Germ fate determinants protect germ precursor cell division by reducing septin and anillin levels at the cell division plane.

Animal cell cytokinesis, or the physical division of one cell into two, is thought to be driven by constriction of an actomyosin contractile ring at the division plane. The mechanisms underlying cell type-specific differences in cytokinesis remain unknown. Germ cells are totipotent cells that pass genetic information to the next generation. Previously, using formincyk-1(ts) mutant Caenorhabditis elegans 4-cell embryos, we found that the P2 germ precursor cell is protected from cytokinesis failure and can divide with greatly reduced F-actin levels at the cell division plane. Here, we identified two canonical germ fate determinants required for P2-specific cytokinetic protection: PIE-1 and POS-1. Neither has been implicated previously in cytokinesis. These germ fate determinants protect P2 cytokinesis by reducing the accumulation of septinUNC-59 and anillinANI-1 at the division plane, which here act as negative regulators of cytokinesis. These findings may provide insight into the regulation of cytokinesis in other cell types, especially in stem cells with high potency.

Germ fate determinants protect germ precursor cell division by restricting septin and anillin levels at the division plane.

Animal cell cytokinesis, or the physical division of one cell into two, is thought to be driven by constriction of an actomyosin contractile ring at the division plane. The mechanisms underlying cell type-specific differences in cytokinesis remain unknown. Germ cells are totipotent cells that pass genetic information to the next generation. Previously, using formin cyk-1 (ts) mutant C. elegans embryos, we found that the P2 germ precursor cell is protected from cytokinesis failure and can divide without detectable F-actin at the division plane. Here, we identified two canonical germ fate determinants required for P2-specific cytokinetic protection: PIE-1 and POS-1. Neither has been implicated previously in cytokinesis. These germ fate determinants protect P2 cytokinesis by reducing the accumulation of septin UNC-59 and anillin ANI-1 at the division plane, which here act as negative regulators of cytokinesis. These findings may provide insight into cytokinetic regulation in other cell types, especially in stem cells with high potency.

Left Ventricular Function and Cardiac Biomarker Release-The Influence of Exercise Intensity, Duration and Mode: A Systematic Review and Meta-Analysis.

OBJECTIVE: We performed a systematic review, meta-analysis and meta-regression of exercise studies that sought to determine the relationship between cardiac troponin (cTn) and left ventricular (LV) function. The second objective was to determine how study-level and exercise factors influenced the variation in the body of literature. DATA SOURCES: A systematic search of Pubmed Central, Science Direct, SPORTDISCUS and MEDLINE databases. ELIGIBILITY CRITERIA: Original research articles published between 1997 and 2018 involving > 30 mins of continuous exercise, measuring cardiac troponin event rates and either LV ejection fraction (LVEF) or the ratio of the peak early (E) to peak late (A) filling velocity (E/A ratio). DESIGN: Random-effects meta-analyses and meta-regressions with four a priori determined covariates (age, exercise heart rate [HR], duration, mass). REGISTRATION: The systematic search strategy was registered on the PROSPERO database (CRD42018102176). RESULTS: Pooled cTn event rates were evident in 45.6% of participants (95% confidence interval (CI) 33.6-58.2); however, the overall effect was non-significant (P > 0.05). There were significant (P < 0.05) reductions in E/A ratio of - 0.38 (SMD = - 1.2, 95% CI - 1.4 to - 1.0), and LVEF of - 2.02% (SMD = - 0.38, 95% CI - 0.7 to - 0.1) pre- to post-exercise. Increased exercise HR was a significant predictor of troponin release and E/A ratio. Participant age was negatively associated with cTn release. There was a significant negative association between E/A ratio with increased rates of cTn release (P < 0.05). CONCLUSIONS: High levels of statistical heterogeneity and methodological variability exist in the majority of EICF studies. Our findings show that exercise intensity and age are the most powerful determinants of cTn release. Diastolic function is influenced by exercise HR and cTn release, which implies that exercise bouts at high intensities are enough to elicit cTn release and reduce LV diastolic function. Future EICF studies should (1) utilise specific echocardiographic techniques such as myocardial speckle tracking, (2) ensure participants are euhydrated during post-exercise measurements, and (3) repeat measures in the hours following exercise to assess symptom progression or recovery. It is also recommended to further explore the relationship between aging, training history, and exercise intensity on cTn release and functional changes.

The α5-GABAAR inverse agonist MRK-016 upregulates hippocampal BDNF expression and prevents cognitive deficits in LPS-treated mice, despite elevations in hippocampal Aß.

Alzheimer's disease is marked by the presence of amyloid-beta (Aß) plaques, elevated central cytokine levels, dysregulation of BDNF-related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central Aß in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK-016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS-induced hippocampal Aß accumulation. Hippocampal Aß was significantly elevated, relative to saline-treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal Aß, and inhibit acquisition of contextual fear. Post-training treatment with MRK restored behavioral expression of fear in LPS-treated animals, despite elevated hippocampal Aß, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS- induced cognitive deficits associated with elevated Aß, and restore hippocampal BDNF expression.

Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin.

Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK-016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline-treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus-dependent paradigm, though this protection occurs independently of recovery of BDNF expression.

Temporally selective contextual encoding in the dentate gyrus of the hippocampus.

A recent model of the hippocampus predicts that the unique properties of the dentate gyrus allow for temporal separation of events. This temporal separation is accomplished in part through the continual generation of new neurons, which, due to a transient window of hyperexcitability, could allow for preferential encoding of information present during their development. Here we obtain in vivo electrophysiological recordings and identify a cell population exhibiting activity that is selective to single contexts when rats experience a long temporal separation between context exposures during training. This selectivity is attenuated as the temporal separation between context exposures is shortened and is further attenuated when neurogenesis is reduced. Our data reveal the existence of a temporal orthogonalizing neuronal code within the dentate gyrus, a hallmark feature of episodic memory.

Improved gross efficiency during long duration submaximal cycling following a short-term high carbohydrate diet.

To assess the effect of dietary manipulation on gross efficiency (GE), 15 trained male cyclists completed 3×2 h tests at submaximal exercise intensity (60% Maximal Minute Power). Using a randomized, crossover design participants consumed an isoenergetic diet (~4 000 kcal.day-1) in the 3 days preceding each test, that was either high in carbohydrate (HighCHO, [70% of the total energy derived from carbohydrate, 20% fat, 10% protein]), low in carbohydrate (LowCHO, [70% fat, 20% carbohydrate, 10% protein]) or contained a moderate amount of carbohydrate (ModCHO, [45% carbohydrate, 45% fat, 10% protein]). GE along with blood lactate and glucose were assessed every 30 min, and heart rate was measured at 5 s intervals throughout. Mean GE was significantly greater following the HighCHO than the ModCHO diet (HighCHO=20.4%±0.1%, ModCHO=19.6±0.2%; P<0.001). Additionally, HighCHO GE was significantly greater after 25 min (P=0.015) and 85 min (P=0.021) than in the LowCHO condition. Heart rate responses in the HighCHO condition were significantly lower than during the LowCHO tests (P=0.005). Diet had no effect on blood glucose or lactate (P>0.05). This study suggests that before the measurement of gross efficiency, participants' diet should be controlled and monitored to ensure the validity of the results obtained.

Reproducibility of limb power outputs and cardiopulmonary responses to exercise using a novel swimming training machine.

The purpose of this study was to determine the reproducibility of limb power outputs and cardiopulmonary responses, to incremental whole-body exercise using a novel swimming training machine. 8 swimmers with a mean age of 23.7 ± 4.6 (yrs), stature 1.77 ± 0.13 (m) and body mass of 74.7 ± 2.8 (kg) gave informed consent and participated in repeat exercise testing on the machine. All subjects performed 2 incremental exercise tests to exhaustion using front crawl movements. From these tests peak oxygen consumption (VO(2peak)), peak heart rate (HR(peak)), peak power output (W (peak)) and individual limb power outputs were determined. Results showed there were no significant differences between test 1 and 2 for any variable at exhaustion, and the CV% ranged from 2.8 to 3.4%. The pooled mean values were; VO(2peak) 3.7 ± 0.65 L.min⁻¹, HR (peak) 178.7 ± 6.6 b.min⁻¹ and W (peak) 349.7 ± 16.5 W. The mean contributions to the total power output from the legs and arms were (37.3 ± 4.1% and 62.7 ± 5.1% respectively). These results show that it is possible to measure individual limb power outputs and cardiopulmonary parameters reproducibly during whole-body exercise using this training machine, at a range of exercise intensities.

Effect of isometric exercise on resting blood pressure: a meta analysis.

Dynamic physical exercise (walking, swimming, and so on) is an important component of lifestyle changes to reduce blood pressure; however, many individuals are unwilling or unable to adopt this lifestyle change. Isometric exercise has not traditionally been recommended as an alternative to dynamic exercise and has not been well studied. A meta-analysis of controlled trials of isometric exercise on resting blood pressure was therefore undertaken. Five trials were identified including a total of 122 subjects. Isometric exercise for <1 h per week reduced systolic blood pressure by 10.4 mm Hg and diastolic blood pressure by 6.7 mm Hg. These changes are similar to those achieved with a single pharmacological agent. These results suggest that isometric exercise may be of value as part of lifestyle advice in maintaining a desirable blood pressure.

Validity and reliability of the Ergomopro powermeter.

The aim of this investigation was to assess the validity and reliability of the Ergomopro powermeter. Nine participants completed trials on a Monark ergometer fitted with Ergomopro and SRM powermeters simultaneously recording power output. Each participant completed multiple trials at power outputs ranging from 50 to 450 W. The work stages recorded were 60 s in duration and were repeated three times. Participants also completed a single trial on a cycle ergometer designed to assess bilateral contributions to work output (Lode Excaliber Sport PFM). The power output during the trials was significantly different between all three systems, (p < 0.01) 231.2 +/- 114.2 W, 233.0 +/- 112.4 W, 227.8 +/- 108.8 W for the Monark, SRM and Ergomopro system, respectively. When the bilateral contributions were factored into the analysis, there were no significant differences between the powermeters (p = 0.58). The reliability of the Ergomopro system (CV%) was 2.31 % (95 % CI 2.13 - 2.52 %) compared to 1.59 % (95 % CI 1.47 to 1.74 %) for the Monark, and 1.37 % (95 % CI 1.26 - 1.50 %) for the SRM powermeter. These results indicate that the Ergomopro system has acceptable accuracy under these conditions. However, based on the reliability data, the increased variability of the Ergomopro system and bilateral balance issues have to be considered when using this device.

The application of machine learning techniques as an adjunct to clinical decision making in alcohol dependence treatment.

With few exceptions, research in the addictive sciences has relied on linear statistics and methodologies. Addiction involves a complex array of nonlinear behaviors. This study applies two machine learning techniques, Bayesian and decision tree classifiers, in the assessment of outcome of an alcohol dependence treatment program. These nonlinear approaches are compared to a standard linear analysis. Seventy-three alcohol-dependent subjects undertaking a 12-week cognitive-behavioral therapy (CBT) program and 66 subjects undertaking an identical program but also prescribed the relapse prevention agent Acamprosate were employed in this study. Demographic, alcohol use, dependence severity, craving, health-related quality of life, and psychological measures at baseline were used to predict abstinence at 12 weeks. Decision trees had a 77% predictive accuracy across both data sets, Bayesian networks 73%, and discriminant analysis 42%. Combined with clinical experience, machine learning approaches offer promise in understanding the complex relationships that underlie treatment outcome for abstinence-based alcohol treatment programs.

Power output measurement during treadmill cycling.

The study aim was to consider the use of a motorised treadmill as a cycling ergometry system by assessing predicted and recorded power output values during treadmill cycling. Fourteen male cyclists completed repeated cycling trials on a motorised treadmill whilst riding their own bicycle fitted with a mobile ergometer. The speed, gradient and loading via an external pulley system were recorded during 20-s constant speed trials and used to estimate power output with an assumption about the contribution of rolling resistance. These values were then compared with mobile ergometer measurements. To assess the reliability of measured power output values, four repeated trials were conducted on each cyclist. During level cycling, the recorded power output was 257.2 +/- 99.3 W compared to the predicted power output of 258.2 +/- 99.9 W (p > 0.05). For graded cycling, there was no significant difference between measured and predicted power output, 268.8 +/- 109.8 W vs. 270.1 +/- 111.7 W, p > 0.05, SEE 1.2 %. The coefficient of variation for mobile ergometer power output measurements during repeated trials ranged from 1.5 % (95 % CI 1.2 - 2.0 %) to 1.8 % (95 % CI 1.5 - 2.4 %). These results indicate that treadmill cycling can be used as an ergometry system to assess power output in cyclists with acceptable accuracy.

Relationships between pulse wave velocity and heart rate variability in healthy men with a range of moderate-to-vigorous physical activity levels.

