Sample records for a2 mimetic u46619

  1. Role of Spm-Cer-S1P signalling pathway in MMP-2 mediated U46619-induced proliferation of pulmonary artery smooth muscle cells: protective role of epigallocatechin-3-gallate.

    PubMed

    Chowdhury, Animesh; Sarkar, Jaganmay; Chakraborti, Tapati; Chakraborti, Sajal

    2015-10-01

    During remodelling of pulmonary artery, marked proliferation of pulmonary artery smooth muscle cells (PASMCs) occurs, which contributes to pulmonary hypertension. Thromboxane A2 (TxA2) has been shown to produce pulmonary hypertension. The present study investigates the inhibitory effect of epigallocatechin-3-gallate (EGCG) on the TxA2 mimetic, U46619-induced proliferation of PASMCs. U46619 at a concentration of 10 nM induces maximum proliferation of bovine PASMCs. Both pharmacological and genetic inhibitors of p(38)MAPK, NF-κB and MMP-2 significantly inhibit U46619-induced cell proliferation. EGCG markedly abrogate U46619-induced p(38)MAPK phosphorylation, NF-κB activation, proMMP-2 expression and activation, and also the cell proliferation. U46619 causes an increase in the activation of sphingomyelinase (SMase) and sphingosine kinase (SPHK) and also increase sphingosine 1 phosphate (S1P) level. U46619 also induces phosphorylation of ERK1/2, which phosphorylates SPHK leading to an increase in S1P level. Both pharmacological and genetic inhibitors of SMase and SPHK markedly inhibit U46619-induced cell proliferation. Additionally, pharmacological and genetic inhibitors of MMP-2 markedly abrogate U46619-induced SMase activity and S1P level. EGCG markedly inhibit U46619-induced SMase activity, ERK1/2 and SPHK phosphorylation and S1P level in the cells. Overall, Sphingomyeline-Ceramide-Sphingosine-1-phosphate (Spm-Cer-S1P) signalling axis plays an important role in MMP-2 mediated U46619-induced proliferation of PASMCs. Importantly, EGCG inhibits U46619 induced increase in MMP-2 activation by modulating p(38)MAPK-NFκB pathway and subsequently prevents the cell proliferation. Copyright © 2015 John Wiley & Sons, Ltd.

  2. Time-dependent inhibition by glyceryl trinitrate of platelet aggregation caused by U46619 (a thromboxane/endoperoxide receptor agonist).

    PubMed Central

    Kampf, G; Ritter, J M

    1994-01-01

    Glyceryl trinitrate is a weak inhibitor of platelet aggregation in vitro. Its effect on platelet aggregation in response to U46619 (a thromboxane/endoperoxide receptor agonist) was studied turbidometrically in platelet-rich plasma from healthy volunteers. The object was to determine whether inhibition was influenced by a period of preincubation between preparation of platelet-rich plasma and addition of glyceryl trinitrate. Incubation was performed at 37 degrees C and 22 degrees C. Samples were removed at intervals and transferred to an aggregometer cuvette at 37 degrees C. Glyceryl trinitrate (100 microM) or an equal volume of distilled water was added 5 min before U46619 (2 microM), and aggregation recorded as change in light transmission. Inhibition by glyceryl trinitrate was markedly time and temperature dependent, with a progressive increase in inhibitory potency between 120 and 300 min preincubation at 37 degrees C but not at 22 degrees C. The explanation of this is unknown but the effect was not influenced by lipopolysaccharide or by cycloheximide, so it does not appear to be due to exposure to endotoxin or to enzyme induction in vitro. PMID:7946941

  3. Dipetalodipin, a Novel Multifunctional Salivary Lipocalin That Inhibits Platelet Aggregation, Vasoconstriction, and Angiogenesis through Unique Binding Specificity for TXA2, PGF2α, and 15(S)-HETE*

    PubMed Central

    Assumpção, Teresa C. F.; Alvarenga, Patricia H.; Ribeiro, José M. C.; Andersen, John F.; Francischetti, Ivo M. B.

    2010-01-01

    Dipetalodipin (DPTL) is an 18 kDa protein cloned from salivary glands of the triatomine Dipetalogaster maxima. DPTL belongs to the lipocalin superfamily and has strong sequence similarity to pallidipin, a salivary inhibitor of collagen-induced platelet aggregation. DPTL expressed in Escherichia coli was found to inhibit platelet aggregation by collagen, U-46619, or arachidonic acid without affecting aggregation induced by ADP, convulxin, PMA, and ristocetin. An assay based on incubation of DPTL with small molecules (e.g. prostanoids, leukotrienes, lipids, biogenic amines) followed by chromatography, mass spectrometry, and isothermal titration calorimetry showed that DPTL binds with high affinity to carbocyclic TXA2, TXA2 mimetic (U-46619), TXB2, PGH2 mimetic (U-51605), PGD2, PGJ2, and PGF2α. It also interacts with 15(S)-HETE, being the first lipocalin described to date to bind to a derivative of 15-lipoxygenase. Binding was not observed to other prostaglandins (e.g. PGE1, PGE2, 8-iso-PGF2α, prostacyclin), leukotrienes (e.g,. LTB4, LTC4, LTD4, LTE4), HETEs (e.g. 5(S)-HETE, 12(S)-HETE, 20-HETE), lipids (e.g. arachidonic acid, PAF), and biogenic amines (e.g. ADP, serotonin, epinephrine, norepinephrine, histamine). Consistent with its binding specificity, DPTL prevents contraction of rat uterus stimulated by PGF2α and induces relaxation of aorta previously contracted with U-46619. Moreover, it inhibits angiogenesis mediated by 15(S)-HETE and did not enhance inhibition of collagen-induced platelet aggregation by SQ29548 (TXA2 antagonist) and indomethacin. A 3-D model for DPTL and pallidipin is presented that indicates the presence of a conserved Arg39 and Gln135 in the binding pocket of both lipocalins. Results suggest that DPTL blocks platelet aggregation, vasoconstriction, and angiogenesis through binding to distinct eicosanoids involved in inflammation. PMID:20889972

  4. Pharmacologic properties of KT2-962 (6-isopropyl-3-[4-(p- chlorobenzenesulfonylamino)-butyl]-azulene-1-sulfonic acid sodium salt); a new TXA2/prostaglandin endoperoxide receptor antagonist.

    PubMed

    Kosakai, K; Wakabayashi, S; Sato, T; Mochizuki, S; Tomiyama, A; Zhou, Q; Satake, N; Shibata, S

    1993-03-01

    Pharmacologic properties of KT2-962 (6-isopropyl-3-[4-(p-chlorobenzenesulfonylamino)butyl]-azulene+ ++-1-sulfonic acid sodium salt, KT) were studied in isolated rat aorta, rat tail artery, rabbit aorta, rabbit renal artery, and pig coronary artery. KT competitively inhibited the contractions induced by thromboxane A2 (TXA2) mimetic, U46619 (pA2 values 9.95, 8.85, 7.87, 8.49, and 9.12, respectively). KT also inhibited the contraction of rabbit aorta induced by prostaglandin2 alpha (PGF2 alpha, pA2 value 7.85) and the contraction of guinea pig ileum induced by LTD4 (pA2 value 5.48) but did not alter the contractions induced by norepinephrine (NE), Ca2+, serotonin, and histamine. KT did not alter the contractions of guinea pig ileum, which did not contract with U46619, induced by PGE2 and PGF2 alpha. KT inhibited the aggregations of rabbit platelets induced by U46619, arachidonic acid, and collagen (IC50 values 7.9, 140, and 16 microM, respectively) but not those induced by ADP. It also inhibited the specific binding of TXA2/PGH2 receptor antagonist, [3H]SQ29,548, to rabbit gel-filtered platelets with an IC50 value of 1.5 x 10(-8) M. In in vivo experiments with mice, oral administration of KT protected the U46619-induced sudden death with the minimum effective dose of 0.3 mg/kg and provided such protection for > 8 h at 1.0 mg/kg. These results indicate that KT is a new nonprostanoid type TXA2/PGH2 receptor antagonist that is orally effective and long acting.

  5. A framework for developing a mimetic tensor artificial viscosity for Lagrangian hydrocodes on arbitrary polygonal and polyhedral meshes (u)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lipnikov, Konstantin; Shashkov, Mikhail

    2011-01-11

    We construct a new mimetic tensor artificial viscosity on general polygonal and polyhedral meshes. The tensor artificial viscosity is based on a mimetic discretization of coordinate invariant operators, divergence of a tensor and gradient of a vector. The focus of this paper is on the symmetric form, div ({mu},{var_epsilon}(u)), of the tensor artificial viscosity where {var_epsilon}(u) is the symmetrized gradient of u and {mu}, is a tensor. The mimetic discretizations of this operator is derived for the case of a full tensor coefficient {mu}, that may reflect a shock direction. We demonstrate performance of the new viscosity for the Nohmore » implosion, Sedov explosion and Saltzman piston problems in both Cartesian and axisymmetric coordinate systems.« less

  6. Thrombosis Is Reduced by Inhibition of COX-1, but Unaffected by Inhibition of COX-2, in an Acute Model of Platelet Activation in the Mouse

    PubMed Central

    Armstrong, Paul C.; Kirkby, Nicholas S.; Zain, Zetty N.; Emerson, Michael; Mitchell, Jane A.; Warner, Timothy D.

    2011-01-01

    Background Clinical use of selective inhibitors of cyclooxygenase (COX)-2 appears associated with increased risk of thrombotic events. This is often hypothesised to reflect reduction in anti-thrombotic prostanoids, notably PGI2, formed by COX-2 present within endothelial cells. However, whether COX-2 is actually expressed to any significant extent within endothelial cells is controversial. Here we have tested the effects of acute inhibition of COX on platelet reactivity using a functional in vivo approach in mice. Methodology/Principal Findings A non-lethal model of platelet-driven thromboembolism in the mouse was used to assess the effects of aspirin (7 days orally as control) diclofenac (1 mg.kg−1, i.v.) and parecoxib (0.5 mg.kg−1, i.v.) on thrombus formation induced by collagen or the thromboxane (TX) A2-mimetic, U46619. The COX inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo. Collagen and U46619 caused in vivo thrombus formation with the former, but not latter, sensitive to oral dosing with aspirin. Diclofenac inhibited COX-1 and COX-2 ex vivo and reduced thrombus formation in response to collagen, but not U46619. Parecoxib inhibited only COX-2 and had no effect upon thrombus formation caused by either agonist. Conclusions/Significance Inhibition of COX-1 by diclofenac or aspirin reduced thrombus formation induced by collagen, which is partly dependent upon platelet-derived TXA2, but not that induced by U46619, which is independent of platelet TXA2. These results are consistent with the model demonstrating the effects of COX-1 inhibition in platelets, but provide no support for the hypothesis that acute inhibition of COX-2 in the circulation increases thrombosis. PMID:21629780

  7. Undiscovered role of endogenous thromboxane A2 in activation of cardiac sympathetic afferents during ischaemia

    PubMed Central

    Fu, Liang-Wu; Guo, Zhi-Ling; Longhurst, John C

    2008-01-01

    Myocardial ischaemia activates blood platelets, which in turn stimulate cardiac sympathetic afferents, leading to chest pain and sympathoexcitatory reflex cardiovascular responses. Previous studies have shown that activated platelets stimulate ischaemically sensitive cardiac sympathetic afferents, and that thromboxane A2 (TxA2) is one of the mediators released from activated platelets during myocardial ischaemia. The present study tested the hypothesis that endogenous TxA2 stimulates cardiac afferents during ischaemia through direct activation of TxA2 (TP) receptors coupled with the phospholipase C–protein kinase C (PLC–PKC) cellular pathway. Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicantes (T2–T5) in anaesthetized cats. Single fields of 39 afferents (conduction velocity = 0.27–3.65 m s−1) were identified in the left or right ventricle initially with mechanical stimulation and confirmed with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 39 cardiac afferents (8 Aδ-, 31 C-fibres) and the responses of these 39 afferents to chemical stimuli were further studied in the following four protocols. In the first protocol, 2.5, 5 and 10 μg of the TxA2 mimetic, U46619, injected into the left atrium (LA), stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BM13,177, a selective TxA2 receptor antagonist, abolished the responses of six afferents to 5 μg of U46619 injected into the left atrium and attenuated the ischaemia-related increase in activity of seven other afferents by 44%. In contrast, cardiac afferents, in the absence of TP receptor blockade responded consistently to repeated administration of U46619 (n = 6) and to recurrent myocardial ischaemia (n = 7). In the fourth protocol, administration of PKC-(19–36), a selective PKC inhibitor, attenuated the responses of six other cardiac afferents to U46619 by 38

  8. Mechanisms of U46619-induced contraction of rat pulmonary arteries in the presence and absence of the endothelium

    PubMed Central

    McKenzie, C; MacDonald, A; Shaw, AM

    2009-01-01

    Background and purpose: Thromboxane A2 and endothelial dysfunction are implicated in the development of pulmonary hypertension. The receptor-transduction pathway for U46619 (9,11-dideoxy-9α, 11α-methanoepoxy prostaglandin F2α)-induced contraction was examined in endothelium-intact (E+) and denuded (E−) rat pulmonary artery rings. Experimental approach: Artery rings were mounted on a wire myograph under a tension of 7–7.5 mN at 37°C and gassed with 95% O2/5% CO2. Isometric recording was made by using Powerlab data collection and Chart 5 software. Key results: Both E+ and E− contractile responses were sensitive to Rho-kinase inhibition and the chloride channel blocker NPPB [5-nitro-2-(3-phenylpropylamino)benzoic acid]. The E+ response was sensitive to the store-operated calcium channel blockers SKF-96365 {1-[B-[3-(4-methoxyphenyl)propoxy]-4-methoxy-phenethyl]-1H-imidazole hydrochloride} and 2-APB (2-amino ethoxy diphenylborate) (75–100 µmol·L−1). The E− response was sensitive to 2-APB (10–30 µmol·L−1), a putative IP3 receptor antagonist, and the calcium and chloride channel blockers nifedipine, DIDS (4,4′-diisothiocyanostilbene-2,2′-disulphonic acid) and niflumic acid but was insensitive to SKF-96365. Inhibiting KV with 4-AP in E+ rings exposed a contraction sensitive to nifedipine, DIDS and niflumic acid, whereas inhibiting BKCa exposed a contraction sensitive to mibefradil, DIDS and niflumic acid. This indicates that removal of the endothelium allows the TP receptor to inhibit KV, which may involve coupling to phospholipase C, because inhibition of phospholipase C with U73122 (1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-y]amino]hexyl]– 1H-pyrrole-2,5-dione) switched the E− pathway to the E+ pathway. Conclusions and implications: The results from this study indicate that distinct transduction pathways can be employed by the TP receptor to produce contraction and that the endothelium is able to influence the coupling of the TP

  9. Chorionic plate arterial function is altered in maternal obesity

    PubMed Central

    Hayward, C.E.; Higgins, L.; Cowley, E.J.; Greenwood, S.L.; Mills, T.A.; Sibley, C.P.; Wareing, M.

    2013-01-01

    Objectives To characterise Chorionic Plate Artery (CPA) function in maternal obesity, and investigate whether leptin exposure reproduces the obese CPA phenotype in normal-BMI women. Study design CPA responses to the thromboxane-A2 mimetic U46619 (pre/post leptin incubation), to the nitric oxide donor sodium nitroprusside (SNP) and the occurrence of tone oscillations (pre/post leptin incubation) were assessed in 46 term placentas from women of normal (18.5–24.9) or obese (>30) Body Mass Index (BMI). Outcome measures Area Under the dose response Curve (AUC), maximum response (Vmax), sensitivity (EC50) to U46619 (pre/post leptin) and SNP; average vessel tone, oscillation amplitude and frequency (pre/post leptin). Results U46619 vasoconstriction was similar between BMI categories (p > 0.05), however vasodilatation to SNP was reduced in obesity (AUC p = 0.02, Vmaxp = 0.04) compared to normal-BMI women. Leptin incubation altered responses to U46619 in both normal-BMI (EC50 at 100 ng/ml leptin; p < 0.05) and obese women (AUC at 50 ng/ml; p < 0.05) but vasomotion was unaffected (p > 0.05). Conclusions Maternal obesity is associated with altered placental vascular function which may adversely affect placental oxygen and nutrient transport, placing the fetus at risk. Leptin incubation altered CPA vascular function but did not reproduce the obese phenotype. PMID:23360794

  10. Thimerosal blocks stimulated but not basal release of endothelium-derived relaxing factor (EDRF) in dog isolated coronary artery.

    PubMed Central

    Crack, P.; Cocks, T.

    1992-01-01

    1. The effect of an acetly-coA lysolecithin acyltransferase inhibitor, thimerosal, on the release of endothelium-derived relaxing factor (EDRF) was examined in the greyhound isolated coronary artery. 2. Thimerosal (1-10 microM) relaxed fully, ring segments of coronary artery which were contracted with the thromboxane A2-mimetic, U46619 (30 nM). The response was endothelium-dependent, slow in both onset and time to reach maximum. The maximum relaxation to the highest concentration of thimerosal (10 microM) was maintained for 10-20 min before the tissue slowly regained active force (1-2 h) to the same or higher level as that prior to the addition of thimerosal. At this time the endothelium-dependent relaxation responses to acetylcholine (ACh), substance P (SP), bradykinin (BK) and the calcium ionophores, ionomycin and A23187 were abolished. The endothelium-dependent contractions to the nitric oxide synthase inhibitors, NG-nitro-L-arginine (L-NNA; 10-100 microM) and NG-monomethyl-L-arginine (L-NMMA: 10-100 microM), however, were unaffected. 3. Thimerosal (10 microM) did not affect the relaxation curve to sodium nitroprusside (SNP) nor the contraction curve to the thromboxane A2-mimetic, U46619. 4. Both the relaxation response to thimerosal and the selective block of the relaxation responses to stimulated EDRF release were unaffected by either indomethacin (10 microM) or superoxide dismutase (150 u ml-1). 5. L-NNA (100 microM) significantly blocked the relaxation curves to thimerosal and A23187 but not that to SNP.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1384915

  11. Pharmacological and histological examinations of regional differences of guinea-pig lung: a role of pleural surface smooth muscle in lung strip contraction.

