A gas density drop in the inner 6 AU of the transition disk around the Herbig Ae star HD 139614

A. Carmona was partly supported by the Spanish Grant AYA 2011-26202. A. Carmona, A. Kospal and Zs. Regaly were partly supported by the Momentum grant of the MTA CSFK Lendulet Disk Research Group of the Hungarian Academy of Sciences. A. Carmona and C. Pinte acknowledge funding from the European Commission’s 7th Framework Program (ECFP7) (contract PERG06-GA-2009-256513) and from Agence Nationale pour la Recherche (ANR) of France under contract ANR-2010-JCJC-0504-01. A. Carmona acknowledges financial support by the European Southern Observatory visitors program. The research leading to these results has received funding from the EC-FP7 under grant agreement no 284405. C. Eiroa is partly supported by the Spanish Grant AYA 2014-55840-P L. A. Cieza was supported by CONICYT-FONDECYT grant number 1140109 and the Millennium Science Initiative (Chilean Ministry of Economy), through grant Nucleus RC130007.Context. Quantifying the gas surface density inside the dust cavities and gaps of transition disks is important to establish their origin. Aims. We seek to constrain the surface density of warm gas in the inner disk of HD 139614, an accreting 9 Myr Herbig Ae star with a (pre-)transition disk exhibiting a dust gap from 2.30.1 to 5.60.3 AU. Methods. We observed HD 139614 with ESO/VLT CRIRES and obtained high-resolution (R~90 000) spectra of CO isotopologues ro-vibrational emission at 4.7 μm. We derive constraints on the disk’s structure by modeling the CO isotopologue line profiles, the spectroastrometric signal, and the rotational diagrams using grids of flat Keplerian disk models. Results. We detected v = 1 → 0 12CO, 2→1 12CO, 1→0 13CO, 1→0 C18O, and 1→0 C17O ro-vibrational lines. Lines are consistent with disk emission and thermal excitation. 12CO v = 1→ 0 lines have an average width of 14 km s-1, Tgas of 450 K and an emitting region from 1 to 15 AU. 13CO and C18O lines are on average 70 and 100 K colder, 1 and 4 km s-1 narrower than 12CO v = 1→ 0, and are dominated by emission at R ≥ 6 AU. The 12CO = 1 → 0 composite line profile indicates that if there is a gap devoid of gas it must have a width narrower than 2 AU. We find that a drop in the gas surface density (δgas) at R = 5 — 6 AU is required to be able to reproduce the line profiles and rotational diagrams of the three CO isotopologues simultaneously. Models without a gas density drop generate 13CO and C18O emission lines that are too broad and warm. The value of gas can range from 10-2 to 10-4 depending on the gas-to-dust ratio of the outer disk. We find that the gas surface density profile at 1 2 AU) gas gap suggest the presence of an embedded < 2 MJ planet at around 4 AU.PostprintPeer reviewe

A Mouse Model of Acrodermatitis Enteropathica: Loss of Intestine Zinc Transporter ZIP4 (Slc39a4) Disrupts the Stem Cell Niche and Intestine Integrity

Loss-of-function of the zinc transporter ZIP4 in the mouse intestine mimics the lethal human disease acrodermatitis enteropathica. This is a rare disease in humans that is not well understood. Our studies demonstrate the paramount importance of ZIP4 in the intestine in this disease and reveal that a root cause of lethality is disruption of the intestine stem cell niche and impaired function of the small intestine. This, in turn, leads to dramatic weight loss and death unless treated with exogenous zinc

Intracellular iron uptake is favored in Hfe-KO mouse primary chondrocytes mimicking an osteoarthritis-related phenotype

HFE-hemochromatosis is a disease characterized by a systemic iron overload phenotype mainly associated with mutations in the HFE protein (HFE) gene. Osteoarthritis (OA) has been reported as one of the most prevalent complications in HFE-hemochromatosis patients, but the mechanisms associated with its onset and progression remain incompletely understood. In this study, we have characterized the response to high iron concentrations of a primary culture of articular chondrocytes isolated from newborn Hfe-KO mice and compared the results with that of a similar experiment developed in cells from C57BL/6 wild-type (wt) mice. Our data provide evidence that both wt- and Hfe-KO-derived chondrocytes, when exposed to 50 mu M iron, develop characteristics of an OA-related phenotype, such as an increased expression of metalloproteases, a decreased extracellular matrix production, and a lower expression level of aggrecan. In addition, Hfe-KO cells also showed an increased expression of iron metabolism markers and MMP3, indicating an increased susceptibility to intracellular iron accumulation and higher levels of chondrocyte catabolism. Accordingly, upon treatment with 50 mu M iron, these chondrocytes were found to preferentially differentiate toward hypertrophy with increased expression of collagen I and transferrin and downregulation of SRY (sex-determining region Y)-box containing gene 9 (Sox9). In conclusion, high iron exposure can compromise chondrocyte metabolism, which, when simultaneously affected by an Hfe loss of function, appears to be more susceptible to the establishment of an OA-related phenotype.European Regional Development FundEuropean Union (EU) [EMBRC.PT Alg-01-0145-FEDER-022121, Norte-01-0145-FEDER-000012]Fundacao para a Ciencia e a TecnologiaPortuguese Foundation for Science and Technology [SFRH/BD/77056/2011]Portuguese Foundation for Science and TechnologyPortuguese Foundation for Science and TechnologyPortuguese Science and Technology FoundationPortuguese Foundation for Science and Technologyinfo:eu-repo/semantics/publishedVersio

Evidence for allosteric regulation of pH-sensitive System A (SNAT2) and System N (SNAT5) amino acid transporter activity involving a conserved histidine residue

System A and N amino acid transporters are key effectors of movement of amino acids across the plasma membrane of mammalian cells. These Na(+)-dependent transporters of the SLC38 gene family are highly sensitive to changes in pH within the physiological range, with transport markedly depressed at pH 7.0. We have investigated the possible role of histidine residues in the transporter proteins in determining this pH-sensitivity. The histidine-modifying agent DEPC (diethyl pyrocarbonate) markedly reduces the pH-sensitivity of SNAT2 and SNAT5 transporters (representative isoforms of System A and N respectively, overexpressed in Xenopus oocytes) in a concentration-dependent manner but does not completely inactivate transport activity. These effects of DEPC were reversed by hydroxylamine and partially blocked in the presence of excess amino acid substrate. DEPC treatment also blocked a reduction in apparent affinity for Na(+) (K(0.5)(Na(+))) of the SNAT2 transporter at low external pH. Mutation of the highly conserved C-terminal histidine residue to alanine in either SNAT2 (H504A) or SNAT5 (H471A) produced a transport phenotype exhibiting reduced, DEPC-resistant pH-sensitivity with no change in K(0.5)(Na(+)) at low external pH. We suggest that the pH-sensitivity of these structurally related transporters results at least partly from a common allosteric mechanism influencing Na(+) binding, which involves an H(+)-modifier site associated with C-terminal histidine residues

Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system

Abstract Background The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these disorders. We aimed to explore further biomarkers of Mn deposition in the central nervous system in two siblings presenting with acute dystonia and hypermanganesemia due to mutations in SLC39A14. These biomarkers may help clinicians to establish faster and accurate diagnosis and to monitor disease progression after chelation therapy is administered. Results A customized gene panel for movement disorders revealed a novel missense variant (c.311G > T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na2CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued. Conclusions Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na2CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects