Why TDP-43? Why not? Mechanisms of metabolic dysfunction in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder for which there is no effective curative treatment available and minimal palliative care. Mutations in the gene encoding the TAR DNA-binding protein 43 (TDP-43) are a well-recognized genetic cause of ALS, and an imbalance in energy homeostasis correlates closely to disease susceptibility and progression. Considering previous research supporting a plethora of downstream cellular impairments originating in the histopathological signature of TDP-43, and the solid evidence around metabolic dysfunction in ALS, a causal association between TDP-43 pathology and metabolic dysfunction cannot be ruled out. Here we discuss how TDP-43 contributes on a molecular level to these impairments in energy homeostasis, and whether the protein’s pathological effects on cellular metabolism differ from those of other genetic risk factors associated with ALS such as superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72) and fused in sarcoma (FUS)

Searching for galaxy clusters in the VST-KiDS Survey

We present the methods and first results of the search for galaxy clusters in the Kilo Degree Survey (KiDS). The adopted algorithm and the criterium for selecting the member galaxies are illustrated. Here we report the preliminary results obtained over a small area (7 sq. degrees), and the comparison of our cluster candidates with those found in the RedMapper and SZ Planck catalogues; the analysis to a larger area (148 sq. degrees) is currently in progress. By the KiDS cluster search, we expect to increase the completeness of the clusters catalogue to z = 0.6-0.7 compared to RedMapper.Comment: 5 pages, 4 figures, to be published in the Proceedings of the Conference "The Universe of Digital Sky Surveys", Naples, November 25-28 201

Abundance and evolution of galaxy clusters in cosmological models with massive neutrino

The time evolution of the number density of galaxy clusters and their mass and temperature functions are used to constrain cosmological parameters in the spatially flat dark matter models containing a fraction of hot particles (massive neutrino) additional to cold and baryonic matter. We test the modified MDM models with cosmic gravitational waves and show that they neither pass the cluster evolution test nor reproduce the observed height of the first acoustic peak in $\Delta T/T$ spectrum, and therefore should be ruled out. The models with a non-zero cosmological constant are in better agreement with observations. We estimate the free cosmological parameters in $\Lambda$MDM with a negligible abundance of gravitational waves, and find that within the parameter ranges $h\in (0.6, 0.7)$, $n\in (0.9, 1.1)$, (i) the value of $\Omega_\Lambda$ is strongly affected by a small fraction of hot dark matter, $f_\nu\equiv\Omega_\nu /\Omega_m\in (0, 0.2)$: $0.45 <\Omega_\Lambda <0.7$ ($1\sigma$ CL), and (ii) the redshift evolution of galaxy clusters alone reveals the following explicit correlation between $\Omega_\Lambda$ and $f_\nu$: $\Omega_\Lambda +0.5f_\nu =0.65\pm 0.1$. The present accuracy of observational data allows only to bound the fraction of hot matter, $f_\nu\in (0, 0.2)$ (the number of massive neutrino species remains undelimited, $N_\nu =1, 2, 3$).Comment: 9 pages, 7 figures, submitted in A&

Forces between elongated particles in a nematic colloid

Using molecular dynamics simulations we study the interactions between elongated colloidal particles (length to breath ratio ≫1) in a nematic host. The simulation results are compared to the results of a Landau–de Gennes elastic free energy. We find that depletion forces dominate for the sizes of the colloidal particles studied. The tangential component of the force, however, allows us to resolve the elastic contribution to the total interaction. We find that this contribution differs from the quadrupolar interaction predicted at large separations. The difference is due to the presence of nonlinear effects, namely, the change in the positions and structure of the defects and their annihilation at small separations

Comparison of structural transformations and superconductivity in compressed Sulfur and Selenium

Density-functional calculations are presented for high-pressure structural phases of S and Se. The structural phase diagrams, phonon spectra, electron-phonon coupling, and superconducting properties of the isovalent elements are compared. We find that with increasing pressure, Se adopts a sequence of ever more closely packed structures (beta-Po, bcc, fcc), while S favors more open structures (beta-Po, simple cubic, bcc). These differences are shown to be attributable to differences in the S and Se core states. All the compressed phases of S and Se considered are calculated to have weak to moderate electron-phonon coupling strengths consistent with superconducting transition temperatures in the range of 1 to 20 K. Our results compare well with experimental data on the beta-Po --> bcc transition pressure in Se and on the superconducting transition temperature in beta-Po S. Further experiments are suggested to search for the other structural phases predicted at higher pressures and to test theoretical results on the electron-phonon interaction and superconducting properties

Transcriptomic analysis of human astrocytes in vitro reveals hypoxia-induced mitochondrial dysfunction, modulation of metabolism, and dysregulation of the immune response

