Formation of Polyglutamine Inclusions in a Wide Range of Non-CNS Tissues in the HdhQ150 Knock-In Mouse Model of Huntington's Disease

BACKGROUND:Huntington's disease (HD) is an inherited progressive neurodegenerative disorder caused by a CAG repeat expansion in the ubiquitously expressed HD gene resulting in an abnormally long polyglutamine repeat in the huntingtin protein. Polyglutamine inclusions are a hallmark of the neuropathology of HD. We have previously shown that inclusion pathology is also present in the peripheral tissues of the R6/2 mouse model of HD which expresses a small N-terminal fragment of mutant huntingtin. To determine whether this peripheral pathology is a consequence of the aberrant expression of this N-terminal fragment, we extend this analysis to the genetically precise knock-in mouse model of HD, HdhQ150, which expresses mutant mouse huntingtin. METHODOLOGY/PRINCIPAL FINDINGS:We have previously standardized the CAG repeat size and strain background of the R6/2 and HdhQ150 knock-in mouse models and found that they develop a comparable and widespread neuropathology. To determine whether HdhQ150 knock-in mice also develop peripheral inclusion pathology, homozygous Hdh(Q150/Q150) mice were perfusion fixed at 22 months of age, and tissues were processed for histology and immunohistochemistry with the anti-huntingtin antibody S830. The peripheral inclusion pathology was almost identical to that found in R6/2 mice at 12 weeks of age with minor differences in inclusion abundance. CONCLUSIONS/SIGNIFICANCE:The highly comparable peripheral inclusion pathology that is present in both the R6/2 and HdhQ150 knock-in models of HD indicates that the presence of peripheral inclusions in R6/2 mice is not a consequence of the aberrant expression of an N-terminal huntingtin protein. It remains to be determined whether peripheral inclusions are a pathological feature of the human disease. Both mouse models carry CAG repeats that cause childhood disease in humans, and therefore, inclusion pathology may be a feature of the childhood rather than the adult forms of HD. It is important to establish the extent to which peripheral pathology causes the peripheral symptoms of HD from the perspective of a mechanistic understanding and future treatment options

Real Time Imaging of Human Progenitor Neurogenesis

Human neural progenitors are increasingly being employed in drug screens and emerging cell therapies targeted towards neurological disorders where neurogenesis is thought to play a key role including developmental disorders, Alzheimer’s disease, and depression. Key to the success of these applications is understanding the mechanisms by which neurons arise. Our understanding of development can provide some guidance but since little is known about the specifics of human neural development and the requirement that cultures be expanded in vitro prior to use, it is unclear whether neural progenitors obey the same developmental mechanisms that exist in vivo. In previous studies we have shown that progenitors derived from fetal cortex can be cultured for many weeks in vitro as undifferentiated neurospheres and then induced to undergo neurogenesis by removing mitogens and exposing them to supportive substrates. Here we use live time lapse imaging and immunocytochemical analysis to show that neural progenitors use developmental mechanisms to generate neurons. Cells with morphologies and marker profiles consistent with radial glia and recently described outer radial glia divide asymmetrically and symmetrically to generate multipolar intermediate progenitors, a portion of which express ASCL1. These multipolar intermediate progenitors subsequently divide symmetrically to produce CTIP2+ neurons. This 3-cell neurogenic scheme echoes observations in rodents in vivo and in human fetal slice cultures in vitro, providing evidence that hNPCs represent a renewable and robust in vitro assay system to explore mechanisms of human neurogenesis without the continual need for fresh primary human fetal tissue. Knowledge provided by this and future explorations of human neural progenitor neurogenesis will help maximize the safety and efficacy of new stem cell therapies by providing an understanding of how to generate physiologically-relevant cell types that maintain their identities when placed in diagnostic or transplantation environments

Nanostructure and Magnetic Field Ordering in Aqueous Fe3O4 Ferrofluids: A Small-Angle Neutron Scattering Study

Despite the importance of reducing production costs, investigating the hierarchical nanostructure and magnetic field ordering of Fe3O4 ferrofluids is also important to improve its application performance. Therefore, we proposed an inexpensive synthesis method in producing the Fe3O4 ferrofluids and investigated their detailed nanostructure as the effect of liquid carrier composition as well as their magnetic field ordering. In the present work, the Fe3O4 ferrofluids were successfully prepared through a coprecipitation route using a central precursor of natural Fe3O4 from iron sand. The nanostructural behaviors of the Fe3O4 ferrofluids, as the effects of the dilution of the Fe3O4 particles with H2O as a carrier liquid, were examined using a small-angle neutron spectrometer (SANS). The Fe3O4 nanopowders were also prepared for comparison. A single lognormal spherical distribution and a mass fractal model were applied to fit the neutron scattering data of the Fe3O4 ferrofluids. The increasing carrier liquid composition of the fluids during dilution process was able to reduce the fractal dimension and led to a shorter length of aggregation chains. However, it did not change the size of the primary particles or building block (approximately 3.8 nm) of the Fe3O4 particles. The neutron scattering of the Fe3O4 ferrofluids under an external magnetic field in the range of 0 to 1 T exhibited in a standard way of anisotropic phenomenon originating from the nanostructural ordering of the Fe3O4 particles. On the other hand, the Fe3O4 powders did not show anisotropic scattering under an external field in the same range. Furthermore, the magnetization curve of the Fe3O4 ferrofluids and nanopowders exhibited a proper superparamagnetic character at room temperature with the respective saturation magnetization of 4.4 emu/g and 34.7 emu/g

