor. To address this critical gap in knowledge, we used single-molecule techniques to measure the kinetics and mechanics of the substeps of the cardiac myosin working stroke in the presence and absence of thin filament regulatory proteins. We found that regulatory proteins gate the calcium-dependent interactions between myosin and the thin filament. At physiologically relevant ATP concentrations, cardiac myosin's mechanics and unloaded kinetics are not affected by thin-filament regulatory proteins. We also measured the load-dependent kinetics of cardiac myosin at physiologically relevant ATP concentrations using an isometric optical clamp, and we found that thin-filament regulatory proteins do not affect either the identity or magnitude of myosin's primary load-dependent transition. Interestingly, at low ATP concentrations at both saturating and physiologically relevant subsaturating calcium concentrations, thin-filament regulatory proteins have a small effect on actomyosin dissociation kinetics, suggesting a mechanism beyond simple steric blocking. These results have important implications for the modeling of cardiac physiology and diseases.

Read to Lead: Developing a Leadership Book Club Curriculum for Graduate Medical Education.

Background: The importance of effective leadership for improving patient care and physician well-being is gaining increased attention in medicine. Despite this, few residency programs have formalized education on leadership in medicine. The most effective ways to train graduate medical education (GME) trainees in leadership are unclear. Methods: Our large internal medicine residency program implemented a book club to develop leadership skills in residency. Through independent reading of the selected book and resident-led small group discussions, we facilitated dialogue on the challenges of leading effectively. Results: A survey-based curricular evaluation demonstrated that 61% of respondents felt that the book club influenced their thoughts about leadership and that 66% of participants would recommend the book club to other residency programs. Lack of time was the main barrier to participation while addition of complementary media or alternative book formats were identified as possible solutions to increase engagement. Conclusions: Leadership book clubs are a practical and effective way to teach leadership during residency. More research is needed to identify the best formats for book club discussion and to develop additional tools to foster future physician leaders.

The Affect Intolerance Scale (AIS), German version: A validation study in a student and clinical sample of patients with trauma-related disorders.

BACKGROUND AND OBJECTIVES: The Affect Intolerance Scale (AIS) assesses two core concepts of emotion regulation: appraisals of negative emotions as threatening and proneness to emotional avoidance. Maladaptive emotion regulation is associated with various psychopathologies. We translated and validated the AIS in a German student and clinical sample of patients with trauma-related disorders. METHODS: 340 patients, 161 with post-traumatic stress disorder and 179 with adjustment disorder, and 322 students were enrolled. We employed exploratory and confirmatory factor analyses in a cross-validation design to investigate construct validity, convergent and discriminant validity, and reliability. RESULTS: We replicated the originally described two-factor structure in both samples. Cronbach's α was 0.947 in the student and 0.950 in the clinical sample. AIS subscales showed moderate to high correlations with convergent and low correlations with discriminant measures. AIS total scores were significantly larger in the clinical sample, controlled for gender and age. LIMITATIONS: This study provides a unified cross-validation model in a clinical and a student sample at the cost of reduced sample sizes. CONCLUSIONS: The AIS is a valid measure of affect intolerance with the discriminative ability to distinguish between patients with trauma-related disorders and students. Test redundancy within both sub-constructs of the AIS might lead to biased estimates but allows for increased test precision, rendering the AIS a tool suitable for individual treatment monitoring.

Single Molecule Mechanics and Kinetics of Cardiac Myosin Interacting with Regulated Thin Filaments.

The cardiac cycle is a tightly regulated process wherein the heart generates force to pump blood to the body during systole and then relaxes during diastole. Disruption of this finely tuned cycle can lead to a range of diseases including cardiomyopathies and heart failure. Cardiac contraction is driven by the molecular motor myosin, which pulls regulated thin filaments in a calcium-dependent manner. In some muscle and non-muscle myosins, regulatory proteins on actin tune the kinetics, mechanics, and load dependence of the myosin working stroke; however, it is not well understood whether or how thin filament regulatory proteins tune the mechanics of the cardiac myosin motor. To address this critical gap in knowledge, we used single-molecule techniques to measure the kinetics and mechanics of the substeps of the cardiac myosin working stroke in the presence and absence of thin filament regulatory proteins. We found that regulatory proteins gate the calcium-dependent interactions between myosin and the thin filament. At physiologically relevant ATP concentrations, cardiac myosin's mechanics and unloaded kinetics are not affected by thin filament regulatory proteins. We also measured the load-dependent kinetics of cardiac myosin at physiologically relevant ATP concentrations using an isometric optical clamp, and we found that thin filament regulatory proteins do not affect either the identity or magnitude of myosin's primary load-dependent transition. Interestingly, at low ATP concentrations, thin filament regulatory proteins have a small effect on actomyosin dissociation kinetics, suggesting a mechanism beyond simple steric blocking. These results have important implications for both disease modeling and computational models of muscle contraction. Significance Statement: Human heart contraction is powered by the molecular motor ß-cardiac myosin, which pulls on thin filaments consisting of actin and the regulatory proteins troponin and tropomyosin. In some muscle and non-muscle systems, these regulatory proteins tune the kinetics, mechanics, and load dependence of the myosin working stroke. Despite having a central role in health and disease, it is not well understood whether the mechanics or kinetics of ß-cardiac myosin are affected by regulatory proteins. We show that regulatory proteins do not affect the mechanics or load-dependent kinetics of the working stroke at physiologically relevant ATP concentrations; however, they can affect the kinetics at low ATP concentrations, suggesting a mechanism beyond simple steric blocking. This has important implications for modeling of cardiac physiology and diseases.

The Influence of Physical Load on Dynamic Postural Control-A Systematic Replication Study.

Dynamic postural control is challenged during many actions in sport such as when landing or cutting. A decrease of dynamic postural control is one possible risk factor for non-contact injuries. Moreover, these injuries mainly occur under loading conditions. Hence, to assess an athlete's injury risk properly, it is essential to know how dynamic postural control is influenced by physical load. Therefore, the study's objective was to examine the influence of maximal anaerobic load on dynamic postural control. Sixty-four sport students (32 males and 32 females, age: 24.11 ± 2.42, height: 175.53 ± 8.17 cm, weight: 67.16 ± 10.08 kg) were tested with the Y-Balance Test before and after a Wingate Anaerobic Test on a bicycle ergometer. In both legs, reach distances (anterior) and composite scores were statistically significantly reduced immediately after the loading protocol. The values almost returned to pre-load levels in about 20 min post-load. Overall, findings indicate an acute negative effect of load on dynamic postural control and a higher potential injury risk during a period of about 20 min post-load. To assess an athlete's sports-specific injury risk, we recommend testing dynamic postural control under loaded conditions.

Statins and cognition in late-life bipolar disorder.

OBJECTIVES: Recent data suggests that statins have positive effects on cognition in older adults. Studies in patients with mood disorders have found contradicting positive and negative effects of statins on mood and cognition, with limited data in bipolar disorder (BD). The objective of this study was to assess the association between statin use and cognition in older adults with BD. METHODS: In a cross-sectional sample of 143 euthymic older adults with BD (age ≥ 50), statin users (n = 48) and nonusers (n = 95) were compared for cognitive outcomes: Global and cognitive domain z-scores were calculated from detailed neuropsychological batteries using normative data from healthy comparators (n = 87). RESULTS: The sample had a mean age of 64.3 (±8.9) years, 65.0% were female, with an average of 15.1 (±2.79) years of education. Statin users did not differ from nonusers on global (-0.60 [±0.69] vs -0.49 [±0.68], t[127] = 0.80, P = .42) or individual cognitive domains z-score. CONCLUSIONS: In older patients with BD, statin use is not independently associated with cognitive impairment. This suggests that in older BD patients, the cognitive dysfunction associated with BD trumps the potential cognitive benefit that is associated with statins in older adults without a psychiatric disorder. Further, statins do not seem to exacerbate this cognitive dysfunction. Future longitudinal studies are needed to confirm these findings.