The role of histone deacetylase 1 in neuronal development of PC12 Cells

Histondeazetylasen entfernen Acetylgruppen von Histonproteinen und haben damit eine wichtige Funktion in der Repression von Genen. Epigentische Mechanismen steuern biologisch bedeutsame Prozesse, unter anderem die Differenzierung von pluripotente Stammzellen zu neuronalen Zellen. Dieser Vorgang wird durch den Erwerb von definierten Genexpressionsmustern charakterisiert. Das Hauptaugenmerk der arbeit liegt in der Untersuchung der Histondeazetylase 1 (HDAC1) in der neuronaler Differenzierung. HDAC1 ist ein Mitglied der Proteinfamilie der Histondeazetylasen und wird in verschiedenen nukleären Regulationskomplexen gefunden. PC12 Zellen sind ein oft verwendetes Modelsystem zur Untersuchung von Differenzierungsprozessen. Behandlung von PC12 Zellen mit neuronalem Wachstumsfaktor (Neuronal Growth Factor (NGF)) induziert neuronale Differenzierung und führt zur Ausbildung von Axon-ähnlichen neuronalen Strukturen. Dieses System erlaubt zusätzlich die Untersuchung unterschiedlicher chemischer Verbindungen zur Inhibierung von Histondeazetylasen. Eine seit kurzem bekannte Verbindung mit dem Namen MS-275 zeigt grosse Spezifität in der Inhibierung von HDAC1 und wird in klinischen Versuchen bereits in der Behandlung von Tumoren des Nervensystems mit viel versprechenden Ergebnissen eingesetzt. In dieser Arbeit wurde eine Methode zur Quantifizierung der neuronalen Differenzierung in PC12 Zellen entwickelt. Es konnte gezeigt werden, dass Behandlung mit MS-275 die NGF induzierte neuronale Differenzierung in PC12 Zellen signifikant verstärkt. Zusätzlich konnte eine erhöhte Expression des neuronalen Markerproteins Neurofilament Medium festgestellt werden. Im Gegenzug dazu führte die ektopische Überexpression von HDAC1 zu einer Blockade der von NGF induzierten neuronalen Differenzierung in PC12 Zellen. Die Ergebnisse dieser Arbeit könnten zu einem besseren Verständnis der Wirkungsweise von Inhibitoren der Histondeazetylasen im Zuge von klinischen Behandlungen beitragen.Histone deacetylases mediate gene repression by the removal of acetyl groups from core histones. Neuronal differentiation relies on a complex signaling network and constitutes a prime example on how epigenetic modifications regulate cell-fate specification. Progression from non-neuronal pluripotent stem cells to a restricted neural lineage is characterized by acquisition and maintenance of distinct patterns of gene expression. The interest of this work was the role of histone deacetylase 1 (HDAC1), a vital member of the protein family of histone deacetylases, in neuronal differentiation, utilizing the rat cell line PC12. HDAC1 constitutes a component of numerous nuclear multi-protein complexes involved in neuronal development and is thereby a potential regulator of neuron-specific gene expression. PC12 cells represent a well established and feasible model system to study various mechanisms involved in neurogenesis. Neuronal growth factor (NGF) induces reversible neuronal differentiation accompanied by the outgrowth of axon-like neuronal structures, a process that can be conveniently assessed and manipulated in this in vitro cell system. A wide collection of histone deacetylase inhibitors (HDIs), varying in specificity for different HDACs, are available to clarify the role of histone deacetylation in the establishment of the neuronal phenotype. The novel HDI MS-275 shows high specificity for HDAC1 and, according to recent clinical trials, represents a promising candidate in the treatment of cancers of the nervous system. A neuronal outgrowth assay was developed to allow standardized quantification of neuronal development and it could thereby be demonstrated that treatment with the HDI MS-275 significantly enhanced NGF-induced differentiation in PC12 cells. In addition, our studies showed induction of the neuronal marker gene neurofilament medium protein upon treatment with MS-275. Conversely, ectopic overexpression of HDAC1 protein in PC12 cells led to a block neuronal differentiation. These results could provide an explanation for the clinical applicability of histone deacetylase inhibitors in the treatment of cancers of the nervous system and demonstrate the significance of epigenetic mechanisms in the process of neurogenesis

