ProNGF Is a Cell-Type-Specific Mitogen for Adult Hippocampal and for Induced Neural Stem Cells

The role of proNGF, the precursor of Nerve Growth Factor (NGF), on the biology of adult neural stem cells (aNSCs) is still unclear. Here I analyzed adult hippo-campal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti-NGF antibody leads to an imbalance of proNGF over mature NGF. I found in-creased proliferation of progenitors but a reduced neurogenesis in the AD11 DG- hippocampus (HP-DG). Also in vitro, AD11 hippocampal neural stem cells (NSCs) pro-liferated more but were unable to differentiate into morphologically mature neu-rons. By treating wild-type (WT) hippocampal progenitors with the uncleavable form of proNGF (proNGF-KR) I demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia-like (RGL) neural stem cells through the induction of cyclin D1 expression. These cells express high level of p75NTR, as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly-dissociated HP-DG or selected in vitro from NSCs by LIF (leukemia inhibitory factor). Clonogenic assay per-formed in the absence of mitogens showed that RGLs respond to proNGF-KR by re-activating their proliferation and thus leading to neurospheres formation. The mito-genic effect of proNGF was further exploited in the expansion of mouse induced Neural Stem Cells (iNSCs). Chronic exposure of iNSCs to proNGF-KR increased their proliferation. Altogether, I demonstrated that proNGF acts as mitogen on hippo-campal and induced neural stem cells.The role of proNGF, the precursor of nerve growth factor (NGF), in the biology of adult neural stem cells (aNSCs) is still unclear. Here, we analyzed adult hippocampal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti-NGF antibody leads to an imbalance of proNGF over mature NGF. We found increased proliferation of progenitors but a reduced neurogenesis in the AD11 dentate gyrus (DG)-hippocampus (HP). Also in vitro, AD11 hippocampal neural stem cells (NSCs) proliferated more, but were unable to differentiate into morphologically mature neurons. By treating wild-type hippocampal progenitors with the uncleavable form of proNGF (proNGF-KR), we demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia-like (RGL) stem cells through the induction of cyclin D1 expression. These cells express high levels of p75NTR, as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly dissociated HP-DG or selected in vitro from NSCs by leukemia inhibitory factor. Clonogenic assay performed in the absence of mitogens showed that RGLs respond to proNGF-KR by reactivating their proliferation and thus leading to neurospheres formation. The mitogenic effect of proNGF was further exploited in the expansion of mouse-induced neural stem cells (iNSCs). Chronic exposure of iNSCs to proNGF-KR increased their proliferation. Altogether, we demonstrated that proNGF acts as mitogen on hippocampal and iNSCs. Stem Cells 2019;37:1223–1237

The emergence of Special and Doubly Special Relativity

Building on our previous work [Phys.Rev.D82,085016(2010)], we show in this paper how a Brownian motion on a short scale can originate a relativistic motion on scales that are larger than particle's Compton wavelength. This can be described in terms of polycrystalline vacuum. Viewed in this way, special relativity is not a primitive concept, but rather it statistically emerges when a coarse graining average over distances of order, or longer than the Compton wavelength is taken. By analyzing the robustness of such a special relativity under small variations in the polycrystalline grain-size distribution we naturally arrive at the notion of doubly-special relativistic dynamics. In this way, a previously unsuspected, common statistical origin of the two frameworks is brought to light. Salient issues such as the role of gauge fixing in emergent relativity, generalized commutation relations, Hausdorff dimensions of representative path-integral trajectories and a connection with Feynman chessboard model are also discussed.Comment: 21 pages, 1 figure, RevTeX4, substantially revised version, accepted in Phys. Rev.

Generalized Uncertainty Principle and the Ramsauer-Townsend Effect

The scattering cross section of electrons in noble gas atoms exhibits a minimum value at electron energies of approximately 1eV. This is the Ramsauer-Townsend effect. In this letter, we study the Ramsauer-Townsend effect in the framework of the Generalized Uncertainty Principle.Comment: 11 pages, 3 figure

Minimum length effects in black hole physics

We review the main consequences of the possible existence of a minimum measurable length, of the order of the Planck scale, on quantum effects occurring in black hole physics. In particular, we focus on the ensuing minimum mass for black holes and how modified dispersion relations affect the Hawking decay, both in four space-time dimensions and in models with extra spatial dimensions. In the latter case, we briefly discuss possible phenomenological signatures.Comment: 29 pages, 12 figures. To be published in "Quantum Aspects of Black Holes", ed. X. Calmet (Springer, 2014

Hawking emission from quantum gravity black holes

We address the issue of modelling quantum gravity effects in the evaporation of higher dimensional black holes in order to go beyond the usual semi-classical approximation. After reviewing the existing six families of quantum gravity corrected black hole geometries, we focus our work on non-commutative geometry inspired black holes, which encode model independent characteristics, are unaffected by the quantum back reaction and have an analytical form compact enough for numerical simulations. We consider the higher dimensional, spherically symmetric case and we proceed with a complete analysis of the brane/bulk emission for scalar fields. The key feature which makes the evaporation of non-commutative black holes so peculiar is the possibility of having a maximum temperature. Contrary to what happens with classical Schwarzschild black holes, the emission is dominated by low frequency field modes on the brane. This is a distinctive and potentially testable signature which might disclose further features about the nature of quantum gravity.Comment: 36 pages, 18 figures, v2: updated reference list, minor corrections, version matching that published on JHE

