Correlative evidence suggests that polyploidization of heart muscle, which occurs naturally in post-natal mammals, creates a barrier to heart regeneration. Here, we move beyond a correlation by ...demonstrating that experimental polyploidization of zebrafish cardiomyocytes is sufficient to suppress their proliferative potential during regeneration. Initially, we determined that zebrafish myocardium becomes susceptible to polyploidization upon transient cytokinesis inhibition mediated by dominant-negative Ect2. Using a transgenic strategy, we generated adult animals containing mosaic hearts composed of differentially labeled diploid and polyploid-enriched cardiomyocyte populations. Diploid cardiomyocytes outcompeted their polyploid neighbors in producing regenerated heart muscle. Moreover, hearts composed of equivalent proportions of diploid and polyploid cardiomyocytes failed to regenerate altogether, demonstrating that a critical percentage of diploid cardiomyocytes is required to achieve heart regeneration. Our data identify cardiomyocyte polyploidization as a barrier to heart regeneration and suggest that mobilizing rare diploid cardiomyocytes in the human heart will improve its regenerative capacity.
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•Cardiomyocytes in adult zebrafish are predominantly mononucleated and diploid•Transient inhibition of Ect2 induces polyploidization of zebrafish cardiomyocytes•Diploid cardiomyocytes outcompete polyploid cardiomyocytes during heart regeneration•Hearts composed of >45% polyploid cardiomyocytes fail to regenerate
It remains unclear why certain non-mammalian species efficiently regenerate their hearts while mammals fail in this endeavor. González-Rosa et al. demonstrate that simply increasing the DNA content of the highly regenerative zebrafish myocardium, to more closely resemble that in mammals, is sufficient to dampen cardiomyocyte proliferative capacity and organ regeneration.
Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to ...understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration.
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•Hypo-innervation of the zebrafish heart impairs heart regeneration•Cholinergic signaling guides myocyte proliferation in zebrafish and neonatal mice•Neonatal mouse vagotomy impairs myocyte proliferation and heart regeneration•Neonatal vagotomy reduces the inflammatory response following heart injury
Mahmoud et al. demonstrate that nerves are required for cardiomyocyte proliferation during both zebrafish and neonatal mouse heart regeneration. The negative effect of hypoinnervation on regeneration can be partially rescued by NRG1 and NGF proteins.
Although women at all career stages are more likely to leave academia than men, early-career women are a particularly high-risk group. Research supports that women are less likely than men to receive ...research funding; however, whether funding success rates vary based on research content is unknown. We addressed gender differences in funding success rates for applications directed to one or more of 13 institutes, representing research communities, over a 15-year period.
We retrospectively reviewed 55,700 grant and 4,087 personnel award applications submitted to the Canadian Institutes of Health Research. We analyzed application success rates according to gender and the primary institute selected by applicants, pooled gender differences in success rates using random effects models, and fitted Poisson regression models to assess the effects of gender, time, and institute. We noted variable success rates among grant applications directed to selected institutes and declining success rates over time. Women submitted 31.1% and 44.7% of grant and personnel award applications, respectively. In the pooled estimate, women had significantly lower grant success (risk ratio RR 0.89, 95% confidence interval CI 0.84-0.94; p < 0.001; absolute difference 3.2%) compared with men, with substantial heterogeneity (I2 = 58%). Compared with men, women who directed grants to the Institutes of Cancer Research (RR 0.86, 95% CI 0.78-0.96), Circulatory and Respiratory Health (RR 0.74, 95% CI 0.66-0.84), Health Services and Policy Research (RR 0.78, 95% CI 0.68-0.90), and Musculoskeletal Health and Arthritis (RR 0.80, 95% CI 0.69-0.93) were significantly less likely to be funded, and those who directed grants to the Institute of Aboriginal People's Health (RR 1.67, 95% CI 1.0-2.7) were more likely to be funded. Overall, women also had significantly lower personnel award success (RR 0.75, 95% CI 0.65-0.86; p < 0.001; absolute difference 6.6%). Regression modelling identified that the effect of gender on grant success rates differed by institute and not time. Study limitations include use of institutes as a surrogate identifier, variability in designation of primary institute, and lack of access to metrics reflecting applicants, coapplicants, peer reviewers, and the peer-review process.
