Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the FUS gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies

Identification of two chickpea multidrug and toxic compound extrusion transporter genes transcriptionally upregulated upon aluminum treatment in root tips

Aluminum (Al) toxicity poses a significant challenge for the yield improvement of chickpea, which is an economically important legume crop with high nutritional value in human diets. The genetic basis of Al-tolerance in chickpea remains unclear. Here, we assessed the Al-tolerance of 8 wild Cicer and one cultivated chickpea (PBA Pistol) accessions by measuring the root elongation in solution culture under control (0 μM Al3+) and Al treatments (15, 30 μM Al3+). Compared to PBA Pistol, the wild Cicer accessions displayed both tolerant and sensitive phenotypes, supporting wild Cicer as a potential genetic pool for Al-tolerance improvement. To identify potential genes related to Al-tolerance in chickpea, genome-wide screening of multidrug and toxic compound extrusion (MATE) encoding genes was performed. Fifty-six MATE genes were identified in total, which can be divided into 4 major phylogenetic groups. Four chickpea MATE genes (CaMATE1-4) were clustered with the previously characterized citrate transporters MtMATE66 and MtMATE69 in Medicago truncatula. Transcriptome data showed that CaMATE1-4 have diverse expression profiles, with CaMATE2 being root-specific. qRT-PCR analyses confirmed that CaMATE2 and CaMATE4 were highly expressed in root tips and were up-regulated upon Al treatment in all chickpea lines. Further measurement of carboxylic acids showed that malonic acid, instead of malate or citrate, is the major extruded acid by Cicer spp. root. Protein structural modeling analyses revealed that CaMATE2 has a divergent substrate-binding cavity from Arabidopsis AtFRD3, which may explain the different acid-secretion profile for chickpea. Pangenome survey showed that CaMATE1-4 have much higher genetic diversity in wild Cicer than that in cultivated chickpea. This first identification of CaMATE2 and CaMATE4 responsive to Al3+ treatment in Cicer paves the way for future functional characterization of MATE genes in Cicer spp., and to facilitate future design of gene-specific markers for Al-tolerant line selection in chickpea breeding programs

The effect of finite-range interactions in classical transport theory

The effect of scattering with non-zero impact parameters between consituents in relativistic heavy ion collisions is investigated. In solving the relativistic Boltzmann equation, the characteristic range of the collision kernel is varied from approximately one fm to zero while leaving the mean-free path unchanged. Modifying this range is shown to significantly affect spectra and flow observables. The finite range is shown to provide effective viscosities, shear, bulk viscosity and heat conductivity, with the viscous coefficients being proportional to the square of the interaction range

Chaotic Diffusion on Periodic Orbits: The Perturbed Arnol'd Cat Map

Chaotic diffusion on periodic orbits (POs) is studied for the perturbed Arnol'd cat map on a cylinder, in a range of perturbation parameters corresponding to an extended structural-stability regime of the system on the torus. The diffusion coefficient is calculated using the following PO formulas: (a) The curvature expansion of the Ruelle zeta function. (b) The average of the PO winding-number squared, $w^{2}$, weighted by a stability factor. (c) The uniform (nonweighted) average of $w^{2}$. The results from formulas (a) and (b) agree very well with those obtained by standard methods, for all the perturbation parameters considered. Formula (c) gives reasonably accurate results for sufficiently small parameters corresponding also to cases of a considerably nonuniform hyperbolicity. This is due to {\em uniformity sum rules} satisfied by the PO Lyapunov eigenvalues at {\em fixed} $w$. These sum rules follow from general arguments and are supported by much numerical evidence.Comment: 6 Tables, 2 Figures (postscript); To appear in Physical Review

Solid-state laser system for laser cooling of Sodium

We demonstrate a frequency-stabilized, all-solid laser source at 589 nm with up to 800 mW output power. The laser relies on sum-frequency generation from two laser sources at 1064 nm and 1319 nm through a PPKTP crystal in a doubly-resonant cavity. We obtain conversion efficiency as high as 2 W/W^2 after optimization of the cavity parameters. The output wavelength is tunable over 60 GHz, which is sufficient to lock on the Sodium D2 line. The robustness, beam quality, spectral narrowness and tunability of our source make it an alternative to dye lasers for atomic physics experiments with Sodium atoms