Effects of quantum gravity on the inflationary parameters and thermodynamics of the early universe

The effects of generalized uncertainty principle (GUP) on the inflationary dynamics and the thermodynamics of the early universe are studied. Using the GUP approach, the tensorial and scalar density fluctuations in the inflation era are evaluated and compared with the standard case. We find a good agreement with the Wilkinson Microwave Anisotropy Probe data. Assuming that a quantum gas of scalar particles is confined within a thin layer near the apparent horizon of the Friedmann-Lemaitre-Robertson-Walker universe which satisfies the boundary condition, the number and entropy densities and the free energy arising form the quantum states are calculated using the GUP approach. A qualitative estimation for effects of the quantum gravity on all these thermodynamic quantities is introduced.Comment: 15 graghes, 7 figures with 17 eps graph

Minimum length, extra dimensions, modified gravity and black hole remnants

We construct a Hilbert space representation of minimum-length deformed uncertainty relation in presence of extra dimensions. Following this construction, we study corrections to the gravitational potential (back reaction on gravity) with the use of correspondingly modified propagator in presence of two (spatial) extra dimensions. Interestingly enough, for $r \rightarrow 0$ the gravitational force approaches zero and the horizon for modified Schwarzschild-Tangherlini space-time disappears when the mass approaches quantum-gravity energy scale. This result points out to the existence of zero-temperature black hole remnants in ADD brane-world model.Comment: 14 pages, 1 figure; Close to the version published in JCA

Ectopic Expression of Neurogenin 2 Alone is Sufficient to Induce Differentiation of Embryonic Stem Cells into Mature Neurons

Recent studies show that combinations of defined key developmental transcription factors (TFs) can reprogram somatic cells to pluripotency or induce cell conversion of one somatic cell type to another. However, it is not clear if single genes can define a cell̀s identity and if the cell fate defining potential of TFs is also operative in pluripotent stem cells in vitro. Here, we show that ectopic expression of the neural TF Neurogenin2 (Ngn2) is sufficient to induce rapid and efficient differentiation of embryonic stem cells (ESCs) into mature glutamatergic neurons. Ngn2-induced neuronal differentiation did not require any additional external or internal factors and occurred even under pluripotency-promoting conditions. Differentiated cells displayed neuron-specific morphology, protein expression, and functional features, most importantly the generation of action potentials and contacts with hippocampal neurons. Gene expression analyses revealed that Ngn2-induced in vitro differentiation partially resembled neurogenesis in vivo, as it included specific activation of Ngn2 target genes and interaction partners. These findings demonstrate that a single gene is sufficient to determine cell fate decisions of uncommitted stem cells thus giving insights into the role of key developmental genes during lineage commitment. Furthermore, we present a promising tool to improve directed differentiation strategies for applications in both stem cell research and regenerative medicine

Comparing two approaches to Hawking radiation of Schwarzschild-de Sitter black holes

We study two different ways to analyze the Hawking evaporation of a Schwarzschild-de Sitter black hole. The first one uses the standard approach of surface gravity evaluated at the possible horizons. The second method derives its results via the Generalized Uncertainty Principle (GUP) which offers a yet different method to look at the problem. In the case of a Schwarzschild black hole it is known that this methods affirms the existence of a black hole remnant (minimal mass $M_{\rm min}$) of the order of Planck mass $m_{\rm pl}$ and a corresponding maximal temperature $T_{\rm max}$ also of the order of $m_{\rm pl}$. The standard $T(M)$ dispersion relation is, in the GUP formulation, deformed in the vicinity of Planck length $l_{\rm pl}$ which is the smallest value the horizon can take. We generalize the uncertainty principle to Schwarzschild-de Sitter spacetime with the cosmological constant $\varLambda=1/m_\varLambda^2$ and find a dual relation which, compared to $M_{\rm min}$ and $T_{\rm max}$, affirms the existence of a maximal mass $M_{\rm max}$ of the order $(m_{\rm pl}/m_\varLambda)m_{\rm pl}$, minimum temperature $T_{\rm min} \sim m_\varLambda$. As compared to the standard approach we find a deformed dispersion relation $T(M)$ close to $l_{\rm pl}$ and in addition at the maximally possible horizon approximately at $r_\varLambda=1/m_\varLambda$. $T(M)$ agrees with the standard results at $l_{\rm pl} \ll r \ll r_\varLambda$ (or equivalently at $M_{\rm min} \ll M \ll M_{\rm max}$).Comment: new references adde

The Level of the Transcription Factor Pax6 Is Essential for Controlling the Balance between Neural Stem Cell Self-Renewal and Neurogenesis

Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells, a mechanism that has marked parallels with the transcriptional control of embryonic stem cell self-renewal