Magnetic Interactions and Transport in (Ga,Cr)As

The magnetic, transport, and structural properties of (Ga,Cr)As are reported. Zincblende Ga$_{1-x}$Cr$_{x}$As was grown by low-temperature molecular beam epitaxy (MBE). At low concentrations, x$\sim$0.1, the materials exhibit unusual magnetic properties associated with the random magnetism of the alloy. At low temperatures the magnetization M(B) increases rapidly with increasing field due to the alignment of ferromagnetic units (polarons or clusters) having large dipole moments of order 10-10$^2$$\mu_B$. A standard model of superparamagnetism is inadequate for describing both the field and temperature dependence of the magnetization M(B,T). In order to explain M(B) at low temperatures we employ a distributed magnetic moment (DMM) model in which polarons or clusters of ions have a distribution of moments. It is also found that the magnetic susceptibility increases for decreasing temperature but saturates below T=4 K. The inverse susceptibility follows a linear-T Curie-Weiss law and extrapolates to a magnetic transition temperature $\theta$=10 K. In magnetotransport measurements, a room temperature resistivity of $\rho$=0.1 $\Omega$cm and a hole concentration of $\sim10^{20}$ cm$^{-3}$ are found, indicating that Cr can also act as a acceptor similar to Mn. The resistivity increases rapidly for decreasing temperature below room temperature, and becomes strongly insulating at low temperatures. The conductivity follows exp[-(T$_1$/T)$^{1/2}$] over a large range of conductivity, possible evidence of tunneling between polarons or clusters.Comment: To appear in PRB 15 Mar 200

Menthol Suppresses Nicotinic Acetylcholine Receptor Functioning in Sensory Neurons via Allosteric Modulation

In this study, we have investigated how the function of native and recombinant nicotinic acetylcholine receptors (nAChRs) is modulated by the monoterpenoid alcohol from peppermint (−) menthol. In trigeminal neurons (TG), we found that nicotine (75 μM)-activated whole-cell currents through nAChRs were reversibly reduced by menthol in a concentration-dependent manner with an IC50 of 111 μM. To analyze the mechanism underlying menthol's action in more detail, we used single channel and whole-cell recordings from recombinant human α4β2 nAChR expressed in HEK tsA201 cells. Here, we found a shortening of channel open time and a prolongation of channel closed time, and an increase in single channel amplitude leading in summary to a reduction in single channel current. Furthermore, menthol did not affect nicotine's EC50 value for currents through recombinant human α4β2 nAChRs but caused a significant reduction in nicotine's efficacy. Taken together, these findings indicate that menthol is a negative allosteric modulator of nAChRs

mTORC1 underlies ageâ related muscle fiber damage and loss by inducing oxidative stress and catabolism

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these ageâ related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1’s activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3’s phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to ageâ related muscle atrophy, and GDF signaling is a proposed mechanism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/1/acel12943-sup-0002-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/2/acel12943.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/3/acel12943-sup-0001-FigS1-S14.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/4/acel12943_am.pd

Search for Supernova Relic Neutrinos at Super-Kamiokande

A search for the relic neutrinos from all past core-collapse supernovae was conducted using 1496 days of data from the Super-Kamiokande detector. This analysis looked for electron-type anti-neutrinos that had produced a positron with an energy greater than 18 MeV. In the absence of a signal, 90% C.L. upper limits on the total flux were set for several theoretical models; these limits ranged from 20 to 130 nu_e bar cm^-2 s^-1. Additionally, an upper bound of 1.2 nu_e bar cm^-2 s^-1 was set for the supernova relic neutrino flux in the energy region E_nu > 19.3 MeV.Comment: 4 pages, 2 figures. Submitted to Physical Review Letters. New version includes corrections to Figure 1. Also, text has been shortened to conform with the space limitations of PR

Solar 8B and hep Neutrino Measurements from 1258 Days of Super-Kamiokande Data

Solar neutrino measurements from 1258 days of data from the Super-Kamiokande detector are presented. The measurements are based on recoil electrons in the energy range 5.0-20.0MeV. The measured solar neutrino flux is 2.32 +- 0.03(stat.) +0.08-0.07(sys.)*10^6cm^{-2}s^{-1}, which is 45.1+-0.5(stat.)+1.6-1.4(sys.)% of that predicted by the BP2000 SSM. The day vs night flux asymmetry is 0.033+-0.022(stat.)+0.013-0.012(sys.). The recoil electron energy spectrum is consistent with no spectral distortion (\chi^2/d.o.f. = 19.0/18). The seasonal variation of the flux is consistent with that expected from the eccentricity of the Earth's orbit (\chi^2/d.o.f. = 3.7/7). For the hep neutrino flux, we set a 90% C.L. upper limit of 40 *10^3cm^{-2}s^{-1}, which is 4.3 times the BP2000 SSM prediction.Comment: 7 pages, 5 figures, submitted to PRL (part of this paper

Search for Dark Matter WIMPs using Upward Through-going Muons in Super-Kamiokande

We present the results of indirect searches for Weakly Interacting Massive Particles (WIMPs) with 1679.6 live days of data from the Super-Kamiokande detector using neutrino-induced upward through-going muons. The search is performed by looking for an excess of high energy muon neutrinos from WIMP annihilations in the Sun, the core of the Earth, and the Galactic Center, as compared to the number expected from the atmospheric neutrino background. No statistically significant excess was seen. We calculate flux limits in various angular cones around each of the above celestial objects. We obtain conservative model-independent upper limits on WIMP-nucleon cross-section as a function of WIMP mass and compare these results with the corresponding results from direct dark matter detection experiments.Comment: 10 pages, 14 figures, Submitted to Phys. Rev.