Magnetic islands have been implemented in the gyrokinetic toroidal code to study the effects of the islands on microturbulence. The pressure profile flattening is verified in the simulation with the islands. Simulations of ion temperature gradient instability find that different toroidal modes are linearly coupled together and that toroidal spectra become broader when the island width increases. The real frequencies and growth rates of different toroidal modes approach each other with the averaged value independent of the island width. The linear mode structures are enhanced at the island separatrices and weakened at the island centers, consistent with the flattening of the pressure profile inside the islands.

NG2 (nerve/glial antigen2)-expressing cells represent the largest population of postnatal progenitors in the central nervous system and have been classified as oligodendroglial progenitor cells, but the fate and function of these cells remain incompletely characterized. Previous studies have focused on characterizing these progenitors in the postnatal and adult subventricular zone and on analyzing the cellular and physiological properties of these cells in white and gray matter regions in the forebrain. In the present study, we examine the types of neural progeny generated by NG2 progenitors in the cerebellum by employing genetic fate mapping techniques using inducible Cre-Lox systems in vivo with two different mouse lines, the Plp-Cre-ER(T2)/Rosa26-EYFP and Olig2-Cre-ER(T2)/Rosa26-EYFP double-transgenic mice. Our data indicate that Olig2/Plp-positive NG2 cells display multipotential properties, primarily give rise to oligodendroglia but, surprisingly, also generate Bergmann glia, which are specialized glial cells in the cerebellum. The NG2+ cells also give rise to astrocytes, but not neurons. In addition, we show that glutamate signaling is involved in distinct NG2+ cell-fate/differentiation pathways and plays a role in the normal development of Bergmann glia. We also show an increase of cerebellar oligodendroglial lineage cells in response to hypoxic-ischemic injury, but the ability of NG2+ cells to give rise to Bergmann glia and astrocytes remains unchanged. Overall, our study reveals a novel Bergmann glia fate of Olig2/Plp-positive NG2 progenitors, demonstrates the differentiation of these progenitors into various functional glial cell types, and provides significant insights into the fate and function of Olig2/Plp-positive progenitor cells in health and disease.

Disrupted sleep has a profound adverse impact on lives of Parkinsons disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD - the MCI-Park mouse - was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities resemble those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.

Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep.

The p38α mitogen-activated protein kinase (MAPK) is one of the serine/threonine kinases regulating a variety of biological processes, including cell-type specification, differentiation and migration. Previous in vitro studies using pharmacological inhibitors suggested that p38 MAPK is essential for oligodendrocyte (OL) differentiation and myelination. To investigate the specific roles of p38α MAPK in OL development and myelination in vivo, we generated p38α conditional knockout (CKO) mice under the PLP and nerve/glial antigen 2 (NG2) gene promoters, as these genes are specifically expressed in OL progenitor cells (OPCs). Our data revealed that myelin synthesis was completely inhibited in OLs differentiated from primary OPC cultures derived from the NG2 Cre-p38α CKO mouse brains. Although an in vivo myelination defect was not obvious after gross examination of these mice, electron microscopic analysis showed that the ultrastructure of myelin bundles was severely impaired. Moreover, the onset of myelination in the corpus callosum was delayed in the knockout mice compared with p38α fl/fl control mice. A delay in OL differentiation in the central nervous system was observed with concomitant downregulation in the expression of OPC- and OL-specific genes such as Olig1 and Zfp488 during early postnatal development. OPC proliferation was not affected during this time. These data indicate that p38α is a positive regulator of OL differentiation and myelination. Unexpectedly, we observed an opposite effect of p38α on remyelination in the cuprizone-induced demyelination model. The p38α CKO mice exhibited better remyelination capability compared with p38α fl/fl mice following demyelination. The opposing roles of p38α in myelination and remyelination could be due to a strong anti-inflammatory effect of p38α or a dual reciprocal regulatory action of p38α on myelin formation during development and on remyelination after demyelination.

Background

The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk.

Methods

We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations.

Results

In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells.

Conclusions

Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.

A search for the rare decay D0→μ+μ- is performed using a data sample, corresponding to an integrated luminosity of 0.9fb-1, of pp collisions collected at a centre-of-mass energy of 7 TeV by the LHCb experiment. The observed number of events is consistent with the background expectations and corresponds to an upper limit of B(D0→μ+μ-)<6.2(7.6)×10-9 at 90% (95%) confidence level. This result represents an improvement of more than a factor twenty with respect to previous measurements. © 2013 CERN.

We present the final combination of CDF and D0 measurements of cross sections for single-top-quark production in proton-antiproton collisions at a center-of-mass energy of 1.96 TeV. The data correspond to total integrated luminosities of up to 9.7 fb^{-1} per experiment. The t-channel cross section is measured to be σ_{t}=2.25_{-0.31}^{+0.29} pb. We also present the combinations of the two-dimensional measurements of the s- vs t-channel cross section. In addition, we give the combination of the s+t channel cross section measurement resulting in σ_{s+t}=3.30_{-0.40}^{+0.52} pb, without assuming the standard model value for the ratio σ_{s}/σ_{t}. The resulting value of the magnitude of the top-to-bottom quark coupling is |V_{tb}|=1.02_{-0.05}^{+0.06}, corresponding to |V_{tb}|>0.92 at the 95% C.L.

Drell-Yan lepton pairs produced in the process pp→â.,"+â.,"-+X through an intermediate γ∗/Z boson have an asymmetry in their angular distribution related to the spontaneous symmetry breaking of the electroweak force and the associated mixing of its neutral gauge bosons. The CDF and D0 experiments have measured the effective-leptonic electroweak mixing parameter sin2θefflept using electron and muon pairs selected from the full Tevatron proton-antiproton data sets collected in 2001-2011, corresponding to 9-10 fb-1 of integrated luminosity. The combination of these measurements yields the most precise result from hadron colliders, sin2θefflept=0.23148±0.00033. This result is consistent with, and approaches in precision, the best measurements from electron-positron colliders. The standard model inference of the on-shell electroweak mixing parameter sin2θW, or equivalently the W-boson mass MW, using the zfitter software package yields sin2θW=0.22324±0.00033 or equivalently, MW=80.367±0.017 GeV/c2.

The CDF and D0 experiments at the Fermilab Tevatron have measured the asymmetry between yields of forward- and backward-produced top and antitop quarks based on their rapidity difference and the asymmetry between their decay leptons. These measurements use the full data sets collected in proton-antiproton collisions at a center-of-mass energy of sqrt[s]=1.96  TeV. We report the results of combinations of the inclusive asymmetries and their differential dependencies on relevant kinematic quantities. The combined inclusive asymmetry is A_{FB}^{tt[over ¯]}=0.128±0.025. The combined inclusive and differential asymmetries are consistent with recent standard model predictions.