Comprehensive analyses of the inotropic compound omecamtiv mecarbil in rat and human cardiac preparations

Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 µM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analyses of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared to effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time-to-peak under all conditions (maximally 2-3 fold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration-dependency with maximal effects at 1 µM. Relaxation time tended to fall under auxotonic and strongly increase under isometric conditions, again with biphasic concentration-dependency. Diastolic tension concentration-dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca2+, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies.

Proprioception and neuromuscular control at return to sport after ankle surgery with the modified Broström procedure

The modified Broström procedure (MBP) is an initial treatment for symptomatic chronic ankle instability (CAI) patients. This study aimed to compare the proprioception and neuromuscular control ability of both affected and unaffected ankles at the time of return to sports after MBP for patients with scores of normal controls. 75 individuals (40 who underwent MBP, 35 normal controls) participated. The dynamic balance test scores were significantly higher in the affected ankle of the patients than in the controls (1.5 ± 0.6° vs. 1.1 ± 0.4°, p < 0.003). The time to peak torque for dorsiflexion (60.8 ± 13.9 ms vs. 52.2 ± 17.5 ms, p < 0.022) and eversion (68.9 ± 19.1 ms vs. 59.3 ± 21.1 ms, p < 0.043) was significantly delayed in the affected ankle of the patients than in the controls. The dynamic balance test and time to peak torque in CAI patients remained significantly reduced at the time of return-to-sport after MBP. Clinicians and therapists should be aware of potential deficits in proprioception and neuromuscular control when determining the timing of return to sports after MBP.

CO2 Emissions Forecast and Emissions Peak Analysis in Shanxi Province, China: An Application of the LEAP Model

Shanxi Province, an important source of coal resources in China, has consumed a large amount of fossil fuels in the past few decades. The CO2 emissions of Shanxi Province have been increasing annually, reaching 541.8 million tons in 2018, 54.6% higher than the national mean. This will have a negative impact on China’s ability to meet its target of peaking CO2 emissions by 2030. To assist China to achieve this target and reduce CO2 emissions in Shanxi Province, this study used the Long-range Energy Alternatives Planning (LEAP) model to analyze the CO2 emissions and peaks in Shanxi Province from 2019 to 2035 under different scenarios. Furthermore, this study analyzed the time to peak CO2 emissions under different emission reduction measures through a sensitivity analysis. The results show that in the absence of other mitigation policy interventions, CO2 emissions in Shanxi Province will increase annually, reaching 1646.2 million tons by 2035. Furthermore, this study shows that if shares of industrial gross domestic product (GDP) in Shanxi, energy intensity reduction in the industrial and transport sectors compared to the base scenario, thermal power, and relative clean energy consumption reach 25%, 30%, 50%, and 50%, respectively, by 2035, then CO2 emissions of Shanxi would peak at 801.2 million tons in 2029 and GDP per capita would increase to USD 2000 by 2035. Finally, according to the results of this study, we have made some recommendations for emission reduction in Shanxi Province. The limitation of this study was that the implementation cost of the abatement policy was not considered.

Timeliness of splenic time-to-peak affects liver tumor CT perfusion measurements

Aim In liver CT perfusion, the dual-input maximum slope (DI-MS) method is commonly used to estimate perfusion to aid diagnosis of tumors. The DI-MS method relies on a model that assumes the splenic time-to-peak (TTP) separates arterial and portal venous perfusion, and occurs prior to venous perfusion. In this preclinical study, we examined how the timeliness of splenic TTP affects DI-MS perfusion calculations of liver tumors. Materials and Methods We analyzed imaging data obtained from 11 New Zealand White rabbits bearing a single implanted VX2 tumor in liver. A liver 320-slice CT perfusion protocol (5,400 images per study) was used to generate images. Times for arterial and portal slopes were recorded, and hepatic arterial perfusion (HAP), portal perfusion (HPP) and perfusion index (HPI) for liver and tumor were separately calculated using manual and automated methods. T-test comparisons and Bland-Altman plot analyses were performed. Results Mean tumor TTP occurred at 9.79 s (SD=3.41) and splenic TTP at 9.75 s (SD=4.47, p=0.98). In 3/11 (27.27%) cases, tumor SP occurred prior to spleen (mean difference=1.33 s, SD=1.15 s). In these cases, mean automated HPP values were 43.8% (SD=52.48) higher compared to manually computed ones. There were statistically significant differences between automated and manual methods for normal liver and tumor HPI and HPP (p<0.01 and p<0.0001, respectively), but not HAP values (p=0.125 and p=0.78, respectively). There was also a statistically significant variation between methods for tumor HPP and HPI (p=0.001, respectively). Conclusion In 320-slice CT perfusion of liver in this preclinical model, we observed that tumor TTP occurred prior to splenic TTP in 27.27% of tumors in liver. This temporal relationship affects tumor perfusion calculations and should be identified to address potential deviations of model assumptions.

