Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: Implication for neuroprotective therapies

Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) administration have been proposed for Huntington's disease (HD) treatment. However, our group has recently reported reduced levels of TrkB in HD mouse models and HD human brain suggesting that besides a decrease on BDNF levels a reduction of TrkB expression could also contribute to diminished neurotrophic support in HD. BDNF can also bind to p75 neurotrophin receptor (p75(NTR)) modulating TrkB signaling. Therefore, in this study we have analyzed the levels of p75(NTR) in several HD models, as well as in HD human brain. Our data demonstrates a p75(NTR)/TrkB imbalance in the striatum of two different HD mouse models, Hdh(Q111/111) homozygous knockin mice and R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75(NTR) levels in a HD cellular model did not affect BDNF-mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant huntingtin striatal cells transfected with p75(NTR) against NMDA-mediated excitotoxicity, which was associated with decreased Akt phosphorylation. Interestingly, lack of Akt activation following BDNF and NMDA treatment correlated with increased PP1 levels. Accordingly, pharmacological inhibition of PP1 by okadaic acid (OA) prevented mutant huntingtin striatal cell death induced by NMDA and BDNF. Altogether, our findings demonstrate that the p75(NTR)/TrkB imbalance induced by mutant huntingtin in striatal cells associated with the aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to increasing striatal vulnerability in HD. On the basis of this data we hypothesize that normalization of p75(NTR) and/or TrkB expression or their signaling will improve BDNF neuroprotective therapies in HD. Cell Death and Disease (2013) 4, e595; doi:10.1038/cddis.2013.116; published online 18 April 201

Quiet Sun magnetic fields from space-borne observations: simulating Hinode's case

We examine whether or not it is possible to derive the field strength distribution of quiet Sun internetwork regions from very high spatial resolution polarimetric observations in the visible. In particular, we consider the case of the spectropolarimeter attached to the Solar Optical Telescope aboard Hinode. Radiative magneto-convection simulations are used to synthesize the four Stokes profiles of the \ion{Fe}{1} 630.2 nm lines. Once the profiles are degraded to a spatial resolution of 0\farcs32 and added noise, we infer the atmospheric parameters by means of Milne-Eddington inversions. The comparison of the derived values with the real ones indicates that the visible lines yield correct internetwork field strengths and magnetic fluxes, with uncertainties smaller than $\sim$150 G, when a stray light contamination factor is included in the inversion. Contrary to the results of ground-based observations at 1\arcsec, weak fields are retrieved wherever the field is weak in the simulation.Comment: Accepted for publication in ApJ Letter

The formation and disintegration of magnetic bright points observed by Sunrise/IMaX

The evolution of the physical parameters of magnetic bright points (MBPs) located in the quiet Sun (mainly in the interwork) during their lifetime is studied. First we concentrate on the detailed description of the magnetic field evolution of three MBPs. This reveals that individual features follow different, generally complex, and rather dynamic scenarios of evolution. Next we apply statistical methods on roughly 200 observed MBP evolutionary tracks. MBPs are found to be formed by the strengthening of an equipartition field patch, which initially exhibits a moderate downflow. During the evolution, strong downdrafts with an average velocity of 2.4 km/s set in. These flows, taken together with the concurrent strengthening of the field, suggest that we are witnessing the occurrence of convective collapses in these features, although only 30% of them reach kG field strengths. This fraction might turn out to be larger when the new 4 m class solar telescopes are operational as observations of MBPs with current state of the art instrumentation could still be suffering from resolution limitations. Finally, when the bright point disappears (although the magnetic field often continues to exist) the magnetic field strength has dropped to the equipartition level and is generally somewhat weaker than at the beginning of the MBP's evolution. Noteworthy is that in about 10% of the cases we observe in the vicinity of the downflows small-scale strong (exceeding 2 km/s) intergranular upflows related spatially and temporally to these downflows.Comment: 19 pages, 13 figures; final version published in "The Astrophysical Journal

Evershed clouds as precursors of moving magnetic features around sunspots

The relation between the Evershed flow and moving magnetic features (MMFs) is studied using high-cadence, simultaneous spectropolarimetric measurements of a sunspot in visible (630.2 nm) and near-infrared (1565 nm) lines. Doppler velocities, magnetograms, and total linear polarization maps are calculated from the observed Stokes profiles. We follow the temporal evolution of two Evershed clouds that move radially outward along the same penumbral filament. Eventually, the clouds cross the visible border of the spot and enter the moat region, where they become MMFs. The flux patch farther from the sunspot has the same polarity of the spot, while the MMF closer to it has opposite polarity and exhibits abnormal circular polarization profiles. Our results provide strong evidence that at least some MMFs are the continuation of the penumbral Evershed flow into the moat. This, in turn, suggests that MMFs are magnetically connected to sunspots.Comment: To appear in ApJ Letters, Vol 649, 2006 September 20 issu

Temporal evolution of the Evershed flow in sunspots. II. Physical properties and nature of Evershed clouds

Context: Evershed clouds (ECs) represent the most conspicuous variation of the Evershed flow in sunspot penumbrae. Aims: We determine the physical properties of ECs from high spatial and temporal resolution spectropolarimetric measurements. Methods: The Stokes profiles of four visible and three infrared spectral lines are subject to inversions based on simple one-component models as well as more sophisticated realizations of penumbral flux tubes embedded in a static ambient field (uncombed models). Results: According to the one-component inversions, the EC phenomenon can be understood as a perturbation of the magnetic and dynamic configuration of the penumbral filaments along which these structures move. The uncombed inversions, on the other hand, suggest that ECs are the result of enhancements in the visibility of penumbral flux tubes. We conjecture that the enhancements are caused by a perturbation of the thermodynamic properties of the tubes, rather than by changes in the vector magnetic field. The feasibility of this mechanism is investigated performing numerical experiments of thick penumbral tubes in mechanical equilibrium with a background field. Conclusions: While the one-component inversions confirm many of the properties indicated by a simple line parameter analysis (Paper I of this series), we tend to give more credit to the results of the uncombed inversions because they take into account, at least in an approximate manner, the fine structure of the penumbra.Comment: Accepted for publication in A&

Regulation of oxygen sensing by ion channels

O2 sensing is of critical importance for cell survival and adaptation of living organisms to changing environments or physiological conditions. O2-sensitive ion channels are major effectors of the cellular responses to hypoxia. These channels are preferentially found in excitable neurosecretory cells (glomus cells of the carotid body, cells in the neuroepithelial bodies of the lung, and neonatal adrenal chromaffin cells), which mediate fast cardiorespiratory adjustments to hypoxia. O2- sensitive channels are also expressed in the pulmonary and systemic arterial smooth muscle cells where they participate in the vasomotor responses to low O2 tension (particularly in hypoxic pulmonary vasoconstriction). The mechanisms underlying O2 sensing and how the O2 sensors interact with the ion channels remain unknown. Recent advances in the field give different support to the various current hypotheses. Besides the participation of ion channels in acute O2 sensing, they also contribute to the gene program developed under chronic hypoxia. Gene expression of T-type calcium channels is upregulated by hypoxia through the same hypoxiainducible factor-dependent signaling pathway utilized by the classical O2-regulated genes. Alteration of acute or chronic O2 sensing by ion channels could participate in the pathophysiology of human diseases, such as sudden infant death syndrome or primary pulmonary hypertension