    PubMed Central

    Wong, W. S.; Bloomquist, S. L.; Bendele, A. M.; Fleisch, J. H.

    1992-01-01

    1. Parenchymal lung strip preparations have been widely used as an in vitro model of peripheral airway smooth muscle. The present study examined functional responses of 4 consecutive guinea-pig lung parenchymal strips isolated from the central region (segment 1) to the distal edge (segment 4) of the lower lung lobe. The middle two segments were designated as segments 2 and 3. 2. Lung segments 1 and 4 exhibited significantly greater contraction than the other 2 segments to KCl when responses were expressed as mg force per mg tissue weight. Contractile responses to bronchospastic agents including histamine, carbachol, endothelin-1, leukotrienes (LT) B4 and D4, and the thromboxane A2-mimetic U46619 demonstrated no significant difference in EC50 values among the 4 lung segments. 3. Contractile responses of segments 1 and 4 to antigen-challenge (ovalbumin), ionophore A23187 and substance P were significantly greater than the other 2 segments with respect to either sensitivity or maximum responsiveness. 4. U46619-induced contractions of the 4 lung segments were relaxed in similar manner by papaverine and theophylline up to 100%, salbutamol up to 80%, and sodium nitroprusside by only 20%. In contrast, sodium nitroprusside markedly reversed U46619-induced contraction of pulmonary arterial rings and bronchial rings. 5. Histological studies identified 2-4 layers of smooth muscle cells underlying the lung pleural surface. Mast cells were prominent in this area. Moreover, morphometric studies showed that segment 4 possessed the least amount of smooth muscle structures from bronchial/bronchiolar wall and vasculatures as compared to the other 3 segments, and a significant difference in this respect was evident between segment 1 and segment 4.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 Figure 6 PMID:1378341

  12. Low-dose thromboxane A2 receptor stimulation promotes closure of the rat ductus arteriosus with minimal adverse effects.

    PubMed

    Yokota, Tomohiro; Aida, Takashi; Ichikawa, Yasuhiro; Fujita, Takayuki; Yokoyama, Utako; Minamisawa, Susumu

    2012-08-01

    Patent ductus arteriosus (PDA) is a common life-threatening complication among premature infants. Although cyclooxygenase inhibitors are frequently used to treat PDA, as they inhibit the synthesis of prostaglandin E(2), the most potent vasodilator in the ductus arteriosus (DA), their efficacy is often limited. As thromboxane A(2) (TXA(2)) induces vascular contraction via the TXA(2) receptor (TP), we hypothesized that TP stimulation would promote DA closure. To measure the inner diameter of the vessels, a rapid whole-body freezing method was used. Injection of the selective TP agonists U46619 and I-BOP constricted the fetal DA at embryonic day 19 (e19) and e21 in a dose-dependent manner. Of note, U46619 also exerted a vasoconstrictive effect on two different types of postnatal PDA models: premature PDA and hypoxia-induced PDA. We also found that U46619 constricted the ex vivo DA ring to a greater extent than it constricted the ex vivo aorta. Furthermore, we found that U46619 at lower concentrations (up to 0.05 mg/g of body weight) had a minimal vasoconstrictive effect on other vessels and did not induce microthrombosis in the pulmonary capillary arteries. Low-dose TP stimulation constricts the DA with minimal adverse effects at least in rat neonates and our results could point to an alternative potent vasoconstrictor for PDA.

  13. Antiaggregant and antivasospastic properties of the new thromboxane A2 receptor antagonist sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate.

    PubMed

    Lardy, C; Rousselot, C; Chavernac, G; Depin, J C; Guerrier, D

    1994-11-01

    LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) was demonstrated to be a potent thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonist in in vitro, ex vivo and in vivo experiments. The specific mechanism of action was studied in [3H]SQ 29548 receptor binding studies (pKi = 7.93) and was shown to be of competitive nature in U 46619-induced platelet aggregation (pA2 = 6.82). TXA2-dependent platelet rich plasma (PRP) aggregation (U 46619, arachidonic acid (AA), collagen, ADP or serotonin second phase) was inhibited in vitro in humans (IC50:0.037-0.65 mumol/l) and different animal species, as well as ex vivo i.v. rat and p.o. guinea-pig AA-induced aggregation (ED50 = 48 and 57 micrograms/kg). The U 46619-induced contractions of aorta, caudal artery and trachea were inhibited in a dose-dependent way (IC50 = 0.07, 0.02 and 0.5 mumol/l respectively). In vivo, both against platelet aggregation and vasoconstriction, LCB 2853 showed an ED50 lower than 1 mg/kg i.v. in rat AA-induced thrombocytopenia or U 46619-induced hypertension (ED50 = 0.25 and 0.16 mg/kg) as well as in AA-induced sudden death in the mouse (ED50 = 0.44 mg/kg). The U 46619-induced bronchoconstriction was blocked after i.v. administration of LCB 2853 (ED50 = 18.4 micrograms/kg). The duration of action observed in different models was 6 h by oral route and between 3 and 5 h by intravenous route. These properties in TXA2-dependent models led to further investigations of the antithrombotic activity of this novel TXA2 antagonist.

  14. Thromboxane A2-induced bi-directional regulation of cerebral arterial tone.

    PubMed

    Neppl, Ronald L; Lubomirov, Lubomir T; Momotani, Ko; Pfitzer, Gabriele; Eto, Masumi; Somlyo, Avril V

    2009-03-06

    Myosin light chain phosphatase plays a critical role in modulating smooth muscle contraction in response to a variety of physiologic stimuli. A downstream target of the RhoA/Rho-kinase and nitric oxide (NO)/cGMP/cyclic GMP-dependent kinase (cGKI) pathways, myosin light chain phosphatase activity reflects the sum of both calcium sensitization and desensitization pathways through phosphorylation and dephosphorylation of the myosin phosphatase targeting subunit (MYPT1). As cerebral blood flow is highly spatio-temporally modulated under normal physiologic conditions, severe perturbations in normal cerebral blood flow, such as in cerebral vasospasm, can induce neurological deficits. In nonpermeabilized cerebral vessels stimulated with U-46619, a stable mimetic of endogenous thromboxane A2 implicated in the etiology of cerebral vasospasm, we observed significant increases in contractile force, RhoA activation, regulatory light chain phosphorylation, as well as phosphorylation of MYPT1 at Thr-696, Thr-853, and surprisingly Ser-695. Inhibition of nitric oxide signaling completely abrogated basal MYPT1 Ser-695 phosphorylation and significantly increased and potentiated U-46619-induced MYPT1 Thr-853 phosphorylation and contractile force, indicating that NO/cGMP/cGKI signaling maintains basal vascular tone through active inhibition of calcium sensitization. Surprisingly, a fall in Ser-695 phosphorylation did not result in an increase in phosphorylation of the Thr-696 site. Although activation of cGKI with exogenous cyclic nucleotides inhibited thromboxane A2-induced MYPT1 membrane association, RhoA activation, contractile force, and regulatory light chain phosphorylation, the anticipated decreases in MYPT1 phosphorylation at Thr-696/Thr-853 were not observed, indicating that the vasorelaxant effects of cGKI are not through dephosphorylation of MYPT1. Thus, thromboxane A2 signaling within the intact cerebral vasculature induces "buffered" vasoconstrictions, in which both the

  15. Self-Assembly of a Modular Polypeptide Based on Blocks of Silk-Mimetic and Elastin-Mimetic Sequences

    DTIC Science & Technology

    2002-04-01

    Silk -Mimetic and Elastin-Mimetic Sequences DISTRIBUTION: Approved for public release, distribution unlimited This paper is part of the following...724 © 2002 Materials Research Society N3.8 Self-Assembly of a Modular Polypeptide based on Blocks of Silk -Mimetic and Elastin- Mimetic Sequences...Chrystelle S. Cazalis, and Vincent P. Conticello* Department of Chemistry, Emory University, Atlanta, GA 30322 ABSTRACT Spider dragline silk fiber displays

  16. Pharmacologic antagonism of thromboxane A2 receptors by trimetoquinol analogs in vitro and in vivo

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shin, Y.; Romstedt, K.J.; Doyle, K.

    1991-01-01

    Although (-)-(S)-trimetoquinol (1-(3,4,5-trimethoxy-benzyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; TMQ) is recognized as a potent bronchodilator, (+)-(R)-TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of (3H)SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (-log IC50) values for U46619-induced aggregation (r = 0.99, P less than 0.01) and serotonin secretion (r = 0.99, Pmore » less than 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P less than 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ greater than or equal to (+)-(R)-TMQ greater than rac-TMQ much greater than (-)-(S)-TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac-iodoTMQ, (+)-(R)-TMQ and rac-TMQ 15 min before the injection of U46619 (800 micrograms/kg, iv) protected mice against U46619-induced sudden death. On the other hand, (-)-(S)-TMQ did not protect animals against death. Protection of U46619-induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3-100 mg/kg.« less

  17. Acute Effects of Prostaglandin E1 and E2 on Vascular Reactivity and Blood Flow in situ in the Chick Chorioallantoic Membrane

    PubMed Central

    Fay, K.; Dunn, B.E.; Gruenloh, S.K.; Narayanan, J.; Jacobs, E.R.; Medhora, M.

    2013-01-01

    1. The chick chorioallantoic membrane (CAM) subserves gas exchange in the developing embryo and shell-less culture affords a unique opportunity for direct observations over time of individual blood vessels to pharmacologic interventions. We tested a number of lipids including prostaglandins PGE1&2 for vascular effects and signaling in the CAM. Application of PGE1&2 induced a decrease in the diameter of large blood vessels and a concentration-dependent, localized, reversible loss of blood flow through small vessels. The loss of flow was also mimicked by misoprostol, an agonist for 3 of 4 known PGE receptors, EP2-4, and by U46619, a thromboxane mimetic. Selective receptor antagonists for EP3 and thromboxane each partially blocked the response. This is a first report of the effects of prostaglandins on vasoreactivity in the CAM. Our model allows the unique ability to examine simultaneous responses of large and small vessels in real time and in vivo. PMID:22858445

  18. Oligosaccharide Mimetics

    NASA Astrophysics Data System (ADS)

    Wessel, Hans Peter; Lucas, Susana Dias

    The important roles of oligosaccharides in physiological and pathophysiological processes have spurred the development of mimetics. Oligosaccharide mimetics discussed in this chapter may possess a linker of two or more atoms such as amide or urea groups that may lead to isosteric linkage replacements but mostly do not. Larger groups that replace a full sugar unit we refer to as spacers and have grouped molecules with flexible acyclic spacers and more rigid cyclic spacers . The employment of pharmacophore models has led to oligosaccharide mimetics with only one sugar unit or finally without any saccharide unit as exemplified in mimotopes.

  19. Insulin Reverses D-Glucose–Increased Nitric Oxide and Reactive Oxygen Species Generation in Human Umbilical Vein Endothelial Cells

    PubMed Central

    González, Marcelo; Rojas, Susana; Avila, Pía; Cabrera, Lissette; Villalobos, Roberto; Palma, Carlos; Aguayo, Claudio; Peña, Eduardo; Gallardo, Victoria; Guzmán-Gutiérrez, Enrique; Sáez, Tamara; Salsoso, Rocío; Sanhueza, Carlos; Pardo, Fabián; Leiva, Andrea; Sobrevia, Luis

    2015-01-01

    Vascular tone is controlled by the L-arginine/nitric oxide (NO) pathway, and NO bioavailability is strongly affected by hyperglycaemia-induced oxidative stress. Insulin leads to high expression and activity of human cationic amino acid transporter 1 (hCAT-1), NO synthesis and vasodilation; thus, a protective role of insulin on high D-glucose–alterations in endothelial function is likely. Vascular reactivity to U46619 (thromboxane A2 mimetic) and calcitonin gene related peptide (CGRP) was measured in KCl preconstricted human umbilical vein rings (wire myography) incubated in normal (5 mmol/L) or high (25 mmol/L) D-glucose. hCAT-1, endothelial NO synthase (eNOS), 42 and 44 kDa mitogen-activated protein kinases (p42/44mapk), protein kinase B/Akt (Akt) expression and activity were determined by western blotting and qRT-PCR, tetrahydrobiopterin (BH4) level was determined by HPLC, and L-arginine transport (0–1000 μmol/L) was measured in response to 5–25 mmol/L D-glucose (0–36 hours) in passage 2 human umbilical vein endothelial cells (HUVECs). Assays were in the absence or presence of insulin and/or apocynin (nicotinamide adenine dinucleotide phosphate-oxidase [NADPH oxidase] inhibitor), tempol or Mn(III)TMPyP (SOD mimetics). High D-glucose increased hCAT-1 expression and activity, which was biphasic (peaks: 6 and 24 hours of incubation). High D-glucose–increased maximal transport velocity was blocked by insulin and correlated with lower hCAT-1 expression and SLC7A1 gene promoter activity. High D-glucose–increased transport parallels higher reactive oxygen species (ROS) and superoxide anion (O2 •–) generation, and increased U46619-contraction and reduced CGRP-dilation of vein rings. Insulin and apocynin attenuate ROS and O2 •– generation, and restored vascular reactivity to U46619 and CGRP. Insulin, but not apocynin or tempol reversed high D-glucose–increased NO synthesis; however, tempol and Mn(III)TMPyP reversed the high D-glucose–reduced BH4

  20. Kinetics of prostaglandin E2 and thromboxane A2 synthesis and suppression of PHA-stimulated peripheral blood mononuclear leucocytes.

    PubMed Central

    Awara, W; Hillier, K; Jones, D

    1986-01-01

    The immunomodulatory effects of thromboxane A2 and prostaglandin E2 on peripheral blood mononuclear leucocytes stimulated with PHA in vitro, and the relationship of this to the time-course of their synthesis in culture, were investigated using prostaglandin E2, a thromboxane A2 synthesis inhibitor (UK37248), a thromboxane A2 mimic (U46619) and a thromboxane A2 receptor blocker (EP045). The inhibitory effect of prostaglandin E2 on PHA-induced human peripheral blood mononuclear leucocyte proliferation diminishes if the addition of PGE2 is delayed. If added 4 hr after a maximum concentration of PHA (5 micrograms/ml), the effect of PGE2 was reduced by 60%. If a submaximal concentration of PHA (1 microgram/ml) was used, the effect of PGE2 was not reduced if added 4 hr later but fell by about 60% after 16 hr. UK37248 moderately inhibited PHA-induced activation while substantially inhibiting thromboxane A2 synthesis and simultaneously enhancing PGE2 synthesis. The enhanced accumulation of PGE2 occurs while sensitivity to PGE2 is dropping. U46619, exogenously applied as a thromboxane A2 mimic, inhibited PHA-induced activation at concentrations that did not significantly alter PGE2 synthesis. EP045, which may modulate the effects of endogenous thromboxane A2 by blocking receptors, did not alter PHA-induced activation. We conclude that thromboxane A2 may have a role in inhibiting PHA-induced activation on the basis of the effect of U46619. However, this study highlights difficulties in utilizing prostaglandin and thromboxane receptor and synthesis inhibitors to examine their endogenous role in the modulation of mitogen-induced activation in vitro. If sensitivity to the purported endogenous substance is limited to the early stages of culture and if only low levels are synthesized at this early stage, then blocking drugs would have little effect. PMID:3468061

  1. NP-184[2-(5-methyl-2-furyl) benzimidazole], a novel orally active antithrombotic agent with dual antiplatelet and anticoagulant activities.

    PubMed

    Kuo, Heng-Lan; Lien, Jin-Cherng; Chung, Ching-Hu; Chang, Chien-Hsin; Lo, Shyh-Chyi; Tsai, I-Chun; Peng, Hui-Chin; Kuo, Sheng-Chu; Huang, Tur-Fu

    2010-06-01

    The established antiplatelet and anticoagulant agents show beneficial effects in the treatment of thromboembolic diseases; however, these drugs still have considerable limitations. The effects of NP-184, a synthetic compound, on platelet functions, plasma coagulant activity, and mesenteric venule thrombosis in mice were investigated. NP-184 concentration-dependently inhibited the human platelet aggregation induced by collagen, arachidonic acid (AA), and U46619, a thromboxane (TX)A(2) mimic, with IC(50) values of 4.5 +/- 0.2, 3.9 +/- 0.1, and 9.3 +/- 0.5 microM, respectively. Moreover, NP-184 concentration-dependently suppressed TXA(2) formations caused by collagen and AA. In exploring effects of NP-184 on enzymes involved in TXA(2) synthesis, we found that NP-184 selectively inhibited TXA(2) synthase activity with an IC(50) value of 4.3 +/- 0.2 microM. Furthermore, NP-184 produced a right shift of the concentration-response curve of U46619, indicating a competitive antagonism on TXA(2)/prostaglandin H(2) receptor. Intriguingly, NP-184 also caused a concentration-dependent prolongation of the activated partial thromboplastin time (aPTT) with no changes in the prothrombin and thrombin time, indicating that it selectively impairs the intrinsic coagulation pathway. Oral administration of NP-184 significantly inhibited thrombus formation of the irradiated mesenteric venules in fluorescein sodium-treated mice without affecting the bleeding time induced by tail transection. However, after oral administration, NP-184 inhibited the ex vivo mouse platelet aggregation triggered by collagen and U46619 and also prolonged aPTT. Taken together, the dual antiplatelet and anticoagulant activities of NP-184 may have therapeutic potential as an oral antithrombotic agent in the treatment of thromboembolic disorders.

