Heart development and regeneration -- a multi‐organ effort

Development of the heart, from early morphogenesis to functional maturation, as well as maintenance of its homeostasis, are tasks requiring collaborative efforts of cardiac tissue and different extra-cardiac organ systems. The brain, lymphoid organs, and gut, are among the interaction partners that can communicate with the heart through a wide array of paracrine signals acting at local or systemic level. Disturbance of cardiac homeostasis following ischemic injury also needs immediate response from these distant organs. Our hearts replace dead muscles with non-contractile fibrotic scars. We have learned from animal models capable of scarless repair that regenerative capability of the heart does not depend only on competency of the myocardium and cardiac-intrinsic factors, but also on long-range molecular signals originating in other parts of the body. Here, we provide an overview of inter-organ signals that take part in development and regeneration of the heart. We highlight recent findings and remaining questions. Finally, we discuss the potential of inter-organ modulatory approaches for possible therapeutic use

Moral Disengagement and Generalized Social Trust as Mediators and Moderators of Rule-Respecting Behaviors During the COVID-19 Outbreak

In this study, we tested a theoretical model with moral disengagement, a mediator, and generalized social trust (GST), a mediator and a moderator of the relationship between personality traits and rule-respecting behaviors (i.e., social distancing and stay-at-home), during the coronavirus disease 2019 (COVID-19) outbreak in Italy. The data were collected on 1520 participants (61% males). General results are threefold: (1) moral disengagement mediated the relationship between emotional stability, narcissism, psychopathy, and social distancing; (2) among components of GST, trust in Government mediated the relationship between psychopathy and social distancing; trust in known others mediated the relationship between emotional stability, agreeableness, and Machiavellianism with total number of exits; trust in unknown others mediated the relationship of emotional stability, agreeableness, conscientiousness, and psychopathy with average daily number of exits; (3) GST moderated the indirect effect of personality traits on rule-respecting behaviors through moral disengagement. The theoretical and practical importance of these results is discussed

Moral disengagement and generalized social trust as mediators and moderators of rule-respecting behaviors during the COVID-19 outbreak

In this study, we tested a theoretical model with moral disengagement, a mediator,and generalized social trust (GST), a mediator and a moderator of the relationshipbetween personality traits and rule-respecting behaviors (i.e., social distancing andstay-at-home), during the coronavirus disease 2019 (COVID-19) outbreak in Italy. Thedata were collected on 1520 participants (61% males). General results are threefold: (1) moral disengagement mediated the relationship between emotional stability, narcissism,psychopathy, and social distancing; (2) among components of GST, trust in Governmentmediated the relationship between psychopathy and social distancing; trust in knownothers mediated the relationship between emotional stability, agreeableness, andMachiavellianism with total number of exits; trust in unknown others mediated therelationship of emotional stability, agreeableness, conscientiousness, and psychopathywith average daily number of exits; (3) GST moderated the indirect effect of personalitytraits on rule-respecting behaviors through moral disengagement. The theoretical andpractical importance of these results is discussed

Glucose-6-phosphate dehydrogenase plays a crucial role in the protection from redox-stress induced apoptosis.

Glucose-6-phosphate dehydrogenase-deleted embryonic stem (ES) cells (G6pdD) proliferate in vitro without special requirements, but when challenged with oxidants fail to sustain glutathione disulphide reconversion to reduced glutathione (GSH), entering a condition of oxidative stress. Here, we investigate the signalling events downstream of GSH oxidation in G6pdD and wild-type (wt) ES cells. We found that G6pdD ES cells are very sensitive to oxidants, activating an apoptotic pathway at oxidant concentrations otherwise sublethal for wt ES cells. We show that the apoptotic pathway activated by low oxidant concentrations is accompanied by mitochondria dysfunction, and it is therefore blocked by the overexpression of Bcl-XL. Bcl-XL does not inhibit the decrease in cellular GSH and reactive oxygen species formation following oxidant treatment. We also found that oxidant treatment in ES cells is followed by the activation of the MEK/ extracellular signal-regulated kinase (ERK) pathway. Interest¬ingly, ERK activation has opposite outcomes in G6pdD ES cells compared to wt, which has a proapoptotic function in the first and a prosurvival function in the latter. We show that this phenomenon can be regulated by the cellular GSH level

Using pERK immunostaining to quantify neuronal activity induced by stress in zebrafish larvae

The larval zebrafish has emerged as a very useful model organism to study the neuronal circuits controlling neuroendocrine and behavioral responses to stress. This protocol describes how to expose zebrafish larvae to hyperosmotic stress and test whether candidate populations of neurons are activated or inhibited by the stressor using a relatively rapid immunofluorescence staining approach. This approach takes advantage of the phosphorylation of the extracellular signal-regulated kinase (ERK) upon neuronal activation. For complete details on the use and execution of this protocol, please refer to Corradi et al. (2022)

Expanding Paramedicine in the Community (EPIC): study protocol for a randomized controlled trial.

BackgroundThe incidence of chronic diseases, including diabetes mellitus (DM), heart failure (HF) and chronic obstructive pulmonary disease (COPD) is on the rise. The existing health care system must evolve to meet the growing needs of patients with these chronic diseases and reduce the strain on both acute care and hospital-based health care resources. Paramedics are an allied health care resource consisting of highly-trained practitioners who are comfortable working independently and in collaboration with other resources in the out-of-hospital setting. Expanding the paramedic's scope of practice to include community-based care may decrease the utilization of acute care and hospital-based health care resources by patients with chronic disease.Methods/designThis will be a pragmatic, randomized controlled trial comparing a community paramedic intervention to standard of care for patients with one of three chronic diseases. The objective of the trial is to determine whether community paramedics conducting regular home visits, including health assessments and evidence-based treatments, in partnership with primary care physicians and other community based resources, will decrease the rate of hospitalization and emergency department use for patients with DM, HF and COPD. The primary outcome measure will be the rate of hospitalization at one year. Secondary outcomes will include measures of health system utilization, overall health status, and cost-effectiveness of the intervention over the same time period. Outcome measures will be assessed using both Poisson regression and negative binomial regression analyses to assess the primary outcome.DiscussionThe results of this study will be used to inform decisions around the implementation of community paramedic programs. If successful in preventing hospitalizations, it has the ability to be scaled up to other regions, both nationally and internationally. The methods described in this paper will serve as a basis for future work related to this study.Trial registrationClinicalTrials.gov: NCT02034045. Date: 9 January 2014

Perception of Time-Discrete Haptic Feedback on the Waist is Invariant with Gait Events

The effectiveness of haptic feedback devices highly depends on the perception of tactile stimuli, which differs across body parts and can be affected by movement. In this study, a novel wearable sensory feedback apparatus made of a pair of pressure-sensitive insoles and a belt equipped with vibrotactile units is presented; the device provides time-discrete vibrations around the waist, synchronized with biomechanically-relevant gait events during walking. Experiments with fifteen healthy volunteers were carried out to investigate users' tactile perception on the waist. Stimuli of different intensities were provided at twelve locations, each time synchronously with one pre-defined gait event (i.e. heel strike, flat foot or toe off), following a pseudo-random stimulation sequence. Reaction time, detection rate and localization accuracy were analyzed as functions of the stimulation level and site and the effect of gait events on perception was investigated. Results revealed that above-threshold stimuli (i.e. vibrations characterized by acceleration amplitudes of 1.92g and 2.13g and frequencies of 100 Hz and 150 Hz, respectively) can be effectively perceived in all the sites and successfully localized when the intertactor spacing is set to 10 cm. Moreover, it was found that perception of time-discrete vibrations was not affected by phase-related gating mechanisms, suggesting that the waist could be considered as a preferred body region for delivering haptic feedback during walking

Dendritic Peptide Release Mediates Interpopulation Crosstalk between Neurosecretory and Preautonomic Networks

SummaryAlthough communication between neurons is considered a function of the synapse, neurons also release neurotransmitter from their dendrites. We found that dendritic transmitter release coordinates activity across distinct neuronal populations to generate integrative homeostatic responses. We show that activity-dependent vasopressin release from hypothalamic neuroendocrine neurons in the paraventricular nucleus stimulates neighboring (∼100 μm soma-to-soma) presympathetic neurons, resulting in a sympathoexcitatory population response. This interpopulation crosstalk was engaged by an NMDA-mediated increase in dendritic Ca2+, influenced by vasopressin’s ability to diffuse in the extracellular space, and involved activation of CAN channels at the target neurons. Furthermore, we demonstrate that this interpopulation crosstalk plays a pivotal role in the generation of a systemic, polymodal neurohumoral response to a hyperosmotic challenge. Because dendritic release is emerging as a widespread process, our results suggest that a similar mechanism could mediate interpopulation crosstalk in other brain systems, particularly those involved in generating complex behaviors.Video Abstrac

Early life stress regulates cardiac development through an IL4-glucocorticoid signaling balance

Stressful experiences early in life can increase the risk of cardiovascular diseases. However, it remains largely unknown how stress influences susceptibility to the disease onset. Here, we show that exposure to brain-processed stress disrupts myocardial growth by reducing cardiomyocyte mitotic activity. Activation of the glucocorticoid receptor (GR), the primary stress response pathway, reduces cardiomyocyte numbers, disrupts trabecular formation, and leads to contractile dysfunction of the developing myocardium. However, a physiological level of GR signaling is required to prevent cardiomyocyte hyperproliferation. Mechanistically, we identify an antagonistic interaction between the GR and the cytokine interleukin-4 (IL-4) as a key player in cardiac development. IL-4 signals transcription of key regulators of cell-cycle progression in cardiomyocytes via signal transducer and activator of transcription 3 (Stat3). GR, on the contrary, inhibits this signaling system. Thus, our findings uncover an interplay between stress and immune signaling pathways critical to orchestrating physiological growth of the heart