Interplay of neuronal networks modulates mammalian circadian rhythms

  The suprachiasmatic nucleus (SCN) functions as a circadian clock that drives 24-hour rhythms in physiology and behavior. The SCN neurons function as cell-autonomous oscillators, and the production of a coherent SCN rhythm is dependent upon synchronization among single cells. We investigated how changes in phase-synchronization between individual cells effect the ability of the SCN to phase-shift its rhythm. Empirical and modelling studies revealed larger phase-shifts in synchronized SCN than in desynchronized SCN. The major external stimulus affecting the SCN is light. We explored the ability of melanopsin and rod- and cone photoreceptors to mediate the effects of light on SCN discharge, and found that melanopsin and cones are able to mediate light responses of the SCN. Studies performed in nocturnal species have indicated that the SCN’s rhythmicity is also influenced by the animal’s own behavioral activity. We assessed the effect behavioral activity on the amplitude of the circadian rhythm in SCN electrical discharge rate in the day-active Arvicanthis ansorgei. The results showed acute enhancements of SCN discharge during episodes of behavioral activity. The studies described in this thesis indicate that the SCN is part of a brain network that includes the retina and areas involved in behavioral activity and sleep.  LUMC / Geneeskund

Molecular and environmental cues in cardiac differentiation of mesenchymal stem cells

In this thesis molecular and environmental cues in cardiac differentiation of mesenchymal stem cells were investigated. The main conclusions were that the cardiac differentiation potential of human mesenchymal stem cells negatively correlates with donor age. This in its own shows a negative relationship with connexin 43 levels in these cells. However, a causal relationship between connexin 43 expression levels and cardiomyogenic differentiation potential only exists for human mesenchymal stem cells from prenatal sources, i.e. while knockdown of connexin 43 expression in fetal human mesenchymal stem cells inhibits their ability to differentiate into cardiomyocytes, connexin 43 overexpression in adult human mesenchymal stem cells does not endow them with cardiomyogenic differentiation capacity. In addition, co-culture studies showed that the alignment and distribution of mesenchymal stem cells affect their electrical integration into host myocardium and are major determinants of their pro-arrhythmic risk. The mechanisms underlying the pro-arrhythmic effects of hMSCs are to some extent comparable to those of cardiac myofibroblasts, cells that are found in fibrotic myocardiumUBL - phd migration 201

The circadian clock, metabolism and obesity

In the last decades, obesity has been on the rise becoming a burden for health care systems. The reasons behind this rise are most likely caused by lifestyle rather than by an increase in gene mutations, because manifestations of genetic alterations would take longer than just a few decades. Lifestyle has a great impact on the circadian system and therefore on the body internal organization of physiological and biochemical processes, regulating various aspects of behavior and metabolism. In the following, I will discuss recent studies delineating relationships between metabolic processes and the circadian system, how metabolites and nutrients regulate the circadian clock and how nuclear receptors can act as metabolic sensors and clock regulators. Finally, I will discuss how clock modulation and feeding patterns influence the development of obesity

Distinct contribution of cone photoreceptor subtypes to the mammalian biological clock

Ambient light detection is important for the synchronization of the circadian clock to the external solar cycle. Light signals are sent to the suprachiasmatic nuclei (SCN), the site of the major circadian pacemaker. It has been assumed that cone photoreceptors con-tribute minimally to synchronization. Here, however, we find that cone photoreceptors are sufficient for mediating entrainment and transmitting photic information to the SCN, as evaluated in mice that have only cones as functional photoreceptors. Using in vivo electrophysiological recordings in the SCN of freely moving cone-only mice, we observed light responses in SCN neuronal activity in response to 60-s pulses of both ultraviolet (UV) (lambda(max) 365 nm) and green (lambda(max) 505 nm) light. Higher irradiances of UV light led to irradiance-dependent enhancements in SCN neuronal activity, whereas higher irradiances of green light led to a reduction in the sustained response with only the transient response remain-ing. Responses in SCN neuronal activity decayed with a half-max time of similar to 9 min for UV light and less than a minute for green light, indicating differential input between short-wavelength-sensitive and mid-wavelength-sensitive cones for the SCN responsiveness. Furthermore, we show that UV light is more effective for photo-entrainment than green light. Based on the lack of a full sustained response in cone-only mice, we confirmed that rapidly alternating light levels, rather than slowly alternating light, caused substantial phase shifts. Together, our data provide strong evidence that cone types contribute to photoentrainment and differentially affect the electrical activity levels of the SCN.Circadian clocks in health and diseas

Cardiovascular imaging research and innovation in 2023

© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.In 2023, cardiovascular imaging has made significant advancements, in terms of technology, pathophysiology, and clinical application. In this review, the most recent research findings in the field of cardiovascular imaging are discussed. Artificial intelligence and large population cohorts, together with several technical improvements, have had a crucial impact on the technological advancements of echocardiography, cardiovascular magnetic resonance, computed tomography (CT), and nuclear medicine. In the field of ischaemic heart disease, it has been demonstrated that appropriate non-invasive imaging strategies improve patients' management and reduce invasive procedures and the need for additional testing at follow-up. Moreover, improvements in plaque characterization with CT are an expanding field of research with relevant implications for the prediction of disease severity, evolution, and response to treatment. In the field of valvular heart disease, imaging techniques have advanced alongside improvements in transcatheter treatment for aortic stenosis, mitral, and tricuspid regurgitation. Finally, in the field of heart failure and cardiomyopathies, cardiovascular imaging has reinforced its crucial role in early diagnosis and risk evaluation, showcasing advanced techniques that outperform traditional methods in predicting adverse outcomes.publishersversionpublishe

