Glioma Associated Stem Cells (GASCs) Isolation and Culture.

Glioma Associated Stem Cells (GASCs) represent a population of nontumorigenic multipotent stem cells hosted in the microenvironment of human gliomas. In vitro, these cells are able, through the release of exosomes, to increase the biological aggressiveness of glioma-initiating cells. The clinical importance of this finding is supported by the strong prognostic value associated with the GASCs surface immunophenotype thus suggesting that this patient-based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor strom

Magnetoluminescence

Pulsar Wind Nebulae, Blazars, Gamma Ray Bursts and Magnetars all contain regions where the electromagnetic energy density greatly exceeds the plasma energy density. These sources exhibit dramatic flaring activity where the electromagnetic energy distributed over large volumes, appears to be converted efficiently into high energy particles and gamma-rays. We call this general process magnetoluminescence. Global requirements on the underlying, extreme particle acceleration processes are described and the likely importance of relativistic beaming in enhancing the observed radiation from a flare is emphasized. Recent research on fluid descriptions of unstable electromagnetic configurations are summarized and progress on the associated kinetic simulations that are needed to account for the acceleration and radiation is discussed. Future observational, simulation and experimental opportunities are briefly summarized.Comment: To appear in "Jets and Winds in Pulsar Wind Nebulae, Gamma-ray Bursts and Blazars: Physics of Extreme Energy Release" of the Space Science Reviews serie

Cardiovascular development: towards biomedical applicability: Regulation of cardiomyocyte differentiation of embryonic stem cells by extracellular signalling

Investigating the signalling pathways that regulate heart development is essential if stem cells are to become an effective source of cardiomyocytes that can be used for studying cardiac physiology and pharmacology and eventually developing cell-based therapies for heart repair. Here, we briefly describe current understanding of heart development in vertebrates and review the signalling pathways thought to be involved in cardiomyogenesis in multiple species. We discuss how this might be applied to stem cells currently thought to have cardiomyogenic potential by considering the factors relevant for each differentiation step from the undifferentiated cell to nascent mesoderm, cardiac progenitors and finally a fully determined cardiomyocyte. We focus particularly on how this is being applied to human embryonic stem cells and provide recent examples from both our own work and that of others

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

A synoptic view of the expression of genes controlling adult neurogenesis of dopaminergic neurones in the olfactory bulb

During neurogenesis nerve cells are generated according to a precise spatio-temporal schedule, so that cohorts of newly-generated neurons settle in defined locations and establish appropriate connections with specific partners. At precise ontogenetic stages, the specification of neural progenitors is subject to complex regulatory mechanisms, needed to determine the neuronal types, the required quantities, and the specific location of their implant. In spite of our expanding knowledge of these phenomena, we miss an ensemble view of the process. To better understand the interplay of the different factors controlling this process, we have studied the variation in the expression of over 40 genes involved in the neuronal differentiation of dopaminergic (DA) neurones during adult neurogenesis in the olfactory bulb at three different stages of maturation. To this end, we have exploited a peculiar property of DA neurones in a transgenic line of animals expressing eGFP under the TH promoter, which is a direct relationship between the intensity of fluorescence and the degree of maturation. Using the fluorescence-activated cell sorting after enzymatic dissociation of the olfactory bulb we have separated the fluorescent cells as a function of their level of fluorescence in three groups, corresponding to immature, intermediate and fully mature DA neurones, and we have performed semiquantitative RT-PCRs. The results provide, for the first time, a synoptic view of how a large number of different factors controlling the dopaminergic differentiation vary their expression during the maturation of DA neurones. We have divided these factors in three groups: 1) Key regulators of the dopaminergic phenotype, 2) Phenotype-independent regulators, and 3) Regulators of OB differentiation through olfactory neuron innervations of the olfactory bulb. The first group includes AP-1, CREB, Dlx1 and 2, Engrailed-1, ER-81, Gsh-2, basic helix-loop-helix transcription factors (Mash1, Id2, and Hes1), Meis-2, Nurr-1, Pax-6, Zic 1 and 3. The second group includes DCX, Ephrin A2, Myst-4Notch-1, Olig-2, Prok-2, PSA- NCAM, genes involved in the reelin cascade (Reelin, APOEr2, VLDLR and Dab1), Shh, Slit 1 and2, Tenascin r, Vax-1. The third group includes ARX, CNG2, Dlx5, FezF1, Big2-Contactin4. For all these genes we provide a quantitative description of the level of expression in three different phases of maturation, a picture that becomes particularly instructive when the variations are looked synoptically. We believe that this will contribute to a better understanding of the complex signaling system required to make dopaminergic neurons in the adult olfactory bulb

The influence of viral infection on a plankton ecosystem undergoing nutrient enrichment

It is increasingly recognised that viruses are a significant active component of oceanic plankton ecosystems. They play an important role in biogeochemical cycles as well as being implicated in observed patterns of species abundance and diversity. The influence of viral infection in plankton ecosystems is not fully understood. Here we use a number of well-founded mathematical models to investigate the interplay of the ecological and epidemiological interactions of plankton and viruses in the sea. Of particular interest is the role of nutrient on the population dynamics. Nutrient forcing has been suggested as a means of absorbing excess anthropogenic atmospheric carbon dioxide by stimulating increased phytoplankton primary productivity. Here we show that enriching nutrient levels in the sea may decrease the amount of infected phytoplankton species thereby additionally enhancing the efficiency of the biological pump, a means by which carbon is transferred from the atmosphere to the deep ocean

Adult cardiac stem cell aging: A reversible stochastic phenomenon?

Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic cellular and molecular changes in cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of cardiac aging have been the subject of intense study, the recent discovery that cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous cardiac stem cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of cell turnover and renewal, has now been replaced by a dynamic model in which cardiac cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. However, CSC aging could be a programmed cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths