Functional EF-hands in neuronal calcium sensor GCAP2 determine its phosphorylation state and subcellular distribution in vivo, and are essential for photoreceptor cell integrity

The neuronal calcium sensor proteins GCAPs (guanylate cyclase activating proteins) switch between Ca2+-free and Ca2+-bound conformational states and confer calcium sensitivity to guanylate cyclase at retinal photoreceptor cells. They play a fundamental role in light adaptation by coupling the rate of cGMP synthesis to the intracellular concentration of calcium. Mutations in GCAPs lead to blindness. The importance of functional EF-hands in GCAP1 for photoreceptor cell integrity has been well established. Mutations in GCAP1 that diminish its Ca2+ binding affinity lead to cell damage by causing unabated cGMP synthesis and accumulation of toxic levels of free cGMP and Ca2+. We here investigate the relevance of GCAP2 functional EF-hands for photoreceptor cell integrity. By characterizing transgenic mice expressing a mutant form of GCAP2 with all EF-hands inactivated (EF(-)GCAP2), we show that GCAP2 locked in its Ca2+-free conformation leads to a rapid retinal degeneration that is not due to unabated cGMP synthesis. We unveil that when locked in its Ca2+-free conformation in vivo, GCAP2 is phosphorylated at Ser201 and results in phospho-dependent binding to the chaperone 14-3-3 and retention at the inner segment and proximal cell compartments. Accumulation of phosphorylated EF(-)GCAP2 at the inner segment results in severe toxicity. We show that in wildtype mice under physiological conditions, 50% of GCAP2 is phosphorylated correlating with the 50% of the protein being retained at the inner segment. Raising mice under constant light exposure, however, drastically increases the retention of GCAP2 in its Ca2+-free form at the inner segment. This study identifies a new mechanism governing GCAP2 subcellular distribution in vivo, closely related to disease. It also identifies a pathway by which a sustained reduction in intracellular free Ca2+ could result in photoreceptor damage, relevant for light damage and for those genetic disorders resulting in 'equivalent-light'' scenarios.

One-sided jet at milliarcsecond scales in LS I +61˚ 303

We present Very Long Baseline Interferometry (VLBI) observations of the high mass X-ray binary LS I +61˚303, carried out with the European VLBI Network (EVN). Over the 11 hour observing run, performed ~10 days after a radio outburst, the radio source showed a constant flux density, which allowed sensitive imaging of the emission distribution. The structure in the map shows a clear extension to the southeast. Comparing our data with previous VLBI observations we interpret the extension as a collimated radio jet as found in several other X-ray binaries. Assuming that the structure is the result of an expansion that started at the onset of the outburst, we derive an apparent expansion velocity of 0:003 c, which, in the context of Doppler boosting, corresponds to an intrinsic velocity of at least 0:4 c for an ejection close to the line of sight. From the apparent velocity in all available epochs we are able to establish variations in the ejection angle which imply a precessing accretion disk. Finally we point out that LS I +61˚303, like SS 433 and Cygnus X-1, shows evidence for an emission region almostorthogonal to the relativistic jet

La "imatge" de la caverna i la temptació constant de corregir Plató: Benjamin Jowett com a exemple

[cat] Les traduccions dels primers capítols del llibre VII de la República de Plató on apareix la famosa imatge de la caverna, εἰκών, presenten una sorprenent i intrigant varietat interpretativa: “al·legoria”, “mite”, “faula”, “paràbola”, “símil”, “comparació”... Aquest article, prenent com a exemple la notable fidelitat al text del traductor victorià de Plató, B. Jowett, i mitjançant una anàlisi rigorosa dels termes que acompanyen la imatge, manté la necessitat de no interpretar ni corregir en aquest cas el gran filòsof idealista o “ideocèntric”, assenyalant alhora, si el capteniment filològic és un altre, les contradiccions resultants i l’ús d’algun terme aliè al lèxic platònic com ara “al·legoria”.