Studies on Myocardial Regeneration

Heart disease is one of the leading causes of adult and child morbidity and mortality. The underlying pathology leads typically to a loss of functional cardiomyocytes that causes heart failure. Because of the insufficient regenerative capacity of the human heart, cardiomyocytes have been thought to be incapable of renewing after the postnatal period. In Paper I, we investigated the capacity of the human heart to generate cardiomycytes. We have taken advantage of the integration of the carbon isotope 14C (carbon-14), generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. Using cardiac Troponin T and I and pericentriolar protein 1 (PCM-1) as a specific marker to isolate cardiomyocyte nuclei by flow cytometry (Paper I and II). We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies. After cardiac infarction the formation of inappropriate scar tissue and cardiac remodeling further contribute to cardiac dysfunction. We provide evidence in Paper III, that inhibition of PDGF signalling reduces scar formation and an augmentation of cardiomyogenesis modulated by increased neoangiogenesis. These findings points to the possibility to therapeutically exploit physiological cardiomyocyte renewal by better understanding processes that modulate cardiac regeneration after heart infarction

Oblicza modernizacji Drugiej Rzeczypospolitej na przykładzie informacyjnych aspektów ogłoszeń prasowych „Przewodnika Katolickiego” (1936) i „Małego Dziennika” (1937)

The article discusses a case of information about widely understood modernization of state and society in late 30’s of the 20th Century on an example of information contained at advertisements of those two magazines. One year’s issue of weekly newspaper („Przewonik Katolicki” from 1936) and daily one („Mały Dziennik” from 1937) have been chosen for query. Both magazines were formally and personally linked with Polish catholic Church. In the article concrete pieces of information, somehow connected with subject of modernization and also history and specificity of both newspapers have been analyzed. On this base it can be claimed that undoubtedly progressive development in the second half of 30’s could be seen in many areas of daily life – this private, personal but also those related with work or social life. In those specific sources the most seen fields or directions of modernization are: promotion of using electricity and electric devices, using gas and gas stoves, advertising modern vehicles and means of transport (bicycles, motorcycles, cars, airplanes), convenience food (made by huge international corporations), medication and cosmetics, promotion of activity-based tourism (trips and pilgrimages), sports equipment. The most seen are: radio, film (movies and cinemas) and photography. Also it can be observed that both magazines promoted modern (of course 80 years ago) methods ant techniques of sale and advertising goods and services

Notch induces cyclin-D1-dependent proliferation during a specific temporal window of neural differentiation in ES cells

AbstractThe Notch signaling pathway controls cell fate choices at multiple steps during cell lineage progression. To produce the cell fate choice appropriate for a particular stage in the cell lineage, Notch signaling needs to interpret the cell context information for each stage and convert it into the appropriate cell fate instruction. The molecular basis for this temporal context-dependent Notch signaling output is poorly understood, and to study this, we have engineered a mouse embryonic stem (ES) cell line, in which short pulses of activated Notch can be produced at different stages of in vitro neural differentiation. Activation of Notch signaling for 6h specifically at day 3 during neural induction in the ES cells led to significantly enhanced cell proliferation, accompanied by Notch-mediated activation of cyclin D1 expression. A reduction of cyclin-D1-expressing cells in the developing CNS of Notch signaling-deficient mouse embryos was also observed. Expression of a dominant negative form of cyclin D1 in the ES cells abrogated the Notch-induced proliferative response, and, conversely, a constitutively active form of cyclin D1 mimicked the effect of Notch on cell proliferation. In conclusion, the data define a novel temporal context-dependent function of Notch and a critical role for cyclin D1 in the Notch-induced proliferation in ES cells

A Realistic Treatment of Geomagnetic Cherenkov Radiation from Cosmic Ray Air Showers

We present a macroscopic calculation of coherent electro-magnetic radiation from air showers initiated by ultra-high energy cosmic rays, based on currents obtained from three-dimensional Monte Carlo simulations of air showers in a realistic geo-magnetic field. We discuss the importance of a correct treatment of the index of refraction in air, given by the law of Gladstone and Dale, which affects the pulses enormously for certain configurations, compared to a simplified treatment using a constant index. We predict in particular a geomagnetic Cherenkov radiation, which provides strong signals at high frequencies (GHz), for certain geometries together with "normal radiation" from the shower maximum, leading to a double peak structure in the frequency spectrum. We also provide some information about the numerical procedures referred to as EVA 1.0.Comment: 15 pages, 26 figure

MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy

Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy

Tracking cell turnover in human brain using 15N-thymidine imaging mass spectrometry

Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly