Challenges for brain repair: insights from adult neurogenesis in birds and mammals

Adult neurogenesis is a widespread phenomenon occurring in many species, including humans. The functional and therapeutic implications of this form of brain plasticity are now beginning to be realized. Comparative approaches to adult neurogenesis will yield important clues about brain repair. Here, we compare adult neurogenesis in birds and mammals. We review recent studies on the glial identity of stem cells that generate new neurons, the different modes of migration used by the newly generated neurons to reach their destinations, and how these systems respond to experimentally induced cell death. We integrate these findings to address how comparative analysis at the molecular level might be used for brain repair

Spatially fractional-order viscoelasticity, non-locality and a new kind of anisotropy

Spatial non-locality of space-fractional viscoelastic equations of motion is studied. Relaxation effects are accounted for by replacing second-order time derivatives by lower-order fractional derivatives and their generalizations. It is shown that space-fractional equations of motion of an order strictly less than 2 allow for a new kind anisotropy, associated with angular dependence of non-local interactions between stress and strain at different material points. Constitutive equations of such viscoelastic media are determined. Explicit fundamental solutions of the Cauchy problem are constructed for some cases isotropic and anisotropic non-locality

Fractional diffusion modeling of ion channel gating

An anomalous diffusion model for ion channel gating is put forward. This scheme is able to describe non-exponential, power-law like distributions of residence time intervals in several types of ion channels. Our method presents a generalization of the discrete diffusion model by Millhauser, Salpeter and Oswald [Proc. Natl. Acad. Sci. USA 85, 1503 (1988)] to the case of a continuous, anomalous slow conformational diffusion. The corresponding generalization is derived from a continuous time random walk composed of nearest neighbor jumps which in the scaling limit results in a fractional diffusion equation. The studied model contains three parameters only: the mean residence time, a characteristic time of conformational diffusion, and the index of subdiffusion. A tractable analytical expression for the characteristic function of the residence time distribution is obtained. In the limiting case of normal diffusion, our prior findings [Proc. Natl. Acad. Sci. USA 99, 3552 (2002)] are reproduced. Depending on the chosen parameters, the fractional diffusion model exhibits a very rich behavior of the residence time distribution with different characteristic time-regimes. Moreover, the corresponding autocorrelation function of conductance fluctuations displays nontrivial features. Our theoretical model is in good agreement with experimental data for large conductance potassium ion channels

Lattice Kinetics of Diffusion-Limited Coalescence and Annihilation with Sources

We study the 1D kinetics of diffusion-limited coalescence and annihilation with back reactions and different kinds of particle input. By considering the changes in occupation and parity of a given interval, we derive sets of hierarchical equations from which exact expressions for the lattice coverage and the particle concentration can be obtained. We compare the mean-field approximation and the continuum approximation to the exact solutions and we discuss their regime of validity.Comment: 24 pages and 3 eps figures, Revtex, accepted for publication in J. Phys.

Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling

Neuroinflammation is characterized by activation of microglial cells, followed by production of nitric oxide (NO), which may have different outcomes on neurogenesis, favoring or inhibiting this process. In the present study, we investigated how the inflammatory mediator NO can affect proliferation of neural stem cells (NSCs), and explored possible mechanisms underlying this effect. We investigated which mechanisms are involved in the regulation of NSC proliferation following treatment with an inflammatory stimulus (lipopolysaccharide plus IFN-gamma), using a culture system of subventricular zone (SVZ)-derived NSCs mixed with microglia cells obtained from wild-type mice (iNOS(+/+)) or from iNOS knockout mice (iNOS(-/-)). We found an impairment of NSC cell proliferation in iNOS(+/+) mixed cultures, which was not observed in iNOS(-/-) mixed cultures. Furthermore, the increased release of NO by activated iNOS(+/+) microglial cells decreased the activation of the ERK/MAPK signaling pathway, which was concomitant with an enhanced nitration of the EGF receptor. Preventing nitrogen reactive species formation with MnTBAP, a scavenger of peroxynitrite (ONOO-), or using the ONOO- degradation catalyst FeTMPyP cell proliferation and ERK signaling were restored to basal levels in iNOS(+/+) mixed cultures. Moreover, exposure to the NO donor NOC-18 (100 mu M), for 48 h, inhibited SVZ-derived NSC proliferation. Regarding the antiproliferative effect of NO, we found that NOC-18 caused the impairment of signaling through the ERK/MAPK pathway, which may be related to increased nitration of the EGF receptor in NSC. Using MnTBAP nitration was prevented, maintaining ERK signaling, rescuing NSC proliferation. We show that NO from inflammatory origin leads to a decreased function of the EGF receptor, which compromised proliferation of NSC. We also demonstrated that NO-mediated nitration of the EGF receptor caused a decrease in its phosphorylation, thus preventing regular proliferation signaling through the ERK/MAPK pathway.Foundation for Science and Technology, (FCT, Portugal); COMPETE; FEDER [PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014, PTDC/SAU-NEU/102612/2008, PTDC/NEU-OSD/0473/2012]; FCT, Portugal [SERH/BPD/78901/2011, SERH/BD/38127/2007, SFRH/BD/77903/2011, SFRH/BD/79308/2011]info:eu-repo/semantics/publishedVersio

Analysis of Fourier transform valuation formulas and applications

The aim of this article is to provide a systematic analysis of the conditions such that Fourier transform valuation formulas are valid in a general framework; i.e. when the option has an arbitrary payoff function and depends on the path of the asset price process. An interplay between the conditions on the payoff function and the process arises naturally. We also extend these results to the multi-dimensional case, and discuss the calculation of Greeks by Fourier transform methods. As an application, we price options on the minimum of two assets in L\'evy and stochastic volatility models.Comment: 26 pages, 3 figures, to appear in Appl. Math. Financ

Randomly Crosslinked Macromolecular Systems: Vulcanisation Transition to and Properties of the Amorphous Solid State

As Charles Goodyear discovered in 1839, when he first vulcanised rubber, a macromolecular liquid is transformed into a solid when a sufficient density of permanent crosslinks is introduced at random. At this continuous equi- librium phase transition, the liquid state, in which all macromolecules are delocalised, is transformed into a solid state, in which a nonzero fraction of macromolecules have spontaneously become localised. This solid state is a most unusual one: localisation occurs about mean positions that are distributed homogeneously and randomly, and to an extent that varies randomly from monomer to monomer. Thus, the solid state emerging at the vulcanisation transition is an equilibrium amorphous solid state: it is properly viewed as a solid state that bears the same relationship to the liquid and crystalline states as the spin glass state of certain magnetic systems bears to the paramagnetic and ferromagnetic states, in the sense that, like the spin glass state, it is diagnosed by a subtle order parameter. In this review we give a detailed exposition of a theoretical approach to the physical properties of systems of randomly, permanently crosslinked macromolecules. Our primary focus is on the equilibrium properties of such systems, especially in the regime of Goodyear's vulcanisation transition.Comment: Review Article, REVTEX, 58 pages, 3 PostScript figure

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

A coordinated DNA damage response promotes adult quiescent neural stem cell activation

Stem and differentiated cells frequently differ in their response to DNA damage, which can determine tissue sensitivity. By exploiting insight into the spatial arrangement of subdomains within the adult neural subventricular zone (SVZ) in vivo, we show distinct responses to ionising radiation (IR) between neural stem and progenitor cells. Further, we reveal different DNA damage responses between neonatal and adult neural stem cells (NSCs). Neural progenitors (transit amplifying cells and neuroblasts) but not NSCs (quiescent and activated) undergo apoptosis after 2 Gy IR. This response is cell type- rather than proliferationdependent and does not appear to be driven by distinctions in DNA damage induction or repair capacity. Moreover, exposure to 2 Gy IR promotes proliferation arrest and differentiation in the adult SVZ. These 3 responses are ataxia telangiectasia mutated (ATM)- dependent and promote quiescent NSC (qNSC) activation, which does not occur in the subdomains that lack progenitors. Neuroblasts arising post-IR derive from activated qNSCs rather than irradiated progenitors, minimising damage compounded by replication or mitosis. We propose that rather than conferring sensitive cell death, apoptosis is a form of rapid cell death that serves to remove damaged progenitors and promote qNSC activation. Significantly, analysis of the neonatal (P5) SVZ reveals that although progenitors remain sensitive to apoptosis, they fail to efficiently arrest proliferation. Consequently, their repopulation occurs rapidly from irradiated progenitors rather than via qNSC activation