Seesaw and noncommutative geometry

The 1-loop corrections to the seesaw mechanism in the noncommutative standard model are computed. Other consequences of the Lorentzian signature in the inner space are summarised.Comment: Dedicated to Alain Connes on the occasion of his 60th birthda

Spectral action and big desert

The values of the Higgs mass are obtained for two possibilities of extending the standard model in a way compatible with the existence of a noncommutative structure at high energies. We assume the existence of a big desert between the low energy electroweak scale and the high energy scale $\Lambda = 1.1\times 10^{17}$ GeV, where noncommutative features become relevant. We conclude that it is extremely difficult to depart from the Higgs mass value $m_H= 175.1^{+5.8}_{-9.8}$ GeV obtained from noncommutative geometry for the standard model with three generations only.Comment: 11 pages, 1 figure, 3 table

Modified Pati-Salam Model from Z7Z_7 orbifolded AdS/CFT

We consider models built on $AdS_5\otimes S^5/\Gamma$ orbifold compactifications of the type $IIB$ superstring, where $\Gamma$ is the abelian group $Z_n$. An attractive three family $\mathcal{N}=0$ SUSY model is found for $n=7$ that is a modified Pati--Salam Model which reduced to the Standard Model after symmetry breaking.Comment: 8 pages, 1 figure, Phenomenology section revised to correct renormalization group equations, typos correcte

Effect of positron-alkali metal atom interactions in the diffuse interstellar medium

In the Milky Way galaxy, positrons, which are responsible for the diffuse 511 keV gamma ray emission observed by space-based gamma ray observatories, are thought to annihilate predominantly through charge exchange interactions with neutral hydrogen. These charge exchange interactions can only take place if positrons have energies greater than 6.8 eV, the minimum energy required to liberate the electron bound to the hydrogen atom and then form positronium, a short-lived bound state composed of a positron-electron pair. Here we demonstrate the importance of positron interactions with neutral alkali metals in the warm interstellar medium (ISM). Positrons may undergo charge exchange with these atoms at any energy. In particular, we show that including positron interactions with sodium at solar abundance in the warm ISM can significantly reduce the annihilation timescale of positrons with energies below 6.8 eV by at least an order of magnitude. We show that including these interactions in our understanding of positron annihilation in the Milky Way rules out the idea that the number of positrons in the Galactic ISM could be maintained in steady state by injection events occurring at a typical periodicity >Myr

The Power of Problem Based Learning beyond its Didactic Attributes

Hybrid courses with a focus on practice-orientated education and self-guided learning phases are on the rise on the higher education sector. Disciplines in Life Sciences implicate a high degree of practical laboratory expertise. The University of Applied Sciences (UAS) in Vienna, Austria, has thus been endeavoured offering students a high qualitative education integrating hybrid courses based on PBL principles, which consist of on-site (including the transmission of necessary background and practical laboratory training) and off-site (including self-study phases) sessions. As practical laboratory units are central in those courses, the restrictive measures, including the transition to a complete online teaching format due to the first Covid-19-pandemic lock-down, had severe effects on the implementation and the quality of the curriculum. According to surveys made specifically to address this problematic situation, it can be concluded that on-site practical units are fundamental for certain disciplines such as Life Sciences

The relationship between substructure in 2D X-ray surface brightness images and weak lensing mass maps of galaxy clusters: A simulation study