Cardiovascular imaging in 2024: review of current research and innovations

Cardiovascular imaging saw significant advancements in 2024, impacting technology, pathophysiology, and clinical applications. This review provides a comprehensive summary of the most impactful research in cardiovascular imaging published in 2024, highlighting technological advancements, as well as research on ischaemic heart disease, valvular heart disease, cardiomyopathies, and heart failure. It emphasizes the crucial role of artificial intelligence, large-scale studies, and technical improvements across echocardiography, cardiovascular magnetic resonance, computed tomography (CT), and nuclear medicine. In the context of ischaemic heart disease, non-invasive imaging strategies improve patient management and reduce invasive coronary angiograms and unnecessary follow-up testing. Computed tomography plaque characterization is a growing area of research, with potential for predicting disease severity, atherosclerosis progression, and clinical outcomes. In valvular heart disease, several imaging studies focused not only on transcatheter treatments for aortic stenosis, mitral regurgitation, and tricuspid regurgitation but also on specific conditions such as mitral valve prolapse and mitral annular disjunction. Finally, for heart failure and cardiomyopathies, imaging plays a vital role in early diagnosis and risk assessment, with newer techniques surpassing traditional methods in providing morpho-function characterization and in predicting long-term outcomes

Light transmittance in human atrial tissue and transthoracic illumination in rats support translatability of optogenetic cardioversion of atrial fibrillation

Background: Optogenetics could offer a solution to the current lack of an ambulatory method for the rapid automated cardioversion of atrial fibrillation (AF), but key translational aspects remain to be studied. Objective: To investigate whether optogenetic cardioversion of AF is effective in the aged heart and whether sufficient light penetrates the human atrial wall. Methods: Atria of adult and aged rats were optogenetically modified to express light-gated ion channels (i.e., red-activatable channelrhodopsin), followed by AF induction and atrial illumination to determine the effectivity of optogenetic cardioversion. The irradiance level was determined by light transmittance measurements on human atrial tissue. Results: AF could be effectively terminated in the remodeled atria of aged rats (97%, n = 6). Subsequently, ex vivo experiments using human atrial auricles demonstrated that 565-nm light pulses at an intensity of 25 mW/mm(2) achieved the complete penetration of the atrial wall. Applying such irradiation onto the chest of adult rats resulted in transthoracic atrial illumination as evidenced by the optogenetic cardioversion of AF (90%, n = 4). Conclusion: Transthoracic optogenetic cardioversion of AF is effective in the aged rat heart using irradiation levels compatible with human atrial transmural light penetration.Thoracic Surger

Human Embryonic and Fetal Mesenchymal Stem Cells Differentiate toward Three Different Cardiac Lineages in Contrast to Their Adult Counterparts

Mesenchymal stem cells (MSCs) show unexplained differences in differentiation potential. In this study, differentiation of human (h) MSCs derived from embryonic, fetal and adult sources toward cardiomyocytes, endothelial and smooth muscle cells was investigated. Labeled hMSCs derived from embryonic stem cells (hESC-MSCs), fetal umbilical cord, bone marrow, amniotic membrane and adult bone marrow and adipose tissue were co-cultured with neonatal rat cardiomyocytes (nrCMCs) or cardiac fibroblasts (nrCFBs) for 10 days, and also cultured under angiogenic conditions. Cardiomyogenesis was assessed by human-specific immunocytological analysis, whole-cell current-clamp recordings, human-specific qRT-PCR and optical mapping. After co-culture with nrCMCs, significantly more hESC-MSCs than fetal hMSCs stained positive for α-actinin, whereas adult hMSCs stained negative. Furthermore, functional cardiomyogenic differentiation, based on action potential recordings, was shown to occur, but not in adult hMSCs. Of all sources, hESC-MSCs expressed most cardiac-specific genes. hESC-MSCs and fetal hMSCs contained significantly higher basal levels of connexin43 than adult hMSCs and co-culture with nrCMCs increased expression. After co-culture with nrCFBs, hESC-MSCs and fetal hMSCs did not express α-actinin and connexin43 expression was decreased. Conduction velocity (CV) in co-cultures of nrCMCs and hESC-MSCs was significantly higher than in co-cultures with fetal or adult hMSCs. In angiogenesis bioassays, only hESC-MSCs and fetal hMSCs were able to form capillary-like structures, which stained for smooth muscle and endothelial cell markers.Human embryonic and fetal MSCs differentiate toward three different cardiac lineages, in contrast to adult MSCs. Cardiomyogenesis is determined by stimuli from the cellular microenvironment, where connexin43 may play an important role

Functional properties of a Brazilian derived mouse embryonic stem cell line

Pluripotent mouse embryonic stem cells (mESC) are cell lines derived from the inner cell mass of blastocyst-stage early mammalian embryos. Since ion channel modulation has been reported to interfere with both growth and differentiation process in mouse and human ESC it is important to characterize the electrophysiological properties of newly generated mESC and compare them to other lines. In this work, we studied the intercellular communication by way of gap junctions in a Brazilian derived mESC (USP-1, generated by Dr. Lygia Pereira's group) and characterized its electrophysiological properties. We used immunofluorescence and RT-PCR to reveal the presence of connexin 43 (Cx43), pluripotency markers and ion channels. Using a co-culture of neonatal mouse cardiomyocytes with mESC, where the heart cells expressed the enhanced Green Fluorescent Protein, we performed dye injections to assess functional coupling between the two cell types observing dye diffusion. The patch-clamp study showed outward currents identified as two types of potassium currents, transient outward potassium current (Ito) and delayed rectifier outward potassium current (Iks), by use of specific drug blockage. Calcium or sodium currents in undifferentiated mESC were not identified. We conclude that USP-1 mESC has functional Cx43 channels establishing intercellular communication among themselves and with cardiomyocytes and has a similar electrophysiological profile compared to other mESC cell lines