SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons.

The mechanism for the earliest response of central neurons to hypoxia-an increase in voltage-gated sodium current (INa)-has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of NaV1.2 channels increases INa. The time-course for SUMOylation of single NaV1.2 channels at the cell surface and changes in INa coincide, and both are prevented by mutation of NaV1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia-induced linkage of SUMO1 to the channels is complete, shifting the voltage-dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of INa in hypoxic brain damage, the SUMO pathway and NaV1.2 are identified as potential targets for neuroprotective interventions

K2P channels and their protein partners.

A decade since their discovery, the K2P channels are recognized as pathways dedicated to regulated background leakage of potassium ions that serve to control neuronal excitability. The recent identification of protein partners that directly interact with K2P channels (SUMO, 14-3-3 and Vpu1) has exposed new regulatory pathways. Reversible linkage to SUMO silences K2P1 plasma membrane channels; phosphorylation of K2P3 enables 14-3-3 binding to affect forward trafficking, whereas it decreases open probability of K2P2; and, Vpu1, an HIV encoded partner, mediates assembly-dependent degradation of K2P3. An operational strategy has emerged: tonic inhibition of K2P channels allows baseline neuronal activity until enhanced potassium leak is required to suppress excitability

Individual IKs channels at the surface of mammalian cells contain two KCNE1 accessory subunits.

KCNE1 (E1) β-subunits assemble with KCNQ1 (Q1) voltage-gated K(+) channel α-subunits to form IKslow (IKs) channels in the heart and ear. The number of E1 subunits in IKs channels has been an issue of ongoing debate. Here, we use single-molecule spectroscopy to demonstrate that surface IKs channels with human subunits contain two E1 and four Q1 subunits. This stoichiometry does not vary. Thus, IKs channels in cells with elevated levels of E1 carry no more than two E1 subunits. Cells with low levels of E1 produce IKs channels with two E1 subunits and Q1 channels with no E1 subunits--channels with one E1 do not appear to form or are restricted from surface expression. The plethora of models of cardiac function, transgenic animals, and drug screens based on variable E1 stoichiometry do not reflect physiology

Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels.

Acute cardiac hypoxia produces life-threatening elevations in late sodium current (ILATE) in the human heart. Here, we show the underlying mechanism: hypoxia induces rapid SUMOylation of NaV1.5 channels so they reopen when normally inactive, late in the action potential. NaV1.5 is SUMOylated only on lysine 442, and the mutation of that residue, or application of a deSUMOylating enzyme, prevents hypoxic reopenings. The time course of SUMOylation of single channels in response to hypoxia coincides with the increase in ILATE, a reaction that is complete in under 100 s. In human cardiac myocytes derived from pluripotent stem cells, hypoxia-induced ILATE is confirmed to be SUMO-dependent and to produce action potential prolongation, the pro-arrhythmic change observed in patients

The truncated and evolving inner accretion disc of the black hole GX 339-4

The nature of accretion onto stellar mass black holes in the low/hard state remains unresolved, with some evidence suggesting that the inner accretion disc is truncated and replaced by a hot flow. However, the detection of relativistic broadened Fe emission lines, even at relatively low luminosities, seems to require an accretion disc extending fully to its innermost stable circular orbit. Modelling such features is however highly susceptible to degeneracies, which could easily bias any interpretation. We present the first systematic study of the Fe line region to track how the inner accretion disc evolves in the low/hard state of the black hole GX 339$-$4. Our four observations display increased broadening of the Fe line over two magnitudes in luminosity, which we use to track any variation of the disc inner radius. We find that the disc extends closer to the black hole at higher luminosities, but is consistent with being truncated throughout the entire low/hard state, a result which renders black hole spin estimates inaccurate at these stages of the outburst. Furthermore, we show that the evolution of our spectral inner disc radius estimates corresponds very closely to the trend of the break frequency in Fourier power spectra, supporting the interpretation of a truncated and evolving disc in the hard state.Comment: Accepted for publication in A&A. Some typos corrected from version

Revealing accretion onto black holes: X-ray reflection throughout three outbursts of GX 339-4

Understanding the dynamics behind black hole state transitions and the changes they reflect in outbursts has become long-standing problem. The X-ray reflection spectrum describes the interaction between the hard X-ray source (the power-law continuum) and the cool accretion disc it illuminates, and thus permits an indirect view of how the two evolve. We present a systematic analysis of the reflection spectrum throughout three outbursts (500+ observations) of the black hole binary GX 339-4, representing the largest study applying a self-consistent treatment of reflection to date. Particular attention is payed to the coincident evolution of the power-law and reflection, which can be used to determine the accretion geometry. The hard state is found to be distinctly reflection weak, however the ratio of reflection to power-law gradually increases as the source luminosity rises. In contrast the reflection is found dominate the power-law throughout most of the soft state, with increasing supremacy as the source decays. We discuss potential dynamics driving this, favouring inner disc truncation and decreasing coronal height for the hard and soft states respectively. Evolution of the ionisation parameter, power-law slope and high-energy cut-off also agree with this interpretation.Comment: Accepted for publication in MNRA

Nonlocal quark model beyond mean field and QCD phase transition

A nonlocal chiral quark model is consistently extended beyond mean field using a strict 1/Nc expansion scheme. The parameters of the nonlocal model are refitted to the physical values of the pion mass and the weak pion decay constant. The size of the 1/Nc correction to the quark condensate is carefully studied in the nonlocal and the usual local Nambu-Jona-Lasinio models. It is found that even the sign of the corrections can be different. This can be attributed to the mesonic cut-off of the local model. It is also found that the 1/Nc corrections lead to a lowering of the temperature of the chiral phase transition in comparison with the mean-field result. On the other hand, near the phase transition the 1/Nc expansion breaks down and a non-perturbative scheme for the inclusion of mesonic correlations is needed in order to describe the phase transition point.Comment: 4 pages, 4 figures, talk at the 3rd Joint International Hadron Structure'09 Conference, Tatranska Strba (Slovak Republic), Aug. 30-Sept. 3, 200

Distributed leadership, trust and online communities

This paper analyses the role of distributed leadership and trust in online communities. The team-based informal ethos of online collaboration requires a different kind of leadership from that in formal positional hierarchies. Such leadership may be more flexible and sophisticated, capable of encompassing ambiguity and rapid change. Online leaders need to be partially invisible, delegating power and distributing tasks. Yet, simultaneously, online communities are facilitated by the high visibility and subtle control of expert leaders. This paradox: that leaders need to be both highly visible and invisible as appropriate, was derived from prior research and tested in the analysis of online community discussions using a pattern-matching process. It is argued that both leader visibility and invisibility are important for the facilitation of trusting collaboration via distributed leadership. Advanced leadership responses to complex situations in online communities foster positive group interaction and decision-making, facilitated through active distribution of specific tasks

A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.

Thousands die each year from sudden infant death syndrome (SIDS). Neither the cause nor basis for varied prevalence in different populations is understood. While 2 cases have been associated with mutations in type Valpha, cardiac voltage-gated sodium channels (SCN5A), the "Back to Sleep" campaign has decreased SIDS prevalence, consistent with a role for environmental influences in disease pathogenesis. Here we studied SCN5A in African Americans. Three of 133 SIDS cases were homozygous for the variant S1103Y. Among controls, 120 of 1,056 were carriers of the heterozygous genotype, which was previously associated with increased risk for arrhythmia in adults. This suggests that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. As risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wild-type channels were subjected to lowered intracellular pH. Only Y1103 channels gained abnormal function, demonstrating late reopenings suppressible by the drug mexiletine. The variant appeared to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Overall, homozygous and rare heterozygous SCN5A missense variants were found in approximately 5% of cases. If our findings are replicated, prospective genetic testing of SIDS cases and screening with counseling for at-risk families warrant consideration