  2. Highly stable and self-repairing membrane-mimetic 2D nanomaterials assembled from lipid-like peptoids

    PubMed Central

    Jin, Haibao; Jiao, Fang; Daily, Michael D.; Chen, Yulin; Yan, Feng; Ding, Yan-Huai; Zhang, Xin; Robertson, Ellen J.; Baer, Marcel D.; Chen, Chun-Long

    2016-01-01

    An ability to develop sequence-defined synthetic polymers that both mimic lipid amphiphilicity for self-assembly of highly stable membrane-mimetic 2D nanomaterials and exhibit protein-like functionality would revolutionize the development of biomimetic membranes. Here we report the assembly of lipid-like peptoids into highly stable, crystalline, free-standing and self-repairing membrane-mimetic 2D nanomaterials through a facile crystallization process. Both experimental and molecular dynamics simulation results show that peptoids assemble into membranes through an anisotropic formation process. We further demonstrated the use of peptoid membranes as a robust platform to incorporate and pattern functional objects through large side-chain diversity and/or co-crystallization approaches. Similar to lipid membranes, peptoid membranes exhibit changes in thickness upon exposure to external stimuli; they can coat surfaces in single layers and self-repair. We anticipate that this new class of membrane-mimetic 2D nanomaterials will provide a robust matrix for development of biomimetic membranes tailored to specific applications. PMID:27402325

  3. Mimetic finite difference method

    NASA Astrophysics Data System (ADS)

    Lipnikov, Konstantin; Manzini, Gianmarco; Shashkov, Mikhail

    2014-01-01

    The mimetic finite difference (MFD) method mimics fundamental properties of mathematical and physical systems including conservation laws, symmetry and positivity of solutions, duality and self-adjointness of differential operators, and exact mathematical identities of the vector and tensor calculus. This article is the first comprehensive review of the 50-year long history of the mimetic methodology and describes in a systematic way the major mimetic ideas and their relevance to academic and real-life problems. The supporting applications include diffusion, electromagnetics, fluid flow, and Lagrangian hydrodynamics problems. The article provides enough details to build various discrete operators on unstructured polygonal and polyhedral meshes and summarizes the major convergence results for the mimetic approximations. Most of these theoretical results, which are presented here as lemmas, propositions and theorems, are either original or an extension of existing results to a more general formulation using polyhedral meshes. Finally, flexibility and extensibility of the mimetic methodology are shown by deriving higher-order approximations, enforcing discrete maximum principles for diffusion problems, and ensuring the numerical stability for saddle-point systems.

  4. Converting One-Face α-Helix Mimetics into Amphiphilic α-Helix Mimetics as Potent Inhibitors of Protein-Protein Interactions.

    PubMed

    Lee, Ji Hoon; Oh, Misook; Kim, Hyun Soo; Lee, Huisun; Im, Wonpil; Lim, Hyun-Suk

    2016-01-11

    Many biologically active α-helical peptides adopt amphiphilic helical structures that contain hydrophobic residues on one side and hydrophilic residues on the other side. Therefore, α-helix mimetics capable of mimicking such amphiphilic helical peptides should possess higher binding affinity and specificity to target proteins. Here we describe an efficient method for generating amphiphilic α-helix mimetics. One-face α-helix mimetics having hydrophobic side chains on one side was readily converted into amphiphilic α-helix mimetics by introducing appropriate charged residues on the opposite side. We also demonstrate that such two-face amphiphilic α-helix mimetics indeed show remarkably improved binding affinity to a target protein, compared to one-face hydrophobic α-helix mimetics. We believe that generating a large combinatorial library of these amphiphilic α-helix mimetics can be valuable for rapid discovery of highly potent and specific modulators of protein-protein interactions.

  5. Inhibitory effects of Atractylodis lanceae rhizoma and Poria on collagen- or thromboxane A2-induced aggregation in rabbit platelets.

    PubMed

    Nasu, Yuiko; Iwashita, Masaya; Saito, Masaki; Fushiya, Shinji; Nakahata, Norimichi

    2009-05-01

    Kami-shoyo-san (Jia-Wei-Xiao-Yao-San), Toki-shakuyaku-san (Dang-Gui-Shao-Yao-San) and Toki-shigyaku-ka-goshuyu-shokyo-to (Dang-Gui-Si-Ni-Jia-Wu-Zhu-Yu-Sheng-Jiang-Tang) are Kampo (traditional Chinese) medicines which are traditionally and effectively used for the treatment of chilly sensation (Hiesho) in Japan, but the active components and their detailed mechanisms have not yet been clarified. Etiologies of Hiesho include poor peripheral blood circulation and platelet aggregability contributes to peripheral blood circulation; therefore, we investigated the effect of Kampo medicines on platelet aggregation using rabbit platelets in vitro. Collagen and U46619, a thromboxane A(2) receptor agonist, caused rabbit platelet aggregation, which was potently inhibited by pretreatment of platelets with Kami-shoyo-san and Toki-shakuyaku-san in vitro. Toki-shigyaku-ka-goshuyu-shokyo-to, however, did not significantly inhibit collagen- or U46619-induced platelet aggregation. Therefore, we examined the effect on platelet aggregation of two herbal medicines, Atractylodis Lanceae Rhizoma and Poria, both of which are contained in Kami-shoyo-san and Toki-shakuyaku-san but not in Toki-shigyaku-ka-goshuyu-shokyo-to. As the results indicate, Atractylodis Lanceae Rhizoma inhibited platelet aggregation induced by collagen but not by U46619. Poria effectively inhibited U46619-induced platelet aggregation and it partially inhibited collagen-induced platelet aggregation. On the other hand, Atractylodis Lanceae Rhizoma and Poria did not inhibit adrenaline/adenosine diphosphate- or adrenaline/serotonin-induced platelet aggregation. These results suggest the possibility that the inhibition of platelet aggregation by two Kampo medicines, Kami-shoyo-san and Toki-shakuyaku-san, is one of the mechanisms underlying the improvement of Hiesho. Furthermore, Atractylodis Lanceae Rhizoma and Poria are possible herbal medicines for the inhibition of platelet aggregation.

  6. The Co-Occurrence of Quotatives with Mimetic Performances.

    ERIC Educational Resources Information Center

    Buchstaller, Isabelle

    2003-01-01

    This paper discusses mimesis, the direct representation and total imitation of an event. It studies the co-occurrence of quotative verbs with mimetic enactment based on two corpora of U.S. American English, both available through the University of Pennsylvania Data Consortium. The Switchboard Corpus has 542 speakers ranging in age from 20-60 years…

  7. Cyclic Peptidic Mimetics of Apollo Peptides Targeting Telomeric Repeat Binding Factor 2 (TRF2) and Apollo Interaction.

    PubMed

    Chen, Xia; Liu, Liu; Chen, Yong; Yang, Yuting; Yang, Chao-Yie; Guo, Tianyue; Lei, Ming; Sun, Haiying; Wang, Shaomeng

    2018-05-10

    Telomeric repeat binding factor 2 (TRF2) is a telomere-associated protein that plays an important role in the formation of the 3' single strand DNA overhang and the "T loop", two structures critical for the stability of the telomeres. Apollo is a 5'-exonuclease recruited by TRF2 to the telomere and contributes to the formation of the 3' single strand DNA overhang. Knocking down of Apollo can induce DNA damage response similar to that caused by the knocking down of TRF2. In this Letter, we report the design and synthesis of a class of cyclic peptidic mimetics of the TRFH binding motif of Apollo (Apollo TBM ). We found conformational control of the C terminal residues of Apollo TBM can effectively improve the binding affinity. We have obtained a crystal structure of a cyclic peptidic Apollo peptide mimetic ( 34 ) complexed with TRF2, which provides valuable guidance to the future design of TRF2 inhibitors.

  8. How Sound Symbolism Is Processed in the Brain: A Study on Japanese Mimetic Words

    PubMed Central

    Okuda, Jiro; Okada, Hiroyuki; Matsuda, Tetsuya

    2014-01-01

    Sound symbolism is the systematic and non-arbitrary link between word and meaning. Although a number of behavioral studies demonstrate that both children and adults are universally sensitive to sound symbolism in mimetic words, the neural mechanisms underlying this phenomenon have not yet been extensively investigated. The present study used functional magnetic resonance imaging to investigate how Japanese mimetic words are processed in the brain. In Experiment 1, we compared processing for motion mimetic words with that for non-sound symbolic motion verbs and adverbs. Mimetic words uniquely activated the right posterior superior temporal sulcus (STS). In Experiment 2, we further examined the generalizability of the findings from Experiment 1 by testing another domain: shape mimetics. Our results show that the right posterior STS was active when subjects processed both motion and shape mimetic words, thus suggesting that this area may be the primary structure for processing sound symbolism. Increased activity in the right posterior STS may also reflect how sound symbolic words function as both linguistic and non-linguistic iconic symbols. PMID:24840874

  9. BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models.

    PubMed

    Morii, Takeshi; Ohtsuka, Kouki; Ohnishi, Hiroaki; Mochizuki, Kazuo; Yoshiyama, Akira; Aoyagi, Takayuki; Hornicek, Francis J; Ichimura, Shoichi

    2014-11-01

    Chondrosarcoma is refractory to conventional chemotherapy. BH-3 mimetics ABT-737 and ABT-263 are synthetic small-molecule inhibitors of anti-apoptotic proteins B-cell lymphoma-2 (Bcl2) and Bcl-xL, which play a critical role in survival of chondrosarcoma cells. Chondrosarcoma cell lines SW-1353 and CS-1 were used as the disease model. We used immunoblotting to assess the expression of target molecules Bcl2 and Bcl-xL, and the apoptotic inducers Bcl2-associated X (Bax) and Bcl2-antagonist/killer (Bak). In vitro growth inhibition by BH-3 mimetics was confirmed by photomicroscopic cell counting and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Apoptotic induction was confirmed by Enzyme-Linked ImmunoSorbent Assay (ELISA). In vivo growth inhibition was assessed in a non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model. Expression of the target and effector molecules was confirmed in chondrosarcoma cell lines. BH3 mimetics significantly inhibited cell growth and induced apoptosis in vitro. Administration of ABT-263 inhibited chondrosarcoma growth and improved survival in a mouse model. BH3 mimetics represent a novel treatment modality for chondrosarcoma. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  10. Wood mimetic hydrogel beads for enzyme immobilization.

    PubMed

    Park, Saerom; Kim, Sung Hee; Won, Keehoon; Choi, Joon Weon; Kim, Yong Hwan; Kim, Hyung Joo; Yang, Yung-Hun; Lee, Sang Hyun

    2015-01-22

    Wood component-based composite hydrogels have potential applications in biomedical fields owing to their low cost, biodegradability, and biocompatibility. The controllable properties of wood mimetic composites containing three major wood components are useful for enzyme immobilization. Here, lipase from Candida rugosa was entrapped in wood mimetic beads containing cellulose, xylan, and lignin by dissolving wood components with lipase in [Emim][Ac], followed by reconstitution. Lipase entrapped in cellulose/xylan/lignin beads in a 5:3:2 ratio showed the highest activity; this ratio is very similar to that in natural wood. The lipase entrapped in various wood mimetic beads showed increased thermal and pH stability. The half-life times of lipase entrapped in cellulose/alkali lignin hydrogel were 31- and 82-times higher than those of free lipase during incubation under denaturing conditions of high temperature and low pH, respectively. Owing to their biocompatibility, biodegradability, and controllable properties, wood mimetic hydrogel beads can be used to immobilize various enzymes for applications in the biomedical, bioelectronic, and biocatalytic fields. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. BM-520, an original TXA2 modulator, inhibits the action of thromboxane A2 and 8-iso-prostaglandin F2alphain vitro and in vivo on human and rodent platelets, and aortic vascular smooth muscles from rodents.

    PubMed

    Rolin, S; Hanson, J; Vastersaegher, C; Cherdon, C; Pratico, D; Masereel, B; Dogne, J M

    2007-08-01

    Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2alpha) are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents able to counteract the actions of these agonists are of great interest in the treatment and prevention of cardiovascular events. Here, we investigated in vitro and in vivo the pharmacological profile of BM-520, a new TP antagonist. In our experiments, this compound showed a great binding affinity for human washed platelets TP receptors, and prevented human platelet activation and aggregation induced by U-46619, arachidonic acid and 8-iso-PGF(2alpha). The TP receptor antagonist property of BM-520 was confirmed by its relaxing effect on rat aorta smooth muscle preparations precontracted with U-46619 and 8-iso-PGF(2alpha). Further, its TP antagonism was also demonstrated in vivo in guinea pig after a single intravenous injection (10 mg kg(-1)). We conclude that this novel TP antagonist could be a promising therapeutic tool in pathologies such as atherosclerosis where an increased production of TXA(2) and 8-iso-PGF(2alpha), as well as TP activation are well-established pathogenic events.

  12. A Novel Peptide Thrombopoietin Mimetic Designing and Optimization Using Computational Approach

    PubMed Central

    Singh, Vimal Kishor; Kumar, Neeraj; Kalsan, Manisha; Saini, Abhishek; Chandra, Ramesh

    2016-01-01

    Thrombopoietin receptor (TPOR) is a cytokine receptor protein present on the cell surface. The activation of TPOR by thrombopoietin (TPO) (a glycoprotein hormone) triggers an intracellular cascade of megakaryocytopoiesis for the formation of platelets. Recent studies on ex vivo megakaryocytopoiesis have evolved the possibilities of therapeutics uses. These findings have paved the way for the development of various TPO alternatives (recombinant TPO, peptide, and non-peptide TPO mimetics), which are useful in regenerative medicine. However, these alternatives possess various limitations such as induction of autoimmune effects, high production cost, low specificity, and hence activity. In the present study, a novel peptidic TPO mimetic was designed through computational studies by studying the binding sites of TPO and TMP to TPOR and analogs of known mimetics. Screening of combinatorial library was done through molecular docking using ClusPro. These studies indicated mimetic-9 as a significant molecule since it was found to have better binding score of −938.8 kcal/mol with seven hydrogen bonds and a high number of hydrophobic interactions, than known mimetic TMP with docking score of −798.4 kcal/mol and TMP dimer with docking score of −811.9 kcal/mol for TPOR. Mimetic9-TPOR complex was further assessed by the molecular dynamics simulation, and their complex was found to be stable with an RMSD value of 0.091 Å. While studying the parameters, mimetic-9 was found to have overall good physiochemical properties with positive grand average hydropathy (GRAVY) score and high instability index score and was found to be localized in the extracellular region. The designed mimetic-9 might prove to be a useful lead molecule for mimicking the role of TPO for in vitro platelet production with higher efficiency. PMID:27630985

  13. A Novel Peptide Thrombopoietin Mimetic Designing and Optimization Using Computational Approach.

    PubMed

    Singh, Vimal Kishor; Kumar, Neeraj; Kalsan, Manisha; Saini, Abhishek; Chandra, Ramesh

    2016-01-01

    Thrombopoietin receptor (TPOR) is a cytokine receptor protein present on the cell surface. The activation of TPOR by thrombopoietin (TPO) (a glycoprotein hormone) triggers an intracellular cascade of megakaryocytopoiesis for the formation of platelets. Recent studies on ex vivo megakaryocytopoiesis have evolved the possibilities of therapeutics uses. These findings have paved the way for the development of various TPO alternatives (recombinant TPO, peptide, and non-peptide TPO mimetics), which are useful in regenerative medicine. However, these alternatives possess various limitations such as induction of autoimmune effects, high production cost, low specificity, and hence activity. In the present study, a novel peptidic TPO mimetic was designed through computational studies by studying the binding sites of TPO and TMP to TPOR and analogs of known mimetics. Screening of combinatorial library was done through molecular docking using ClusPro. These studies indicated mimetic-9 as a significant molecule since it was found to have better binding score of -938.8 kcal/mol with seven hydrogen bonds and a high number of hydrophobic interactions, than known mimetic TMP with docking score of -798.4 kcal/mol and TMP dimer with docking score of -811.9 kcal/mol for TPOR. Mimetic9-TPOR complex was further assessed by the molecular dynamics simulation, and their complex was found to be stable with an RMSD value of 0.091 Å. While studying the parameters, mimetic-9 was found to have overall good physiochemical properties with positive grand average hydropathy (GRAVY) score and high instability index score and was found to be localized in the extracellular region. The designed mimetic-9 might prove to be a useful lead molecule for mimicking the role of TPO for in vitro platelet production with higher efficiency.

  14. Black hole solutions in mimetic Born-Infeld gravity

    NASA Astrophysics Data System (ADS)

    Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

    2018-01-01

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite.

  15. Black hole solutions in mimetic Born-Infeld gravity.

    PubMed

    Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

    2018-01-01

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite.

  16. Black hole solutions in mimetic Born-Infeld gravity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. Here, we find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularitymore » is found to be infinite.« less

  17. Black hole solutions in mimetic Born-Infeld gravity

    DOE PAGES

    Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

    2018-01-23

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. Here, we find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularitymore » is found to be infinite.« less

  18. Reciprocal regulation of platelet responses to P2Y and thromboxane receptor activation.

    PubMed

    Barton, J F; Hardy, A R; Poole, A W; Mundell, S J

    2008-03-01

    Thromboxane A(2) and ADP are two major platelet agonists that stimulate two sets of G protein-coupled receptors to activate platelets. Although aggregation responses to ADP and thromboxane desensitize, there are no reports currently addressing whether activation by one agonist may heterologously desensitize responses to the other. To demonstrate whether responses to ADP or U46619 may be modulated by prior treatment of platelets with the alternate agonist, revealing a level of cross-desensitization between receptor systems. Here we show that pretreatment of platelets with either agonist substantially desensitizes aggregation responses to the other agonist. Calcium responses to thromboxane receptor activation are desensitized by preactivation of P2Y(1) but not P2Y(12) receptors. This heterologous desensitization is mediated by a protein kinase C (PKC)-independent mechanism. Reciprocally, calcium responses to ADP are desensitized by pretreatment of platelets with the thromboxane analogue, U46619, and P2Y(12)-mediated inhibition of adenylate cyclase is also desensitized by pretreatment with U46619. In this direction, desensitization is comprised of two components, a true heterologous component that is PKC-independent, and a homologous component that is mediated through stimulated release of dense granule ADP. This study reveals cross-desensitization between ADP and thromboxane receptor signaling in human platelets. Cross-desensitization is mediated by protein kinases, involving PKC-dependent and independent pathways, and indicates that alterations in the activation state of one receptor may have effects upon the sensitivity of the other receptor system.

  19. Instabilities in mimetic matter perturbations

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Firouzjahi, Hassan; Gorji, Mohammad Ali; Mansoori, Seyed Ali Hosseini, E-mail: firouz@ipm.ir, E-mail: gorji@ipm.ir, E-mail: shosseini@shahroodut.ac.ir, E-mail: shossein@ipm.ir

    2017-07-01

    We study cosmological perturbations in mimetic matter scenario with a general higher derivative function. We calculate the quadratic action and show that both the kinetic term and the gradient term have the wrong sings. We perform the analysis in both comoving and Newtonian gauges and confirm that the Hamiltonians and the associated instabilities are consistent with each other in both gauges. The existence of instabilities is independent of the specific form of higher derivative function which generates gradients for mimetic field perturbations. It is verified that the ghost instability in mimetic perturbations is not associated with the higher derivative instabilitiesmore » such as the Ostrogradsky ghost.« less

  20. Instabilities in mimetic matter perturbations

    NASA Astrophysics Data System (ADS)

    Firouzjahi, Hassan; Gorji, Mohammad Ali; Mansoori, Seyed Ali Hosseini

    2017-07-01

    We study cosmological perturbations in mimetic matter scenario with a general higher derivative function. We calculate the quadratic action and show that both the kinetic term and the gradient term have the wrong sings. We perform the analysis in both comoving and Newtonian gauges and confirm that the Hamiltonians and the associated instabilities are consistent with each other in both gauges. The existence of instabilities is independent of the specific form of higher derivative function which generates gradients for mimetic field perturbations. It is verified that the ghost instability in mimetic perturbations is not associated with the higher derivative instabilities such as the Ostrogradsky ghost.

  1. Large-scale structure in mimetic Horndeski gravity

    NASA Astrophysics Data System (ADS)

    Arroja, Frederico; Okumura, Teppei; Bartolo, Nicola; Karmakar, Purnendu; Matarrese, Sabino

    2018-05-01

    In this paper, we propose to use the mimetic Horndeski model as a model for the dark universe. Both cold dark matter (CDM) and dark energy (DE) phenomena are described by a single component, the mimetic field. In linear theory, we show that this component effectively behaves like a perfect fluid with zero sound speed and clusters on all scales. For the simpler mimetic cubic Horndeski model, if the background expansion history is chosen to be identical to a perfect fluid DE (PFDE) then the mimetic model predicts the same power spectrum of the Newtonian potential as the PFDE model with zero sound speed. In particular, if the background is chosen to be the same as that of LCDM, then also in this case the power spectrum of the Newtonian potential in the mimetic model becomes indistinguishable from the power spectrum in LCDM on linear scales. A different conclusion may be found in the case of non-adiabatic perturbations. We also discuss the distinguishability, using power spectrum measurements from LCDM N-body simulations as a proxy for future observations, between these mimetic models and other popular models of DE. For instance, we find that if the background has an equation of state equal to ‑0.95 then we will be able to distinguish the mimetic model from the PFDE model with unity sound speed. On the other hand, it will be hard to do this distinction with respect to the LCDM model.

  2. Bio-mimetic Flow Control

    NASA Astrophysics Data System (ADS)

    Choi, Haecheon

    2009-11-01

    Bio-mimetic engineering or bio-mimetics is the application of biological methods and systems found in nature to the study and design of engineering systems and modern technology (from Wikipedia). The concept itself is old, but successful developments have been made recently, especially in the research field of flow control. The objective of flow control based on the bio-mimetic approach is to develop novel concepts for reducing drag, increasing lift and enhancing aerodynamic performance. For skin friction reduction, a few ideas have been suggested such as the riblet from shark, compliant surface from dolphin, microbubble injection and multiple front-body curvature from penguin, and V-shaped protrusion from sailfish. For form drag reduction, several new attempts have been also made recently. Examples include the V-shaped spanwise grooves from saguaro cactus, overall shape of box fish, longitudinal grooves on scallop shell, bill of swordfish, hooked comb on owl wing, trailing-edge protrusion on dragonfly wing, and fillet. For the enhancement of aerodynamic performance, focuses have been made on the birds, fish and insects: e.g., double layered feather of landing bird, leading-edge serration of humpback-whale flipper, pectoral fin of flying fish, long tail on swallowtail-butterfly wing, wing flapping motion of dragonfly, and alula in birds. Living animals adapt their bodies to better performance in multi purposes, but engineering requires single purpose in most cases. Therefore, bio-mimetic approaches often produce excellent results more than expected. However, they are sometimes based on people's wrong understanding of nature and produce unwanted results. Successes and failures from bio-mimetic approaches in flow control will be discussed in the presentation.

  3. Anisotropic mimetic cosmology

    NASA Astrophysics Data System (ADS)

    Abbassi, M. H.; Jozani, A.; Sepangi, H. R.

    2018-06-01

    We consider a mimetic set up in which the mimetic scalar is coupled to a vector field. It is shown that such a field with a timelike component does not contribute to the background equations and yet produces healthy isocurvature perturbations with respect to ghost and gradient instabilities in spite of the absence of any propagating curvature perturbations at the level of the quadratic action. We then consider a vector field with spacelike components, which leads to an anisotropic Bianchi universe, and show that the ghost and gradient instabilities are absent in the limit of high momenta and that the propagating curvature perturbations have healthy UV behavior.

  4. Farnesyltransferase inhibitors: CAAX mimetics based on different biaryl scaffolds.

    PubMed

    Straniero, Valentina; Pallavicini, Marco; Chiodini, Giuseppe; Ruggeri, Paola; Fumagalli, Laura; Bolchi, Cristiano; Corsini, Alberto; Ferri, Nicola; Ricci, Chiara; Valoti, Ermanno

    2014-07-01

    Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed as farnesyltransferase (FTase) inhibitors (FTIs) by replacing AA with o-aryl or o-heteroaryl substituted p-hydroxy- or p-aminobenzoic acid, while maintaining the replacement of C with 1,4-benzodioxan-2-ylmethyl or 2-amino-4-thiazolylacetyl residue as in previous CAAX mimetics. Both FTase inhibition and antiproliferative effect were showed by two thiazole derivatives, namely those with 1-naphthyl (10 and 10a) or 3-furanyl (15 and 15a) in the central spacer, and by the benzodioxane derivative with 2-thienyl (6 and 6a) in the same position. Accumulation of unprenylated RAS was demonstrated in cells incubated with 15a. Consistently with FTIs literature, such results delineate the biaryl scaffold not only as a spacer but also as a sensible area of these mimetic molecules, where modifications at the branching aromatic ring are not indifferent and should be matter of further investigation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Petri, Marcelo H.; Tellier, Céline; Michiels, Carine

    2013-11-15

    Highlights: •EV-077 reduced TNF-α induced inflammation in endothelial cells. •The thromboxane mimetic U69915 enhanced vascular smooth muscle cell proliferation. •EV-077 inhibited smooth muscle cell proliferation. -- Abstract: The prothrombotic mediator thromboxane A{sub 2} is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels ofmore » different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy.« less

  6. B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins.

    PubMed

    Renault, Thibaud T; Elkholi, Rana; Bharti, Archana; Chipuk, Jerry E

    2014-09-19

    The B cell lymphoma-2 (BCL-2) family is the key mediator of cellular sensitivity to apoptosis during pharmacological interventions for numerous human pathologies, including cancer. There is tremendous interest to understand how the proapoptotic BCL-2 effector members (e.g. BCL-2-associated X protein, BAX) cooperate with the BCL-2 homology domain only (BH3-only) subclass (e.g. BCL-2 interacting mediator of death, BIM; BCL-2 interacting-domain death agonist, BID) to induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis and whether these mechanisms may be pharmacologically exploited to enhance the killing of cancer cells. Indeed, small molecule inhibitors of the anti-apoptotic BCL-2 family members have been designed rationally. However, the success of these "BH3 mimetics" in the clinic has been limited, likely due to an incomplete understanding of how these drugs function in the presence of multiple BCL-2 family members. To increase our mechanistic understanding of how BH3 mimetics cooperate with multiple BCL-2 family members in vitro, we directly compared the activity of several BH3-mimetic compounds (i.e. ABT-263, ABT-737, GX15-070, HA14.1, TW-37) in biochemically defined large unilamellar vesicle model systems that faithfully recapitulate BAX-dependent mitochondrial outer membrane permeabilization. Our investigations revealed that the presence of BAX, BID, and BIM differentially regulated the ability of BH3 mimetics to derepress proapoptotic molecules from anti-apoptotic proteins. Using mitochondria loaded with fluorescent BH3 peptides and cells treated with inducers of cell death, these differences were supported. Together, these data suggest that although the presence of anti-apoptotic BCL-2 proteins primarily dictates cellular sensitivity to BH3 mimetics, additional specificity is conferred by proapoptotic BCL-2 proteins. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Antibody mimetics: promising complementary agents to animal-sourced antibodies.

    PubMed

    Baloch, Abdul Rasheed; Baloch, Abdul Wahid; Sutton, Brian J; Zhang, Xiaoying

    2016-01-01

    Despite their wide use as therapeutic, diagnostic and detection agents, the limitations of polyclonal and monoclonal antibodies have inspired scientists to design the next generation biomedical agents, so-called antibody mimetics that offer many advantages over conventional antibodies. Antibody mimetics can be constructed by protein-directed evolution or fusion of complementarity-determining regions through intervening framework regions. Substantial progress in exploiting human, butterfly (Pieris brassicae) and bacterial systems to design and select mimetics using display technologies has been made in the past 10 years, and one of these mimetics [Kalbitor® (Dyax)] has made its way to market. Many challenges lie ahead to develop mimetics for various biomedical applications, especially those for which conventional antibodies are ineffective, and this review describes the current characteristics, construction and applications of antibody mimetics compared to animal-sourced antibodies. The possible limitations of mimetics and future perspectives are also discussed.

  8. Equol is more active than soy isoflavone itself to compete for binding to thromboxane A(2) receptor in human platelets.

    PubMed

    Muñoz, Yenny; Garrido, Argelia; Valladares, Luis

    2009-03-01

    Several dietary intervention studies examining the health effect of soy isoflavones allude to the importance of equol in establishing the cardiovascular response to soy protein. Although, the specific mechanism by which this action occurs has not been established. The aim of this study was to investigate the inhibitory effect of soy-isoflavones and the metabolite of daidzein, equol, on agonist-induced platelet responses dependent on thromboxane A(2) (TxA(2)) receptor. Competitive radioligand binding assay was used to screen for affinity of these compounds to the TxA(2) receptor. The effect of equol on platelet activation, evaluate through of release of the ATP, by analogs of TxA(2) was analyzed. The effect of equol on platelet aggregation was investigated with ADP, U46619 (a TxA(2) mimic) and the calcium ionophore A23187. The data showed that aglycone isoflavones and equol bind to TxA(2) receptor in the micromol/L range, whereas their glucoside derivates had very low binding activity for this receptor. Under equilibrium conditions, the following order of the relative affinity in inhibiting [(3)H]-SQ29585 binding was: equol>genistein>daidzein>glycitein>genistin, daidzin, glycitin. Equol interaction was reversible and competitive for labeled-SQ29548 with not apparent decrease in the number of TxA(2) binding sites. In addition, from platelet activation studies, equol effectively inhibited ATP secretion elicited by the TxA(2) analog U46619. On the other hand, equol inhibited the platelet aggregation induced by U46619 and A23187, while it failed to inhibit that induced by ADP. The aglycone isoflavones from soy, and particularly equol, have been found to have biological effects attributable to thromboxane A(2) receptor antagonism. These findings may help elucidate how dietary isoflavone modulate platelet function and explain why soy-rich foods are claimed to have beneficial effects in the prevention of thrombotic events.

  9. Mixed mimetic spectral element method for Stokes flow: A pointwise divergence-free solution

    NASA Astrophysics Data System (ADS)

    Kreeft, Jasper; Gerritsma, Marc

    2013-05-01

    In this paper we apply the recently developed mimetic discretization method to the mixed formulation of the Stokes problem in terms of vorticity, velocity and pressure. The mimetic discretization presented in this paper and in Kreeft et al. [51] is a higher-order method for curvilinear quadrilaterals and hexahedrals. Fundamental is the underlying structure of oriented geometric objects, the relation between these objects through the boundary operator and how this defines the exterior derivative, representing the grad, curl and div, through the generalized Stokes theorem. The mimetic method presented here uses the language of differential k-forms with k-cochains as their discrete counterpart, and the relations between them in terms of the mimetic operators: reduction, reconstruction and projection. The reconstruction consists of the recently developed mimetic spectral interpolation functions. The most important result of the mimetic framework is the commutation between differentiation at the continuous level with that on the finite dimensional and discrete level. As a result operators like gradient, curl and divergence are discretized exactly. For Stokes flow, this implies a pointwise divergence-free solution. This is confirmed using a set of test cases on both Cartesian and curvilinear meshes. It will be shown that the method converges optimally for all admissible boundary conditions.

  10. Characterization of airway and vascular responses in murine lungs

    PubMed Central

    Held, Heinz-Dieter; Martin, Christian; Uhlig, Stefan

    1999-01-01

    We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision-cut lung slices. Airways: The EC50 (μM) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5>serotonin, 0.7/2.0>U46619 (TP-receptor agonist), 0.1/0.06>endothelin-1, 0.1/0.05. In the IPL, maximum increase in airway resistance (RL) was 0.6, 0.4, 0.8 and 11 cmH2O s ml−1, respectively. Adenosine (⩽1 mM), bombesin (⩽100 μM), histamine (⩽10 mM), LTC4 (⩽1 μM), PAF (0.25 μM) and substance P (⩽100 μM) had only weak effects (<5% of Mch) on RL. Vessels: The EC50 (μM) for vasoconstriction in the IPL was LTC4, 0.06>U46619, 0.052O, respectively. At 250 nM, the activity of PAF was comparable to that of LTC4. At 100 μM only, substance P caused a largely variable increase in PAP. Serotonin, adenosine, bombesin, histamine and Mch had no or only very small effects on PAP. Hyperresponsiveness: In both the IPL and slices, U46619 in subthreshold concentrations (10 nM) reduced the EC50 to 0.6 μM. In the IPL, U46619 raised the maximum airway response to Mch 5 fold and the maximum PAF-induced vasoconstriction 4 fold. Conclusion: Murine precision-cut lung slices maintain important characteristics of the whole organ. The maximum reagibility of murine airways to endogenous mediators is serotoninU46619U46619U46619 raises the possibility that thromboxane contributes directly to airway hyperresponsiveness in various experimental and clinical settings. PMID:10205008

  11. Glycosaminoglycan-Mimetic Signals Direct the Osteo/Chondrogenic Differentiation of Mesenchymal Stem Cells in a Three-Dimensional Peptide Nanofiber Extracellular Matrix Mimetic Environment.

    PubMed

    Arslan, Elif; Guler, Mustafa O; Tekinay, Ayse B

    2016-04-11

    Recent efforts in bioactive scaffold development focus strongly on the elucidation of complex cellular responses through the use of synthetic systems. Designing synthetic extracellular matrix (ECM) materials must be based on understanding of cellular behaviors upon interaction with natural and artificial scaffolds. Hence, due to their ability to mimic both the biochemical and mechanical properties of the native tissue environment, supramolecular assemblies of bioactive peptide nanostructures are especially promising for development of bioactive ECM-mimetic scaffolds. In this study, we used glycosaminoglycan (GAG) mimetic peptide nanofiber gel as a three-dimensional (3D) platform to investigate how cell lineage commitment is altered by external factors. We observed that amount of fetal bovine serum (FBS) presented in the cell media had synergistic effects on the ability of GAG-mimetic nanofiber gel to mediate the differentiation of mesenchymal stem cells into osteogenic and chondrogenic lineages. In particular, lower FBS concentration in the culture medium was observed to enhance osteogenic differentiation while higher amount FBS promotes chondrogenic differentiation in tandem with the effects of the GAG-mimetic 3D peptide nanofiber network, even in the absence of externally administered growth factors. We therefore demonstrate that mesenchymal stem cell differentiation can be specifically controlled by the combined influence of growth medium components and a 3D peptide nanofiber environment.

  12. Structural basis for highly effective HIV-1 neutralization by CD4-mimetic miniproteins revealed by 1.5 Å co-crystal structure of gp120 and M48U1

    PubMed Central

    Acharya, Priyamvada; Luongo, Timothy; Louder, Mark K.; McKee, Krisha; Yang, Yongping; Kwon, Young Do; Mascola, John R.; Kessler, Pascal; Martin, Loïc; Kwong, Peter D.

    2014-01-01

    The interface between HIV-1 gp120 envelope glycoprotein and CD4 receptor contains an unusual interfacial cavity, the “Phe43 cavity”, which miniprotein mimetics of CD4 with non-natural extensions can potentially utilize to enhance their neutralization of HIV-1. Here we report co-crystal structures of HIV-1 gp120 with miniproteins M48U1 and M48U7, which insert cyclohexylmethoxy and 5-hydroxypentylmethoxy extensions, respectively, into the Phe43 cavity. Both inserts displayed flexibility and hydrophobic interactions, but the M48U1 insert showed better shape complementarity with the Phe43 cavity than the M48U7 insert. Subtle alteration in gp120 conformation played a substantial role in optimizing fit. With M48U1, these translated into a YU2-gp120 affinity of 0.015 nM and neutralization of all 180-circulating HIV-1 strains tested, except clade-A/E isolates with non-canonical Phe43 cavities. Ligand chemistry, shape complementary, surface burial, and gp120 conformation act in concert to modulate binding of ligands to the gp120-Phe43 cavity and, when optimized, can effect near pan-neutralization of HIV-1. PMID:23707685

  13. Cosmological perturbations in mimetic Horndeski gravity

    NASA Astrophysics Data System (ADS)

    Arroja, Frederico; Bartolo, Nicola; Karmakar, Purnendu; Matarrese, Sabino

    2016-04-01

    We study linear scalar perturbations around a flat FLRW background in mimetic Horndeski gravity. In the absence of matter, we show that the Newtonian potential satisfies a second-order differential equation with no spatial derivatives. This implies that the sound speed for scalar perturbations is exactly zero on this background. We also show that in mimetic G3 theories the sound speed is equally zero. We obtain the equation of motion for the comoving curvature perturbation (first order differential equation) and solve it to find that the comoving curvature perturbation is constant on all scales in mimetic Horndeski gravity. We find solutions for the Newtonian potential evolution equation in two simple models. Finally we show that the sound speed is zero on all backgrounds and therefore the system does not have any wave-like scalar degrees of freedom.

  14. Late time cosmological dynamics with a nonminimal extension of the mimetic matter scenario

    NASA Astrophysics Data System (ADS)

    Hosseinkhan, N.; Nozari, K.

