Controls on the Basal Water Pressure in Subglacial Channels Near the Margin of the Greenland Ice Sheet

Assuming a channelized drainage system in steady state, we investigate the influence of enhanced surface melting on the water pressure in subglacial channels, compared to that of changes in conduit geometry, ice rheology and catchment variations. The analysis is carried out for a specific part of the western Greenland ice-sheet margin between 66 degrees N and 66 degrees 30' N using new high-resolution digital elevation models of the subglacial topography and the ice-sheet surface, based on an airborne ice-penetrating radar survey in 2003 and satellite repeat-track interferometric synthetic aperture radar analysis of European Remote-sensing Satellite 1 and 2 (ERS-1/-2) imagery, respectively. The water pressure is calculated up-glacier along a likely subglacial channel at distances of 1, 5 and 9 km from the outlet at the ice margin, using a modified version of Rothlisberger's equation. Our results show that for the margin of the western Greenland ice sheet, the water pressure in subglacial channels is not sensitive to realistic variations in catchment size and mean surface water input compared to small changes in conduit geometry and ice rheology.

Effect of chlorzoxazone in patients with downbeat nystagmus: A pilot trial

Objective: Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus with different symptoms such as unsteadiness of gait, postural instability, and blurred vision with reduced visual acuity (VA) and oscillopsia. However, different symptomatic therapeutic principles are required, such as 3,4-diaminopyridine and 4-aminopyridine, that effectively suppress DBN. Chlorzoxazone (CHZ) is a nonselective activator of small conductance calcium-activated potassium (SK) channels that modifies the activity of cerebellar Purkinje cells. We evaluated the effects of this agent on DBN in an observational proof-of-concept pilot study. Methods: Ten patients received CHZ 500 mg 3 times a day for 1 or 2 weeks. Slow-phase velocity of DBN, VA, postural sway, and the drug's side effects were evaluated. Recordings were conducted at baseline, 90 minutes after first administration, and after 1 or 2 weeks. Results: Mean slow-phase velocity significantly decreased from a baseline of 2.74°/s ± 2.00 to 2.29°/s ± 2.12 (mean ± SD) 90 minutes after first administration and to 2.04°/s ± 2.24 (p < 0.001; post hoc both p = 0.024) after long-term treatment. VA significantly increased and postural sway in posturography showed a tendency to decrease on medication. Fifty percent of patients did not report any side effects. The most common reported side effect was abdominal discomfort and dizziness. Conclusions: The treatment with the SK-channel activator CHZ is a potentially new therapeutic agent for the symptomatic treatment of DBN. Classification of evidence: This study provides Class IV evidence that CHZ 500 mg 3 times a day may improve eye movements and visual fixation in patients with DBN.

Search for resonant diboson production in the lvjj decay channels with the ATLAS detector at 7 TeV

A search for resonant diboson production using a data sample corresponding to 4.7 fb(-1) of integrated luminosity collected by the ATLAS experiment at the Large Hadron Collider in pp collisions at root s = 7 TeV is presented. The search for a narrow resonance in the WW or WZ mass distribution is conducted in a final state with an electron or a muon, missing transverse momentum, and at least two jets. No significant excess is observed and limits are set using three benchmark models: WW resonance masses below 940 and 710 GeV are excluded at 95% confidence level for spin-2 Randall-Sundrum and bulk Randall-Sundrum gravitons, respectively; WZ resonance masses below 950 GeV are excluded at 95% confidence level for a spin-1 extended gauge model W' boson.

Ubiquitylation of voltage-gated sodium channels.

Ion channel proteins are regulated by different types of posttranslational modifications. The focus of this review is the regulation of voltage-gated sodium channels (Navs) upon their ubiquitylation. The amiloride-sensitive epithelial sodium channel (ENaC) was the first ion channel shown to be regulated upon ubiquitylation. This modification results from the binding of ubiquitin ligase from the Nedd4 family to a protein-protein interaction domain, known as the PY motif, in the ENaC subunits. Many of the Navs have similar PY motifs, which have been demonstrated to be targets of Nedd4-dependent ubiquitylation, tagging them for internalization from the cell surface. The role of Nedd4-dependent regulation of the Nav membrane density in physiology and disease remains poorly understood. Two recent studies have provided evidence that Nedd4-2 is downregulated in dorsal root ganglion (DRG) neurons in both rat and mouse models of nerve injury-induced neuropathic pain. Using two different mouse models, one with a specific knockout of Nedd4-2 in sensory neurons and another where Nedd4-2 was overexpressed with the use of viral vectors, it was demonstrated that the neuropathy-linked neuronal hyperexcitability was the result of Nav1.7 and Nav1.8 overexpression due to Nedd4-2 downregulation. These studies provided the first in vivo evidence of the role of Nedd4-2-dependent regulation of Nav channels in a disease state. This ubiquitylation pathway may be involved in the development of symptoms and diseases linked to Nav-dependent hyperexcitability, such as pain, cardiac arrhythmias, epilepsy, migraine, and myotonias.

A pentasymmetric open channel blocker for Cys-loop receptor channels.

γ-Aminobutyric acid type A receptors (GABAA receptors) are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. These receptors show near five-fold symmetry that is most pronounced in the second trans-membrane domain M2 lining the Cl- ion channel. To take advantage of this inherent symmetry, we screened a variety of aromatic anions with matched symmetry and found an inhibitor, pentacyanocyclopentdienyl anion (PCCP-) that exhibited all characteristics of an open channel blocker. Inhibition was strongly dependent on the membrane potential. Through mutagenesis and covalent modification, we identified the region α1V256-α1T261 in the rat recombinant GABAA receptor to be important for PCCP- action. Introduction of positive charges into M2 increased the affinity for PCCP- while PCCP- prevented the access of a positively charged molecule into M2. Interestingly, other anion selective cys-loop receptors were also inhibited by PCCP-, among them the Drosophila RDL GABAA receptor carrying an insecticide resistance mutation, suggesting that PCCP- could serve as an insecticide.

Ubiquitin-specific protease USP2-45 acts as a molecular switch to promote α2δ-1-induced downregulation of Ca v1.2 channels

Availability of voltage-gated calcium channels (Cav) at the plasma membrane is paramount to maintaining the calcium homeostasis of the cell. It is proposed that the ubiquitylation/de-ubiquitylation balance regulates the density of ion channels at the cell surface. Voltage-gated calcium channels Cav1.2 have been found to be ubiquitylated under basal conditions both in vitro and in vivo. In a previous study, we have shown that Cav1.2 channels are ubiquitylated by neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4-1) ubiquitin ligases, but the identity of the counterpart de-ubiquitylating enzyme remained to be elucidated. Regarding sodium and potassium channels, it has been reported that the action of the related isoform Nedd4-2 is counteracted by the ubiquitin-specific protease (USP) 2-45. In this study, we show that USP 2-45 also de-ubiquitylates Cav channels. We co-expressed USPs and Cav1.2 channels together with the accessory subunits β2 and α2δ-1, in tsA-201 and HEK-293 mammalian cell lines. Using whole-cell current recordings and surface biotinylation assays, we show that USP2-45 specifically decreases both the amplitude of Cav currents and the amount of Cav1.2 subunits inserted at the plasma membrane. Importantly, co-expression of the α2δ-1 accessory subunit is necessary to support the effect of USP2-45. We further show that USP2-45 promotes the de-ubiquitylation of both Cav1.2 and α2δ-1 subunits. Remarkably, α2δ-1, but not Cav1.2 nor β2, co-precipitated with USP2-45. These results suggest that USP2-45 binding to α2δ-1 promotes the de-ubiquitylation of both Cav1.2 and α2δ-1 subunits, in order to regulate the expression of Cav1.2 channels at the plasma membrane.

Efficient and Robust Host–Guest Antenna Composite for Light Harvesting

We report discovery of a new efficient and robust antenna composite for light harvesting. The organic dye hostasol red (HR) is strongly luminescent in aprotic solvents but only weakly luminescent in potassium zeolite L (ZL) at ambient conditions. We observed a dramatic increase of the luminescence quantum yield of HR–ZL composites if some or all exchangeable potassium cations of ZL are substituted by an organic imidazolium cation (IMZ+) and if the acceptor HR is embedded in the middle part of the channels, so that it is fully protected by the environment of the perylene dye tb-DXP. This led to the discovery of a highly efficient donor,acceptor-ZL antenna material where tb-DXP acts as donor and HR acts as acceptor. The material has a donor-to-acceptor (D/A) absorption ratio of more than 100:1 and a nearly quantitative FRET efficiency. Synthesis of this host–guest material is reported. We describe a successful procedure for achieving full sealing of the ZL channel entrances such that the guests cannot escape. This new material is of great interest for applications in luminescent solar concentrator (LSC) devices because the efficiency killing self-absorption is very low.