A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents

Publication date: Available online 5 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sourabh Mundra, Vandana Thakur, Angelica M. Bello, Sumit Rathore, Mohd Asad, Lianhu Wei, Jane Yang, Sai Kumar Chakka, Radhakrishnan Mahesh, Pawan Malhotra, Asif Mohmmed, Lakshmi P. Kotra
The prokaryotic ATP-dependent ClpP protease, localized in the relict plastid of malaria parasite, represents a potential drug target. In the present study, we utilized in silico structure-based screening and medicinal chemistry approaches to identify a novel pyrimidine series of compounds inhibiting P. falciparum ClpP protease activity and evaluated their antiparasitic activities. Structure-activity relationship indicated that morpholine moiety at C2, an aromatic substitution at N3 and a 4-oxo moiety on the pyrimidine are important for potent inhibition of ClpP enzyme along with antiparasiticidal activity. Compound 33 exhibited potent antiparasitic activity (EC₅₀ 9.0 ± 0.2 μM), a 9-fold improvement over the antiparasitic activity of the hit molecule 6. Treatment of blood stage P. falciparum cultures with compound 33 caused morphological and developmental abnormalities in the parasites; further, compound 33 treatment hindered apicoplast development indicating the targeting of apicoplast.

Graphical abstract

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In vitro antitumor activity of novel benzimidazole-based Cu(II) complexes

Publication date: Available online 5 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jiyong Hu, Yan Guo, Jin'an Zhao, Junshuai Zhang
Four benzimidazole-based Cu(II) complexes: Cu2(p–2-bmp)2Br4 (1), Cu2(p–2-bmp)2Cl4 (2), Cu2(p-2-bmb)2(DMF)2Br4·(CHCl3) (3), and Cu(p-2-bmb)(NO3)2·(CHCl3) (4) were isolated and characterized, where p–2-bmp is 1-((2-(pyridine-2-yl)-1H-benzoimidazol-1-yl)methyl)-1H- pyridine and p-2-bmb is 1-((2-(pyridin-2-yl)-1-benzoimidazol-1-yl)methyl)-1H-benzotriazole. Complexes 1 and 2 have binuclear configurations, 3 has a mononuclear structure, and 4 has a one-dimensional (1-D) chain skeleton. To evaluate their potential anticancer effects on human carcinoma cells, anti-proliferation, DNA binding and cleavage, and apoptosis elicitation were examined. Compared with complexes 2, 3, and 4, complex 1 exhibited potent in vitro cytotoxicity toward four cell lines (MCF7, EC109, SH-SY5Y and QBC939), with SH-SY5Y cells demonstrating the most sensitivity. Therefore, further in-depth investigations were performed using complex 1. Absorption titration experiments, circular dichroism spectroscopic studies, and ethidium bromide displacement assays suggested that complex 1 binds to DNA through intercalation, significantly cleaves supercoiled pBR322 DNA, and inhibits DNA transcription. Cell cycle analysis revealed that SH-SY5Y cells were arrested in the G2/M phase after treatment with complex 1. Membrane permeability analysis and nuclear staining of SH-SY5Y cells showed that complex 1 could induce apoptosis.

Graphical abstract

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Conformationally constrained peptides target the allosteric kinase dimer interface and inhibit EGFR activation

Publication date: Available online 5 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Melody D. Fulton, Laura E. Hanold, Zheng Ruan, Sneha Patel, Aaron M. Beedle, Natarajan Kannan, Eileen J. Kennedy
Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimized using molecular modeling. Peptides were constrained using peptide "stapling" to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt. To our knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. This study presents a novel, alternative targeting site for allosteric inhibition of EGFR.

Graphical abstract

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Structure-Activity Relationship Study of Small Molecule Inhibitors of the DEPTOR-mTOR Interaction

Publication date: Available online 6 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E. Jung, Alan Lichtenstein
DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure-activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads – namely compounds 3g, 3k, 4d, 4e and 4g – all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest.

Graphical abstract

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Structure and diversity of human dendritic spines evidenced by a new three-dimensional reconstruction procedure for Golgi staining and light microscopy

Publication date: Available online 5 September 2017
Source:Journal of Neuroscience Methods
Author(s): Roman Reberger, Aline Dall'Oglio, Claudio R. Jung, Alberto A. Rasia-Filho
BackgroundDifferent approaches aim to unravel detailed morphological features of neural cells. Dendritic spines are multifunctional units that reflect cellular connectivity, synaptic strength and plasticity.New MethodA novel three-dimensional (3D) reconstruction procedure is introduced for visualization of dendritic spines from human postmortem brain tissue using brightfield microscopy. The segmentation model was based on thresholding the intensity values of the dendrite spine image along 'z' stacks. We used median filtering and removed false positives. Fine adjustments during image processing confirmed that the reconstructed image of the spines corresponded to the actual original data.ResultsExamples are shown for the cortical amygdaloid nucleus and the CA3 hippocampal area. Structure of spine heads and necks was evaluated at different angles. Our 3D reconstruction images display dendritic spines either isolated or in clusters, in a continuum of shapes and sizes, from simple to more elaborated forms, including the presence of spinule and complex 'thorny excrescences'.Comparison with Existing MethodsThe procedure has the advantages already described for the adapted "single-section" Golgi method, since it provides suitable results using human brains fixed in formalin for long time, is relatively easy, requires minimal equipment, and uses an algorithm for 3D reconstruction that provides high quality images and more precise morphological data.ConclusionThe procedure described here allows the reliable visualization and study of human dendritic spines with broad applications for normal controls and pathological studies.



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Histochemical features of aluminum chloride histiocytic reaction and the use of PAS stain to provide a clue to prior subtle biopsy sites

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Tail-Anchored Protein Insertion by a Single Get1/2 Heterodimer

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Benjamin E. Zalisko, Charlene Chan, Vladimir Denic, Ronald S. Rock, Robert J. Keenan
The Get1/2 transmembrane complex drives the insertion of tail-anchored (TA) proteins from the cytosolic chaperone Get3 into the endoplasmic reticulum membrane. Mechanistic insight into how Get1/2 coordinates this process is confounded by a lack of understanding of the basic architecture of the complex. Here, we define the oligomeric state of full-length Get1/2 in reconstituted lipid bilayers by combining single-molecule and bulk fluorescence measurements with quantitative in vitro insertion analysis. We show that a single Get1/2 heterodimer is sufficient for insertion and demonstrate that the conserved cytosolic regions of Get1 and Get2 bind asymmetrically to opposing subunits of the Get3 homodimer. Altogether, our results define a simplified model for how Get1/2 and Get3 coordinate TA protein insertion.

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Teaser

Tail-anchored membrane proteins are inserted into the endoplasmic reticulum via the post-translational GET pathway. Zalisko et al. combine single-molecule and bulk fluorescence measurements with quantitative in vitro insertion assays to define the architecture of the heterodimeric Get1/2 insertase and its engagement with the soluble chaperone Get3.


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Cbln1 and Cbln4 Are Structurally Similar but Differ in GluD2 Binding Interactions

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Chen Zhong, Jinlong Shen, Huibing Zhang, Guangyi Li, Senlin Shen, Fang Wang, Kuan Hu, Longxing Cao, Yongning He, Jianping Ding
SummaryUnlike cerebellin 1 (Cbln1), which bridges neurexin (Nrxn) receptors and δ-type glutamate receptors in a trans-synaptic triad, Cbln4 was reported to have no or weak binding for the receptors despite sharing ∼70% sequence identity with Cbln1. Here, we report crystal structures of the homotrimers of the C1q domain of Cbln1 and Cbln4 at 2.2 and 2.3 Å resolution, respectively. Comparison of the structures suggests that the difference between Cbln1 and Cbln4 in GluD2 binding might be because of their sequence and structural divergence in loop CD. Surprisingly, we show that Cbln4 binds to Nrxn1β and forms a stable complex with the laminin, nectin, sex-hormone binding globulin (LNS) domain of Nrxn1β. Furthermore, the negative-stain electron microscopy reconstruction of hexameric full-length Cbln1 at 13 Å resolution and that of the Cbln4/Nrxn1β complex at 19 Å resolution suggest that Nrxn1β binds to the N-terminal region of Cbln4, probably through strand β10 of the S4 insert.

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Cbln1 and Cbln4 share high sequence identity but have divergent functions. Zhong et al. find that Cbln4 forms a complex with Nrxn1β. Using crystal structures of the C1q domain of Cbln1 and Cbln4 and negative-stain EM reconstructions of Cbln1 and Cbln4/Nrxn1β, the authors examine similarities and divergence between Cbln1 and Cbln4.


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Dynamics of Presynaptic Diacylglycerol in a Sensory Neuron Encode Differences between Past and Current Stimulus Intensity

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Hayao Ohno, Naoko Sakai, Takeshi Adachi, Yuichi Iino
Memorizing the intensity of sensory stimuli enables animals to successfully deal with changing environmental conditions and contributes to cognitive functions such as auditory and visual working memory. However, how nervous systems process past and current stimulus intensity is largely unknown at the molecular level. Here, we employ in vivo diacylglycerol (DAG) imaging in the ASER taste neuron of Caenorhabditis elegans and demonstrate that associative learning between ambient salt concentrations and food can be explained by changes in presynaptic DAG. The abundance of DAG is regulated in response to external salt concentration changes via sensory transduction in ASER and can encode differences between past and current salt concentrations. The DAG dynamics are modulated downstream of the synaptic insulin/phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates the behavioral plasticity induced by starvation. These results provide insights into how a single neuron stores past input intensity and generates appropriate behavioral responses.

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Animals adapt to environmental changes by memorizing the intensity of sensory stimuli. By employing diacylglycerol imaging and behavioral analyses, Ohno et al. show the in vivo dynamics of neuronal diacylglycerol and present insights into how a single neuron processes past and current stimulus intensity.


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Local Nucleation of Microtubule Bundles through Tubulin Concentration into a Condensed Tau Phase

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Amayra Hernández-Vega, Marcus Braun, Lara Scharrel, Marcus Jahnel, Susanne Wegmann, Bradley T. Hyman, Simon Alberti, Stefan Diez, Anthony A. Hyman
Non-centrosomal microtubule bundles play important roles in cellular organization and function. Although many diverse proteins are known that can bundle microtubules, biochemical mechanisms by which cells could locally control the nucleation and formation of microtubule bundles are understudied. Here, we demonstrate that the concentration of tubulin into a condensed, liquid-like compartment composed of the unstructured neuronal protein tau is sufficient to nucleate microtubule bundles. We show that, under conditions of macro-molecular crowding, tau forms liquid-like drops. Tubulin partitions into these drops, efficiently increasing tubulin concentration and driving the nucleation of microtubules. These growing microtubules form bundles, which deform the drops while remaining enclosed by diffusible tau molecules exhibiting a liquid-like behavior. Our data suggest that condensed compartments of microtubule bundling proteins could promote the local formation of microtubule bundles in neurons by acting as non-centrosomal microtubule nucleation centers and that liquid-like tau encapsulation could provide both stability and plasticity to long axonal microtubule bundles.

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Hernández-Vega et al. show that tau forms liquid-like drops in vitro. Tubulin gets enriched in these drops, enabling microtubule bundles polymerization within drops. Microtubule bundles deform tau drops, reshaping them into rod-like structures. Microtubules in these structures remain as stable bundles. The findings have potential implications for tau function in axonal projections.


