Magnetic resonance imaging brain atrophy assessment in primary age-related tauopathy (PART)

Alzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Recently, primary age-related tauopathy (PART) has been described as a new anatomopathological disorder where NFTs are the main feature in the absence of neuritic plaques. However, since PART has mainly been studied in post-mortem patient brains, not much is known about the clinical or neuroimaging characteristics of PART. Here, we studied the clinical brain imaging characteristics of PART focusing on neuroanatomical vulnerability by applying a previously validated multiregion visual atrophy scale. We analysed 26 cases with confirmed PART with paired clinical magnetic resonance imaging (MRI) acquisitions. In this selected cohort we found that upon correcting for the effect of age, there is increased atrophy in the medial temporal region with increasing Braak staging (r = 0.3937, p = 0.0466). Upon controlling for Braak staging effect, predominantly two regions, anterior temporal (r = 0.3638, p = 0.0677) and medial temporal (r = 0.3836, p = 0.053), show a trend for increased atrophy with increasing age. Moreover, anterior temporal lobe atrophy was associated with decreased semantic memory/language (r = - 0.5823, p = 0.0056; and r = - 0.6371, p = 0.0019, respectively), as was medial temporal lobe atrophy (r = - 0.4445, p = 0.0435). Overall, these findings support that PART is associated with medial temporal lobe atrophy and predominantly affects semantic memory/language. These findings highlight that other factors associated with aging and beyond NFTs could be involved in PART pathophysiology.NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG062428–01 (PI James Leverenz, MD) P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P30 AG062421–01 (PI Bradley Hyman, MD, PhD), P30 AG062422–01 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P30 AG062429–01(PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P30 AG062715–01 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD). NIH grants to JFC (R01AG054008, R01NS095252, R01AG062348, RF1AG060961), the Tau Consortium, and Alzheimer’s Association (NIRG- 469 15-363188

Gitana: a SQL-based Git Repository Inspector

International audienceSoftware development projects are notoriously complex and difficult to deal with. Several support tools such as issue tracking, code review and Source Control Management (SCM) systems have been introduced in the past decades to ease development activities. While such tools efficiently track the evolution of a given aspect of the project (e.g., bug reports), they provide just a partial view of the project and often lack of advanced querying mechanisms limiting themselves to command line or simple GUI support. This is particularly true for projects that rely on Git, the most popular SCM system today. In this paper, we propose a conceptual schema for Git and an approach that, given a Git repository, exports its data to a relational database in order to (1) promote data integration with other existing SCM tools and (2) enable writing queries on Git data using standard SQL syntax. To ensure efficiency, our approach comes with an incremental propagation mechanism that refreshes the database content with the latest modifications. We have implemented our approach in Gitana, an open-source tool available on GitHub

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition

Scutoids are a geometrical solution to three-dimensional packing of epithelia

As animals develop, tissue bending contributes to shape the organs into complex three-dimensional structures. However, the architecture and packing of curved epithelia remains largely unknown. Here we show by means of mathematical modelling that cells in bent epithelia can undergo intercalations along the apico-basal axis. This phenomenon forces cells to have different neighbours in their basal and apical surfaces. As a consequence, epithelial cells adopt a novel shape that we term “scutoid”. The detailed analysis of diverse tissues confirms that generation of apico-basal intercalations between cells is a common feature during morphogenesis. Using biophysical arguments, we propose that scutoids make possible the minimization of the tissue energy and stabilize three-dimensional packing. Hence, we conclude that scutoids are one of nature's solutions to achieve epithelial bending. Our findings pave the way to understand the three-dimensional organization of epithelial organs

Magnetic structure and enhanced T-N of the rare-earth intermetallic compound TbRhIn5: Experiments and mean-field model

In this work the physical properties of the intermetallic compound TbRhIn5 were investigated by means of temperature-dependent magnetic susceptibility, electrical resistivity, heat-capacity, and resonant x-ray magnetic diffraction experiments. TbRhIn5 is an intermetallic compound that orders antiferromagnetically at T-N=45.5 K, the highest ordering temperature among the existing RRhIn5 (1-1-5, R=rare earth) materials, which in contrast to what is expected from a de Gennes scaling along the RRhIn5 series. The x-ray resonant diffraction data have allowed us to solve the magnetic structure of TbRhIn5. Below T-N, we found a commensurate antiferromagnetic structure with a propagation vector (1/2,0,1/2) and the Tb moments oriented along the c axis. Strong (over two orders of magnitude) dipolar enhancements of the magnetic Bragg peaks were observed at both Tb absorption edges L-II and L-III, indicating a fairly high polarization of the Tb 5d levels. Using a mean-field model including an isotropic first-neighbor exchange interaction (J(R-R)) and the tetragonal crystalline electrical field (CEF), we evaluate the influence of the CEF effects in the physical properties of TbRhIn5. The results reported here seem to corroborate a general trend of CEF-driven effects on T-N along the RRhIn5 series.742

Sialic Acid Glycobiology Unveils Trypanosoma cruzi Trypomastigote Membrane Physiology.

Trypanosoma cruzi, the flagellate protozoan agent of Chagas disease or American trypanosomiasis, is unable to synthesize sialic acids de novo. Mucins and trans-sialidase (TS) are substrate and enzyme, respectively, of the glycobiological system that scavenges sialic acid from the host in a crucial interplay for T. cruzi life cycle. The acquisition of the sialyl residue allows the parasite to avoid lysis by serum factors and to interact with the host cell. A major drawback to studying the sialylation kinetics and turnover of the trypomastigote glycoconjugates is the difficulty to identify and follow the recently acquired sialyl residues. To tackle this issue, we followed an unnatural sugar approach as bioorthogonal chemical reporters, where the use of azidosialyl residues allowed identifying the acquired sugar. Advanced microscopy techniques, together with biochemical methods, were used to study the trypomastigote membrane from its glycobiological perspective. Main sialyl acceptors were identified as mucins by biochemical procedures and protein markers. Together with determining their shedding and turnover rates, we also report that several membrane proteins, including TS and its substrates, both glycosylphosphatidylinositol-anchored proteins, are separately distributed on parasite surface and contained in different and highly stable membrane microdomains. Notably, labeling for α(1,3)Galactosyl residues only partially colocalize with sialylated mucins, indicating that two species of glycosylated mucins do exist, which are segregated at the parasite surface. Moreover, sialylated mucins were included in lipid-raft-domains, whereas TS molecules are not. The location of the surface-anchored TS resulted too far off as to be capable to sialylate mucins, a role played by the shed TS instead. Phosphatidylinositol-phospholipase-C activity is actually not present in trypomastigotes. Therefore, shedding of TS occurs via microvesicles instead of as a fully soluble form

Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain

Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum: an in vitro and in vivo approach

<div><p>Abstract Background: Considering the high toxicity and limited therapies available for treating visceral leishmaniasis (VL), the drug repositioning approach represents a faster way to deliver new therapies to the market. Methods: In this study, we described for the first time the activity of a potent antiarrhythmic, amiodarone (AMD), against L. (L.)infantum and its in vitro and in vivo activity. Results: The evaluation against promastigotes has shown that amiodarone presents leishmanicidal effect against the extracellular form, with an IC50 value of 10 μM. The activity was even greater against amastigotes in comparison with promastigotes with an IC50 value of 0.5 μM. The selectivity index in relation to the intracellular form demonstrated that the antiparasitic activity was approximately 56 times higher than its toxicity to mammalian cells. Investigation of the in vivo AMD activity in the L. infantum-infected hamster model showed that 51 days after the initial infection, amiodarone was unable to reduce the parasite burden in the spleen and liver when treated for 10 consecutive days, intraperitoneally, at 50 mg/kg/day, as determined by qPCR. Although not statistically significant, AMD was able to reduce the parasite burden by 20% in the liver when treated for 10 consecutive days, orally, at 100 mg/kg/day; no reduction in the spleen was found by qPCR. Conclusions: Our findings may help further drug design studies seeking new AMD derivatives that may provide new candidates with an in vitro selectivity close to or even greater than that observed in the prototype delivering effectiveness in the experimental model of VL.</p></div

Effect of Gas Atmosphere on Catalytic Behaviour of Zirconia, Ceria and Ceria Zirconia Catalysts in Valeric Acid Ketonization

[EN] Ketonization of valeric acid, which can be obtained by lignocellulosic biomass conversion, was carried out in a fixed bed flow reactor over ZrO2, 5-20 % CeO2/ZrO2 and CeO2 both under hydrogen and nitrogen stream at 628 K and atmospheric pressure. Regardless gas-carrier 10 wt% CeO2/ZrO2 was found to show higher catalytic activity compared to zirconia per se as well as other ceria modified zirconia while ceria per se exhibited very low catalytic activity. All catalysts provided higher acid conversion in H-2 than in N-2 whereas selectivity to 5-nonanone was insensitive to gas atmosphere. XRD, FTIR, UV-Vis DRS, XPS, HRTEM methods were applied to characterize catalysts in reduced and unreduced states simulating corresponding reaction conditions during acid ketonization. XRD did not reveal any changes in zirconia and ceria/zirconia lattice parameters as well as crystalline phase depending on gas atmosphere while insertion of ceria in zirconia caused notable increase in lattice parameter indicating some distortion of crystalline structure. According to XPS, FTIR and UV-Vis methods, the carrier gas was found to affect catalyst surface composition leading to alteration in Lewis acid sites ratio. Appearance of Zr3+ cations was observed on the ZrO2 surface after hydrogen pretreatment whereas only Zr4+ cations were determined using nitrogen as a gas-carrier. These changes of catalyst's surface cation composition affected corresponding activity in ketonization probably being crucial for reaction mechanism involving metal cations catalytic centers for acid adsorption and COO- stabilization at the initial step.Financial support from the Russian Foundation of Basic Research (RFBR Grant No 11-03-94001-CSIC) is gratefully acknowledged. This work was supported by the Federal Program "Scientific and Educational Cadres of Russia'' (Grant No 2012-1.5-12-000-1013-002). The authors also wish to thank Dr. Evgeniy Gerasimov, Dr. Igor Prosvirin, Dr. Demid Demidov from the Department of Physicochemical Methods at the Boreskov Institute of Catalysis for TEM and XPS measurements.Zaytseva, YA.; Panchenko, VN.; Simonov, MN.; Shutilov, AA.; Zenkovets, GA.; Renz, M.; Simakova, IL.... (2013). Effect of Gas Atmosphere on Catalytic Behaviour of Zirconia, Ceria and Ceria Zirconia Catalysts in Valeric Acid Ketonization. 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