    2018-02-01

    We investigate an extension of mimetic gravity in which mimetic matter is nonminimally coupled to the Ricci scalar. We derive the background field equations and show that, as the minimal case, the nonminimal mimetic matter can behave as dark matter or dark energy. By adopting some well-known potentials, we study the dynamics of the scale factor and the equation of state parameter in detail. As the effective mimetic dark energy, this model explains the late time cosmic acceleration and its equation of state parameter crosses the phantom divide. We extend our analysis to the dynamical system approach and the phase space trajectories of the model. We obtain an attractor line which corresponds to the late time cosmic acceleration. By comparing this nonminimal mimetic matter scenario with observational data for the LCDM, we show that the confidence levels of this model overlap with those of Planck 2015 TT, TE, EE + Low P + Lensing + BAO data in the LCDM model.

  15. Alpha 2-adrenoceptors and endothelium-dependent relaxation in canine large arteries.

    PubMed Central

    Angus, J. A.; Cocks, T. M.; Satoh, K.

    1986-01-01

    Ring preparations from the carotid, coronary, renal, mesenteric and femoral arteries of the dog were precontracted with the thromboxane mimetic U46619, after ensuring that the resting conditions were comparable from the Laplace relationship. In the presence of prazosin (1 microM) and propranolol (3 microM), noradrenaline (NA) relaxed the arteries in the order coronary greater than carotid greater than femoral greater than renal = mesenteric. When maximum relaxation to nitroglycerin (10 microM) was taken to be 100% the maximum relaxation to noradrenaline in each artery was: coronary 70%; carotid 34%; femoral 19%; renal 7% and mesenteric 2%. In endothelium-intact arteries UK14304 mimicked the relaxation responses to NA and idazoxan shifted the curves to both agonists to the right, consistent with an alpha 2-adrenoceptor classification. Substance P relaxed the arteries in the same order as for NA but showed higher efficacy i.e.: coronary 100%; carotid 80%; femoral 71% renal 49%; and mesenteric 41%. Removal of the endothelium abolished the relaxation to NA. We conclude that endothelium-dependent relaxation to NA and substance P varies greatly across 5 large arteries of the dog. This may indicate that endothelium-derived relaxing factor (EDRF) release is site-dependent or that the efficacy of EDRF on smooth muscle varies; being greatest in the coronary and weakest in the renal and mesenteric arteries. PMID:2427147

  16. Research progress of nanoparticles as enzyme mimetics

    NASA Astrophysics Data System (ADS)

    Hu, XiaoNa; Liu, JianBo; Hou, Shuai; Wen, Tao; Liu, WenQi; Zhang, Ke; He, WeiWei; Ji, YingLu; Ren, HongXuan; Wang, Qi; Wu, XiaoChun

    2011-10-01

    Natural enzymes as biological catalysts possess remarkable advantages, especially their highly efficient and selective catalysis under mild conditions. However, most natural enzymes are proteins, thus exhibiting an inherent low durability to harsh reaction conditions. Artificial enzyme mimetics have been pursued extensively to avoid this drawback. Quite recently, some inorganic nanoparticles (NPs) have been found to exhibit unique enzyme mimetics. In addition, their much higher stability overcomes the inherent disadvantage of natural enzymes. Furthermore, easy mass-production and low cost endow them more benefits. As a new member of artificial enzyme mimetics, they have received intense attention. In this review article, major progress in this field is summarized and future perspectives are highlighted.

  17. Age-related changes in mitochondrial antioxidant enzyme Trx2 and TXNIP-Trx2-ASK1 signal pathways in the auditory cortex of a mimetic aging rat model: changes to Trx2 in the auditory cortex.

    PubMed

    Sun, Hai-Ying; Hu, Yu-Juan; Zhao, Xue-Yan; Zhong, Yi; Zeng, Ling-Ling; Chen, Xu-Bo; Yuan, Jie; Wu, Jing; Sun, Yu; Kong, Wen; Kong, Wei-Jia

    2015-07-01

    Age-associated degeneration in the central auditory system, which is defined as central presbycusis, can impair sound localization and speech perception. Research has shown that oxidative stress plays a central role in the pathological process of central presbycusis. Thioredoxin 2 (Trx2), one member of thioredoxin family, plays a key role in regulating the homeostasis of cellular reactive oxygen species and anti-apoptosis. The purpose of this study was to explore the association between Trx2 and the phenotype of central presbycusis using a mimetic aging animal model induced by long-term exposure to d-galactose (d-Gal). We also explored changes in thioredoxin-interacting protein (TXNIP), apoptosis signal regulating kinase 1 (ASK1) and phosphorylated ASK1 (p-ASK1) expression, as well as the Trx2-TXNIP/Trx2-ASK1 binding complex in the auditory cortex of mimetic aging rats. Our results demonstrate that, compared with control groups, the levels of Trx2 and Trx2-ASK1 binding complex were significantly reduced, whereas TXNIP, ASK1 p-ASK1 expression, and Trx2-TXNIP binding complex were significantly increased in the auditory cortex of the mimetic aging groups. Our results indicated that changes in Trx2 and the TXNIP-Trx2-ASK1 signal pathway may participate in the pathogenesis of central presbycusis. © 2015 FEBS.

  18. A novel thromboxane A2 receptor D304N variant that abrogates ligand binding in a patient with a bleeding diathesis.

    PubMed

    Mumford, Andrew D; Dawood, Ban B; Daly, Martina E; Murden, Sherina L; Williams, Michael D; Protty, Majd B; Spalton, Jennifer C; Wheatley, Mark; Mundell, Stuart J; Watson, Steve P

    2010-01-14

    We investigated the cause of mild mucocutaneous bleeding in a 14-year-old male patient (P1). Platelet aggregation and ATP secretion induced by arachidonic acid and the thromboxane A(2) receptor (TxA(2)R) agonist U46619 were reduced in P1 compared with controls, whereas the responses to other platelet agonists were retained. P1 was heterozygous for a transversion within the TBXA2R gene predictive of a D304N substitution in the TxA(2)R. In Chinese hamster ovary-K1 cells expressing the variant D304N TxA(2)R, U46619 did not increase cytosolic free Ca(2+) concentration, indicating loss of receptor function. The TxA(2)R antagonist [(3)H]-SQ29548 showed an approximate 50% decrease in binding to platelets from P1 but absent binding to Chinese hamster ovary-K1 cells expressing variant D304N TxA(2)R. This is the second naturally occurring TxA(2)R variant to be associated with platelet dysfunction and the first in which loss of receptor function is associated with reduced ligand binding. D304 lies within a conserved NPXXY motif in transmembrane domain 7 of the TxA(2)R that is a key structural element in family A G protein-coupled receptors. Our demonstration that the D304N substitution causes clinically significant platelet dysfunction by reducing ligand binding establishes the importance of the NPXXY motif for TxA(2)R function in vivo.

  19. Recovering a MOND-like acceleration law in mimetic gravity

    NASA Astrophysics Data System (ADS)

    Vagnozzi, Sunny

    2017-09-01

    We reconsider the recently proposed mimetic gravity, focusing in particular on whether the theory is able to reproduce the inferred flat rotation curves of galaxies. We extend the theory by adding a non-minimal coupling between matter and mimetic field. Such coupling leads to the appearance of an extra force which renders the motion of test particles non-geodesic. By studying the weak field limit of the resulting equations of motion, we demonstrate that in the Newtonian limit the acceleration law induced by the non-minimal coupling reduces to a modified Newtonian dynamics (MOND)-like one. In this way, it is possible to reproduce the successes of MOND, namely the explanation for the flat galactic rotation curves and the Tully-Fisher relation, within the framework of mimetic gravity, without the need for particle dark matter. The scale-dependence of the recovered acceleration scale opens up the possibility of addressing the missing mass problem not only on galactic but also on cluster scales: we defer a full study of this issue, together with a complete analysis of fits to spiral galaxy rotation curves, to an upcoming companion paper.

  20. A review of underwater bio-mimetic propulsion: cruise and fast-start

    NASA Astrophysics Data System (ADS)

    Chao, Li-Ming; Cao, Yong-Hui; Pan, Guang

    2017-08-01

    This paper reviews recent developments in the understanding of underwater bio-mimetic propulsion. Two impressive models of underwater propulsion are considered: cruise and fast-start. First, we introduce the progression of bio-mimetic propulsion, especially underwater propulsion, where some primary conceptions are touched upon. Second, the understanding of flapping foils, considered as one of the most efficient cruise styles of aquatic animals, is introduced, where the effect of kinematics and the shape and flexibility of foils on generating thrust are elucidated respectively. Fast-start propulsion is always exhibited when predator behaviour occurs, and we provide an explicit introduction of corresponding zoological experiments and numerical simulations. We also provide some predictions about underwater bio-mimetic propulsion.

  1. Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension

    PubMed Central

    Roghair, Robert D.; Segar, Jeffrey L.; Sharma, Ram V.; Zimmerman, Matthew C.; Jagadeesha, D. K.; Segar, Emily M.; Scholz, Thomas D.; Lamb, Fred S.

    2009-01-01

    Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces organ-specific alterations in postnatal cardiovascular physiology. To determine whether early gestation corticosteroid exposure alters coronary reactivity before the development of systemic hypertension, dexamethasone (0.28 mg·kg−1 · day−1) was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term, 145 days). Vascular responsiveness was assessed in endothelium-intact coronary arteries isolated from 1-wk-old steroid-exposed and age-matched control lambs (N = 6). Calcium imaging was performed in fura 2-loaded primary cultures of vascular smooth muscle cells (VSMC) from the harvested coronary arteries. Early gestation steroid exposure did not significantly alter mean arterial blood pressure or coronary reactivity to KCl, thromboxane A2 mimetic U-46619, or ANG II. Steroid exposure significantly increased coronary artery vasoconstriction to acetylcholine and endothelin-1. Vasodilatation to adenosine, but not nitroprusside or forskolin, was significantly attenuated following early gestation steroid exposure. Endothelin-1 or U-46619 stimulation resulted in a comparable increase in intracellular calcium concentration ([Ca2+]i) in coronary VSMC isolated from either dexamethasone-treated or control animals. However, the ANG II- or KCl-mediated increase in [Ca2+]i in control VSMC was significantly attenuated in VSMC harvested from dexamethasone-treated lambs. Coronary expression of muscle voltage-gated l-type calcium channel α-1 subunit protein was not significantly altered by steroid exposure, whereas endothelial nitric oxide synthase expression was attenuated. These findings demonstrate that early gestation glucocorticoid exposure elicits primary alterations in coronary responsiveness before the development of systemic hypertension. Glucocorticoid-induced alterations in coronary physiology may provide a mechanistic link between an adverse

  2. Progress of Mimetic Enzymes and Their Applications in Chemical Sensors.

    PubMed

    Yang, Bin; Li, Jianping; Deng, Huan; Zhang, Lianming

    2016-11-01

    The need to develop innovative and reformative approaches to synthesize chemical sensors has increased in recent years because of demands for selectivity, stability, and reproducibility. Mimetic enzymes provide an efficient and convenient method for chemical sensors. This review summarizes the application of mimetic enzymes in chemical sensors. Mimetic enzymes can be classified into five categories: hydrolases, oxidoreductases, transferases, isomerases, and induced enzymes. Potential and recent applications of mimetic enzymes in chemical sensors are reviewed in detail, and the outlook of profound development has been illustrated.

  3. Caloric Restriction, CR Mimetics, and Healthy Aging in Okinawa: Controversies and Clinical Implications

    PubMed Central

    Willcox, Bradley J.; Willcox, Donald Craig

    2014-01-01

    Purpose of Review To examine the role of two nutritional factors implicated in the healthy aging of the Okinawans: caloric restriction (CR); and traditional foods with potential CR-mimetic properties. Recent Findings CR is a research priority for the U.S. National Institute on Aging. However, little is known regarding health effects in humans. Some CR-related outcomes, such as cause-specific mortality and lifespan, are not practical for human clinical trials. Therefore, epidemiological data on older Okinawans, who experienced a CR-like diet for close to half their lives, are of special interest. The nutritional data support mild CR (10–15%) and high consumption of foods that may mimic the biological effects of CR, including sweet potatoes, marine-based carotenoid-rich foods, and turmeric. Phenotypic evidence is consistent with CR (including short stature, low body weight, lean BMI), less age-related chronic disease (including cardiovascular diseases, cancer, and dementia) and longer lifespan (mean and maximum). Summary Both CR and traditional Okinawan functional foods with CR-mimetic properties likely had roles in the extended healthspan and lifespan of the Okinawans. More research is needed on health consequences of CR and foods with CR-mimetic properties to identify possible nutritional interventions for healthy aging. PMID:24316687

  4. Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin.

    PubMed

    Uhlig, S; Nüsing, R; von Bethmann, A; Featherstone, R L; Klein, T; Brasch, F; Müller, K M; Ullrich, V; Wendel, A

    1996-05-01

    Lipopolysaccharides (LPS), widely used to study the mechanisms of gram-negative sepsis, increase airway resistance by constriction of terminal bronchioles. The role of the cyclooxygenase (COX) isoenzymes and their prostanoid metabolites in this process was studied. Pulmonary resistance, the release of thromboxane (TX) and the expression of COX-2 mRNA were measured in isolated blood-free perfused rat lungs exposed to LPS. LPS induced the release of TX and caused increased airway resistance after about 30 min. Both TX formation and LPS-induced bronchoconstriction were prevented by treatment with the unspecific COX inhibitor acetyl salicylic acid, the specific COX-2 inhibitor CGP-28238, dexamethasone, actinomycin D, or cycloheximide. LPS-induced bronchoconstriction was also inhibited by the TX receptor antagonist BM-13177. The TX-mimetic compound, U-46619, increased airway resistance predominantly by constricting terminal bronchioles. COX-2-specific mRNA in lung tissue was elevated after LPS exposure, and this increase was attenuated by addition of dexamethasone or of actinomycin D. In contrast to LPS, platelet-activating factor (PAF) induced immediate TX release and bronchoconstriction that was prevented by acetyl salicylic acid, but not by CGP-28238. LPS elicits the following biochemical and functional changes in rat lungs: (i) induction of COX-2; (ii) formation of prostaglandins and TX; (iii) activation of the TX receptor on airway smooth muscle cells; (iv) constriction of terminal bronchioles; and (v) increased airway resistance. In contrast to LPS, the PAF-induced TX release is likely to depend on COX-1.

  5. ω-Conotoxin GVIA Mimetics that Bind and Inhibit Neuronal Cav2.2 Ion Channels

    PubMed Central

    Tranberg, Charlotte Elisabet; Yang, Aijun; Vette, Irina; McArthur, Jeffrey R.; Baell, Jonathan B.; Lewis, Richard J.; Tuck, Kellie L.; Duggan, Peter J.

    2012-01-01

    The neuronal voltage-gated N-type calcium channel (Cav2.2) is a validated target for the treatment of neuropathic pain. A small library of anthranilamide-derived ω-Conotoxin GVIA mimetics bearing the diphenylmethylpiperazine moiety were prepared and tested using three experimental measures of calcium channel blockade. These consisted of a 125I-ω-conotoxin GVIA displacement assay, a fluorescence-based calcium response assay with SH-SY5Y neuroblastoma cells, and a whole-cell patch clamp electrophysiology assay with HEK293 cells stably expressing human Cav2.2 channels. A subset of compounds were active in all three assays. This is the first time that compounds designed to be mimics of ω-conotoxin GVIA and found to be active in the 125I-ω-conotoxin GVIA displacement assay have also been shown to block functional ion channels in a dose-dependent manner. PMID:23170089

  6. Meal-induced platelet activation in diabetes mellitus type 1 or type 2 is related to postprandial insulin rather than glucose levels.

    PubMed

    Spectre, Galia; Stålesen, Ragnhild; Östenson, Claes-Göran; Hjemdahl, Paul

    2016-05-01

    Postprandial platelet activation was related to postprandial insulin rather than glucose levels in a previous meal insulin study in type 2 diabetes mellitus (T2DM). We therefore compared postprandial platelet activation in type 1 (T1DM) patients without insulin secretion and T2DM patients with high postprandial insulin levels. Patients with T1DM (n=11) and T2DM (n=12) were studied before and 90min after a standardized meal without premeal insulin. Five T1DM patients volunteered for a restudy with their regular premeal insulin. Platelet activation was assessed by flow cytometry, with and without the thromboxane analogue U46619 or ADP, and by whole blood aggregometry (Multiplate®). Effects of insulin (100μU/mL) in vitro were also studied. Before the meal, glucose, insulin and platelet activation markers other than platelet-leukocyte aggregates (PLAs) were similar in T1DM and T2DM; PLAs were higher in T1DM. Postprandial glucose levels increased more markedly in T1DM (to 22.1±1.4 vs. 11.2±0.6mmol/L) while insulin levels increased only in T2DM (from 24.4±4.4 to 68.8±12.3μU/mL). Platelet P-selectin expression, fibrinogen binding and PLA formation stimulated by U46619 were markedly enhanced (approximately doubled) and whole blood aggregation stimulated by U46619 was increased (p<0.05 for all) after the meal in T2DM patients but not in T1DM patients. The pilot study with premeal insulin in T1DM patients showed postprandial platelet activation when postprandial insulin levels increased. In vitro insulin mildly activated platelets in both groups. Postprandial platelet activation via the thromboxane pathway is related to postprandial hyperinsulinemia and not to postprandial hyperglycaemia in patients with diabetes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Structurally homogeneous nanosheets from self-assembly of a collagen-mimetic peptide.

    PubMed

    Jiang, Tao; Xu, Chunfu; Zuo, Xiaobing; Conticello, Vincent P

    2014-08-04

    A collagen-mimetic peptide, NSIII, has been designed with three sequential blocks having positive, neutral, and negative charges, respectively. The non-canonical imino acid, (2S,4S)-4-aminoproline (amp), was used to specify the positive charges at the Xaa positions of (Xaa-Yaa-Gly) triads in the N-terminal domain of NSIII. Peptide NSIII underwent self-assembly from aqueous solution to form a highly homogeneous population of nanosheets. Two-dimensional crystalline sheets formed in which the length of the peptide defined the height of the sheets. These results contrasted with prior results on a similar multi-domain collagen-mimetic polypeptides in which the sheets had highly polydisperse distribution of sizes in the (x/y)- and (z)-dimensions. The structural differences between the two nanosheet assemblies were interpreted in terms of the relative stereoelectronic effects of the different aminoproline derivatives on the local triple helical conformation of the peptides. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Syntheses of vanadyl and zinc(II) complexes of 1-hydroxy-4,5,6-substituted 2(1H)-pyrimidinones and their insulin-mimetic activities.

    PubMed

    Yamaguchi, Mika; Wakasugi, Kei; Saito, Ryota; Adachi, Yusuke; Yoshikawa, Yutaka; Sakurai, Hiromu; Katoh, Akira

    2006-02-01

    Control of the glucose level in the blood plasma has been achieved in vitro and in vivo by administration of vanadium and zinc in form of inorganic salts. It has been shown that elements are poorly absorbed in their inorganic forms and required high doses which have been associated with undesirable side effects. Many researchers, therefore, have focused on metal complexes that were prepared from VOSO(4) or ZnSO(4) and low-molecular-weight bidentate ligands. Seven kinds of 1-hydroxy-4,6-disubstituted and 1-hydroxy-4,5,6-trisubstituted-2(1H)-pyrimidinones were synthesized by reaction of N-benzyloxyurea and beta-diketones and subsequent removal of the protecting group. Six kinds of 1-hydroxy-4-(substituted)amino-2(1H)-pyrimidinones were synthesized by the substitution reaction of 1-benzyloxy-4-(1',2',4'-triazol-1'-yl)-2(1H)-pyrimidinone with various alkyl amines or amino acids. Treatment with VOSO(4) and ZnSO(4) or Zn(OAc)(2) afforded vanadyl(IV) and zinc(II) complexes which were characterized by means of (1)H NMR, IR, EPR, and UV-vis spectroscopies, and combustion analysis. The in vitro insulin-mimetic activity of these complexes was evaluated from 50% inhibitory concentrations (IC(50)) on free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. Vanadyl complexes of 4,6-disubstituted-2(1H)-pyrimidinones showed higher insulin-mimetic activities than those of 4,5,6-trisubstituted ones. On the other hand, Zn(II) complexes showed lower insulin-mimetic activities than VOSO(4) and ZnSO(4) as positive controls. It was found that the balance of the hydrophilicity and/or hydrophobicity is important for higher insulin-mimetic activity. The in vivo insulin-mimetic activity was evaluated with streptozotocin (STZ)-induced diabetic rats. Blood glucose levels were lowered from hyperglycemic to normal levels after the treatment with bis(1,2-dihydro-4,6-dimethyl-2-oxo-1-pyrimidinolato)oxovanadium(IV) by daily intraperitoneal injections. The improvement in

  9. Inhibiting NANOG Enhances Efficacy of BH3 Mimetics | Center for Cancer Research

    Cancer.gov

    BCL-2 family proteins regulate cell fate. Some members promote cell survival while others induce programmed cell death. A third group, the BH3-only members, modulates the activities of the rest of the family. Some cancers, including those of the colon and rectum, express elevated levels of pro-survival BCL-2 members, which may protect cancer cells from chemotherapy. BH3 mimetics are novel therapies that target and inhibit these pro-survival family members. Two in particular, ABT-737 and ABT-199, have activity against multiple cancer types, though neither targets the protein MCL-1, which is related to the BCL-2 family and causes resistance to the BH3 mimetics. Recent studies have revealed that the embryonic regulator NANOG and the related gene NANOGP8 can indirectly regulate MCL-1 via the kinase AKT. Abid Mattoo, Ph.D., J. Milburn Jessup, M.D., and colleagues of CCR’s Laboratory of Experimental Carcinogenesis, hypothesized that combining NANOG or NANOGP8 inhibition with a BH3 mimetic would enhance the latter’s anticancer activity.

  10. Dormancy as exaptation to protect mimetic seeds against deterioration before dispersal

    PubMed Central

    Brancalion, Pedro H. S.; Novembre, Ana D. L. C.; Rodrigues, Ricardo R.; Marcos Filho, Júlio

    2010-01-01

    Background and Aims Mimetic seeds simulate the appearance of fleshy fruits and arilled seeds without producing nutritive tissues as a reward for seed dispersers. In this strategy of seed dispersal, seeds may remain attached to the mother plant for long periods after maturity, increasing their availability to naïve seed dispersers. The hypothesis that seed coat impermeability in many tropical Fabaceae with mimetic seeds serves as an exaptation to protect the seeds from deterioration and rotting while awaiting dispersal was investigated. Methods Seed coat impermeability was evaluated in five mimetic-seeded species of tropical Fabaceae in south-eastern Brazil (Abarema langsdorffii, Abrus precatorius, Adenanthera pavonina, Erythrina velutina and Ormosia arborea) and in Erythrina speciosa, a ‘basal’ species in its genus, which has monochromatic brown seeds and no mimetic displays. Seed hardness was evaluated as a defence against accelerated ageing (humid chamber at 41 °C for 144 h). Seed development and physiological potential of O. arborea was evaluated and the effect of holding mature seeds in pods on the mother plant in the field for a period of 1 year under humid tropical conditions was compared with seeds stored under controlled conditions (15 °C and 40 % relative air humidity). Key Results All five mimetic-seeded species, and E. speciosa, showed strong coat impermeability, which protected the seeds against deterioration in accelerated ageing. Most O. arborea seeds only became dormant 2 months after pod dehiscence. Germination of seeds after 1 year on the plant in a humid tropical climate was 56 %, compared with 80 % for seeds stored in controlled conditions (15 °C, 45 % relative humidity). Seedling shoot length after 1 year did not differ between seed sources. Conclusions Dormancy acts in mimetic-seeded species as an exaptation to reduce seed deterioration, allowing an increase in their effective dispersal period and mitigating the losses incurred by low

  11. NEC violation in mimetic cosmology revisited

    DOE PAGES

    Ijjas, Anna; Ripley, Justin; Steinhardt, Paul J.

    2016-06-28

    In the context of Einstein gravity, if the null energy condition (NEC) is satisfied, the energy density in expanding space–times always decreases while in contracting space–times the energy density grows and the universe eventually collapses into a singularity. In particular, no non-singular bounce is possible. It is, though, an open question if this energy condition can be violated in a controlled way, i.e., without introducing pathologies, such as unstable negative-energy states or an imaginary speed of sound. In this letter, we will re-examine the claim that the recently proposed mimetic scenario can violate the NEC without pathologies. We show thatmore » mimetic cosmology is prone to gradient instabilities even in cases when the NEC is satisfied (except for trivial examples). Most interestingly, the source of the instability is always the Einstein–Hilbert term in the action. The matter stress-energy component does not contribute spatial gradient terms but instead makes the problematic curvature modes dynamical. Finally, we also show that mimetic cosmology can be understood as a singular limit of known, well-behaved theories involving higher-derivative kinetic terms and discuss ways of removing the instability.« less

  12. NEC violation in mimetic cosmology revisited

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ijjas, Anna; Ripley, Justin; Steinhardt, Paul J.

    In the context of Einstein gravity, if the null energy condition (NEC) is satisfied, the energy density in expanding space–times always decreases while in contracting space–times the energy density grows and the universe eventually collapses into a singularity. In particular, no non-singular bounce is possible. It is, though, an open question if this energy condition can be violated in a controlled way, i.e., without introducing pathologies, such as unstable negative-energy states or an imaginary speed of sound. In this letter, we will re-examine the claim that the recently proposed mimetic scenario can violate the NEC without pathologies. We show thatmore » mimetic cosmology is prone to gradient instabilities even in cases when the NEC is satisfied (except for trivial examples). Most interestingly, the source of the instability is always the Einstein–Hilbert term in the action. The matter stress-energy component does not contribute spatial gradient terms but instead makes the problematic curvature modes dynamical. Finally, we also show that mimetic cosmology can be understood as a singular limit of known, well-behaved theories involving higher-derivative kinetic terms and discuss ways of removing the instability.« less

  13. Design and synthesis of type-III mimetics of ShK toxin

    NASA Astrophysics Data System (ADS)

    Baell, Jonathan B.; Harvey, Andrew J.; Norton, Raymond S.

    2002-04-01

    ShK toxin is a structurally defined, 35-residue polypeptide which blocks the voltage-gated Kv1.3 potassium channel in T-lymphocytes and has been identified as a possible immunosuppressant. Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. ShK toxin is a challenging target for mimetic design as its binding epitope consists of relatively weakly binding residues, some of which are discontinuous. We discuss here our investigations into the design and synthesis of 1st generation, small molecule mimetics of ShK toxin and highlight any principles relevant to the generic design of type-III mimetics of continuous and discontinuous binding epitopes. We complement our approach with attempted pharmacophore-based database mining.

  14. Novel direct factor Xa inhibitory compounds from Tenebrio molitor with anti-platelet aggregation activity.

    PubMed

    Lee, Wonhwa; Kim, Mi-Ae; Park, InWha; Hwang, Jae Sam; Na, MinKyun; Bae, Jong-Sup

    2017-11-01

    Tenebrio molitor is an edible insect that has antimicrobial, anticancer, and antihypertensive effects. The aim of this study was to identify the unreported bioactive compounds from T. molitor larvae with inhibitory activities against factor Xa (FXa) and platelet aggregation. Isolated compounds were evaluated for their anti-FXa and anti-platelet aggregation properties by monitoring clotting time, platelet aggregation, FXa activity, and thrombus formation. A diketopiperazine (1, cyclo( L -Pro- L -Tyr)) and a phenylethanoid (2, N-acetyltyramine) were isolated and inhibited the catalytic activity of FXa in a mixed inhibition model and inhibited platelet aggregation induced by adenosine diphosphate (ADP) and U46619. They inhibited ADP- and U46619-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) and the expression of P-selectin and PAC-1 in platelets. They also improved the production of nitric oxide and inhibited the oversecretion of endothelin-1 compared to that of the ADP- or U46619-treated group. In an animal model of arterial and pulmonary thrombosis, the isolated compounds showed enhanced antithrombotic effects. They also elicited anticoagulant effects in mice. Compounds 1-2 inhibited ADP-, collagen-, or U46619-induced platelet aggregation and showed similar anti-thrombotic efficacy to rivaroxaban, a positive control. Therefore, 1-2 could serve as candidates and provide scaffolds for the development of new anti-FXa and anti-platelet drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Bio-Mimetic Sensors Based on Molecularly Imprinted Membranes

    PubMed Central

    Algieri, Catia; Drioli, Enrico; Guzzo, Laura; Donato, Laura

    2014-01-01

    An important challenge for scientific research is the production of artificial systems able to mimic the recognition mechanisms occurring at the molecular level in living systems. A valid contribution in this direction resulted from the development of molecular imprinting. By means of this technology, selective molecular recognition sites are introduced in a polymer, thus conferring it bio-mimetic properties. The potential applications of these systems include affinity separations, medical diagnostics, drug delivery, catalysis, etc. Recently, bio-sensing systems using molecularly imprinted membranes, a special form of imprinted polymers, have received the attention of scientists in various fields. In these systems imprinted membranes are used as bio-mimetic recognition elements which are integrated with a transducer component. The direct and rapid determination of an interaction between the recognition element and the target analyte (template) was an encouraging factor for the development of such systems as alternatives to traditional bio-assay methods. Due to their high stability, sensitivity and specificity, bio-mimetic sensors-based membranes are used for environmental, food, and clinical uses. This review deals with the development of molecularly imprinted polymers and their different preparation methods. Referring to the last decades, the application of these membranes as bio-mimetic sensor devices will be also reported. PMID:25196110

  16. Nuclear Receptors and AMPK: Can Exercise Mimetics Cure Diabetes?

    PubMed Central

    Wall, Christopher E.; Yu, Ruth T.; Atkins, Anne R.; Downes, Michael; Evans, Ronald M.

    2016-01-01

    Endurance exercise can lead to systemic improvements in insulin sensitivity and metabolic homeostasis, and is an effective approach to combat metabolic diseases. Pharmacological compounds that recapitulate the beneficial effects of exercise, also known as “exercise mimetics,” have the potential to improve disease symptoms of metabolic syndrome. These drugs, which can increase energy expenditure, suppress hepatic gluconeogenesis, and induce insulin sensitization, have accordingly been highly scrutinized for their utility in treating metabolic diseases including diabetes. Nevertheless, the identity of an efficacious exercise mimetic still remains elusive. In this article, we will highlight several nuclear receptors and cofactors that are putative molecular targets for exercise mimetics, and review recent studies that provide advancements in our mechanistic understanding of how exercise mimetics exert their beneficial effects. We will also discuss evidence from clinical trials utilizing these compounds in human subjects to evaluate their efficacy in treating diabetes. PMID:27106806

  17. Significant in vivo anti-inflammatory activity of Pytren4Q-Mn a superoxide dismutase 2 (SOD2) mimetic scorpiand-like Mn (II) complex.

    PubMed

    Serena, Carolina; Calvo, Enrique; Clares, Mari Paz; Diaz, María Luisa; Chicote, Javier U; Beltrán-Debon, Raúl; Fontova, Ramón; Rodriguez, Alejandro; García-España, Enrique; García-España, Antonio

    2015-01-01

    The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight. We have recently reported that two SOD mimetic compounds, the Mn(II) complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q Mn(II) complexes, in cultured macrophages and in a murine model of inflammation, by measuring the degree of protection they could provide against the cellular injury produced by lipopolisacharide, a bacterial endotoxin. In this report we show that the Mn(II) complex of Pytren4Q but not that of Pytren2Q effectively protected human cultured THP-1 macrophages and whole mice from the inflammatory effects produced by LPS. These results obtained with two molecules that are isomers highlight the importance of gathering experimental data from animal models of disease in assessing the potential of candidate molecules. The effective anti-inflammatory activity of the Mn(II) complex of Pytren4Q in addition to its low toxicity, water solubility and ease of production would suggest it is worth taking into consideration for future pharmacological studies.

  18. Dispersal of mimetic seeds of three species of Ormosia (Leguminosae)

    USGS Publications Warehouse

    Foster, M.S.; DeLay, L.S.

    1998-01-01

    Seeds with 'imitation arils' appear wholly or partially covered by pulp or aril but actually carry no fleshy material. The mimetic seed hypothesis to explain this phenomenon proposes a parasitic relationship in which birds are deceived into dispersing seeds that resemble bird-dispersed fruits, without receiving a nutrient reward. The hard-seed for grit hypothesis proposes a mutualistic relationship in which large, terrestrial birds swallow the exceptionally hard 'mimetic' seeds as grit for grinding the softer seeds on which they feed. They defecate, dispersing the seeds, and abrade the seed surface, enhancing germination. Any fruit mimicry is incidental. Fruiting trees of Ormosia spp. (Leguminosae: Papilionoideae) were observed to ascertain mechanisms of seed dispersal and the role of seemingly mimetic characteristics of the seeds in that dispersal. Seed predation and seed germination were also examined. Ormosia isthamensis and O. macrocalyx (but not O. bopiensis) deceived arboreally-foraging frugivorous birds into taking their mimetic seeds, although rates of seed dispersal were low. These results are consistent with the mimetic seed hypothesis. On the other hand, the rates of disappearance of seeds from the ground under the Ormosia trees, hardness of the seeds, and enhancement of germination with the abrasion of the seed coat are all consistent with the hard-seed for grit hypothesis.

  19. Mimetic compact stars

    NASA Astrophysics Data System (ADS)

    Momeni, D.; Moraes, P. H. R. S.; Gholizade, H.; Myrzakulov, R.

    Modified gravity models have been constantly proposed with the purpose of evading some standard gravity shortcomings. Recently proposed by Chamseddine and Mukhanov, the Mimetic Gravity arises as an optimistic alternative. Our purpose in this work is to derive Tolman-Oppenheimer-Volkoff equations and solutions for such a gravity theory. We solve them numerically for quark star and neutron star cases. The results are carefully discussed.

  20. Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells.

    PubMed

    Petri, Marcelo H; Tellier, Céline; Michiels, Carine; Ellertsen, Ingvill; Dogné, Jean-Michel; Bäck, Magnus

    2013-11-15

    The prothrombotic mediator thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Synthesis, molecular docking and biological evaluation as HDAC inhibitors of cyclopeptide mimetics by a tandem three-component reaction and intramolecular [3+2] cycloaddition.

    PubMed

    Pirali, Tracey; Faccio, Valeria; Mossetti, Riccardo; Grolla, Ambra A; Di Micco, Simone; Bifulco, Giuseppe; Genazzani, Armando A; Tron, Gian Cesare

    2010-02-01

    Novel macrocyclic peptide mimetics have been synthesized by exploiting a three-component reaction and an azide-alkyne [3 + 2] cycloaddition. The prepared compounds were screened as HDAC inhibitors allowing us to identify a new compound with promising biological activity. In order to rationalize the biological results, computational studies have also been performed.

  2. Calorimetric studies of the interactions of metalloenzyme active site mimetics with zinc-binding inhibitors.

    PubMed

    Robinson, Sophia G; Burns, Philip T; Miceli, Amanda M; Grice, Kyle A; Karver, Caitlin E; Jin, Lihua

    2016-07-19

    The binding of drugs to metalloenzymes is an intricate process that involves several interactions, including binding of the drug to the enzyme active site metal, as well as multiple interactions between the drug and the enzyme residues. In order to determine the free energy contribution of Zn(2+) binding by known metalloenzyme inhibitors without the other interactions, valid active site zinc structural mimetics must be formed and binding studies need to be performed in biologically relevant conditions. The potential of each of five ligands to form a structural mimetic with Zn(2+) was investigated in buffer using Isothermal Titration Calorimetry (ITC). All five ligands formed strong 1 : 1 (ligand : Zn(2+)) binary complexes. The complexes were used in further ITC experiments to study their interaction with 8-hydroxyquinoline (8-HQ) and/or acetohydroxamic acid (AHA), two bidentate anionic zinc-chelating enzyme inhibitors. It was found that tetradentate ligands were not suitable for creating zinc structural mimetics for inhibitor binding in solution due to insufficient coordination sites remaining on Zn(2+). A stable binary complex, [Zn(BPA)](2+), which was formed by a tridentate ligand, bis(2-pyridylmethyl)amine (BPA), was found to bind one AHA in buffer or a methanol : buffer mixture (60 : 40 by volume) at pH 7.25 or one 8-HQ in the methanol : buffer mixture at pH 6.80, making it an effective structural mimetic for the active site of zinc metalloenzymes. These results are consistent with the observation that metalloenzyme active site zinc ions have three residues coordinated to them, leaving one or two sites open for inhibitors to bind. Our findings indicate that Zn(BPA)X2 can be used as an active site structural mimetic for zinc metalloenzymes for estimating the free energy contribution of zinc binding to the overall inhibitor active site interactions. Such use will help aid in the rational design of inhibitors to a variety of zinc metalloenzymes.