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The SET1 Complex Selects Actively Transcribed Target Genes via Multivalent Interaction with CpG Island Chromatin

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): David A. Brown, Vincenzo Di Cerbo, Angelika Feldmann, Jaewoo Ahn, Shinsuke Ito, Neil P. Blackledge, Manabu Nakayama, Michael McClellan, Emilia Dimitrova, Anne H. Turberfield, Hannah K. Long, Hamish W. King, Skirmantas Kriaucionis, Lothar Schermelleh, Tatiana G. Kutateladze, Haruhiko Koseki, Robert J. Klose
Chromatin modifications and the promoter-associated epigenome are important for the regulation of gene expression. However, the mechanisms by which chromatin-modifying complexes are targeted to the appropriate gene promoters in vertebrates and how they influence gene expression have remained poorly defined. Here, using a combination of live-cell imaging and functional genomics, we discover that the vertebrate SET1 complex is targeted to actively transcribed gene promoters through CFP1, which engages in a form of multivalent chromatin reading that involves recognition of non-methylated DNA and histone H3 lysine 4 trimethylation (H3K4me3). CFP1 defines SET1 complex occupancy on chromatin, and its multivalent interactions are required for the SET1 complex to place H3K4me3. In the absence of CFP1, gene expression is perturbed, suggesting that normal targeting and function of the SET1 complex are central to creating an appropriately functioning vertebrate promoter-associated epigenome.

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Brown et al. show that the SET1 complex is driven to active CpG island promoters via the CFP1 protein, which engages in multivalent chromatin binding to recognize both non-methylated DNA and H3K4me3. This is necessary for normal H3K4me3 at active gene promoters and appropriate regulation of gene expression.


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Mpp6 Incorporation in the Nuclear Exosome Contributes to RNA Channeling through the Mtr4 Helicase

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Sebastian Falk, Fabien Bonneau, Judith Ebert, Alexander Kögel, Elena Conti
The RNA-degrading exosome mediates the processing and decay of many cellular transcripts. In the yeast nucleus, the ubiquitous 10-subunit exosome core complex (Exo-9–Rrp44) functions with four conserved cofactors (Rrp6, Rrp47, Mtr4, and Mpp6). Biochemical and structural studies to date have shed insights into the mechanisms of the exosome core and its nuclear cofactors, with the exception of Mpp6. We report the 3.2-Å resolution crystal structure of a S. cerevisiae Exo-9–Mpp6 complex, revealing how linear motifs in the Mpp6 middle domain bind Rrp40 via evolutionary conserved residues. In particular, Mpp6 binds near a tryptophan residue of Rrp40 that is mutated in human patients suffering from pontocerebellar hypoplasia. Using biochemical assays, we show that Mpp6 is required for the ability of Mtr4 to extend the trajectory of an RNA entering the exosome core, suggesting that it promotes the channeling of substrates from the nuclear helicase to the processive RNase.

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Falk et al. provide insights into the structure and function of the nuclear RNA exosome. The authors elucidate how the nuclear cofactor Mpp6 is recruited to the exosome core complex and show that it facilitates the threading of RNA substrates from the Mtr4 helicase to the Rrp44 RNase.


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Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Jonathan M. Goodwin, William E. Dowdle, Rowena DeJesus, Zuncai Wang, Philip Bergman, Marek Kobylarz, Alicia Lindeman, Ramnik J. Xavier, Gregory McAllister, Beat Nyfeler, Gregory Hoffman, Leon O. Murphy
Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that ferritin and its binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a form of selective autophagy. By using genome-scale functional screening, we identify an alternative lysosomal transport pathway for ferritin that requires FIP200, ATG9A, VPS34, and TAX1BP1 but lacks involvement of the ATG8 lipidation machinery that constitutes classical macroautophagy. TAX1BP1 binds directly to NCOA4 and is required for lysosomal trafficking of ferritin under basal and iron-depleted conditions. Under basal conditions ULK1/2-FIP200 controls ferritin turnover, but its deletion leads to TAX1BP1-dependent activation of TBK1 that regulates redistribution of ATG9A to the Golgi enabling continued trafficking of ferritin. Cells expressing an amyotrophic lateral sclerosis (ALS)-associated TBK1 allele are incapable of degrading ferritin suggesting a molecular mechanism that explains the presence of iron deposits in patient brain biopsies.

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Teaser

Goodwin et al. employ functional CRISPR screening approaches to show lysosomal ferritin turnover is autophagy-independent, revealing a role for TBK1 in iron homeostasis.


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Strong Clonal Relatedness between Serum and Gut IgA despite Different Plasma Cell Origins

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Rasmus Iversen, Omri Snir, Maria Stensland, José E. Kroll, Øyvind Steinsbø, Ilma R. Korponay-Szabó, Knut E.A. Lundin, Gustavo A. de Souza, Ludvig M. Sollid
Mucosal antigens induce generation of lamina propria plasma cells (PCs) that secrete dimeric immunoglobulin A (IgA) destined for transport across the epithelium. In addition, blood contains monomeric IgA. To study the relationship between mucosal and systemic antibody responses, we took advantage of celiac disease patient samples for isolation of gut PCs as well as serum IgA and IgG reactive with a gluten-derived peptide or the autoantigen transglutaminase 2. Proteomic analysis of serum IgA revealed antigen-specific V-gene preferences, which matched those found in gut PCs. Further, gut PC CDR-H3 sequences were abundant in serum IgA but also detectable in serum IgG. Our data indicate that the same B cell clones that give rise to gut PCs also contribute to the serum antibody pool. However, serum IgA antibodies had a molecular composition distinct from that of IgA antibodies secreted in the gut, suggesting that individual B cell clones give rise to different PC populations.

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The relationship between mucosal antibody responses and antibodies in blood is not clearly understood. Iversen et al. use proteomics to characterize antibodies in serum and gut biopsy specimens obtained from celiac disease patients. Serum and gut IgA are derived from the same B cell clones but produced by different plasma cells.


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KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Tirtha Kamal Das, Ross Leigh Cagan
Gene fusions are increasingly recognized as important cancer drivers. The KIF5B-RET gene has been identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation, including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. The KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation, including invadopodia-like processes. Through a combination of genetic and biochemical studies, we demonstrate that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB-vesicle-dependent RET-SRC-EGFR-FGFR signaling hub. We demonstrate that drugs designed to inhibit RET alone work poorly in KIF5B-RET-transformed cells. However, combining the RET inhibitor sorafenib with drugs that target EGFR, microtubules, or FGFR led to strong efficacy in both Drosophila and human cell line KIF5B-RET models. This work demonstrates the utility of exploring the full biology of fusions to identify rational therapeutic strategies.

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Das and Cagan find that each portion of the KIF5B-RET fusion oncoprotein recruits different components to assemble a multi-kinase oncogenic signaling hub that promotes invadopodia formation. This suggests that multiple kinase components of this KIF5B-RET hub need to be simultaneously targeted therapeutically.


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ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Stephanie Zimmermann, Lennart Pfannkuch, Munir A. Al-Zeer, Sina Bartfeld, Manuel Koch, Jianping Liu, Cindy Rechner, Meike Soerensen, Olga Sokolova, Alla Zamyatina, Paul Kosma, André P. Mäurer, Frithjof Glowinski, Klaus-Peter Pleissner, Monika Schmid, Volker Brinkmann, Alexander Karlas, Michael Naumann, Marion Rother, Nikolaus Machuy, Thomas F. Meyer
Activation of transcription factor NF-κB is a hallmark of infection with the gastric pathogen Helicobacter pylori, associated with inflammation and carcinogenesis. Genome-wide RNAi screening revealed numerous host factors involved in H. pylori-, but not IL-1β- and TNF-α-dependent NF-κB regulation. Pathway analysis including CRISPR/Cas9-knockout and recombinant protein technology, immunofluorescence microscopy, immunoblotting, mass spectrometry, and mutant H. pylori strains identified the H. pylori metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (βHBP) as a cagPAI type IV secretion system (T4SS)-dependent effector of NF-κB activation in infected cells. Upon pathogen-host cell contact, TIFA forms large complexes (TIFAsomes) including interacting host factors, such as TRAF2. NF-κB activation, TIFA phosphorylation, and TIFAsome formation depend on a functional ALPK1 kinase, highlighting the ALPK1-TIFA axis as a core innate immune pathway. ALPK1-TIFA-mediated NF-κB activation was independent of CagA protein translocation, indicating that CagA translocation and HBP delivery to host cells are distinct features of the pathogen's T4SS.

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Zimmermann et al. identify pathogen and host factors involved in NF-κB activation after infection with type IV secretion-proficient Helicobacter pylori. Central hits are ALPK1 and TIFA. ALPK1 is necessary for phosphorylation-dependent formation of TIFA complexes (TIFAsomes) with TRAF2. This yields HBP-ALPK1-TIFA-TRAF2-NF-κB as the core-regulon of H. pylori-induced innate immune activation.


http://ift.tt/2gKSUBt

Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Florine E.M. Scholte, Marko Zivcec, John V. Dzimianski, Michelle K. Deaton, Jessica R. Spengler, Stephen R. Welch, Stuart T. Nichol, Scott D. Pegan, Christina F. Spiropoulou, Éric Bergeron
Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines.

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Teaser

Using reverse genetics, Scholte et al. report that OTU catalytic activity is critical for Crimean-Congo hemorrhagic fever virus replication, and deubiquitinase activity suppresses the antiviral response to infection. These findings provide insights in the multifunctional properties of viral OTUs and support development of OTU-specific therapeutics.


http://ift.tt/2gJXH6c

Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Xiao Ling Li, Murugan Subramanian, Matthew F. Jones, Ritu Chaudhary, Deepak K. Singh, Xinying Zong, Berkley Gryder, Sivasish Sindri, Min Mo, Aaron Schetter, Xinyu Wen, Swetha Parvathaneni, Dickran Kazandjian, Lisa M. Jenkins, Wei Tang, Fathi Elloumi, Jennifer L. Martindale, Maite Huarte, Yuelin Zhu, Ana I. Robles, Susan M. Frier, Frank Rigo, Maggie Cam, Stefan Ambs, Sudha Sharma, Curtis C. Harris, Mary Dasso, Kannanganattu V. Prasanth, Ashish Lal
Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.

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For a cell to divide, the tumor suppressor protein p53 must be kept at low levels. Li et al. find that a long noncoding RNA PURPL allows cancer cells to divide by keeping p53 levels low. PURPL binds to the p53 regulator MYBBP1A to suppress p53 levels and facilitate cell proliferation.


http://ift.tt/2gLW741

A Single TCF Transcription Factor, Regardless of Its Activation Capacity, Is Sufficient for Effective Trilineage Differentiation of ESCs

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Steven Moreira, Enio Polena, Victor Gordon, Solen Abdulla, Sujeivan Mahendram, Jiayi Cao, Alexandre Blais, Geoffrey A. Wood, Anna Dvorkin-Gheva, Bradley W. Doble
Co-expression and cross-regulation of the four TCF/LEFs render their redundant and unique functions ambiguous. Here, we describe quadruple-knockout (QKO) mouse ESCs lacking all full-length TCF/LEFs and cell lines rescued with TCF7 or TCF7L1. QKO cells self-renew, despite gene expression patterns that differ significantly from WT, and display delayed, neurectoderm-biased, embryoid body (EB) differentiation. QKO EBs have no contracting cardiomyocytes and differentiate poorly into mesendoderm but readily generate neuronal cells. QKO cells and TCF7L1-rescued cells cannot efficiently activate TCF reporters, whereas TCF7-rescued cells exhibit significant reporter responsiveness. Surprisingly, despite dramatically different transactivation capacities, re-expression of TCF7L1 or TCF7 in QKO cells restores their tri-lineage differentiation ability, with similar lineage marker expression patterns and beating cardiomyocyte frequencies observed in EBs. Both factors also similarly affect the transcriptome of QKO cells. Our data reveal that a single TCF, regardless of its activation capacity, is sufficient for effective trilineage differentiation of ESCs.

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Moreira et al. describe the generation and characterization of mouse ESCs lacking all four full-length TCF/LEF factors. By knocking in single epitope-tagged TCF/LEFs, they reveal redundancies in the abilities of "activating" and "repressive" TCFs to rescue the differentiation deficits of the quadruple-knockout cells.


http://ift.tt/2gJXG28

mTORC2 Signaling Selectively Regulates the Generation and Function of Tissue-Resident Peritoneal Macrophages

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Min-Hee Oh, Samuel L. Collins, Im-Hong Sun, Ada J. Tam, Chirag H. Patel, Matthew L. Arwood, Yee Chan-Li, Jonathan D. Powell, Maureen R. Horton
Tissue-resident macrophages play critical roles in sentinel and homeostatic functions as well as in promoting inflammation and immunity. It has become clear that the generation of these cells is highly dependent upon tissue-specific cues derived from the microenvironment that, in turn, regulate unique differentiation programs. Recently, a role for GATA6 has emerged in the differentiation programming of resident peritoneal macrophages. We identify a critical role for mTOR in integrating cues from the tissue microenvironment in regulating differentiation and metabolic reprogramming. Specifically, inhibition of mTORC2 leads to enhanced GATA6 expression in a FOXO1 dependent fashion. Functionally, inhibition of mTORC2 promotes peritoneal resident macrophage generation in the resolution phase during zymosan-induced peritonitis. Also, mTORC2-deficient peritoneal resident macrophages displayed increased functionality and metabolic reprogramming. Notably, mTORC2 activation distinguishes tissue-resident macrophage proliferation and differentiation from that of M2 macrophages. Overall, our data implicate a selective role for mTORC2 in the differentiation of tissue-resident macrophages.

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Oh et al. identify the mTORC2-FOXO1 axis as playing a critical role in integrating cues from the microenvironment to regulate metabolic reprogramming, differentiation, and function of peritoneal tissue-resident macrophages.


http://ift.tt/2gJS8EZ

Heparin Increases Food Intake through AgRP Neurons

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Canjun Zhu, Pingwen Xu, Yanlin He, Yexian Yuan, Tao Wang, Xingcai Cai, Lulu Yu, Liusong Yang, Junguo Wu, Lina Wang, Xiaotong Zhu, Songbo Wang, Ping Gao, Qianyun Xi, Yongliang Zhang, Yong Xu, Qingyan Jiang, Gang Shu
Although the widely used anticoagulant drug heparin has been shown to have many other biological functions independent of its anticoagulant role, its effects on energy homeostasis are unknown. Here, we demonstrate that heparin level is negatively associated with nutritional states and that heparin treatment increases food intake and body weight gain. By using electrophysiological, pharmacological, molecular biological, and chemogenetic approaches, we provide evidence that heparin increases food intake by stimulating AgRP neurons and increasing AgRP release. Our results support a model whereby heparin competes with insulin for insulin receptor binding on AgRP neurons, and by doing so it inhibits FoxO1 activity to promote AgRP release and feeding. Heparin may be a potential drug target for food intake regulation and body weight control.

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Teaser

Zhu et al. demonstrate that heparin competes with insulin for insulin receptor binding on AgRP neurons, and by doing so it inhibits FoxO1 activity to promote AgRP release and feeding. Heparin is identified as a potential drug target for food intake regulation and body weight control.


http://ift.tt/2gKpVhc

The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Sandro Goruppi, Maria-Giuseppina Procopio, Seunghee Jo, Andrea Clocchiatti, Victor Neel, G. Paolo Dotto
The connection between signaling pathways activating cancer-associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses the gene expression program(s), leading to stromal senescence and CAF activation. Deregulated GLI signaling can also contribute to CAF conversion. Here, we report that compromised CSL function depends on GLI activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL upregulates the expression of the ULK3 kinase, which binds and activates GLI2. Increased ULK3 also induces autophagy, which is unlinked from GLI and CAF activation. ULK3 upregulation occurs in the CAFs of several tumor types, and ULK3 silencing suppresses the tumor-enhancing properties of these cells. Thus, ULK3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention.

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Teaser

Goruppi et al. demonstrate that CSL, a transcriptional repressor mediating Notch signaling, suppresses the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) by controlling the expression of autophagy kinase ULK3, which, in turn, activates GLI signaling. Their studies connect two key pathways involved in CAF activation and identify a target for stroma-focused anti-cancer intervention.


http://ift.tt/2gKP2Rd

The Prohormone VGF Regulates β Cell Function via Insulin Secretory Granule Biogenesis

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Samuel B. Stephens, Robert J. Edwards, Masato Sadahiro, Wei-Jye Lin, Cheng Jiang, Stephen R. Salton, Christopher B. Newgard
The prohormone VGF is expressed in neuroendocrine and endocrine tissues and regulates nutrient and energy status both centrally and peripherally. We and others have shown that VGF-derived peptides have direct action on the islet β cell as secretagogues and cytoprotective agents; however, the endogenous function of VGF in the β cell has not been described. Here, we demonstrate that VGF regulates secretory granule formation. VGF loss-of-function studies in both isolated islets and conditional knockout mice reveal a profound decrease in stimulus-coupled insulin secretion. Moreover, VGF is necessary to facilitate efficient exit of granule cargo from the trans-Golgi network and proinsulin processing. It also functions to replenish insulin granule stores following nutrient stimulation. Our data support a model in which VGF operates at a critical node of granule biogenesis in the islet β cell to coordinate insulin biosynthesis with β cell secretory capacity.

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Teaser

Stephens et al. find that the granin protein, VGF, regulates key aspects of pancreatic islet β cell function. These studies highlight a role for VGF in the maintenance and replenishment of insulin granules during nutrient stimulation by promoting exit of granule cargo from the trans-Golgi network and facilitating granule formation.


http://ift.tt/2gJXCiU

A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA)n Repeats Associated with Friedreich’s Ataxia

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Ryan J. McGinty, Franco Puleo, Anna Y. Aksenova, Julia A. Hisey, Alexander A. Shishkin, Erika L. Pearson, Eric T. Wang, David E. Housman, Claire Moore, Sergei M. Mirkin
Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich's ataxia. Whereas the length of an expandable repeat is the main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact the likelihood of expansions and disease progression. Detection of these modifiers may lead to understanding and treating repeat expansion diseases. Here, we describe a method for the rapid, genome-wide identification of trans modifiers for repeat expansion in a yeast experimental system. Using this method, we found that missense mutations in the endoribonuclease subunit (Ysh1) of the mRNA cleavage and polyadenylation complex dramatically increase the rate of (GAA)n repeat expansions but only when they are actively transcribed. These expansions correlate with slower transcription elongation caused by the ysh1 mutation. These results reveal an interplay between RNA processing and repeat-mediated genome instability, confirming the validity of our approach.

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Teaser

McGinty et al. developed a genetic screen in S. cerevisiae to identify genes promoting expansions of (GAA)n repeats. The authors uncovered the unexpected involvement of essential RNA-processing gene, YSH1. Mutation in YSH1 leads to slow transcription elongation, promoting DSBs, whose repair via HR causes repeat expansions.


http://ift.tt/2f1H9mJ

An Intestine-Derived Neuropeptide Controls Avoidance Behavior in Caenorhabditis elegans

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Kiho Lee, Eleftherios Mylonakis
Adjusting to a continuously changing environment is a key feature of life. For metazoans, environmental changes include alterations in the gut microbiota, which can affect both memory and behavior. The bacteriovorous nematode Caenorhabditis elegans discriminates between pathogenic and non-pathogenic food sources, avoiding the consumption of pathogens. Here, we demonstrate the role of the intestine in regulating C. elegans avoidance to Pseudomonas aeruginosa by an insulin-like neuropeptide encoded by ins-11. The transcriptional expression of ins-11 is controlled through transcription factor hlh-30 and the p38 mitogen-activated protein kinase (MAPK) pathway. ins-11 negatively controls signal pathways in neurons that regulate aversive learning behavior. Attenuation of ins-11 increased avoidance behavior and survival on pathogenic bacteria but decreased opportunities to find a food source as well as lowered energy storage and the number of viable progeny. Our findings support a role for the intestine in avoidance and identify an advantageous role for negative feedback that allows C. elegans to actively balance noxious and favorable environments.

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Teaser

Lee and Mylonakis describe the inhibitory role of a neuropeptide that is encoded by ins-11 and is expressed in intestine. The neuropeptide prevents abnormal activation of neurons that stimulate aversive learning behavior in C. elegans. ins-11 allows nematodes to adjust when they move between pathogenic and non-pathogenic microbes.


http://ift.tt/2f1AtoA

High-Yield Methods for Accurate Two-Alternative Visual Psychophysics in Head-Fixed Mice

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Christopher P. Burgess, Armin Lak, Nicholas A. Steinmetz, Peter Zatka-Haas, Charu Bai Reddy, Elina A.K. Jacobs, Jennifer F. Linden, Joseph J. Paton, Adam Ranson, Sylvia Schröder, Sofia Soares, Miles J. Wells, Lauren E. Wool, Kenneth D. Harris, Matteo Carandini
Research in neuroscience increasingly relies on the mouse, a mammalian species that affords unparalleled genetic tractability and brain atlases. Here, we introduce high-yield methods for probing mouse visual decisions. Mice are head-fixed, facilitating repeatable visual stimulation, eye tracking, and brain access. They turn a steering wheel to make two alternative choices, forced or unforced. Learning is rapid thanks to intuitive coupling of stimuli to wheel position. The mouse decisions deliver high-quality psychometric curves for detection and discrimination and conform to the predictions of a simple probabilistic observer model. The task is readily paired with two-photon imaging of cortical activity. Optogenetic inactivation reveals that the task requires mice to use their visual cortex. Mice are motivated to perform the task by fluid reward or optogenetic stimulation of dopamine neurons. This stimulation elicits a larger number of trials and faster learning. These methods provide a platform to accurately probe mouse vision and its neural basis.

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Teaser

Burgess et al. introduce methods to probe visual discrimination and its neural basis in head-fixed mice. Mice turn a steering wheel to make two alternative choice, and their behavior matches a simple probabilistic observer. The task engages and requires the visual cortex. Optogenetic stimulation of dopaminergic neurons can replace water control.


http://ift.tt/2f1qAXQ

Reply to Letter to the Editor Re: “Ultrasound Findings on Hands and Wrists of Patients with Systemic Lupus Erythematosus: Relationship with Physical Examination”

Publication date: Available online 5 September 2017
Source:Ultrasound in Medicine & Biology
Author(s): Carolina Freitas Lins, Mittermayer Barreto Santiago




http://ift.tt/2wG6R7O

Skullcapflavone II attenuates ovalbumin-induced allergic rhinitis through the blocking of Th2 cytokine production and mast cell histamine release

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Thi Tho Bui, Chun Hua Piao, Chang Ho Song, Ok Hee Chai
Allergic rhinitis is a common heterogeneous chronic upper airway disorder and is an IgE-mediated inflammation characterized by one or more nasal symptoms such as sneezing, itching, nasal discharge, rhinorrhea, post nasal drainage and nasal blockage. In the present study, the effects of skullcapflavone II (SCFII) on upper airway inflammation, Th2 cytokines, and NF-κB signaling in an ovalbumin (OVA)-induced allergic rhinitis (AR) murine model in vivo were investigated. OVA-induced AR mice increased nasal symptoms, eosinophils and mast cells infiltration into nasal cavity, OVA-specific IgE/IgG1 and histamine in serum, Th2 cytokines including IL-13 and GATA3, and NF-κB signaling in NALF and lung homogenate. Interestingly, treatment of SCFII reduced the levels of OVA-specific IgE/IgG1 and histamine in serum, of Th2 cytokines and of NF-κB signaling in the NALF and the lung homogenate, and histopathological changes in the nasal tissue and the lung. Also, dexamethasone suppressed such increases. The results of this study suggested that SCFII may ameliorate allergic inflammation of upper airway in AR mice model by blocking the Th2 cytokine production, the NF-κB signal pathway and the mast cell histamine release. Taken together, we suggest that SCFII may be used as a therapeutic agent for patients with Th2-mediated or mast cell-mediated allergic diseases.



http://ift.tt/2j0ZDIc

Protective effects of ghrelin in ventilator-induced lung injury in rats

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Guang Li, Jiao Liu, Wen-Fang Xia, Chen-Liang Zhou, Li-Qiong Lv
Ghrelin has exhibited potent anti-inflammatory effects on various inflammatory diseases. The aim of this study was to investigate the potential effects of ghrelin on a model of ventilator-induced lung injury (VILI) established in rats. Male Sprague-Dawley rats were randomly divided into three groups: low volume ventilation (LV, Vt=8ml/kg) group, a VILI group (Vt=30ml/kg), and a VILI group pretreated with ghrelin (GH+VILI). For the LV group, for the VILI and GH+VILI groups, the same parameters were applied except the tidal volume was increased to 40ml/kg. After 4h of MV, blood gas, lung elastance, and levels of inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and (MIP)-2 and total protein in bronchoalveolar lavage fluid (BALF) were analyzed. Myeloperoxidase (MPO), (TLR)-4, and NF-κB, were detected in lung tissues. Water content (wet-to-dry ratio) and lung morphology were also evaluated. The VILI group had a higher acute lung injury (ALI) score, wet weight to dry ratio, MPO activity, and concentrations of inflammatory mediators (TNF-α, IL-6, IL-1β, and MIP-2) in BALF, as well as higher levels of TLR4 and NF-κB expression than the LV group (P<0.05). All histopathologic ALI, the inflammatory profile, and pulmonary dynamics have been improved by ghrelin pretreatment (P<0.05). Ghrelin pretreatment also decreased TLR4 expression and NF-κB activity compared with the VILI group (P<0.05). Ghrelin pretreatment attenuated VILI in rats by reducing MV-induced pulmonary inflammation and might represent a novel therapeutic candidate for protection against VILI.



http://ift.tt/2wDJ6i8

Protective effects of wogonin against disease progression in different hepatic pathological conditions

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Shailendra Kapoor




http://ift.tt/2j259Ky

The Evolution of the Use of [beta]-Blockers to Treat Heart Failure: A Conversation With Finn Waagstein, MD.

Author: Waagstein, Finn MD; Rutherford, John D. MB ChB

Page: 889-893

http://ift.tt/2j2Eiht

Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]).

Author: Pasupathy, Sivabaskari BS, PhD; Tavella, Rosanna BS, PhD; Grover, Suchi MBBS, PhD; Raman, Betty MBBS; Procter, Nathan E.K. BS, PhD; Du, Yang Timothy MBBS; Mahadavan, Gnanadevan MBBS, PhD; Stafford, Irene BS; Heresztyn, Tamila BS; Holmes, Andrew BS, PhD; Zeitz, Christopher MBBS, PhD; Arstall, Margaret MBBS, PhD; Selvanayagam, Joseph MBBS, PhD; Horowitz, John D. MBBS, PhD; Beltrame, John F. BS, BMBS, PhD

Page: 894-903

http://ift.tt/2eDOpnT

Combination Therapy to Target Reperfusion Injury After ST-Segment-Elevation Myocardial Infarction: A More Effective Approach to Cardioprotection.

Author: Hausenloy, Derek J. MBChB, PhD; Yellon, Derek M. PhD, DSc

Page: 904-906

http://ift.tt/2j2E2iv

Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes).

Author: Easton, J. Donald MD; Aunes, Maria MD; Albers, Gregory W. MD; Amarenco, Pierre MD; Bokelund-Singh, Sara MSc; Denison, Hans MD, PhD; Evans, Scott R. PhD; Held, Peter MD, PhD; Jahreskog, Marianne RN; Jonasson, Jenny PhD; Minematsu, Kazuo MD, PhD; Molina, Carlos A. MD; Wang, Yongjun MD; Wong, K.S. Lawrence MD; Johnston, S. Claiborne MD, PhD; For the SOCRATES Steering Committee and Investigators; Ameriso, Sebastia F.; Donnan, Geoffrey; Lemmens, Robin; Massaro, Ayrton; Titianova, Ekaterina; Hill, Michael D.; Lavados, Pablo; Skoloudik, David; Rother, Joachim; Norbert, Szegedi; Agnelli, Giancarlo; Bornstein, Natan; Tanahashi, Norio; Gongora, Angel Arauz; Pretell, Edwin; San Jose, Maria Cristina Z.; Czlonkowska, Anna; Bajenaru, Ovidiu; Stakhovskaya, Ludmila; Brozman, Miroslav; Kim, Jong-Sung; Wahlgren, Nils; Michel, Patrik; Lee, Tsong Hai; Suwanwela, Nijasri Charnnarong; Kutluk, Kursad; Moskovko, Sergii; Kasner, Scott; Laskowitz, Daniel; Clark, Wayne; Nguyen, Huy Thang; Ameriso, Sebastian; Lepera, Sandra; Romano, Marina; Paulon, David; Ioli, Pablo; Zurru, Cristina; Bruera, Guadalupe; Jure, Lorena; Klein, Francisco; Povedano, Guillermo; Levi, Christopher; Phan, Thanh; Markus, Romesh; Anderson, Craig; Sabet, Arman; Davis, Stephen; Lee, Andrew; Kleinig, Timothy; Wong, Andrew; Krause, Martin; Jannes, Jim; Wijeratne, Tissa; Lemmens, Robin; Hemelsoet, Dimitri; Peeters, Andre; Tack, Philippe; Vanacker, Peter; Laloux, Patrice; Van Landegem, William; Vanhooren, Geert; Desfontaines, Philippe; Van Orshoven, Marc; Oliveira, Fabio; Friedrich, Mauricio; Brondani, Rosane; Gagliardi, Rubens; Fabio, Soraia; Dracoulakis, Marianna; Bazan, Rodrigo; Marrone, Luiz; Pontes Neto, Octavio; Silva, Gisele; Kowacs, Pedro; Titianova, Ekaterina; Stamenova, Paraskeva; Daskalov, Marin; Staikov, Ivan; Baldaranov, Dimo; Maslarov, Dimitar; Lilovski, Hristo; Petkov, Plamen; Petrova, Neli; Mavrov, Radoslav; Markova, Veska; Petrova, Valeria; Beleva, Tanya; Kralev, Borislav; Sotirov, Nikolay; Lekova, Veska; Hristov, Dimcho; Ermenkova, Vera; Mateev, Lyudmil; Mitkova, Rumeliya; Haralanov, Liybomir; Ikonomov, Rosen; Mihailova, Margarita; Georgiev, Ivan; Shuaib, Ashfaq; Hachinski, Vladimir; Boulanger, Jean-Martin; Mann, Sharan; Hassan, Ayman; Mackey, Ariane; Menon, Bijoy; Minuk, Jeffrey; Siddiqui, Muzaffar; Eustace, Marsha; Vieira, Lucia; Selchen, Daniel; Beaudry, Michel; Stotts, Grant; Lavados, Pablo; Castro, Angel; Gasic, Kristo; Rivas, Rodrigo; Sanchez, Pablo; Roldan, Andres; Grossmann, Ingrid; Figueroa, Christian; Li, Jimei; Xu, Xiaolin; Chen, Huisheng; Li, Xiaohong; Yang, Yi; Zhang, Chunsheng; Wang, Baojun; Li, Guanglai; Wang, Dong; Lin, Hong; Tang, Yamei; Xu, Anding; Wang, Yanjiang; Hong, Wenke; Song, Zhi; Zhang, Xu; Jin, Xiaoping; Xu, Yun; Yan, Fuling; Zheng, Weihong; Wang, Xiaoping; Dong, Qiang; Zhao, Zhongxin; Zhang, Baorong; Zhong, Wangtao; Wen, Guoqiang; Xu, Jun; Li, Guozhong; Dong, Xueshuang; Tian, Xiangyang; Zhang, Zhaohui; Xu, En; Liu, Kaixiang; Chen, Jun; Skoda, Ondrej; Skoloudik, David; Ehler, Edvard; Vaclavik, Daniel; Sanak, Daniel; Klimosova, Sylva; Vitkova, Eva; Fiksa, Jan; Mikulik, Robert; Neumann, Jiri; Plny, Richard; Leys, Didier; Sibon, Igor; Mas, Jean-Louis; Alamowitch, Sonia; Pico, Fernando; Hosseini, Hassan; Mahagne, Marie-Helene; Touze, Emmanuel; Vadot, Wilfried; Vannier, Stephane; Nighoghossian, Norbert; Samson, Yves; Garnier, Pierre; Ellie, Emmanuel; Guillon, Benoit; Timsit, Serge; Giroud, Maurice; Philippeau, Frederic; Bagan-Triquenot, Aude; Wolff, Valerie; Raposo, Nicolas; Obadia, Michel; Debiais, Severine; Grimaud, Jerome; Illouz, Stephane; Smadja, Didier; Urbanczyk, Cedric; Rother, Joachim; Berrouschot, Jorg; Weimar, Christian; Gahn, Georg; Soda, Hassan; Klimpe, Sven; Nabavi, Darius; Glahn, Jorg; Kohrmann, Martin; Krause, Lars; Terborg, Christoph; Urban, Peter; Steiner, Thorsten; Ferbert, Andreas; Dziewas, Rainer; Seidel, Gunter; Thomalla, Gotz; Li, Richard; Fong, Wing Chi; Cheung, Raymond; Szegedi, Norbert; Pozsegovits, Krisztian; Valikovics, Attila; Panczel, Gyula; Rozsa, Csilla; Nemeth, Laszlo; Dioszeghy, Peter; Ovary, Csaba; Csanyi, Attila; Kerenyi, Levente; Nagy, Valeria; Komoly, Samuel; Bereczki, Daniel; Molnar, Sandor; Kondakor, Istvan; Tanne, David; Raphaeli, Guy; Telman, Gregory; Bornstein, Natan; Leker, Ronen; Lampl, Yair; Agnelli, Giancarlo; Corea, Francesco; Ricci, Stefano; Guidetti, Donata; Malferrari, Giovanni; Marcheselli, Simona; Micieli, Giuseppe; Zini, Andrea; Di Lazzaro, Vincenzo; Gandolfo, Carlo; Salmaggi, Andrea; Tassi, Rossana; Rasura, Maurizia; Orlandi, Giovanni; Comi, Giancarlo; Ricci, Stefano; Mancuso, Michelangelo; Delodovici, Marialuisa; Bovi, Paolo; Consoli, Domenico; Utsugisawa, Kimiaki; Fujita, Tsuneo; Kurihara, Hideyuki; Maruki, Chikashi; Hayashi, Takeshi; Ogiichi, Tsuneaki; Kumagai, Morio; Takenaka, Katsunobu; Toyoda, Kazunori; Takamatsu, Kazuhiro; Ogami, Ryo; Kin, Shigenari; Aoki, Takeshi; Takizawa, Katsumi; Omori, Shigehiro; Umezawa, Takehiko; Toba, Yasuyuki; Nonoyama, Yutaka; Nakagawa, Hidemitsu; Naka, Takashi; Morimoto, Masanori; Matsumoto, Shuichi; Hitotsumatsu, Tsutomu; Shingaki, Tatsuya; Okuda, Satoshi; Ota, Mamoru; Sakai, Nobuyuki; Yamada, Takeshi; Niwa, Jun; Fujita, Hitoshi; Moriki, Akihito; Yoshino, Kimihiro; Fukushima, Yoshihisa; Mori, Takahisa; Sato, Atsushi; Kusano, Yoshikazu; Kubo, Michiya; Yamazaki, Masashi; Ooasa, Takao; Nishizaki, Takafumi; Kitagawa, Naoki; Yasaka, Masahiro; Manabe, Yasuhiro; Yoshioka, Akira; Ishihara, Masayuki; Kagawa, Takato; Ichihashi, Toshikazu; Matsuoka, Hideki; Ito, Yasuhiro; Yamasaki, Masahiro; Takaba, Hitonori; Saito, Hisatoshi; Sato, Masahiro; Fukuda, Kazumasa; Endo, Sumio; Kidooka, Minoru; Umemura, Toshitaka; Kikkawa, Yuriko; Toru, Shuta; Yamada, Kentaro; Sakai, Hideki; Asari, Jun; Ezura, Masayuki; Nitta, Hisashi; Nagano, Keiko; Ochiai, Jun; Sakai, Keiichi; Kobayashi, Yasutaka; Yoshii, Yasuhiro; Miake, Hirotomo; Takita, Tomohiro; Taniguchi, Hidekazu; Kuroki, Kazuhiko; Mizota, Takamitsu; Yamamoto, Kenichi; Nakane, Hiroshi; Iwanaga, Takeshi; Chiba, Kei; Yoshimoto, Tetsuyuki; Torii, Tsuyoshi; Kitagawa, Takeo; Takashima, Hiroshi; Shirasaki, Naoki; Dehara, Makoto; Wada, Naomichi; Hamada, Kensuke; Kato, Noriyuki; Go, Yoshinori; Izumi, Ichiro; Ninomiya, Hirotomo; Kumai, Junichiro; Nakajima, Yoshikazu; Kaku, Yasuhiko; Isayama, Yukihiro; Kawanishi, Masahiro; Noda, Shinya; Yamamoto, Kazuhide; Hazama, Takanori; Takahashi, Hiroshi; Tanaka, Yohei; Hata, Takashi; Kazekawa, Kiyoshi; Furui, Eisuke; Hondo, Hideki; Sato, Nobuyuki; Kusunoki, Katsusuke; Nanri, Kazunori; Abe, Satoshi; Sasaoka, Noboru; Kuroyanagi, Takayuki; Suzuki, Hisahiko; Fukuyama, Kouzou; Nakahara, Kimihiro; Gongora, Fernando; Gongora, Angel Arauz; Cantu Brito, Carlos; Villarreal Careaga, Jorge; Vazquez Alfaro, Rosalia; Aguayo Leytte, Geronimo; Berrospi, Percy; Chavez, Carlos; Pretell, Edwin; Rodriguez, Liliana; Custodio, Nilton; Castaneda, Cesar; Perez, Julio; San Jose, Maria Cristina; Baroque, Alejandro; Collantes, Epifania; Aquino, Abdias; Diaz, Alejandro; Roxas, Artemio Jr; Lokin, Johnny; Advincula, Joel; Calderon, Emerito; Navarro, Jose; Hiyadan, John; Surdilla, Arturo; Czlonkowska, Anna; Ryglewicz, Danuta; Krychowiak, Grzegorz; Fryze, Waldemar; Sobolewski, Piotr; Nowak, Ryszard; Fiszer, Urszula; Papierowska, Beata; Zielinska-Turek, Justyna; Lasek-Bal, Anetta; Kolodziejska, Ewa; Kaminska, Anna; Adamkiewicz, Bozena; Tutaj, Andrzej; Szkopek, Dorota; Musiatowicz, Krzysztof; Bak, Zbigniew; Brzozowski, Slawomir; Brola, Waldemar; Ferens, Antoni; Zalisz, Marek; Rejdak, Konrad; Rudzinska, Monika; Bajenaru, Ovidiu; Panea, Cristina; Simu, Mihaela; Balasa, Rodica; Cuciureanu, Iulian; Popescu, Bogdan; Sabau, Monica; Roman-Filip, Corina; Pimenov, Leonid; Gekht, Alla; Milto, Anna; Shchukin, Ivan; Parfenov, Vladimir; Stakhovskaya, Liudmila; Arkhipov, Mikhail; Sokolova, Nadezhda; Bogdanov, Enver; Esin, Radiy; Khasanova, Dina; Golikov, Konstantin; Melnikova, Elena; Zaslavskiy, Leonid; Voznyuk, Igor; Nazarov, Alexander; Akhmadeeva, Leila; Iakupova, Aida; Shamalov, Nikolay; Belskaya, Galina; Chuprina, Svetlana; Denisova, Olga; Drozdova, Ekaterina; Karakulova, Yuliya; Sholomov, Ilya; Spirin, Nikolay; Vostrikova, Elena; Mordvintseva, Elena; Grigoryeva, Vera; Zateyshchikov, Dmitry; Gorbachev, Vladimir; Chefranova, Zhanna; Dudarev, Mikhail; Nilk, Rostislav; Rozhdestvenskiy, Alexey; Gurcik, Ladislav; Dvorak, Miloslav; Krastev, Georgi; Kurca, Egon; Vyletelka, Juraj; Brozman, Miroslav; Kim, Jong Sung; Bae, Hee-Joon; Kim, Yong-Won; Kim, Joon-Tae; Cha, Jae-Kwan; Nam, Hyo Suk; Chang, Dae-Il; Lee, Yong-Seok; Oh, Kyungmi; Yu, Sung-Wook; Sohn, Sung-Il; Lee, Jun; Cho, Han Jin; Kim, Eung-Gyu; Rha, Joung-Ho; Kim, Seo Hyun; Molina Cateriano, Carlos; Serena Leal, Joaquin; Vivancos Mora, Jose; Rodriguez Yanez, Manuel; Roquer Gonzalez, Jaume; Purroy Garcia, Francisco; Gomis Cortina, Meritxell; Masjuan Vallejo, Jaime; Arenillas Lara, Juan; Segura Martin, Tomas; Herrero, Jose Antonio Egido; Tembl Ferrairo, Jose Ignacio; Gallego Cullere, Jaime; Moniche Alvarez, Francisco; Steinberg, Anna; Callander, Margarita; Laska, Ann Charlotte; Bokemark, Lena; Mooe, Thomas; Kall, Tor-Bjorn; Welin, Lennart; Sjoblom, Lars; Hambraeus, Joakim; Teichert, Jorg; Wannberg, Hans; Sanner, Johan; Ramstromer, Bo; Zieden, Bo; Hau, Stefan Olsson; Gustafsson, Claes; Michel, Patrik; Kahles, Timo; Lyrer, Philippe; Arnold, Marcel; Liesch, Martin; Medlin, Friedrich; Cereda, Carlo; Kagi, Georg; Luft, Andreas; Carrera, Emmanuel; Lee, Tsong-Hai; Po, Helen L.; Chern, Chang-Ming; Lien, Li-Ming; Chan, Lung; Liu, Chung-Hsiang; Wu, Shey-Lin; Lee, Jiann-Der; Chen, Chih-Hung; Lin, Huey-Juan; Lin, Ruey-Tay; Chen, Wei-Hsi; Sun, Yu; Suwanwela, Nijasri Charnnarong; Tantirittisak, Tasanee; Muengtaweepongsa, Sombat; Nilanont, Yongchai; Tiamkao, Somsak; Udommongkol, Chesda; Watcharasaksilp, Kanokwan; Jantararotai, Witoon; Kutluk, Kursad; Sirin, Hadiye; Ince, Birsen; Asil, Talip; Arsava, Murat; Incesu, Tulay Kurt; Tireli, Hulya; Kucukoglu, Hayriye; Ak, Fikri; Unal, Ali; Ozturk, Serefnur; Uzuner, Nevzat; Chmyr, Galyna; Lebedynets, Volodymyr; Nikonov, Vadym; Shulga, Lyudmyla; Smolanka, Volodymyr; Moskovko, Sergii; Khavunka, Marta; Yavorska, Valentyna; Tomakh, Nataliya; Kozyolkin, Olexandr; Litovaltseva, Galyna; Lansberg, Maarten; Bernstein, Richard; Brown, David; Clark, Wayne; Dissin, Jonathan; Graffagnino, Carmelo; Harris, Jonathan; Hicks, William; Kasner, Scott; Katzan, Irene; Kramer, Jeffrey; Willey, Joshua; Silliman, Scott; Starkman, Sidney; Thaler, David; Tremwel, Margaret; Concha, Mauricio; Rajamani, Kumar; Dandapani, Bhuvaneswari; Silver, Brian; Deal, Nathan; Chang, Ira; Hassan, Ameer; Rudolph, Steven; Fischer, Kenneth; Kirshner, Howard; Logan, William; Mallenbaum, Sidney; Hefzy, Hebah; Latorre, Julius; Levine, Steven; Ciabarra, Anthony; Dafer, Rima; Anyanwu, Benjamin; Cherian, Laurel; Panezai, Spozhmy; Khanna, Anna; Dodds, Jodi; Torbey, Michel; Gebel, James; Woo, Henry; Chiu, David; Androulakis, Xiao; Burgin, William; Pineda, Maria; Yilmaz, Engin; Altafullah, Irfan; Boutwell, Christine; Cruz-Flores, Salvador; Sapkota, Biggya; Fayad, Pierre; Jacoby, Michael; Rafiq, Shahid; Salgado, Efrain; Lafranchise, Eugene; Felton, Warren; Madhavan, Ramesh; Zaidat, Osama; Pieper, Connie; Riviello, Ralph; Burnett, Aaron; Fischer, Michelle; Gentile, Nina; Calder, Christopher; Dietrich, Dennis; Cross, Jonathan; Blankenship, Larry; Dafer, Rima; Montoya, Liliana; Grogan, Wendell; Young, Mark; Khan, Farrukh; Campbell, Duane; Daboul, Nizar; Espinoza, Andrey; Cullis, Paul; Concepcion, Gilberto; Wulff, John; Afzal, Haider; Jaffrani, Naseem; Reiter, William; Arshad, Tamjeed; Lukovits, Timothy; Welker, James; Chang, Fen Lei; Badruddin, Aamir; Babikian, Viken; Menon, Ravi; Sander, James; Springer, Mellanie; Nanda, Ashish; Mas, Luis; Rajan, Raj; Silverman, Bruce; Hefzy, Hebah; Huang, David; Carpenter, David; Clark, Joni; Ching, Marilou; Santhakumar, Sunitha; Gould, Jeffrey; Bansal, Vibhav; Vidal, Gabriel; Mikesell, Timothy; Brick, John; French, William; Shah, Qaisar; Holmstedt, Christine; Ishag-Osman, Nadir; Kostis, John; Shehadeh, Abbas; Sethi, Pramodkumak; Imam, Asher; Mccomas, Carl; Tran, Duc; Gebreyohanns, Mehari; Wiseman, Brian; Malik, Maheen; Schwarcz, Aron; Altschul, Dorothea; Castaldo, John; Alshekhlee, Amer; Gancher, Stephen; Krish, Nagesh; Nguyen-Huynh, Mai; Tremwell, Margaret; Sharma, Jitendra; Lee, Lance; Neil, William; Siddiqui, Fazeel; Malek, Ali; Romero, Charles; Huy, Thang Nguyen; Hoang, Hoa; Nguyen, Thang; Nguyen, Anh; Nguyen, Hung

Page: 907-916

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Use of a Single Baseline Versus Multiyear 24-Hour Urine Collection for Estimation of Long-Term Sodium Intake and Associated Cardiovascular and Renal Risk.

Author: Olde Engberink, Rik H.G. MD; van den Hoek, Thomas C. MD; van Noordenne, Nicky D. MD; van den Born, Bert-Jan H. MD, PhD; Peters-Sengers, Hessel MSc; Vogt, Liffert MD, PhD

Page: 917-926

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Transcription Factor RUNX1 Regulates Platelet PCTP (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events: Differential Effects of RUNX1 Variants.

Author: Mao, Guangfen MD *; Songdej, Natthapol MD, MPH *; Voora, Deepak MD *; Goldfinger, Lawrence E. PhD; Del Carpio-Cano, Fabiola E. MS; Myers, Rachel A. PhD; Rao, A. Koneti MBBS

Page: 927-939

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Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium.

Author: Verma, Suresh K. PhD; Garikipati, Venkata N.S. PhD; Krishnamurthy, Prasanna PhD; Schumacher, Sarah M. PhD; Grisanti, Laurel A. PhD; Cimini, Maria BS; Cheng, Zhongjian PhD; Khan, Mohsin PhD; Yue, Yujia BS; Benedict, Cindy PhD; Truongcao, May M. BS; Rabinowitz, Joseph E. PhD; Goukassian, David A. MD; Tilley, Douglas PhD; Koch, Walter J. PhD; Kishore, Raj PhD

Page: 940-953

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The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies.

Author: Baekgaard, Josefine S. BSc; Viereck, Soren MD; Moller, Thea Palsgaard MD; Ersboll, Annette Kjaer MSc, PhD; Lippert, Freddy MD; Folke, Fredrik MD, PhD

Page: 954-965

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Chronic Myocardial Infarction: Where Is It Located?.

Author: Goldwasser, Diego MD; Elizari, Marcelo V. MD; Bayes de Luna, Antonio MD, PhD

Page: 966-968

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Effect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease.

Author: Kappel, Ben A. MD, PhD; Lehrke, Michael MD; Schutt, Katharina MD; Artati, Anna PhD; Adamski, Jerzy PhD; Lebherz, Corinna MD; Marx, Nikolaus MD

Page: 969-972

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Letter by Jiang et al Regarding Article, "Fire Simulation and Cardiovascular Health in Firefighters".

Author: Jiang, Xiao-Wei MD; Yang, Cheng-Zhi MD; Qiao, Shu-Bin MD, PhD

Page: 973

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Letter by Jin-Shan and Xue-Bin Regarding Article, "Fire Simulation and Cardiovascular Health in Firefighters".

Author: Jin-Shan, He MD; Xue-Bin, Li MD

Page: 974-975

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Response by Hunter and Mills to Letters Regarding Article, "Fire Simulation and Cardiovascular Health in Firefighters".

Author: Hunter, Amanda L. MBChB; Mills, Nicholas L. MBChB, PhD

Page: 976-977

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Methodological Standards for Meta-Analyses and Qualitative Systematic Reviews of Cardiac Prevention and Treatment Studies: A Scientific Statement From the American Heart Association.

Author: Rao, Goutham MD, FAHA, Chair; Lopez-Jimenez, Francisco MD, MSc, FAHA, Vice Chair; Boyd, Jack MD; D'Amico, Frank PhD; Durant, Nefertiti H. MD, MPH; Hlatky, Mark A. MD, FAHA; Howard, George DrPH, FAHA; Kirley, Katherine MD, MS; Masi, Christopher MD, PhD; Powell-Wiley, Tiffany M. MD, MPH, FAHA; Solomonides, Anthony E. DPhil, MMath; West, Colin P. MD, PhD; Wessel, Jennifer PhD; On behalf of the American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; and Stroke Council

Page: e172-e194

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Correction to: Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association.

Author:

Page: e195

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Correction to: Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association.

Author:

Page: e196

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Correction to: Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Author:

Page: e197

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Inhibition of GABA A receptor improved special memory impairment in the local model of demyelination in rat hippocampus

Publication date: 15 January 2018
Source:Behavioural Brain Research, Volume 336
Author(s): Alireza Mousavi Majd, Forough Ebrahim Tabar, Arghavan Afghani, Sahand Ashrafpour, Samaneh Dehghan, Mohammad Gol, Manouchehr Ashrafpour, Fereshteh Pourabdolhossein
Cognitive impairment and memory deficit are common features in multiple Sclerosis patients. The mechanism of memory impairment in MS is unknown, but neuroimaging studies suggest that hippocampal demyelination is involved. Here, we investigate the role of GABA A receptor on spatial memory in the local model of hippocampal demyelination. Demyelination was induced in male Wistar rats by bilaterally injection of lysophosphatidylcholine (LPC) 1% into the CA1 region of the hippocampus. The treatment groups were received daily intraventricular injection of bicuculline (0.025, 0.05μg/2μl/animal) or muscimol (0.1, 0.2μg/2μl/animal) 5days after LPC injection. Morris Water Maze was used to evaluate learning and memory in rats. We used Luxol fast blue staining and qPCR to assess demyelination extention and MBP expression level respectively. Immunohistochemistry (IHC) for CD45 and H&E staining were performed to assess inflammatory cells infiltration. Behavioral study revealed that LPC injection in the hippocampus impaired learning and memory function. Animals treated with both doses of bicuculline improved spatial learning and memory function; however, muscimol treatment had no effect. Histological and MBP expression studies confirmed that demylination in LPC group was maximal. Bicuculline treatment significantly reduced demyelination extension and increased the level of MBP expression. H&E and IHC results showed that bicuculline reduced inflammatory cell infiltration in the lesion site. Bicuculline improved learning and memory and decreased demyelination extention in the LPC-induced hippocampal demyelination model. We conclude that disruption of GABAergic homeostasis in hippocampal demyelination context may be involved in memory impairment with the implications for both pathophysiology and therapy.



http://ift.tt/2eIIamr

Long-term behavioral sensitization to apomorphine is independent of conditioning and increases conditioned pecking, but not preference, in pigeons

Publication date: 15 January 2018
Source:Behavioural Brain Research, Volume 336
Author(s): Patrick Anselme, Neslihan Edeş, Sepideh Tabrik, Onur Güntürkün
When rodents are given a free choice between a variable option and a constant option, they may prefer variability. This preference is even sometimes increased following repeated administration of a dopamine agonist. The present study was the first to examine preference for variability under the systemic administration of a dopamine agonist, apomorphine (Apo), in birds. Experiment 1 tested the drug-free preference and the propensity to choose of pigeons for a constant over a variable delay. It appeared that they preferred and decided more quickly to peck at the optimal delay option. Experiment 2 assessed the effects of a repeated injection of Apo on delay preference, in comparison with previous control tests within the same individuals. Apo treatment might have decreased the number of pecks at the constant option across the different experimental phases, but failed to induce a preference for the variable option. In Experiment 3, two groups of pigeons (Apo-sensitized and saline) were used in order to avoid inhomogeneity in treatments. They had to choose between a 50% probability option and a 5-s delay option. Conditioned pecking and the propensity to choose were higher in the Apo-sensitized pigeons, but, in each group, the pigeons showed indifference between the two options. This experiment also showed that long-term behavioral sensitization to Apo can occur independently of a conditioning process. These results suggest that Apo sensitization can enhance the attractiveness of conditioned cues, while having no effect on the development of a preference for variable-delay and probabilistic schedules of reinforcement.



http://ift.tt/2gELE6A

Non-uraemic calciphylaxis: a diagnostic and management challenge for the burns team

Abstract

Calciphylaxis is a rare systemic condition usually seen in patients with end-stage renal disease. It is characterised by pathological calcification of dermal blood vessels, causing ischaemia and necrosis in the skin and subcutaneous fat. The lesions are usually small but, in extreme cases, may be very extensive and may mimic necrotising fasciitis, prompting extensive surgical debridement. We describe the challenges faced in managing such a case. A 38-year-old female patient was admitted to another hospital with widespread progressive truncal skin necrosis. A provisional diagnosis of necrotising fasciitis was made, and she underwent debridement of 32% of her total body surface area (TBSA). However, her condition rapidly deteriorated and she was transferred to our burn centre for further management. Diagnosis of calciphylaxis was based on clinical features and confirmed by tissue biopsy. Characteristic findings of progressive skin and fat necrosis at the wound margins with healthy underlying fascia and muscle were recognised from previously treated cases of calciphylaxis; however, the absence of renal disease proved misleading. Non-uraemic calciphylaxis is very rare but can, as in this case, be associated with alcoholic liver disease. At our centre, the patient required prolonged ventilation and supportive treatment in burns critical care, combined with intensive wound management, repeated episodes of debridement, temporary wound cover using human skin allografts and reconstruction using split-thickness autograft. We report this case to alert others to this rare condition as a possible diagnosis in patients presenting with extensive panniculitis. We discuss associations, diagnostic difficulties, novel therapies and the importance of multidisciplinary care in managing these complex cases.

Level of evidence: Level V, diagnostic study.

http://ift.tt/2j0fCX4

Erhuang Formula ameliorates renal damage in adenine–induced chronic renal failure rats via inhibiting inflammatory and fibrotic responses

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Chun-yan Zhang, Jian-yong Zhu, Ying Ye, Miao Zhang, Li-jun Zhang, Su-juan Wang, Ya-nan Song, Hong Zhang
AimsThe present study aimed to evaluate the protective effects of Erhuang Formula (EHF) and explore its pharmacological mechanisms on adenine-induced chronic renal failure (CRF).Materials and methodsThe compounds in EHF were analyzed by HPLC/MS. Adenine-induced CRF rats were administrated by EHF. The effects were evaluated by renal function examination and histology staining. Immunostaining of some proteins related cell adhesion was performedin renal tissues, including E-cadherin, β-catenin, fibronectin and laminin. The qRT-PCR was carried out determination of gene expression related inflammation and fibrosis including NF-κB, TNF-α, TGF-β1, α-SMA and osteopontin (OPN).ResultsTen compounds in EHF were identified including liquiritigenin, farnesene, vaccarin, pachymic acid, cycloastragenol, astilbin, 3,5,6,7,8,3′,4′-heptemthoxyflavone, physcion, emodin and curzerene. Abnormal renal function and histology had significant improvements by EHF treatment. The protein expression of β-catenin, fibronectin and laminin were significantly increased and the protein expression of E-cadherin significantly decreased in CRF groups. However, these protein expressions were restored to normal levels in EHF group. Furthermore, low expression of PPARγ and high expression of NF-κB, TNF-α, TGF-β1, α-SMA and OPN were substantially restored by EHF treatment in a dose-dependent manner.ConclusionsEHF ameliorated renal damage in adenine-induced CRF rats, and the mechanisms might involve in the inhibition of inflammatory and fibrotic responses and the regulation of PPARγ, NF-κB and TGF-β signaling pathways.



http://ift.tt/2eDEfUy

A novel ventricular restraint device (ASD) repetitively deliver Salvia miltiorrhiza to epicardium have good curative effects in heart failure management

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Muhammad Naveed, Li Wenhua, Wang Gang, Imran Shair Mohammad, Muhammad Abbas, Xiaoqian Liao, Mengqi Yang, Li Zhang, Xiaolin Liu, Xiaoming Qi, Yineng Chen, Lv Jiadi, Linlan Ye, Wang Zhijie, Chen Ding Ding, Yu Feng, Zhou Xiaohui
A novel ventricular restraint is the non-transplant surgical option for the management of an end-stage dilated heart failure (HF). To expand the therapeutic techniques we design a novel ventricular restraint device (ASD) which has the ability to deliver a therapeutic drug directly to the heart. We deliver a Traditional Chinese Medicine (TCM) Salvia miltiorrhiza (Danshen Zhusheye) through active hydraulic ventricular support drug delivery system (ASD) and we hypothesize that it will show better results in HF management than the restraint device and drug alone. SD rats were selected and divided into five groups (n=6), Normal, HF, HF+SM (IV), HF+ASD, HF+ASD+SM groups respectively. Post myocardial infarction (MI), electrocardiography (ECG) showed abnormal heart function in all groups and HF+ASD+SM group showed a significant therapeutic improvement with respect to other treatment HF, HF+ASD, and HF+SM (IV) groups on day 30. The mechanical functions of the heart such as heart rate, LVEDP, and LVSP were brought to normal when treated with ASD+SM and show significant (P value<0.01) compared to other groups. BNP significantly declines in HF+ASD+SM group animals compared with other treatment groups. Masson's Trichrome staining was used to study histopathology of cardiac myocytes and quantification of fibrosis was assessed. The large blue fibrotic area was observed in HF, HF+ASD, and HF+SM (IV) groups while HF+ASD+SM showed negligible fibrotic myocyte at the end of study period (30days). This study proves that novel ASD device augments the therapeutic effect of the drug and delivers Salvia miltiorrhiza to the cardiomyocytes significantly as well as provides additional support to the dilated ventricle by the heart failure.



http://ift.tt/2gEtQbO

Long non-coding RNA HOTTIP promotes hypoxia-induced epithelial-mesenchymal transition of malignant glioma by regulating the miR-101/ZEB1 axis

Publication date: November 2017
Source:Biomedicine & Pharmacotherapy, Volume 95
Author(s): Shanyi Zhang, Weiwei Wang, Guoxin Liu, Shule Xie, Qunxing Li, Yingru Li, Zhaoyu Lin
Hypoxia is a universal characteristic of solid tumor and involving cancer metastasis via epithelial–mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) are known to regulate carcinogenesis and metastasis of various cancers. The aim of this study was to identify the function role of lncRNAs in the hypoxia-induced EMT of malignant glioma. We used U87 and U251 cell lines were treated under hypoxia to induce EMT, then lncRNA microarray analyse was performed between U87-hypoxia and parental cell line. The relative expression of lncRNA and HIF-1α were detected by qRT-PCR between glioma tissues without metastasis and that with metastasis. Hypoxia could induce EMT and increase HOTTIP expression in glioma cells. Among the different expressions of lncRNAs, HOTTIP was the most upregulated lncRNA in glioma cells treated by hypoxia. High levels of HOTTIP and HIF-1α were correlated with glioma metastasis and poor patient prognosis. Knockdown of HIF-1α and HOTTIP blocked hypoxia-induced EMT, and suppressed invasion and migration of glioma cells. Finally, HOTTIP sponged endogenous miR-101 and inhibited its activity, which resulted in increased ZEB1 expression and promoted process of EMT. HIF-1α/HOTTIP/miR-101/ZEB1 axis plays essential role in hypoxia-induced EMT and metastasis of glioma, and HOTTIP may serve as a therapeutic target to reverse EMT and prevent glioma progression.



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Newer Technologies in Breast Cancer Imaging: Dedicated Cone-Beam Breast CT

Publication date: Available online 5 September 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Avice M. O'Connell, Andrew Karellas, Srinivasan Vedantham, Daniel T. Kawakyu-O'Connor
Dedicated breast computed tomography (CT) is the latest in a long history of breast imaging techniques dating back to the 1960s. Breast Imaging is performed both for cancer screening as well as for diagnostic evaluation of symptomatic patients. Dedicated breast CT received United States Food and Drug Administration (US FDA) approval for diagnostic use in 2015 and is slowly gaining recognition for its value in diagnostic 3D imaging of the breast, and also for injected contrast-enhanced imaging applications. Conventional mammography has known limitations in sensitivity and specificity, especially in dense breasts. Breast Tomosynthesis was US FDA approved in 2011 and is now widely used. Dedicated breast CT is the next technological advance, combining real 3D imaging with the ease of contrast administration. The lack of painful compression and manipulation of the breasts also makes dedicated breast CT much more acceptable for the patients.



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Factors Associated with Contralateral Deep Venous Thrombosis after Iliocaval Venous Stenting

Publication date: Available online 5 September 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): S.A. Khairy, R.J. Neves, O. Hartung, G.J. O'Sullivan
BackgroundThe majority of iliac venous obstructions occur on the left side, and endovascular therapy has become the first line treatment for this condition. A left common iliac venous stent will protrude into the inferior vena cava (IVC) to some extent, thereby covering the contralateral common iliac vein (CIV) outflow. This may increase the risk of thrombosis of the contralateral iliac vein. The aim of this paper was to determine the rate of, and factors associated with, contralateral lower limb venous thrombosis after stenting, and to evaluate the results of salvage revascularisation.MethodsA total of 376 patients (102 from UCH, Galway, Ireland, 2008–16, and 274 from, CHU Nord, Marseille, France, 2000–15) with symptomatic acute or chronic left iliocaval venous obstruction were retrospectively evaluated. Either duplex ultrasound scanning (DUS) or computed tomographic venography (CTV) was used for pre- and post-operative imaging. Data were collected from the PACS system (IMPAX, Agfa, BE) of the Radiology Department, UCH, Galway, and from the electronic medical records of Vascular Surgery department, CHU Nord, Marseille.ResultsThe median age of stented patients was 46 (range 15–86 years), 80% were female (301/376). Following left CIV stent placement, 2.7% (10/376) later presented with a right (contralateral) iliac deep venous thrombosis (DVT). Acute DVT (p=.001), non-compliance with the prescribed 6 months anticoagulation (p = 0.05), pre-operative contralateral internal iliac vein (IIV) thrombosis (p = 0.001), and pre-existing IVC filter placement (p = 0.003) were all statistically significantly associated with contralateral DVT. All patients with symptomatic contralateral iliac DVT underwent clot removal in the acute phase. The primary patency of these limbs was 100% at 3 years.ConclusionStent placement across the iliocaval confluence from the left CIV is associated with a low but definite rate of contralateral iliac vein thrombosis. Acute DVT, pre-operative contralateral IIV thrombosis, pre-existing IVC filters, and anticoagulation non-compliance are significant risk factors.



http://ift.tt/2vKb2Cb

Development of a Prediction Model for Diagnosis of Acute Poisoning in Patients with Altered Mental Status and Absent History of Alcohol/Drug Ingestion

Publication date: Available online 5 September 2017
Source:The Journal of Emergency Medicine
Author(s): Robert Camilleri
BackgroundDiagnosis of acute poisoning in patients with altered mental status and absent history is a challenging diagnostic problem in clinical practice.ObjectiveThe aims of the study were to develop a simple clinical tool to stratify risk of acute poisoning in patients with altered mental states and no history of alcohol/drug ingestion, and develop a prediction model using initial observations from which a simple risk score could be derived.MethodsThe study was carried out on non-trauma patients aged 15 years and older admitted with altered mental states and no history of alcohol or drug ingestion. Univariate analysis and logistic regression were carried out and a score was derived and validated.ResultsThere were 607 patients included, with mean age of 60.3 years and 54% were male. The regression model performed moderately well on both the training and validation sets with areas under the receiver operating characteristic curve of 0.834 and 0.844, respectively. The risk score correlated with the regression model (R² = 0.969). At cutoff thresholds of 20% for the model and 2 for the score, sensitivity and specificity of the regression model (67.6% and 85.6%) and the score (67.6% and 85.4%) were moderate, while positive predictive values were low (43.4%) and negative predictive values were high (94.2%) for both the regression model and the score.ConclusionsA prediction model with a derived risk score was developed with a high negative predictive value and may have potential in assessing risk of poisoning in altered mental status and may have value in a prehospital environment or at triage.



http://ift.tt/2eDc3Bi

Characteristics of size-resolved atmospheric inorganic and carbonaceous aerosols in urban Shanghai

Publication date: October 2017
Source:Atmospheric Environment, Volume 167
Author(s): X.X. Ding, L.D. Kong, C.T. Du, A. Zhanzakova, H.B. Fu, X.F. Tang, L. Wang, X. Yang, J.M. Chen, T.T. Cheng
Size-segregated aerosol particles were collected with a 10-stage Micro-Orifice Uniform Deposit Impactor (MOUDI) at an urban site in Shanghai, China for four non-consecutive months representing four seasons from 2015 to 2016. Chemical composition, including water-soluble ions as well as organic carbon (OC), elemental carbon (EC) and secondary organic carbon (SOC) of size-resolved (0.056–18 μm) atmospheric aerosols in four seasons and in different polluted cases were studied. The size distributions of sulfate, nitrate and ammonium (SNA) and carbonaceous aerosol (OC, EC and SOC) were discussed and the potential sources of PM1.8-associated secondary species (SO4²⁻, NO3⁻, SNA and SOC) in different seasons were identified by potential source contribution function (PSCF) model. Results showed that atmospheric ultrafine and fine particle pollution in Shanghai were very serious during the study period. Most of the water-soluble ions tended to be enriched in fine particles, especially being abundant in the droplet mode in polluted cases. Compared with sulfate, size distributions of nitrate and ammonium presented more significant seasonal variations and showed distinctive characteristics in polluted days. Abundant nitrate was concentrated in fine particles in cold seasons (spring and winter), whereas it was enriched in coarse mode during summer and autumn. The droplet mode sulfate with high concentration did not result in the aggravation of air pollution, while the nucleation mode sulfate may have made a great contribution to the air pollution in urban Shanghai. It was also found that the formation of air pollution in urban Shanghai had a significant link with nitrate and ammonium, especially with nitrate and ammonium in condensation mode and droplet mode, and the contribution of sulfate to the pollution formation in Shanghai would somehow be surpassed by the increasing nitrate and ammonium. OC and EC concentrations from spring to winter were found to be 11.10, 7.10, 12.30, 20.16, and 3.73, 2.84, 4.63, 7.10 μg m⁻³, respectively, distinctly presenting the summer minima and winter maxima in this study. The maximum OC/EC was in the droplet mode and the minimum was in the nucleation mode for both clean and polluted days. The great contribution of SOC to OC in droplet mode and the occurrence of PM pollution necessarily had an important bearing on the SOC formation in droplet mode particles. Particle acidity may play a key role in secondary organic aerosol formation and the particles with the size of 0.056–0.1 μm was the most sensitive particles to acid catalysis in SOA formation. The similar PSCF results of PM1.8-associated SOC to those of SO4²⁻, NO3⁻ and SNA indicated possible connections between the formation of SOC and secondary inorganic species in PM.

