Structural insights on TRPV5 gating by endogenous modulators.

TRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and calmodulin (CaM) have been shown to directly bind to TRPV5 and activate or inactivate the channel, respectively. Using cryo-electron microscopy (cryo-EM), we determined TRPV5 structures in the presence of dioctanoyl PI(4,5)P2 and CaM. The PI(4,5)P2 structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with PI(4,5)P2 induce conformational rearrangements in the lower gate, opening the channel. The CaM structure reveals two TRPV5 C-terminal peptides anchoring a single CaM molecule and that calcium inhibition is mediated through a cation-π interaction between Lys116 on the C-lobe of calcium-activated CaM and Trp583 at the intracellular gate of TRPV5. Overall, this investigation provides insight into the endogenous modulation of TRPV5, which has the potential to guide drug discovery

Investigation of temporal bone asymmetry in cases with unilateral tinnitus: morphometric and multicentric clinical study

The aim of this multicentric study was to compare the anatomical structures of temporal bone in patients with unilateral tinnitus with their healthy ears. We also aimed at evaluating whether age and gender-related asymmetrical changes occur in temporal bones or not. Fifty two ears of 26 patients who had unilateral tinnitus were included into the retrospective study. The patients who had subjective nonpulsatile tinnitus and who previously had temporal computed tomography according to their file records were accepted to study. Temporal CT scans and audiometric results of patients were examined retrospectively. Middle ear volume, diameter of internal acoustic meats and diameter of jugular bulb were evaluated by both anatomist and radiologist, interobserverly. Internal acoustic meats and jugular bulb were found larger in the ears that had tinnitus than healthy ears; however, there was no statistically significance. The stereological morphometrical study of temporal bone asymmetry in humans correlate with sex is of importance for both otolarygologs and anatomists. These results will contribute to data on middle ear volume, internal acustic meats and jugular bulb sizes

Beating the confusion limit: The necessity of high angular resolution for probing the physics of Sagittarius A* and its environment: Opportunities for LINC-NIRVANA (LBT), GRAVITY (VLTI) and and METIS (E-ELT)

The super-massive 4 million solar mass black hole (SMBH) SgrA* shows variable emission from the millimeter to the X-ray domain. A detailed analysis of the infrared light curves allows us to address the accretion phenomenon in a statistical way. The analysis shows that the near-infrared flux density excursions are dominated by a single state power law, with the low states of SgrA* limited by confusion through the unresolved stellar background. We show that for 8-10m class telescopes blending effects along the line of sight will result in artificial compact star-like objects of 0.5-1 mJy that last for about 3-4 years. We discuss how the imaging capabilities of GRAVITY at the VLTI, LINC-NIRVANA at the LBT and METIS at the E-ELT will contribute to the investigation of the low variability states of SgrA*.Comment: 19 pages, 5 figure, Conf. Proc. SPIE Astronomical Telescopes + Instrumentation 1 - 6 July 2012. Amsterdam No. 8445-

Quantitative trait loci conferring grain mineral nutrient concentrations in durum wheat 3 wild emmer wheat RIL population

Mineral nutrient malnutrition, and particularly deficiency in zinc and iron, afflicts over 3 billion people worldwide. Wild emmer wheat, Triticum turgidum ssp. dicoccoides, genepool harbors a rich allelic repertoire for mineral nutrients in the grain. The genetic and physiological basis of grain protein, micronutrients (zinc, iron, copper and manganese) and macronutrients (calcium, magnesium, potassium, phosphorus and sulfur) concentration was studied in tetraploid wheat population of 152 recombinant inbred lines (RILs), derived from a cross between durum wheat (cv. Langdon) and wild emmer (accession G18-16). Wide genetic variation was found among the RILs for all grain minerals, with considerable transgressive effect. A total of 82 QTLs were mapped for 10 minerals with LOD score range of 3.2–16.7. Most QTLs were in favor of the wild allele (50 QTLs). Fourteen pairs of QTLs for the same trait were mapped to seemingly homoeologous positions, reflecting synteny between the A and B genomes. Significant positive correlation was found between grain protein concentration (GPC), Zn, Fe and Cu, which was supported by significant overlap between the respective QTLs, suggesting common physiological and/or genetic factors controlling the concentrations of these mineral nutrients. Few genomic regions (chromosomes 2A, 5A, 6B and 7A) were found to harbor clusters of QTLs for GPC and other nutrients. These identified QTLs may facilitate the use of wild alleles for improving grain nutritional quality of elite wheat cultivars, especially in terms of protein, Zn and Fe

The S-Star Cluster at the Center of the Milky Way: On the nature of diffuse NIR emission in the inner tenth of a parsec

Sagittarius A*, the super-massive black hole at the center of the Milky Way, is surrounded by a small cluster of high velocity stars, known as the S-stars. We aim to constrain the amount and nature of stellar and dark mass associated with the cluster in the immediate vicinity of Sagittarius A*. We use near-infrared imaging to determine the $K_\mathrm{s}$-band luminosity function of the S-star cluster members, and the distribution of the diffuse background emission and the stellar number density counts around the central black hole. This allows us to determine the stellar light and mass contribution expected from the faint members of the cluster. We then use post-Newtonian N-body techniques to investigate the effect of stellar perturbations on the motion of S2, as a means of detecting the number and masses of the perturbers. We find that the stellar mass derived from the $K_\mathrm{s}$-band luminosity extrapolation is much smaller than the amount of mass that might be present considering the uncertainties in the orbital motion of the star S2. Also the amount of light from the fainter S-cluster members is below the amount of residual light at the position of the S-star cluster after removing the bright cluster members. If the distribution of stars and stellar remnants is strongly enough peaked near Sagittarius A*, observed changes in the orbital elements of S2 can be used to constrain both their masses and numbers. Based on simulations of the cluster of high velocity stars we find that at a wavelength of 2.2 $\mu$m close to the confusion level for 8 m class telescopes blend stars will occur (preferentially near the position of Sagittarius A*) that last for typically 3 years before they dissolve due to proper motions.Comment: 14 pages, 11 figures, minor changes to match the published version in Astronomy & Astrophysic

Epithelial barrier hypothesis and the development of allergic and autoimmune diseases

The “epithelial barrier hypothesis” proposes that genetic predisposition to epithelial barrier damage, exposure to various epithelial barrier–damaging agents and chronic periepithelial inflammation are responsible for the development of allergic and autoimmune diseases. Particularly, the introduction of more than 200,000 new chemicals to our daily lives since the 1960s has played a major role in the pandemic increase of these diseases. The epithelial barrier constitutes the first line of physical, chemical, and immunological defence against external factors. A leaky epithelial barrier initiates the translocation of the microbiome from the surface of affected tissues to interepithelial and even deeper subepithelial areas. In tissues with a defective epithelial barrier, colonization of opportunistic pathogens, decreased microbiota biodiversity, local inflammation, and impaired regeneration and remodelling takes place. A dysregulated immune response against commensals and opportunistic pathogens starts. Migration of inflammatory cells to other tissues and their contribution to tissue injury and inflammation in the affected tissues are key events in the development and exacerbation of many chronic inflammatory diseases. Understanding the underlying factors that affect the integrity of epithelial barriers is essential to find preventive measures or effective treatments to restore its function. The aim of this review is to assess the origins of allergic and autoimmune diseases within the framework of the epithelial barrier hypothesis