  3. Temperature-sensitive elastin-mimetic dendrimers: Effect of peptide length and dendrimer generation to temperature sensitivity.

    PubMed

    Kojima, Chie; Irie, Kotaro; Tada, Tomoko; Tanaka, Naoki

    2014-06-01

    Dendrimers are synthetic macromolecules with unique structure, which are a potential scaffold for peptides. Elastin is one of the main components of extracellular matrix and a temperature-sensitive biomacromolecule. Previously, Val-Pro-Gly-Val-Gly peptides have been conjugated to a dendrimer for designing an elastin-mimetic dendrimer. In this study, various elastin-mimetic dendrimers using different length peptides and different dendrimer generations were synthesized to control the temperature dependency. The elastin-mimetic dendrimers formed β-turn structure by heating, which was similar to the elastin-like peptides. The elastin-mimetic dendrimers exhibited an inverse phase transition, largely depending on the peptide length and slightly depending on the dendrimer generation. The elastin-mimetic dendrimers formed aggregates after the phase transition. The endothermal peak was observed in elastin-mimetic dendrimers with long peptides, but not with short ones. The peptide length and the dendrimer generation are important factors to tune the temperature dependency on the elastin-mimetic dendrimer. Copyright © 2013 Wiley Periodicals, Inc.

  4. Beyond Antibodies as Binding Partners: The Role of Antibody Mimetics in Bioanalysis.

    PubMed

    Yu, Xiaowen; Yang, Yu-Ping; Dikici, Emre; Deo, Sapna K; Daunert, Sylvia

    2017-06-12

    The emergence of novel binding proteins or antibody mimetics capable of binding to ligand analytes in a manner analogous to that of the antigen-antibody interaction has spurred increased interest in the biotechnology and bioanalytical communities. The goal is to produce antibody mimetics designed to outperform antibodies with regard to binding affinities, cellular and tumor penetration, large-scale production, and temperature and pH stability. The generation of antibody mimetics with tailored characteristics involves the identification of a naturally occurring protein scaffold as a template that binds to a desired ligand. This scaffold is then engineered to create a superior binder by first creating a library that is then subjected to a series of selection steps. Antibody mimetics have been successfully used in the development of binding assays for the detection of analytes in biological samples, as well as in separation methods, cancer therapy, targeted drug delivery, and in vivo imaging. This review describes recent advances in the field of antibody mimetics and their applications in bioanalytical chemistry, specifically in diagnostics and other analytical methods.

  5. On (in)stabilities of perturbations in mimetic models with higher derivatives

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zheng, Yunlong; Shen, Liuyuan; Mou, Yicen

    2017-08-01

    Usually when applying the mimetic model to the early universe, higher derivative terms are needed to promote the mimetic field to be dynamical. However such models suffer from the ghost and/or the gradient instabilities and simple extensions cannot cure this pathology. We point out in this paper that it is possible to overcome this difficulty by considering the direct couplings of the higher derivatives of the mimetic field to the curvature of the spacetime.

  6. Fabrication of hierarchical feather-mimetic polymer nanofibres

    NASA Astrophysics Data System (ADS)

    Ouyang, Shenshen; Wang, Tao; Zhong, Longgang; Peng, Meiling; Yao, Juming; Wang, Sheng

    2018-01-01

    In this study, hierarchically feather-mimetic structures formed of poly(m-phenylene isophthalamide) (PMIA) nanofibres were prepared by electrospinning and subsequent crystallisation for superwettability applications. X-ray diffraction measurementsand scanning electron microscopy show that a feather-mimetic structure of crystallised nanoflakes was formed following a hydrothermal treatment process. The nanoflakes formed a nanosized fine texture on top of a coarser-textured membrane, which greatly improved the membrane roughness and yielded a hierarchical topography. After fluorination, the membrane exhibited superamphiphobicity, with surface contact angles of 151° and 136° for water and hexadecane, respectively. The method provides new insight for the design and development of functional bionic membranes based on PMIA.

  7. A novel approach to oral apoA-I mimetic therapy[S

    PubMed Central

    Chattopadhyay, Arnab; Navab, Mohamad; Hough, Greg; Gao, Feng; Meriwether, David; Grijalva, Victor; Springstead, James R.; Palgnachari, Mayakonda N.; Namiri-Kalantari, Ryan; Su, Feng; Van Lenten, Brian J.; Wagner, Alan C.; Anantharamaiah, G. M.; Farias-Eisner, Robin; Reddy, Srinivasa T.; Fogelman, Alan M.

    2013-01-01

    Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide, 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR−/−) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice (P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions (P < 0.0001); HDL cholesterol and PON were inversely correlated (P < 0.0001). After feeding WD + 6F: i) intact 6F was detected in small intestine (but not in plasma); ii) small intestine LPA was decreased compared with WD + EV (P < 0.0469); and iii) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions (P < 0.0179). These data suggest that 6F acts in the small intestine and provides a novel approach to oral apoA-I mimetic therapy. PMID:23378594

  8. Synthetic analogues of flavonoids with improved activity against platelet activation and aggregation as novel prototypes of food supplements.

    PubMed

    Del Turco, Serena; Sartini, Stefania; Cigni, Giulia; Sentieri, Cassandra; Sbrana, Silverio; Battaglia, Debora; Papa, Angela; Da Settimo, Federico; La Motta, Concettina; Basta, Giuseppina

    2015-05-15

    We investigated the ability of quercetin and apigenin to modulate platelet activation and aggregation, and compared the observed efficacy with that displayed by their synthetic analogues 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-ones, 1-4, and 2,3-diphenyl-4H-pyrido[1,2-a]pyrimidin-4-ones, 5-7. Platelet aggregation was explored through a spectrophotometric assay on platelet-rich plasma (PRP) treated with the thromboxane A2 mimetic U46619, collagen and thrombin in presence/absence of various bioisosteres of flavonoids (12.5-25-50-100 μM). The platelet density, (mean platelet component, MPC), was measured by the Advia 120 Hematology System as a marker surrogate of platelet activation. The induced P-selectin expression, which reflects platelet degranulation/activation, was quantified by flow cytometry on PRP. Our synthetic compounds modulated significantly both platelet activation and aggregation, thus turning out to be more effective than the analogues quercetin and apigenin when tested at a concentration fully consistent with their use in vivo. Accordingly, they might be used as food supplements to increase the efficacy of natural flavonoids. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Immunopharmacology of lipid A mimetics.

    PubMed

    Bowen, William S; Gandhapudi, Siva K; Kolb, Joseph P; Mitchell, Thomas C

    2013-01-01

    The structural core of bacterial lipopolysaccharide, lipid A, has played a role in medicine since the 1890s when William Coley sought to harness its immunostimulatory properties in the form of a crude bacterial extract. Recent decades have brought remarkable clarity to the structure of lipid A and the multicomponent endotoxin receptor system that evolved to detect it. A range of therapeutically useful versions of lipid A now exists, including preparations of detoxified lipid A, synthetic copies of naturally occurring biological intermediates such as lipid IVa, and synthetic mimetics. These agents are finding use as vaccine adjuvants, antagonists and immunostimulants whose structural features have been refined to potentiate efficacy while decreasing the risk of inflammatory side effects. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside.

    PubMed

    Vela, Laura; Marzo, Isabel

    2015-08-01

    Bcl-2 proteins are key determinants in the life-death balance. In recent years, proteins in this family have been identified as drug targets in the design of new anti-tumor therapies. Advances in the knowledge of the mechanism of action of anti-apoptotic and pro-apoptotic members of the Bcl-2 family have enabled the development of the so-called 'BH3 mimetics'. These compounds act by inhibiting anti-apoptotic proteins of the family, imitating the function of the BH3-only subset of pro-apoptotic members. Combinations of BH3-mimetics with anti-tumor drugs are being evaluated in both preclinical models and clinical trials. Recent advances in these approaches will be reviewed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Female preferences drive the evolution of mimetic accuracy in male sexual displays.

    PubMed

    Coleman, Seth William; Patricelli, Gail Lisa; Coyle, Brian; Siani, Jennifer; Borgia, Gerald

    2007-10-22

    Males in many bird species mimic the vocalizations of other species during sexual displays, but the evolutionary and functional significance of interspecific vocal mimicry is unclear. Here we use spectrographic cross-correlation to compare mimetic calls produced by male satin bowerbirds (Ptilonorhynchus violaceus) in courtship with calls from several model species. We show that the accuracy of vocal mimicry and the number of model species mimicked are both independently related to male mating success. Multivariate analyses revealed that these mimetic traits were better predictors of male mating success than other male display traits previously shown to be important for male mating success. We suggest that preference-driven mimetic accuracy may be a widespread occurrence, and that mimetic accuracy may provide females with important information about male quality. Our findings support an alternative hypothesis to help explain a common element of male sexual displays.

  12. Primordial cosmology in mimetic born-infeld gravity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bouhmadi-Lopez, Mariam; Chen, Che -Yu; Chen, Pisin

    Here, the Eddington-inspired-Born-Infeld (EiBI) model is reformulated within the mimetic approach. In the presence of a mimetic field, the model contains non-trivial vacuum solutions which could be free of spacetime singularity because of the Born-Infeld nature of the theory. We study a realistic primordial vacuum universe and prove the existence of regular solutions, such as primordial inflationary solutions of de Sitter type or bouncing solutions. Besides, the linear instabilities present in the EiBI model are found to be avoidable for some interesting bouncing solutions in which the physical metric as well as the auxiliary metric are regular at the backgroundmore » level.« less

  13. Primordial cosmology in mimetic born-infeld gravity

    DOE PAGES

    Bouhmadi-Lopez, Mariam; Chen, Che -Yu; Chen, Pisin

    2017-11-29

    Here, the Eddington-inspired-Born-Infeld (EiBI) model is reformulated within the mimetic approach. In the presence of a mimetic field, the model contains non-trivial vacuum solutions which could be free of spacetime singularity because of the Born-Infeld nature of the theory. We study a realistic primordial vacuum universe and prove the existence of regular solutions, such as primordial inflationary solutions of de Sitter type or bouncing solutions. Besides, the linear instabilities present in the EiBI model are found to be avoidable for some interesting bouncing solutions in which the physical metric as well as the auxiliary metric are regular at the backgroundmore » level.« less

  14. Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins.

    PubMed

    Hewitt, Sarah H; Filby, Maria H; Hayes, Ed; Kuhn, Lars T; Kalverda, Arnout P; Webb, Michael E; Wilson, Andrew J

    2017-01-17

    Protein surface mimetics achieve high-affinity binding by exploiting a scaffold to project binding groups over a large area of solvent-exposed protein surface to make multiple cooperative noncovalent interactions. Such recognition is a prerequisite for competitive/orthosteric inhibition of protein-protein interactions (PPIs). This paper describes biophysical and structural studies on ruthenium(II) tris(bipyridine) surface mimetics that recognize cytochrome (cyt) c and inhibit the cyt c/cyt c peroxidase (CCP) PPI. Binding is electrostatically driven, with enhanced affinity achieved through enthalpic contributions thought to arise from the ability of the surface mimetics to make a greater number of noncovalent interactions than CCP with surface-exposed basic residues on cyt c. High-field natural abundance 1 H, 15 N HSQC NMR experiments are consistent with surface mimetics binding to cyt c in similar manner to CCP. This provides a framework for understanding recognition of proteins by supramolecular receptors and informing the design of ligands superior to the protein partners upon which they are inspired. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Hypoxia and alkalinization inhibit endothelium-derived nitric oxide but not endothelium-derived hyperpolarizing factor responses in porcine coronary artery.

    PubMed

    Shimizu, S; Paul, R J

    1999-10-01

    We investigated the mechanisms by which hypoxia and alkalinization inhibit the endothelium-dependent relaxation to Substance P (SP) in porcine coronary artery. In a KCl contracture, the major component of the SP response is endothelium-derived nitric oxide (EDNO), whereas with receptor-mediated 9,11-dideoxy-llalpha, 9alpha-epoxymethanoprostaglandin F(2alpha) (U46619) stimulation, the SP response is dependent on both EDNO and endothelium-derived hyperpolarization factor. Intracellular alkalinization by NH(4)Cl reduced the peak of SP responses when arteries were contracted with KCl, whereas with U46619 stimulation, the peak was little effected but the duration was shortened. In endothelial cell-denuded arteries, alkalinization with NH(4)Cl shifted the sodium nitroprusside concentration-relaxation relations rightward. The effects of NH(4)Cl in SP- and sodium nitroprusside-induced relaxations were attenuated by decreasing extracellular pH (pH(o)) from 7.4 to 7.2, which normalized intracellular pH (pH(i)) to control levels. In contrast, in U46619 contractures, the SP response in the presence of a NO synthase inhibitor was unaffected by NH(4)Cl. Moreover, hypoxia blunted but did not abolish the responses to SP for U46619 contractures; addition of KCl, however, abolished the SP response under hypoxia. Endothelial [Ca(2+)](i) was measured with fura-2 differentially loaded only into endothelial cells on intact arteries. Despite the attenuation of the SP response in KCl contractures by NH(4)Cl or hypoxia, endothelial [Ca(2+)](i) responses were unchanged. Our results suggest that hypoxia and alkalinization inhibit EDNO but not endothelium-derived hyperpolarization factor relaxations through a mechanism(s) not involving endothelial cell [Ca(2+)](i). Inhibition of EDNO relaxation by alkalinization with NH(4)Cl is likely to occur at the level of activation of guanylate cyclase and/or at a step downstream in smooth muscle.

  16. Arginine mimetic structures in biologically active antagonists and inhibitors.

    PubMed

    Masic, Lucija Peterlin

    2006-01-01

    Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the

  17. Superoxide Dismutase Mimetic, MnTE-2-PyP, Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension, Pulmonary Vascular Remodeling, and Activation of the NALP3 Inflammasome

    PubMed Central

    Villegas, Leah R.; Kluck, Dylan; Field, Carlie; Oberley-Deegan, Rebecca E.; Woods, Crystal; Yeager, Michael E.; El Kasmi, Karim C.; Savani, Rashmin C.; Bowler, Russell P.

    2013-01-01

    Abstract Aims: Pulmonary hypertension (PH) is characterized by an oxidant/antioxidant imbalance that promotes abnormal vascular responses. Reactive oxygen species, such as superoxide (O2•−), contribute to the pathogenesis of PH and vascular responses, including vascular remodeling and inflammation. This study sought to investigate the protective role of a pharmacological catalytic antioxidant, a superoxide dismutase (SOD) mimetic (MnTE-2-PyP), in hypoxia-induced PH, vascular remodeling, and NALP3 (NACHT, LRR, and PYD domain-containing protein 3)–mediated inflammation. Results: Mice (C57/BL6) were exposed to hypobaric hypoxic conditions, while subcutaneous injections of MnTE-2-PyP (5 mg/kg) or phosphate-buffered saline (PBS) were given 3× weekly for up to 35 days. SOD mimetic-treated groups demonstrated protection against increased right ventricular systolic pressure, indirect measurements of pulmonary artery pressure, and RV hypertrophy. Vascular remodeling was assessed by Ki67 staining to detect vascular cell proliferation, α-smooth muscle actin staining to analyze small vessel muscularization, and hyaluronan (HA) measurements to assess extracellular matrix modulation. Activation of the NALP3 inflammasome pathway was measured by NALP3 expression, caspase-1 activation, and interleukin 1-beta (IL-1β) and IL-18 production. Hypoxic exposure increased PH, vascular remodeling, and NALP3 inflammasome activation in PBS-treated mice, while mice treated with MnTE-2-PyP showed an attenuation in each of these endpoints. Innovation: This study is the first to demonstrate activation of the NALP3 inflammasome with cleavage of caspase-1 and release of active IL-1 β and IL-18 in chronic hypoxic PH, as well as its attenuation by the SOD mimetic, MnTE-2-PyP. Conclusion: The ability of the SOD mimetic to scavenge extracellular O2•− supports our previous observations in EC-SOD-overexpressing mice that implicate extracellular oxidant/antioxidant imbalance in hypoxic PH

  18. Regression of aortic valve stenosis by ApoA-I mimetic peptide infusions in rabbits

    PubMed Central

    Busseuil, D; Shi, Y; Mecteau, M; Brand, G; Kernaleguen, A-E; Thorin, E; Latour, J-G; Rhéaume, E; Tardif, J-C

    2008-01-01

    Background and purpose: Aortic valve stenosis (AVS) is the most common valvular heart disease, and standard curative therapy remains open heart surgical valve replacement. The aim of our experimental study was to determine if apolipoprotein A-I (ApoA-I) mimetic peptide infusions could induce regression of AVS. Experimental approach: Fifteen New Zealand White male rabbits received a cholesterol-enriched diet and vitamin D2 until significant AVS was detected by echocardiography. The enriched diet was then stopped to mimic cholesterol-lowering therapy and animals were allocated randomly to receive saline (control group, n=8) or an ApoA-I mimetic peptide (treated group, n=7), three times per week for 2 weeks. Serial echocardiograms and post mortem valve histology were performed. Key results: Aortic valve area increased significantly by 25% in the treated group after 14 days of treatment (P=0.012). Likewise, aortic valve thickness decreased by 21% in the treated group, whereas it was unchanged in controls (P=0.0006). Histological analysis revealed that the extent of lesions at the base of valve leaflets and sinuses of Valsalva was smaller in the treated group compared with controls (P=0.032). The treatment also reduced calcification, as revealed by the loss of the positive relationship observed in the control group (r=0.87, P=0.004) between calcification area and aortic valve thickness. Conclusions and implications: Infusions of ApoA-I mimetic peptide lead to regression of experimental AVS. These positive results justify the further testing of high-density lipoprotein (HDL)-based therapies in patients with valvular aortic stenosis. Regression of aortic stenosis, if achieved safely, could transform the clinical treatment of this disease. PMID:18414386

  19. Structural basis for dual roles of Aar2p in U5 snRNP assembly

    PubMed Central

    Weber, Gert; Cristão, Vanessa F.; Santos, Karine F.; Jovin, Sina Mozaffari; Heroven, Anna C.; Holton, Nicole; Lührmann, Reinhard; Beggs, Jean D.; Wahl, Markus C.