Graphical abstract

http://ift.tt/2j19FJx

Fluorescence spectroscopy in the visible range for the assessment of UVB radiation effects in hairless mice skin

Publication date: December 2017
Source:Photodiagnosis and Photodynamic Therapy, Volume 20
Author(s): Carolina de Paula Campos, Camila de Paula D'Almeida, Marcelo Saito Nogueira, Lilian Tan Moriyama, Sebastião Pratavieira, Cristina Kurachi
Ultraviolet (UV) radiation may induce skin alterations as observed in photoaging. Some recognized modifications are epidermal hyperplasia, amorphous deposition of degraded elastic fibers and reduction in the number of collagen fibers. They alter the tissue biochemical properties that can be interrogated by steady state fluorescence spectroscopy (SSFS). In this study, we monitored the changes in endogenous fluorescence emission from hairless mice skin during a protocol of photoaging using UVB irradiation. To perform the fluorescence spectroscopy, it was used a violet laser (408nm) to induce the native fluorescence that is emitted in the visible range. Under 408nm excitation, the emission spectrum showed bands with peaks centered around 510, 633 and 668nm for irradiated and control groups. A relative increase of the fluorescence at 633nm emission on the flank was observed with time when compared to the ventral skin at the same animal and the non-irradiated control group. We correlated the emission at 633nm with protoporphyrin IX (PpIX), and our hypothesis is that the PpIX metabolism in the photoaged and aged skin are different. PpIX fluorescence intensity in the photoaged skin is higher and more heterogeneous than in the aged skin. Notwithstanding, more spectroscopic and biochemistry studies investigating the 510 and 633nm emission are needed to confirm this hypothesis.



http://ift.tt/2wFHRO0

Periopathogens differ in terms of the susceptibility to toluidine blue O-mediated photodynamic inactivation

Publication date: December 2017
Source:Photodiagnosis and Photodynamic Therapy, Volume 20
Author(s): Zuzanna Oruba, Przemysław Łabuz, Wojciech Macyk, Maria Chomyszyn-Gajewska
BackgroundThe main goal of periodontal therapy is to eliminate the infection spreading in periodontium. Antimicrobial photodynamic therapy may be applied in order to eradicate pathogens remaining in periodontal tissues after conventional mechanical debridement, to improve the treatment results. The aim of this in vitro study was to evaluate the susceptibility of selected key periopathogens to toluidine blue O-mediated photodynamic inactivation and the influence of photosensitizer's concentration and light dose on the effectiveness of this process.MethodsFollowing bacterial strains were used in the experiments: Porphyromonas gingivalis ATCC 33277, Aggregatibacter actinomyctemecomitans ATCC 33384, Fusobacterium nucleatum ATCC 10953. Toluidine blue O (TBO) was used in concentration ranging from 0.004 to 0.5mg/mL. Irradiation was performed by a non-laser red light source.ResultsComplete eradication of P. gingivalis was obtained upon the application of TBO in the concentration of 0.1mg/mL and the highest light dose. A, actinomycetemcomitans was, in turn, not susceptible to photodynamic inactivation regardless of the dosimetric parameters applied. High viability reductions were also obtained for F. nucleatum, however no complete eradication. The effectiveness of photodynamic inactivation of susceptible periopathogens was dependent on the light dose and photosensitizer's concentration.ConclusionsPeriopathogens differ in terms of their susceptibility to photodynamic inactivation. Antimicrobial PDT may be valuable in the treatment of those cases of periodontal disease, in which P. gingivalis is a dominating pathogen. Microbiological examination prior to clinical application of aPDT may be recommended.



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Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin

Publication date: December 2017
Source:Photodiagnosis and Photodynamic Therapy, Volume 20
Author(s): Cathrine Elisabeth Olsen, Simen Sellevold, Theodossis Theodossiou, Sebastian Patzke, Kristian Berg
The low curative response to current treatment regimens for most soft tissue sarcomas indicates a strong need for alternative treatment strategies and predictive markers for treatment outcome. PCI (photochemical internalization) is a novel treatment strategy to translocate drugs into cytosol that otherwise would have been degraded in lysosomes. Two highly geno-and phenotypically different uterine and vulvar leiomyosarcoma cell lines, MES-SA and SK-LMS-1, were treated with bleomycin (BLM) activated by PCI (PCIBLM). The MES-SA cells were much more sensitive to PCIBLM than the SK-LMS-1 cells and the treatment induced a 7–8 fold higher increase in DNA double-strand breaks at the same dose of light as measure by γH2AX staining. A 3-fold higher induction of apoptosis and stronger activation of Bax and p21 was also measured in the P53WT MES-SA cells, compared to the P53mut SK-LMS-1 cells. The basal formation of reactive oxygen species (ROS) was 3-fold higher in SK-LMS-1 cells than in the MES-SA cells and SK-LMS-1 cells expressed glutathione peroxidase 1 (GPx1) and more superoxide dismutase 2 (SOD2) than the MES-SA cells. Glutathione depletion with the glutathione synthetase inhibitor buthionine sulfoximine increased the cytotoxic effect of the photochemical treatment (PDT) most strongly in the SK-LMS-1 cells, and reduced PCIBLM-induced H2AX activation in the MES-SA cells, but not in the SK-LMS-1 cells. The results indicate PCIBLM as a potential novel treatment strategy for soft tissue sarcomas, with antioxidant enzymes, in particular GPx1, and the P53 status as potential predictive markers for response to PCIBLM.

Graphical abstract

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Contrast enhanced ultrasound imaging can predict vascular-targeted photodynamic therapy induced tumor necrosis in small animals

Publication date: Available online 5 September 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): F.H. Cornelis, K. Kim, J.C. Durack, S. Jebiwott, A. Scherz, G. Srimathveeravalli, J.A. Coleman
AimsTo evaluate the accuracy of contrast-enhanced ultrasound (CEUS) for monitoring tumor necrosis following WST-11 vascular targeted photodynamic therapy (VTP) using imaging-pathology correlation.MethodsRenal adenocarcinoma cells were injected into the hindlimb of 13 BalB/c mice resulting in tumors ranging from 9.8 to 194.3mm³. US guidance was used to place a laser fiber into the tumor, and VTP was performed. CEUS was performed prior to animal sacrifice, 24hours post-VTP. Whole tumors were extracted for histopathologic analysis using H&E and TUNEL staining. Pathology samples corresponding to the CEUS imaging plane were prepared in order to compare the size and extents of tumor necrosis.ResultsTumor necrosis following VTP appeared as a central region of non-enhancement on CEUS, while viable tumor appeared as patchy regions of enhancement in the tumor periphery. The region of tumor necrosis measured in mean 66% and 64.8% of total tumor area on CEUS and pathology respectively (p=0.2). The size and location of the necrosis on CEUS images and pathology samples were found correlative with no inter-observer difference (weighted kappa of 0.771 and 0.823, respectively).ConclusionCEUS allows accurate monitoring of VTP induced tumor necrosis in a small animal model.



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Efficacy of Erythrosine and Cyanidin-3-glucoside Mediated Photodynamic Therapy on Porphyromonas Gingivalis Biofilms using Green Light Laser.

Publication date: Available online 5 September 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Aroon Teerakapong, Teerasak Damrongrungruang, Sajee Sattayut, Noppawan Phumala Morales, Surada Tantananugool
BackgroundThe purpose of this in vitro study was to evaluate the efficacy of erythrosine and cyanidin-3-glucoside as photosensitizers in PDT for the elimination of Porphyromonas gingivalis (P. gingivalis) biofilms.MethodsP. gingivalis biofilms were prepared from a chronic periodontitis subject. Erythrosine and cyanidin-3-glucoside were prepared and randomly allocated as follows: 110, 220, 330, and 440μM erythrosine; 101, 202, 303, and 404μM anthocyanin; and 440μM erythrosine+404μM cyanidin-3-glucoside. There were 18 PDT experimental groups (non-irradiated/irradiated with a 532-nm green light diode laser at 1.29J/cm² for 60seconds). The 3 controls were grouped as follows: biofilms exposed to the photosensitizers alone, biofilms exposed to the laser alone, and biofilms exposed to 0.12% chlorhexidine. All sample groups were cultured at 1, 3 and 6hrs after PDT and incubated in an anaerobic chamber at 37°C for 4 days. The surviving fraction was calculated from the log10 CFU/ml. The 330 and 440μM erythrosine and the 440μM erythrosine+404μM cyanidin-3-glucoside were mixed with spin traps (TEMPO, DMPO), and the electron spin resonance spectra were evaluated.ResultsThe log10 CFU/ml measurements showed that the PDT groups with 330μM or 440μM erythrosine and 440μM erythrosine+404μM cyanidin-3-glucoside had statistically significant differences from the other groups (one-way ANOVA and Bonferroni's multiple comparison test, p- value≤0.05).ConclusionsPDT using 330μM erythrosine, 440μM erythrosine or 440μM erythrosine+404μM cyanidin-3-glucoside irradiated with the laser more effectively inhibited P. gingivalis in biofilms.



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The histone lysine methyltransferase Ezh2 is required for maintenance of the intestine integrity and for caudal fin regeneration in zebrafish

Publication date: Available online 5 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Barbara Dupret, Pamela Völkel, Constance Vennin, Robert-Alain Toillon, Xuefen Le Bourhis, Pierre-Olivier Angrand
The histone lysine methyltransferase EZH2, as part of the Polycomb Repressive Complex 2 (PRC2), mediates H3K27me3 methylation which is involved in gene expression program repression. Through its action, EZH2 controls cell-fate decisions during the development and the differentiation processes. Here, we report the generation and the characterization of an ezh2-deficient zebrafish line. In contrast to its essential role in mouse early development, loss of ezh2 function does not affect zebrafish gastrulation. Ezh2 zebrafish mutants present a normal body plan but die at around 12 dpf with defects in the intestine wall, due to enhanced cell death. Thus, ezh2-deficient zebrafish can initiate differentiation toward the different developmental lineages but fail to maintain the intestinal homeostasis. Expression studies revealed that ezh2 mRNAs are maternally deposited. Then, ezh2 is ubiquitously expressed in the anterior part of the embryos at 24 hpf, but its expression becomes restricted to specific regions at later developmental stages. Pharmacological inhibition of Ezh2 showed that maternal Ezh2 products contribute to early development but are dispensable to body plan formation. In addition, ezh2-deficient mutants fail to properly regenerate their spinal cord after caudal fin transection suggesting that Ezh2 and H3K27me3 methylation might also be involved in the process of regeneration in zebrafish.

Graphical abstract

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Concurrent uptake and metabolism of dyestuffs through bio-assisted phytoremediation: a symbiotic approach

Abstract

Manipulation of bio-technological processes in treatment of dyestuffs has attracted considerable attention, because a large proportion of these synthetic dyes enter into natural environment during synthesis and dyeing operations that contaminates different ecosystems. Moreover, these dyestuffs are toxic and difficult to degrade because of their synthetic origin, durability, and complex aromatic molecular structures. Hence, bio-assisted phytoremediation has recently emerged as an innovative cleanup approach in which microorganisms and plants work together to transform xenobiotic dyestuffs into nontoxic or less harmful products. This manuscript will focus on competence and potential of plant-microbe synergistic systems for treatment of dyestuffs, their mixtures and real textile effluents, and effects of symbiotic relationship on plant performances during remediation process and will highlight their metabolic activities during bio-assisted phytodegradation and detoxification.

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Role of an estradiol regulatory factor-hydroxysteroid dehydrogenase (HSD) in Toxoplasma gondii infection and pathogenicity

Publication date: Available online 5 September 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Xiao Zhang, Jing Liu, Muzi Li, Yong Fu, Taotao Zhang, Qian Han, Qun Liu
Toxoplasma gondii is an apicomplexan parasite that infects most species of warm-blooded animals, including humans, and causes abortions and severe damage to the fetal central nervous system. During pregnancy, the prevalence of toxoplasmosis increases throughout the second and third quarter of gestation, while the hormones progesterone and estradiol simultaneously increase. Thus, it has been suggested that these hormones could affect parasite reproduction. This study was mainly focused on an estradiol regulatory factor-Hydroxysteroid dehydrogenase (HSD) gene in T. gondii.Our data showed that estradiol promoted Pru (Type II) and VEG (Type III) infection and thus significantly contributed to the pathogenicity of T. gondii in mice. Subsequently, we found that this phenomenon may relate to the interplay of T. gondii and estradiol. We reported that estradiol can enter T. gondii tachyzoites. Bioinformatics analysis showed that T. gondii may have a residual estradiol metabolism-related gene HSD. To verify the gene function, HEK293T cells were transiently transfected with Tg-HSD and gene expression was induced. Then, HPLC (high-performance liquid chromatography) analysis showed that Tg-HSD can efficiently transform estrone into estradiol. Moreover, Tg-HSD −overexpressing parasites showed significantly enhanced pathogenicity and upregulation of estradiol levels in mice. In conclusion, estradiol can promote T. gondii infection in vitro and in vivo, and this may be related to its Tg- HSD gene.



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