Matter-Antimatter Asymmetry in the Large Hadron Collider

The matter-antimatter asymmetry is one of the greatest challenges in the modern physics. The universe including this paper and even the reader him(her)self seems to be built up of ordinary matter only. Theoretically, the well-known Sakharov's conditions remain the solid framework explaining the circumstances that matter became dominant against the antimatter while the universe cools down and/or expands. On the other hand, the standard model for elementary particles apparently prevents at least two conditions out of them. In this work, we introduce a systematic study of the antiparticle-to-particle ratios measured in various $NN$ and $AA$ collisions over the last three decades. It is obvious that the available experimental facilities turn to be able to perform nuclear collisions, in which the matter-antimatter asymmetry raises from $\sim 0$ at AGS to $\sim 100$ at LHC. Assuming that the final state of hadronization in the nuclear collisions takes place along the freezeout line, which is defined by a constant entropy density, various antiparticle-to-particle ratios are studied in framework of the hadron resonance gas (HRG) model. Implementing modified phase space and distribution function in the grand-canonical ensemble and taking into account the experimental acceptance, the ratios of antiparticle-to-particle over the whole range of center-of-mass-energies are very well reproduced by the HRG model. Furthermore, the antiproton-to-proton ratios measured by ALICE in $pp$ collisions is also very well described by the HRG model. It is likely to conclude that the LHC heavy-ion program will produce the same particle ratios as the $pp$ program implying the dynamics and evolution of the system would not depend on the initial conditions. The ratios of bosons and baryons get very close to unity indicating that the matter-antimatter asymmetry nearly vanishes at LHC.Comment: 9 pages, 5 eps-figures, revtex4-styl

Space-time evolution and HBT analysis of relativistic heavy ion collisions in a chiral SU(3) x SU(3) model

The space-time dynamics and pion-HBT radii in central heavy ion-collisions at CERN-SPS and BNL-RHIC are investigated within a hydrodynamic simulation. The dependence of the dynamics and the HBT-parameters on the EoS is studied with different parametrisations of a chiral SU(3) sigma-omega model. The selfconsistent collective expansion includes the effects of effective hadron masses, generated by the nonstrange and strange scalar condensates. Different chiral EoS show different types of phase transitions and even a crossover. The influence of the order of the phase transition and of the difference in the latent heat on the space-time dynamics and pion-HBT radii is studied. A small latent heat, i.e. a weak first-order chiral phase transition, or even a smooth crossover leads to distinctly different HBT predictions than a strong first order phase transition. A quantitative description of the data, both at SPS energies as well as at RHIC energies, appears difficult to achieve within the ideal hydrodynamical approach using the SU(3) chiral EoS. A strong first-order quasi-adiabatic chiral phase transition seems to be disfavored by the pion-HBT data from CERN-SPS and BNL-RHIC

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

GLE1 mutations cause lethal congenital contracture syndrome 1 (LCCS1), a severe autosomal recessive fetal motor neuron disease, and more recently have been associated with amyotrophic lateral sclerosis (ALS). The gene encodes a highly conserved protein with an essential role in mRNA export. The mechanism linking Gle1 function to motor neuron degeneration in humans has not been elucidated, but increasing evidence implicates abnormal RNA processing as a key event in the pathogenesis of several motor neuron diseases. Homozygous gle1−/− mutant zebrafish display various aspects of LCCS, showing severe developmental abnormalities including motor neuron arborization defects and embryonic lethality. A previous gene expression study on spinal cord from LCCS fetuses indicated that oligodendrocyte dysfunction may be an important factor in LCCS. We therefore set out to investigate the development of myelinating glia in gle1−/− mutant zebrafish embryos. While expression of myelin basic protein (mbp) in hindbrain oligodendrocytes appeared relatively normal, our studies revealed a prominent defect in Schwann cell precursor proliferation and differentiation in the posterior lateral line nerve. Other genes mutated in LCCS have important roles in Schwann cell development, thereby suggesting that Schwann cell deficits may be a common factor in LCCS pathogenesis. These findings illustrate the potential importance of glial cells such as myelinating Schwann cells in motor neuron diseases linked to RNA processing defects

A historical perspective on the discovery of statins

Cholesterol is essential for the functioning of all human organs, but it is nevertheless the cause of coronary heart disease. Over the course of nearly a century of investigation, scientists have developed several lines of evidence that establish the causal connection between blood cholesterol, atherosclerosis, and coronary heart disease. Building on that knowledge, scientists and the pharmaceutical industry have successfully developed a remarkably effective class of drugs—the statins—that lower cholesterol levels in blood and reduce the frequency of heart attacks