In this paper, we undertake a study to determine what insight can be reliably gleaned from the comparison of the X-ray and the weak lensing mass maps of galaxy clusters. We do this by investigating the 2D substructure within three high-resolution cosmological simulations of galaxy clusters. Our main results focus on non-radiative gas dynamics, but we also consider the effects of radiative cooling at high redshift. For our analysis, we use a novel approach, based on unsharp-masking, to identify substructures in 2D surface mass density and X-ray surface brightness maps. At full resolution (~ 15 h^-1 kpc), this technique is capable of identifying almost all self-bound dark matter subhaloes with M>10^12 h^-1 M_sun. We also report a correlation between the mass of a subhalo and the area of its corresponding 2D detection; such a correlation, once calibrated, could provide a useful estimator for substructure mass. Comparing our 2D mass and X-ray substructures, we find a surprising number of cases where the matching fails: around one third of galaxy-sized substructures have no X-ray counterpart. Some interesting cases are also found at larger masses, in particular the cores of merging clusters where the situation can be complex. Finally, we degrade our mass maps to what is currently achievable with weak-lensing observations (~100 h^-1 kpc at z=0.2). While the completeness mass limit increases by around an order of magnitude, a mass-area correlation remains. Our paper clearly demonstrates that the next generation of lensing surveys should start to reveal a wealth of information on cluster substructure. (Abridged)Comment: 30 pages, 27 figures, 3 tables. Accepted for publication in MNRAS. High resolution version available at http://www.physics.ox.ac.uk/users/powell/clustersubs_highres.pd

Matching conditions and Higgs mass upper bounds revisited

Matching conditions relate couplings to particle masses. We discuss the importance of one-loop matching conditions in Higgs and top-quark sector as well as the choice of the matching scale. We argue for matching scales $\mu_{0,t} \simeq m_t$ and $\mu_{0,H} \simeq max[ m_t, M_H ]$. Using these results, the two-loop Higgs mass upper bounds are reanalyzed. Previous results for $\Lambda\approx$ few TeV are found to be too stringent. For $\Lambda=10^{19}$ GeV we find $M_H < 180 \pm 4\pm 5$ GeV, the first error indicating the theoretical uncertainty, the second error reflecting the experimental uncertainty due to $m_t=175\pm6$ GeV.Comment: 20 pages, 6 figures; uses epsf and rotate macro

The Delay of Population III Star Formation by Supersonic Streaming Velocities

It has recently been demonstrated that coherent relative streaming velocities of order 30 km / s between dark matter and gas permeated the universe on scales below a few Mpc directly after recombination. We here use a series of high-resolution moving-mesh calculations to show that these supersonic motions significantly influence the virialization of the gas in minihalos, and delay the formation of the first stars. As the gas streams into minihalos with bulk velocities around 1 km / s at z ~ 20, the additional momentum and energy input reduces the gas fractions and central densities of the halos, increasing the typical virial mass required for efficient cooling by a factor of three, and delaying Population III star formation by dz ~ 4. Since the distribution of the magnitude of the streaming velocities is narrowly peaked around a non-negligible value, this effect is important in most regions of the universe. As a consequence, the increased minimum halo mass implies a reduction of the absolute number of minihalos that can be expected to cool and form Population III stars by up to an order of magnitude. We further find that the streaming velocities increase the turbulent velocity dispersion of the minihalo gas, which could affect its ability to fragment and hence alter the mass function of the first stars.Comment: 6 pages, 5 figures, accepted for publication in Ap

X-ray Properties of Young Early Type Galaxies: I. X-ray Luminosity Function of LMXBs

We have compared the combined X-ray luminosity function (XLF) of LMXBs detected in Chandra observations of young, post-merger elliptical galaxies, with that of typical old elliptical galaxies. We find that the XLF of the 'young' sample does not present the prominent high luminosity break at LX > 5 x 1038 erg s-1 found in the old elliptical galaxy XLF. The 'young' and 'old' XLFs differ with a 3{\sigma} statistical significance (with a probability less than 0.2% that they derive from the same underlying parent distribution). Young elliptical galaxies host a larger fraction of luminous LMXBs (LX > 5 x 1038 erg s-1) than old elliptical galaxies and the XLF of the young galaxy sample is intermediate between that of typical old elliptical galaxies and that of star forming galaxies. This observational evidence may be related to the last major/minor mergers and the associated star formation.Comment: 18 pages, 4 figures, accepted for publication in Ap