Gender disparity existed overall in grant and personnel award success rates, especially for grants directed to selected research communities. Funding agencies should monitor for gender differences in grant success rates overall and by research content.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Previous studies demonstrate that the regenerative zebrafish heart responds to injury by upregulating Notch receptors in the endocardium and epicardium. Moreover, global suppression of Notch activity ...following injury impairs cardiomyocyte proliferation and induces scarring. However, the lineage-specific requirements for Notch signaling and full array of downstream targets remain unidentified. Here, we demonstrate that inhibition of endocardial Notch signaling following ventricular amputation compromises cardiomyocyte proliferation and stimulates fibrosis. RNA sequencing uncovered reduced levels of two transcripts encoding secreted Wnt antagonists, Wif1 and Notum1b, in Notch-suppressed hearts. Like Notch receptors, wif1 and notum1b are induced following injury in the endocardium and epicardium. Small-molecule-mediated activation of Wnt signaling is sufficient to impair cardiomyocyte proliferation and induce scarring. Last, Wnt pathway suppression partially restored cardiomyocyte proliferation in hearts experiencing endocardial Notch inhibition. Taken together, our data demonstrate that Notch signaling supports cardiomyocyte proliferation by dampening myocardial Wnt activity during zebrafish heart regeneration.
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•EC Notch signaling is required for regenerative cardiomyocyte proliferation.•EC Notch augments expression of secreted Wnt antagonists notum1b and wif1.•Hyperactivated Wnt signaling suppresses regenerative cardiomyocyte proliferation.•Wnt inhibition boosts cardiomyocyte proliferation in EC Notch-suppressed hearts.
The highly regenerative zebrafish heart responds to injury by upregulating Notch receptors in the endocardium and epicardium to support myocardial proliferation and regeneration. Zhao et al. demonstrate that endocardial (EC) Notch signaling augments the expression of secreted endocardial Wnt antagonists that dampen myocardial Wnt signaling to support regenerative cardiomyocyte renewal.
We present the fourth in a series of catalogs of gamma-ray bursts (GRBs) observed with Fermi's Gamma-ray Burst Monitor (Fermi-GBM). It extends the six year catalog by four more years, now covering ...the 10 year time period from trigger enabling on 2008 July 12 to 2018 July 11. During this time period GBM triggered almost twice a day on transient events, 2356 of which we identified as cosmic GRBs. Additional trigger events were due to solar flare events, magnetar burst activities, and terrestrial gamma-ray flashes. The intention of the GBM GRB catalog series is to provide updated information to the community on the most important observables of the GBM-detected GRBs. For each GRB the location and main characteristics of the prompt emission, the duration, peak flux, and fluence are derived. The latter two quantities are calculated for the 50-300 keV energy band, where the maximum energy release of GRBs in the instrument reference system is observed and also for a broader energy band from 10-1000 keV, exploiting the full energy range of GBM's low-energy detectors. Furthermore, information is given on the settings of the triggering criteria and exceptional operational conditions during years 7 to 10 in the mission. This fourth catalog is an official product of the Fermi-GBM science team, and the data files containing the complete results are available from the High-Energy Astrophysics Science Archive Research Center.
The human heart’s failure to replace ischemia-damaged myocardium with regenerated muscle contributes significantly to the worldwide morbidity and mortality associated with coronary artery disease. ...Remarkably, certain vertebrate species, including the zebrafish, achieve complete regeneration of amputated or injured myocardium through the proliferation of spared cardiomyocytes. Nonetheless, the genetic and cellular determinants of natural cardiac regeneration remain incompletely characterized. Here, we report that cardiac regeneration in zebrafish relies on Notch signaling. Following amputation of the zebrafish ventricular apex, Notch receptor expression becomes activated specifically in the endocardium and epicardium, but not the myocardium. Using a dominant negative approach, we discovered that suppression of Notch signaling profoundly impairs cardiac regeneration and induces scar formation at the amputation site. We ruled out defects in endocardial activation, epicardial activation, and dedifferentiation of compact myocardial cells as causative for the regenerative failure. Furthermore, coronary endothelial tubes, which we lineage traced from preexisting endothelium in wild-type hearts, formed in the wound despite the myocardial regenerative failure. Quantification of myocardial proliferation in Notch-suppressed hearts revealed a significant decrease in cycling cardiomyocytes, an observation consistent with a noncell autonomous requirement for Notch signaling in cardiomyocyte proliferation. Unexpectedly, hyperactivation of Notch signaling also suppressed cardiomyocyte proliferation and heart regeneration. Taken together, our data uncover the exquisite sensitivity of regenerative cardiomyocyte proliferation to perturbations in Notch signaling.