Hypoxia is a feature of neurodegenerative diseases, and can both directly and indirectly impact on neuronal function through modulation of glial function. Astrocytes play a key role in regulating homeostasis within the central nervous system, and mediate hypoxia-induced changes in response to reduced oxygen availability. The current study performed a detailed characterization of hypoxia-induced changes in the transcriptomic profile of astrocytes in vitro. Human astrocytes were cultured under normoxic (5% CO2, 95% air) or hypoxic conditions (1% O2, 5% CO2, 94% N2) for 24 h, and the gene expression profile assessed by microarray analysis. In response to hypoxia 4904 genes were significantly differentially expressed (1306 upregulated and 3598 downregulated, FC ≥ 2 and p ≤ 0.05). Analysis of the significant differentially expressed transcripts identified an increase in immune response pathways, and dysregulation of signalling pathways, including HIF-1 (p = 0.002), and metabolism, including glycolysis (p = 0.006). To assess whether the hypoxia-induced metabolic gene changes observed affected metabolism at a functional level, both the glycolytic and mitochondrial flux were measured using an XF bioanalyser. In support of the transcriptomic data, under physiological conditions hypoxia significantly reduced mitochondrial respiratory flux (p = 0.0001) but increased basal glycolytic flux (p = 0.0313). However, when metabolically stressed, hypoxia reduced mitochondrial spare respiratory capacity (p = 0.0485) and both glycolytic capacity (p = 0.0001) and glycolytic reserve (p &lt; 0.0001). In summary, the current findings detail hypoxia-induced changes in the astrocyte transcriptome in vitro, identifying potential targets for modifying the astrocyte response to reduced oxygen availability in pathological conditions associated with ischaemia/hypoxia, including manipulation of mitochondrial function, metabolism, and the immune response

Lipid metabolism in astrocytic structure and function

Astrocytes are the most abundant glial cell in the central nervous system and are involved in multiple processes including metabolic homeostasis, blood brain barrier regulation and neuronal crosstalk. Astrocytes are the main storage point of glycogen in the brain and it is well established that astrocyte uptake of glutamate and release of lactate prevents neuronal excitability and supports neuronal metabolic function. However, the role of lipid metabolism in astrocytes in relation to neuronal support has been until recently, unclear. Lipids play a fundamental role in astrocyte function, including energy generation, membrane fluidity and cell to cell signaling. There is now emerging evidence that astrocyte storage of lipids in droplets has a crucial physiological and protective role in the central nervous system. This pathway links β-oxidation in astrocytes to inflammation, signalling, oxidative stress and mitochondrial energy generation in neurons. Disruption in lipid metabolism, structure and signalling in astrocytes can lead to pathogenic mechanisms associated with a range of neurological disorders

A No-Go Theorem for the Nonabelian Topological Mass Mechanism in Four Dimensions

We prove that there is no power-counting renormalizable nonabelian generalization of the abelian topological mass mechanism in four dimensions. The argument is based on the technique of consistent deformations of the master equation developed by G. Barnich and one of the authors. Recent attempts involving extra fields are also commented upon.Comment: 12 pages, latex fil

Magnetic fields in supernova remnants and pulsar-wind nebulae

We review the observations of supernova remnants (SNRs) and pulsar-wind nebulae (PWNe) that give information on the strength and orientation of magnetic fields. Radio polarimetry gives the degree of order of magnetic fields, and the orientation of the ordered component. Many young shell supernova remnants show evidence for synchrotron X-ray emission. The spatial analysis of this emission suggests that magnetic fields are amplified by one to two orders of magnitude in strong shocks. Detection of several remnants in TeV gamma rays implies a lower limit on the magnetic-field strength (or a measurement, if the emission process is inverse-Compton upscattering of cosmic microwave background photons). Upper limits to GeV emission similarly provide lower limits on magnetic-field strengths. In the historical shell remnants, lower limits on B range from 25 to 1000 microGauss. Two remnants show variability of synchrotron X-ray emission with a timescale of years. If this timescale is the electron-acceleration or radiative loss timescale, magnetic fields of order 1 mG are also implied. In pulsar-wind nebulae, equipartition arguments and dynamical modeling can be used to infer magnetic-field strengths anywhere from about 5 microGauss to 1 mG. Polarized fractions are considerably higher than in SNRs, ranging to 50 or 60% in some cases; magnetic-field geometries often suggest a toroidal structure around the pulsar, but this is not universal. Viewing-angle effects undoubtedly play a role. MHD models of radio emission in shell SNRs show that different orientations of upstream magnetic field, and different assumptions about electron acceleration, predict different radio morphology. In the remnant of SN 1006, such comparisons imply a magnetic-field orientation connecting the bright limbs, with a non-negligible gradient of its strength across the remnant.Comment: 20 pages, 24 figures; to be published in SpSciRev. Minor wording change in Abstrac

Noise reduction in 3D noncollinear parametric amplifier

We analytically find an approximate Bloch-Messiah reduction of a noncollinear parametric amplifier pumped with a focused monochromatic beam. We consider type I phase matching. The results are obtained using a perturbative expansion and scaled to a high gain regime. They allow a straightforward maximization of the signal gain and minimization of the parametric fluorescence noise. We find the fundamental mode of the amplifier, which is an elliptic Gaussian defining the optimal seed beam shape. We conclude that the output of the amplifier should be stripped of higher order modes, which are approximately Hermite-Gaussian beams. Alternatively, the pump waist can be adjusted such that the amount of noise produced in the higher order modes is minimized.Comment: 18 pages, 9 figures, accepted to Applied Physics