Improved Activation and Hemodynamic Response Function of Olfactory fMRI Using Simultaneous Multislice with Reduced TR Acquisition

Objectives. The respiration could decrease the time synchronization between odor stimulation and data acquisition, consequently deteriorating the functional activation and hemodynamic response function (HRF) in olfactory functional magnetic resonance imaging (fMRI) with a conventional repetition time (TR). In this study, we aimed to investigate whether simultaneous multislice (SMS) technology with reduced TR could improve the blood oxygen level-dependent (BOLD) activation and optimize HRF modeling in olfactory fMRI. Methods. Sixteen young healthy subjects with normal olfaction underwent olfactory fMRI on a 3T MRI scanner using a 64 channel head coil. FMRI data were acquired using SMS acceleration at three different TRs: 3000 ms, 1000 ms, and 500 ms. Both metrics of BOLD activation (activated voxels, mean, and maximum t -scores) and the HRF modeling (response height and time to peak) were calculated in the bilateral amygdalae, hippocampi, and insulae. Results. The 500 ms and 1000 ms TRs both significantly improved the number of activated voxels, mean, and maximum t -score in the amygdalae and insulae, compared with a 3000 ms TR (all P < 0.05 ). But the increase of these metrics in the hippocampi did not reach a statistical significance (all P > 0.05 ). No significant difference in any BOLD activation metrics between TR 500 ms and 1000 ms was observed in all regions of interest (ROIs) (all P > 0.05 ). The HRF curves showed that higher response height and shorter time to peak in all ROIs were obtained at 500 ms and 1000 ms TRs compared to 3000 ms TR. TR 500 ms had a more significant effect on response height than TR 1000 ms in the amygdalae ( P = 0.017 ), and there was no significant difference in time to peak between TR 500 ms and 1000 ms in all ROIs (all P > 0.05 ). Conclusions. The fast image acquisition technique of SMS with reduced TR could significantly improve the functional activation and HRF curve in olfactory fMRI.

Sex Differences in Neck Strength Force and Activation Patterns in Collegiate Contact Sport

The purpose of this study was to assess changes in cervical musculature throughout contact-heavy collegiate ice hockey practices during a regular season of NCAA Division III ice hockey teams. In this cross-sectional study, 36 (male n = 13; female n = 23) ice hockey players participated. Data were collected over 3 testing sessions (baseline; pre-practice; post-practice). Neck circumference, neck length, head-neck segment length, isometric strength and electromyography (EMG) activity for flexion and extension were assessed. Assessments were completed approximately 1h before a contact-heavy practice and 15 min after practice. For sternocleidomastoid (SCM) muscles, males had significantly greater peak force and greater time to peak force versus females. For both left and right SCMs, both sexes had significantly greater peak EMG activity pre-practice versus baseline, and right (dominant side) SCM time to peak EMG activity was decreased post-practice compared to pre-practice. There were no significant differences for EMG activity of the upper trapezius musculature, over time or between sexes. Sex differences observed in SCM force and activation patterns of the dominant side SCM may contribute to head stabilization during head impacts. Our study is the first investigation to report changes in cervical muscle strength in men’s and women’s ice hockey players in the practical setting.

Phosphatidylinositol-4,5-Bisphosphate Binding to Amphiphysin-II Modulates T-Tubule Remodeling: Implications for Heart Failure

BIN1 (amphyphysin-II) is a structural protein involved in T-tubule (TT) formation and phosphatidylinositol-4,5-bisphosphate (PIP2) is responsible for localization of BIN1 to sarcolemma. The goal of this study was to determine if PIP2-mediated targeting of BIN1 to sarcolemma is compromised during the development of heart failure (HF) and is responsible for TT remodeling. Immunohistochemistry showed co-localization of BIN1, Cav1.2, PIP2, and phospholipase-Cβ1 (PLCβ1) in TTs in normal rat and human ventricular myocytes. PIP2 levels were reduced in spontaneously hypertensive rats during HF progression compared to age-matched controls. A PIP Strip assay of two native mouse cardiac-specific isoforms of BIN1 including the longest (cardiac BIN1 #4) and shortest (cardiac BIN1 #1) isoforms as well human skeletal BIN1 showed that all bound PIP2. In addition, overexpression of all three BIN1 isoforms caused tubule formation in HL-1 cells. A triple-lysine motif in a short loop segment between two helices was mutated and replaced by negative charges which abolished tubule formation, suggesting a possible location for PIP2 interaction aside from known consensus binding sites. Pharmacological PIP2 depletion in rat ventricular myocytes caused TT loss and was associated with changes in Ca2+ release typically found in myocytes during HF, including a higher variability in release along the cell length and a slowing in rise time, time to peak, and decay time in treated myocytes. These results demonstrate that depletion of PIP2 can lead to TT disruption and suggest that PIP2 interaction with cardiac BIN1 is required for TT maintenance and function.

Influences of Spillway Section Morphologies on Landslide Dam Breaching

Spillway excavation is often adopted as a precautionary engineering measure for disaster mitigation before landslide dam breaching. Based on the landslide dam breach mechanisms, this paper focuses on developing a numerical model to comprehensively discuss the issue based on three documented landslide dam failures, such as Tangjiashan, Xiaogangjian, and Baige landslide dams. The spillway cross section morphologies were modeled with different sizes under common shape (i.e., an inverted trapezoid) and slope conditions. The influence of cross section on dam breach processes was analyzed under conditions of different depth, bottom width, slope ratio in the cross and longitudinal sections, with/without spillway. The following conclusions can be drawn: 1) excavation of a spillway can effectively reduce the peak breach flow, therefore delay the time to peak; 2) the peak breach flow dramatically decreases and the time to peak delays as the spillway depth increases; 3) the peak breach flow changes little and the time to peak occurs earlier with the increment in spillway bottom width; 4) the peak breach flow decreases and the time to peak delays with the decrease of slope ratio in cross section in the spillway; 5) the slope ratio in the longitudinal section has little influence on the breach process. Hence, if conditions permit, the spillway with large spillway depth, small bottom width, and gentle slope ratio in the cross section is the preferable section morphology for the emergency disposal of the landslide dam.