Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy

Glial cells actively participate in synaptic transmission. They clear molecules from the synaptic cleft, receive signals from neurons and, in turn, release molecules that can modulate signaling between neuronal elements. Whether glial-derived transmitters can contribute to enduring changes in postsynaptic efficacy, however, remains to be established. In rat hypothalamic paraventricular nucleus, we demonstrate an increase in the amplitude of miniature excitatory postsynaptic currents in response to norepinephrine that requires the release of ATP from glial cells. The increase in quantal efficacy, which likely results from an insertion of AMPA receptors, is secondary to the activation of P2X(7) receptors, an increase in postsynaptic calcium and the activation of phosphatidylinositol 3-kinase. The gliotransmitter ATP, therefore, contributes directly to the regulation of postsynaptic efficacy at glutamatergic synapses in the CNS.     

Water-Soluble Copper Ink for the Inkjet Fabrication of Flexible Electronic Components

The aim of this work is preparation and investigation of copper conductive paths by printing with a different type of functional ink. The solutions based on copper-containing complex compounds were used as inks instead of dispersions of metal nanoparticles. Thermal characteristics of synthesized precursors were studied by thermogravimetry in an argon atmosphere. Based on the comparison of decomposition temperature, the dimethylamine complex of copper formate was found to be more suitable precursor for the formation of copper layers. Structure and performance of this compound was studied in detail by X-ray diffraction, test of wettability, printing on flexible substrate, and electrical measurements.     

Economic consequences of severe bleeding in patients with acute coronary syndrome in the USA

Introduction  

Previous studies have demonstrated increased costs associated with bleeding in clinical trials, but none have yet examined the association of bleeding with costs/charges in a real-world setting. This study examines the association between health care charges and severe bleeding events among patients with acute coronary syndrome (ACS) in a real-world US setting.     

Protective effects of Hibiscus tiliaceus L. methanolic extract to V79 cells against cytotoxicity and genotoxicity induced by hydrogen peroxide and tert-butyl-hydroperoxide

Plants of the genus Hibiscus thrives produce a diversity of molecules with bioactive properties. In a previous study of Hibiscus tiliaceus L. methanolic extract (HME) using bacteria and yeast, as test media, it has been shown that HME strongly inhibited the mutagenic action of H₂O₂ or tert-butyl-hydroperoxide (t-BHP). Here, our interest is to evaluate the genotoxicity and the antigenotoxic/antimutagenic properties of HME using oxidative challenge with H₂O₂ and t-BHP in V79 cells. We determined cytotoxicity using clonal survival assay; evaluated DNA damage using the comet assay and the micronucleus test in binucleated cells besides of the lipid peroxidation degree and the reduced glutathione content. We examined the ability of HME in quenching hydroxyl radical by means of a HPLC-based method utilizing the hypoxanthine/xanthine oxidase assay. At concentrations ranging from 0.001 to 0.1 mg/mL, HME was not cytotoxic, genotoxic or mutagenic. Treatment with non-cytotoxic concentrations of HME increased cell survival after H₂O₂ and t-BHP exposure and prevented DNA damage. The pre-treatment with HME also was able to decrease the mutagenic effect of these genotoxins, evaluated using the micronucleus test. HME prevented the increase in lipid peroxidation and decrease in GSH content in response to the oxidative challenge. Therefore, the ability in preventing against H₂O₂- and t-BHP-induced GSH depletion and lipid peroxidation was probably a major contribution to the cytoprotective effects. Moreover, HME acts as a hydroxyl radical scavenger. In summary, HME did not have a harmful or inhibitory effect on the growth of V79 cells and presented antioxidant activity, consequently, both antigenotoxic and antimutagenic effects against oxidative DNA damage.     

Prolonged presynaptic posttetanic cyclic GMP signaling in Drosophila motoneurons

Ca²⁺ can stimulate cyclic nucleotide synthesis, but it is not known whether this signaling occurs in nerve terminals in response to activity. Here, in vivo imaging of Drosophila motoneuron terminals shows that activity rapidly induces a long-lasting signal from a transgenically expressed optical indicator based on the epac1 (exchange protein directly activated by cAMP 1) cAMP-binding domain. The epac1-cAMP sensor (camps) response in synaptic boutons depends on extracellular Ca²⁺ and ryanodine receptor-mediated Ca²⁺-induced Ca²⁺ release from the endoplasmic reticulum. However, mutations that inhibit rutabaga Ca²⁺-stimulated adenylyl cyclase and dunce cAMP-specific phosphodiesterase (PDE) have no effect. Instead, the activity-dependent presynaptic epac1-camps signal reflects elevation of cGMP in response to nitric oxide-activated guanylyl cyclase. Posttetanic presynaptic cGMP is long-lived because of limited PDE activity. Thus, nerve terminal biochemical signaling induced by brief bouts of activity temporally summates on a time scale orders of magnitude longer than fast transmission.     

Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty‐eight patients

Objective

To describe the clinical and laboratory features of macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus (SLE).

Methods

Cases of juvenile SLE–associated macrophage activation syndrome were provided by investigators belonging to 3 pediatric rheumatology networks or were found in the literature. Patients who had evidence of macrophage hemophagocytosis on bone marrow aspiration were considered to have definite macrophage activation syndrome, and those who did not have such evidence were considered to have probable macrophage activation syndrome. Clinical and laboratory findings in patients with macrophage activation syndrome were contrasted with those of 2 control groups composed of patients with active juvenile SLE without macrophage activation syndrome. The ability of each feature to discriminate macrophage activation syndrome from active disease was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve.

Results

The study included 38 patients (20 with definite macrophage activation syndrome and 18 with probable macrophage activation syndrome). Patients with definite and probable macrophage activation syndrome were comparable with regard to all clinical and laboratory features of the syndrome, except for a greater frequency of lymphadenopathy, leukopenia, and thrombocytopenia in patients with definite macrophage activation syndrome. Overall, clinical features had better specificity than sensitivity, except for fever, which was highly sensitive but had low specificity. Among laboratory features, the best sensitivity and specificity was achieved using hyperferritinemia, followed by increased levels of lactate dehydrogenase, hypertriglyceridemia, and hypofibrinogenemia. Based on the results of statistical analysis, preliminary diagnostic guidelines for macrophage activation syndrome in juvenile SLE were developed.

Conclusion

Our findings indicate that the occurrence of unexplained fever and cytopenia, when associated with hyperferritinemia, in a patient with juvenile SLE should raise the suspicion of macrophage activation syndrome. We propose preliminary guidelines for this syndrome in juvenile SLE to facilitate timely diagnosis and correct classification of patients.

     

Evaluation of the cytotoxic and antimutagenic effects of biflorin, an antitumor 1,4 o-naphthoquinone isolated from Capraria biflora L

Biflorin is a natural quinone isolated from Capraria biflora L. Previous studies demonstrated that biflorin inhibits in vitro and in vivo tumor cell growth and presents potent antioxidant activity. In this paper, we report concentration-dependent cytotoxic, genotoxic, antimutagenic, and protective effects of biflorin on Salmonella tiphymurium, yeast Saccharomyces cerevisiae, and V79 mammalian cells, using different approaches. In the Salmonella/microsome assay, biflorin was not mutagenic to TA97a TA98, TA100, and TA102 strains. However, biflorin was able to induce cytotoxicity in haploid S. cerevisiae cells in stationary and exponential phase growth. In diploid yeast cells, biflorin did not induce significant mutagenic and recombinogenic effects at the employed concentration range. In addition, the pre-treatment with biflorin prevented the mutagenic and recombinogenic events induced by hydrogen peroxide (H₂O₂) in S. cerevisiae. In V79 mammalian cells, biflorin was cytotoxic at higher concentrations. Moreover, at low concentrations biflorin pre-treatment protected against H₂O₂-induced oxidative damage by reducing lipid peroxidation and DNA damage as evaluated by normal and modified comet assay using DNA glycosylases. Our results suggest that biflorin cellular effects are concentration dependent. At lower concentrations, biflorin has significant antioxidant and protective effects against the cytotoxicity, genotoxicity, mutagenicity, and intracellular lipid peroxidation induced by H₂O₂ in yeast and mammalian cells, which can be attributed to its hydroxyl radical-scavenging property. However, at higher concentrations, biflorin is cytotoxic and genotoxic.     

Smurf2 regulates IL17RB by proteasomal degradation of its novel binding partner DAZAP2

IL17RB is the receptor for IL17E, the only member of IL17 family promoting Th2 reactions. The mechanism of IL17BR regulation is poorly understood. We previously demonstrated that expression of IL17RB is induced on human macrophages by IL4 and enhanced by TGFβ. In the present study we investigated the immediate signaling targets of IL17RB. Using Yeast Two Hybrid screening we identified DAZAP2 as a binding partner of IL17RB. We established that 2 SH2-binding domains of DAZAP2 are essential for its binding to IL17RB. Deletion of these domains or substitution of tyrosines to alanines abrogates the binding. In IL17RB DAZAP2-binding domain was mapped to the region between aa 329 and 347 within its cytoplasmic part. Confocal microscopy revealed that in primary human macrophages that do not express IL17RB DAZAP2 is predominantly localized in the nucleus, while in IL17RB positive macrophages a portion of DAZAP2 is visualized in the cytoplasm. Stimulation of IL17RB with its ligand IL17E induces accumulation of DAZAP2 in the cytoplasm. Further we established that DAZAP2 interacts with Smurf2 an E3 ubiquitin ligase which induces proteasome-dependent degradation of the protein. In summary we established a new mechanism of IL17RB regulation-Smurf2 dependent degradation of its adaptor protein DAZAP2.