Pulse wave velocity (PWV) is associated with heart rate variability (HRV) in 24-39-year-old men. This study of 40-65-year-old men ranging in moderate-to-vigorous physical activity levels investigated whether (a) PWV is related to spectral HRV, (b) using normalised units for HRV influences that relationship, and (c) HRV predicts PWV when other factors, including age and blood pressure, are accounted for. Subjects were healthy men (N=115), mean (SD) age 50.8 (7.1) years. Carotid-femoral PWV was measured using Complior. HRV was derived from a 5 min ECG for total, high-frequency, and low-frequency power (TP, HF, and LF, respectively), the LF/HF ratio, and normalised units for HF (HFnu) and LF (LFnu). Non-parametric data were natural log-transformed. PWV was 8.5 (1.4) m s-1. TP, HF, LF, LF/HF, HFnu and LFnu were 1908 (2195) m s2, 577 (1034) m s2, 457 (514) m s2, 1.5 (1.3), 46.8 (17.9), and 49.4 (19.4), respectively. PWV was inversely associated with TP (R2=0.061, p=0.008), HF (R2=0.095, p=0.001), LF (R2=0.086, p=0.002) and HFnu (R2=0.040, p=0.031), but was not associated with LF/HF (R2=0.020, p=0.136) or LFnu (R2=0.028 p=0.076). Only age and systolic blood pressure (adjusted R2=0.306, p<0.001) predicted PWV in multivariate analysis. This study has shown that PWV was weakly associated with TP and HF. The use of normalised units only influenced the relationship between PWV and LF. Finally, relationships between PWV and HRV are mediated through age and systolic blood pressure in this population of men ranging in moderate-to-vigorous physical activity level.

Reliability of sprint test indices in well-trained cyclists.

The study aim was to assess reliability of repeated laboratory sprint tests in well-trained endurance cyclists. Eleven male cyclists (mean +/- standard deviation: 27 +/- 6 yr, 1.79 +/- 0.04 m, 70.1 +/- 3.3 kg) performed a maximal 30-second sprint test on four separate occasions using their own bicycle fitted with an SRM powermeter on a Kingcycle air-braked ergometer. Peak power output (W (peak)), mean power (W (mean)) and an index of fatigue (FI) were calculated. Three minutes post sprint, capillarised blood lactate measurements were taken and analysed. No significant differences (p > 0.05) were found between trials for W (peak), W (mean), FI and blood lactate concentration. Repeatability of W (peak), W (mean), and fatigue index improved across trials 2 and 3 when compared to trials 1 and 2. The highest CV for these variables was recorded between trials 3 and 4. The CV for W (peak) was 4.5 +/- 1.6 %, W (mean) 2.4 +/- 1.2 %, and FI 17.2 +/- 7.1 %. Intraclass reliability coefficients were 0.93 (95 % CI 0.84 - 0.98), 0.94 (95 % CI 0.86 - 0.98) and 0.89 (95 % CI 0.69 - 0.95) respectively. Blood lactate concentration ranged between 5.35 and 14.52 mmol.l(-1), with a mean CV of 12.1 +/- 4.2 %. The CV for trials 2 and 3 revealed the highest CV for blood lactate concentration (15.1 %). The lowest CV for this variable (10.2 %) was recorded between trials 3 and 4. The intraclass reliability coefficient for blood lactate concentration was 0.79 (95 % CI 0.58 - 0.93). The results of this study indicate that there is no improvement in the reliability of sprint test indices when assessing well-trained, experienced cyclists, riding on their own cycle equipment.

On learning context-free and context-sensitive languages.

The long short-term memory (LSTM) is not the only neural network which learns a context sensitive language. Second-order sequential cascaded networks (SCNs) are able to induce means from a finite fragment of a context-sensitive language for processing strings outside the training set. The dynamical behavior of the SCN is qualitatively distinct from that observed in LSTM networks. Differences in performance and dynamics are discussed.

'Gentle caring experience'. Seeking alternative health care in Canada.

The starting point for this paper is a review of the literature, which seeks to explain the use of alternative medicines, therapies and practices in developed countries. Using the Statistics Canada 1996-97 National Population Health Survey--Health File, we then examine the profile of alternative service users. Our analysis shows that use of alternative health care is still limited to a relatively small segment of Canadians whose profile is similar to those in other developed countries. Women are more likely than men to use alternative medicines, therapies and practices, as are those who have higher incomes and are better educated. To move what has been an essentially empirical discussion forward, we explore critiques of conventional medical practice and propose that the analysis of alternative health care be situated within the geographies of consumption.