A personalized mechanical ventilation approach for patients with adult respiratory distress syndrome (ARDS) based on lung physiology and morphology, ARDS etiology, lung imaging, and biological ...phenotypes may improve ventilation practice and outcome. However, additional research is warranted before personalized mechanical ventilation strategies can be applied at the bedside. Ventilatory parameters should be titrated based on close monitoring of targeted physiologic variables and individualized goals. Although low tidal volume (V
) is a standard of care, further individualization of V
may necessitate the evaluation of lung volume reserve (e.g., inspiratory capacity). Low driving pressures provide a target for clinicians to adjust V
and possibly to optimize positive end-expiratory pressure (PEEP), while maintaining plateau pressures below safety thresholds. Esophageal pressure monitoring allows estimation of transpulmonary pressure, but its use requires technical skill and correct physiologic interpretation for clinical application at the bedside. Mechanical power considers ventilatory parameters as a whole in the optimization of ventilation setting, but further studies are necessary to assess its clinical relevance. The identification of recruitability in patients with ARDS is essential to titrate and individualize PEEP. To define gas-exchange targets for individual patients, clinicians should consider issues related to oxygen transport and dead space. In this review, we discuss the rationale for personalized approaches to mechanical ventilation for patients with ARDS, the role of lung imaging, phenotype identification, physiologically based individualized approaches to ventilation, and a future research agenda.
Efforts to mitigate the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing Corona Virus Disease-19 (COVID-19) have largely relied on broad compliance with ...public health recommendations yet navigating the high volume of evolving information can be challenging. We assessed self-reported public perceptions related to COVID-19 including, beliefs (e.g., severity, concerns, health), knowledge (e.g., transmission, information sources), and behaviors (e.g., physical distancing) to understand perspectives in Canada and to inform future public health initiatives.
We administered a national online survey aiming to obtain responses from 2000 adults in Canada. Respondent sampling was stratified by age, sex, and region. We used descriptive statistics to summarize responses and tested for regional differences using chi-squared tests, followed by weighted logistic regression.
We collected 1,996 eligible questionnaires between April 26th and May 1st, 2020. One-fifth (20%) of respondents knew someone diagnosed with COVID-19, but few had tested positive themselves (0.6%). Negative impacts of pandemic conditions were evidenced in several areas, including concerns about healthcare (e.g. sufficient equipment, 52%), pandemic stress (45%), and worsening social (49%) and mental/emotional (39%) health. Most respondents (88%) felt they had good to excellent knowledge of virus transmission, and predominantly accessed (74%) and trusted (60%) Canadian news television, newspapers/magazines, or non-government news websites for COVID-19 information. We found high compliance with distancing measures (80% reported self-isolating or always physical distancing). We identified associations between region and self-reported beliefs, knowledge, and behaviors related to COVID-19.
We found that information about COVID-19 is largely acquired through domestic news sources, which may explain high self-reported compliance with prevention measures. The results highlight the broader impact of a pandemic on the general public's overall health and wellbeing, outside of personal infection. The study findings should be used to inform public health communications during COVID-19 and future pandemics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Physician wellness is vital to career satisfaction, provision of high quality patient care, and the successful education of the next generation of physicians. Despite this, the number of physicians ...experience symptoms of burnout is rising. To assess the impact of organizational culture on physicians' professional fulfillment and burnout, we surveyed full-time Department of Medicine members at the University of Toronto. A cross-sectional survey assessed: physician factors (age, gender, minority status, disability, desire to reduce clinical workload); workplace culture (efforts to create a collegial environment, respectful/civil interactions, confidence to address unprofessionalism without reprisal, witnessed and/or personally experienced unprofessionalism); professional fulfillment and burnout using the Stanford Professional Fulfillment Index. We used multivariable linear regression to examine the relationship of measures of workplace culture on professional fulfillment and burnout (scores 0-10), controlling for physician factors. Of 419 respondents (52.0% response rate), we included 400 with complete professional fulfillment and burnout data in analyses (60% less than or equal to age 50, 45% female). Mean scores for professional fulfillment and burnout were 6.7±1.9 and 2.8±1.9, respectively. Controlling for physician factors, professional fulfillment was associated with satisfaction with efforts to create a collegial environment (adjusted beta 0.45, 95% CI 0.21 to 0.70) and agreement that colleagues were respectful/civil (adjusted beta 0.85, 95% CI 0.53 to 1.17). Lower professional fulfillment was associated with higher burnout scores. Controlling for professional fulfillment and physician factors, lower confidence in taking action to address unprofessionalism (adjusted beta -0.22, 95% CI -0.40 to -0.03) was associated with burnout. Organizational culture and physician factors had an impact on professional fulfillment and burnout. Professional fulfillment partially mediated the relationship between organizational culture and burnout. Strategies that promote inclusion, respect and civility, and safe ways to report workplace unprofessionalism are needed in academic medicine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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