    2013-01-01

    Yeast U5 small nuclear ribonucleoprotein particle (snRNP) is assembled via a cytoplasmic precursor that contains the U5-specific Prp8 protein but lacks the U5-specific Brr2 helicase. Instead, pre-U5 snRNP includes the Aar2 protein not found in mature U5 snRNP or spliceosomes. Aar2p and Brr2p bind competitively to a C-terminal region of Prp8p that comprises consecutive RNase H-like and Jab1/MPN-like domains. To elucidate the molecular basis for this competition, we determined the crystal structure of Aar2p in complex with the Prp8p RNase H and Jab1/MPN domains. Aar2p binds on one side of the RNase H domain and extends its C terminus to the other side, where the Jab1/MPN domain is docked onto a composite Aar2p–RNase H platform. Known Brr2p interaction sites of the Jab1/MPN domain remain available, suggesting that Aar2p-mediated compaction of the Prp8p domains sterically interferes with Brr2p binding. Moreover, Aar2p occupies known RNA-binding sites of the RNase H domain, and Aar2p interferes with binding of U4/U6 di-snRNA to the Prp8p C-terminal region. Structural and functional analyses of phospho-mimetic mutations reveal how phosphorylation reduces affinity of Aar2p for Prp8p and allows Brr2p and U4/U6 binding. Our results show how Aar2p regulates both protein and RNA binding to Prp8p during U5 snRNP assembly. PMID:23442228

  20. Extended mimetic gravity: Hamiltonian analysis and gradient instabilities

    NASA Astrophysics Data System (ADS)

    Takahashi, Kazufumi; Kobayashi, Tsutomu

    2017-11-01

    We propose a novel class of degenerate higher-order scalar-tensor theories as an extension of mimetic gravity. By performing a noninvertible conformal transformation on "seed" scalar-tensor theories which may be nondegenerate, we can generate a large class of theories with at most three physical degrees of freedom. We identify a general seed theory for which this is possible. Cosmological perturbations in these extended mimetic theories are also studied. It is shown that either of tensor or scalar perturbations is plagued with gradient instabilities, except for a special case where the scalar perturbations are presumably strongly coupled, or otherwise there appear ghost instabilities.

  1. René Girard and the Mimetic Nature of Eating Disorders.

    PubMed

    Strand, Mattias

    2018-03-07

    French historian and literary critic René Girard (1923-2015), most widely known for the concepts of mimetic desire and scapegoating, also engaged in the discussion of the surge of eating disorders in his 1996 essay Eating Disorders and Mimetic Desire. This article explores Girard's ideas on the mimetic nature and origin of eating disorders from a clinical psychiatric perspective and contextualizes them within the field of eating disorders research as well as in relation to broader psychological, sociological and anthropological models of social comparison and non-consumption. Three main themes in Girard's thinking on the topic of eating disorders are identified and explored: the 'end of prohibitions' as a driving force in the emergence of eating disorders, eating disorders as a phenomenon specific to modernity, and the significance of 'conspicuous non-consumption' in the emergence of eating disorders.

  2. Elementary dispersion analysis of some mimetic discretizations on triangular C-grids

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Korn, P., E-mail: peter.korn@mpimet.mpg.de; Danilov, S.; A.M. Obukhov Institute of Atmospheric Physics, Moscow

    2017-02-01

    Spurious modes supported by triangular C-grids limit their application for modeling large-scale atmospheric and oceanic flows. Their behavior can be modified within a mimetic approach that generalizes the scalar product underlying the triangular C-grid discretization. The mimetic approach provides a discrete continuity equation which operates on an averaged combination of normal edge velocities instead of normal edge velocities proper. An elementary analysis of the wave dispersion of the new discretization for Poincaré, Rossby and Kelvin waves shows that, although spurious Poincaré modes are preserved, their frequency tends to zero in the limit of small wavenumbers, which removes the divergence noisemore » in this limit. However, the frequencies of spurious and physical modes become close on shorter scales indicating that spurious modes can be excited unless high-frequency short-scale motions are effectively filtered in numerical codes. We argue that filtering by viscous dissipation is more efficient in the mimetic approach than in the standard C-grid discretization. Lumping of mass matrices appearing with the velocity time derivative in the mimetic discretization only slightly reduces the accuracy of the wave dispersion and can be used in practice. Thus, the mimetic approach cures some difficulties of the traditional triangular C-grid discretization but may still need appropriately tuned viscosity to filter small scales and high frequencies in solutions of full primitive equations when these are excited by nonlinear dynamics.« less

  3. The selective Bcl-2 inhibitor venetoclax, a BH3 mimetic, does not dysregulate intracellular Ca2+ signaling.

    PubMed

    Vervloessem, Tamara; Ivanova, Hristina; Luyten, Tomas; Parys, Jan B; Bultynck, Geert

    2017-06-01

    Anti-apoptotic B cell-lymphoma-2 (Bcl-2) proteins are emerging as therapeutic targets in a variety of cancers for precision medicines, like the BH3-mimetic drug venetoclax (ABT-199), which antagonizes the hydrophobic cleft of Bcl-2. However, the impact of venetoclax on intracellular Ca 2+ homeostasis and dynamics in cell systems has not been characterized in detail. Here, we show that venetoclax did not affect Ca 2+ -transport systems from the endoplasmic reticulum (ER) in permeabilized cell systems. Venetoclax (1μM) did neither trigger Ca 2+ release by itself nor affect agonist-induced Ca 2+ release in a variety of intact cell models. Among the different cell types, we also studied two Bcl-2-dependent cancer cell models with a varying sensitivity towards venetoclax, namely SU-DHL-4 and OCI-LY-1, both diffuse large B-cell lymphoma cell lines. Acute application of venetoclax did also not dysregulate Ca 2+ signaling in these Bcl-2-dependent cancer cells. Moreover, venetoclax-induced cell death was independent of intracellular Ca 2+ overload, since Ca 2+ buffering using BAPTA-AM did not suppress venetoclax-induced cell death. This study therefore shows that venetoclax does not dysregulate the intracellular Ca 2+ homeostasis in a variety of cell types, which may underlie its limited toxicity in human patients. Furthermore, venetoclax-induced cell death in Bcl-2-dependent cancer cells is not mediated by intracellular Ca 2+ overload. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Healthy imperfect dark matter from effective theory of mimetic cosmological perturbations

    NASA Astrophysics Data System (ADS)

    Hirano, Shin'ichi; Nishi, Sakine; Kobayashi, Tsutomu

    2017-07-01

    We study the stability of a recently proposed model of scalar-field matter called mimetic dark matter or imperfect dark matter. It has been known that mimetic matter with higher derivative terms suffers from gradient instabilities in scalar perturbations. To seek for an instability-free extension of imperfect dark matter, we develop an effective theory of cosmological perturbations subject to the constraint on the scalar field's kinetic term. This is done by using the unifying framework of general scalar-tensor theories based on the ADM formalism. We demonstrate that it is indeed possible to construct a model of imperfect dark matter which is free from ghost and gradient instabilities. As a side remark, we also show that mimetic F(Script R) theory is plagued with the Ostrogradsky instability.

  5. Supramolecular assembly of multifunctional maspin-mimetic nanostructures as a potent peptide-based angiogenesis inhibitor

    DOE PAGES

    Zha, R. Helen; Sur, Shantanu; Boekhoven, Job; ...

    2014-11-08

    Aberrant angiogenesis plays a large role in pathologies ranging from tumor growth to macular degeneration. Anti-angiogenic proteins have thus come under scrutiny as versatile, potent therapeutics but face problems with purification and tissue retention. We report here on the synthesis of supramolecular nanostructures that mimic the anti-angiogenic activity of maspin, a class II tumor suppressor protein. These maspin-mimetic nanostructures are formed via self-assembly of small peptide amphiphiles containing the g-helix motif of maspin. Using tubulogenesis assays with human umbilical vein endothelial cells, we demonstrate that maspin-mimetic nanostructures show anti-angiogenic activity at concentrations that are significantly lower than those necessary formore » the g-helix peptide. Furthermore, in vivo assays in the chick chorioallantoic membrane show maspin-mimetic nanostructures to be effective over controls at inhibiting angiogenesis. Thus, in conclusion, the nanostructures investigated here offer an attractive alternative to the use of anti-angiogenic recombinant proteins in the treatment of cancer or other diseases involving abnormal blood vessel formation.« less

  6. An In Ovo Model for Testing Insulin-mimetic Compounds.

    PubMed

    Haselgrübler, Renate; Stübl, Flora; Stadlbauer, Verena; Lanzerstorfer, Peter; Weghuber, Julian

    2018-04-23

    Elevated blood glucose levels in type 2 diabetes mellitus (T2DM), a complex and multifactorial metabolic disease, are caused by insulin resistance and β-cell failure. Various strategies, including the injection of insulin or the usage of insulin-sensitizing drugs, were pursued to treat T2DM or at least reduce the symptoms. In addition, the application of herbal compounds has attracted increasing attention. Thus, it is necessary to find efficient test systems to identify and characterize insulin-mimetic compounds. Here we developed a modified chick embryo model, which enables testing of synthetic compounds and herbal extracts with insulin-mimetic properties. Using a fluorescence microscopy-based primary screen, which quantifies the translocation of Glucose transporter 4 (Glut4) to the plasma membrane, we were able to identify compounds, mainly herbal extracts, which lead to an increase of intracellular glucose concentrations in adipocytes. However, the efficacy of these substances requires further verification in a living organism. Thus, we used an in-ovo approach to identify their blood glucose-reducing properties. The approval by an ethics committee is not needed since the use of chicken embryos during the first two-thirds of embryonic development is not considered an animal experiment. Here, the application of this model is described in detail.

  7. Methylidynetrisphosphonates: Promising C1 building block for the design of phosphate mimetics

    PubMed Central

    Romanenko, Vadim D

    2013-01-01

    Summary Methylidynetrisphosphonates are representatives of geminal polyphosphonates bearing three phosphonate (PO3H2) groups at the bridged carbon atom. Like well-known methylenebisphosphonates (BPs), they are characterized by a P–C–P backbone structure and are chemically stable mimetics of the endogenous metabolites, i.e., inorganic pyrophosphates (PPi). Because of its analogy to PPi and an ability to chelate metal ions, the 1,1,1-trisphosphonate structure is of great potential as a C1 building block for the design of phosphate mimetics. The purpose of this review is to present a concise summary of the state of the art in trisphosphonate chemistry with particular emphasis on the synthesis, structure, reactions, and potential medicinal applications of these compounds. PMID:23766816

  8. CD4 mimetics sensitize HIV-1-infected cells to ADCC.

    PubMed

    Richard, Jonathan; Veillette, Maxime; Brassard, Nathalie; Iyer, Shilpa S; Roger, Michel; Martin, Loïc; Pazgier, Marzena; Schön, Arne; Freire, Ernesto; Routy, Jean-Pierre; Smith, Amos B; Park, Jongwoo; Jones, David M; Courter, Joel R; Melillo, Bruno N; Kaufmann, Daniel E; Hahn, Beatrice H; Permar, Sallie R; Haynes, Barton F; Madani, Navid; Sodroski, Joseph G; Finzi, Andrés

    2015-05-19

    HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

  9. CD4 mimetics sensitize HIV-1-infected cells to ADCC

    PubMed Central

    Richard, Jonathan; Veillette, Maxime; Brassard, Nathalie; Iyer, Shilpa S.; Roger, Michel; Martin, Loïc; Pazgier, Marzena; Schön, Arne; Freire, Ernesto; Routy, Jean-Pierre; Smith, Amos B.; Park, Jongwoo; Jones, David M.; Courter, Joel R.; Melillo, Bruno N.; Kaufmann, Daniel E.; Hahn, Beatrice H.; Permar, Sallie R.; Haynes, Barton F.; Madani, Navid; Sodroski, Joseph G.; Finzi, Andrés

    2015-01-01

    HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection. PMID:25941367

  10. Social variables exert selective pressures in the evolution and form of primate mimetic musculature.

    PubMed

    Burrows, Anne M; Li, Ly; Waller, Bridget M; Micheletta, Jerome

    2016-04-01

    Mammals use their faces in social interactions more so than any other vertebrates. Primates are an extreme among most mammals in their complex, direct, lifelong social interactions and their frequent use of facial displays is a means of proximate visual communication with conspecifics. The available repertoire of facial displays is primarily controlled by mimetic musculature, the muscles that move the face. The form of these muscles is, in turn, limited by and influenced by phylogenetic inertia but here we use examples, both morphological and physiological, to illustrate the influence that social variables may exert on the evolution and form of mimetic musculature among primates. Ecomorphology is concerned with the adaptive responses of morphology to various ecological variables such as diet, foliage density, predation pressures, and time of day activity. We present evidence that social variables also exert selective pressures on morphology, specifically using mimetic muscles among primates as an example. Social variables include group size, dominance 'style', and mating systems. We present two case studies to illustrate the potential influence of social behavior on adaptive morphology of mimetic musculature in primates: (1) gross morphology of the mimetic muscles around the external ear in closely related species of macaque (Macaca mulatta and Macaca nigra) characterized by varying dominance styles and (2) comparative physiology of the orbicularis oris muscle among select ape species. This muscle is used in both facial displays/expressions and in vocalizations/human speech. We present qualitative observations of myosin fiber-type distribution in this muscle of siamang (Symphalangus syndactylus), chimpanzee (Pan troglodytes), and human to demonstrate the potential influence of visual and auditory communication on muscle physiology. In sum, ecomorphologists should be aware of social selective pressures as well as ecological ones, and that observed morphology might

  11. Interaction of GABA-mimetics with the taurine transporter (TauT, Slc6a6) in hyperosmotic treated Caco-2, LLC-PK1 and rat renal SKPT cells.

    PubMed

    Rasmussen, Rune Nørgaard; Lagunas, Candela; Plum, Jakob; Holm, René; Nielsen, Carsten Uhd

    2016-01-20

    The aim of the present study was to investigate if basic GABA-mimetics interact with the taurine transporter (TauT, Slc6a6), and to find a suitable cell based model that is robust towards extracellular changes in osmolality during uptake studies. Taurine uptake was measured in human Caco-2 cells, porcine LLC-PK1 cells, and rat SKPT cells using radiolabelled taurine. Hyperosmotic conditions were obtained by incubation with raffinose (final osmolality of 500mOsm) for 24h prior to the uptake experiments. Expression of the taurine transporter, TauT, was investigated at the mRNA level by real-time PCR. Uptake of the GABA-mimetics gaboxadol and vigabatrin was investigated in SKPT cells, and quantified by liquid scintillation or HPLC-MS/MS analysis, respectively. The uptake rate of [(3)H]-taurine was Na(+) and Cl(-) and concentration dependent with taurine with an apparent Vmax of 6.3±1.6pmolcm(-2)min(-1) and a Km of 24.9±15.0μM. β-alanine, nipecotic acid, gaboxadol, GABA, vigabatrin, δ-ALA and guvacine inhibited the taurine uptake rate in a concentration dependent manner. The order of affinity for TauT was β-alanine>GABA>nipecotic acid>guvacine>δ-ALA>vigabatrin>gaboxadol with IC50-values of 0.04, 1.07, 2.02, 4.19, 4.94, 31.4 and 39.9mM, respectively. In conclusion, GABA mimetics inhibited taurine uptake in hyperosmotic rat renal SKPT cells. SKPT cells, which seem to be a useful model for investigating taurine transport in the short-term presence of high concentrations of osmolytes. Furthermore, analogues of β-alanine appear to have higher affinities for TauT than GABA-analogues. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Bio-mimetic mineralization potential of collagen hydrolysate obtained from chromium tanned leather waste.

    PubMed

    Banerjee, Pradipta; Madhu, S; Chandra Babu, N K; Shanthi, C

    2015-04-01

    Hydroxyapatite (HA) ceramics serve as an alternative to autogenous-free bone grafting by virtue of their excellent biocompatibility. However, chemically synthesized HA lacks the strong load-bearing capacity as required by bone. The bio-mimetic growth of HA crystals on collagen surface provides a feasible solution for synthesizing bone substitutes with the desired properties. This study deals with the utilization of the collagen hydrolysate recovered from leather waste as a substrate for promoting HA crystal growth. Bio-mimetic growth of HA was induced by subjecting the hydrolysate to various mineralization conditions. Parameters that would have a direct effect on crystal growth were varied to determine the optimal conditions necessary. Maximum mineralization was achieved with a combination of 10mM of CaCl2, 5mM of Na2HPO4, 100mM of NaCl and 0.575% glutaraldehyde at a pH of 7.4. The metal-protein interactions leading to formation of HA were identified through Fourier-transform infrared (FTIR) spectroscopy and x-ray diffraction (XRD) studies. The crystal dimensions were determined to be in the nanoscale range by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The size and crystallinity of bio-mimetically grown HA indicate that hydrolysate from leather waste can be used as an ideal alternative substrate for bone growth. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Prey from the eyes of predators: Color discriminability of aposematic and mimetic butterflies from an avian visual perspective.

    PubMed

    Su, Shiyu; Lim, Matthew; Kunte, Krushnamegh

    2015-11-01

    Predation exerts strong selection on mimetic butterfly wing color patterns, which also serve other functions such as sexual selection. Therefore, specific selection pressures may affect the sexes and signal components differentially. We tested three predictions about the evolution of mimetic resemblance by comparing wing coloration of aposematic butterflies and their Batesian mimics: (a) females gain greater mimetic advantage than males and therefore are better mimics, (b) due to intersexual genetic correlations, sexually monomorphic mimics are better mimics than female-limited mimics, and (c) mimetic resemblance is better on the dorsal wing surface that is visible to predators in flight. Using a physiological model of avian color vision, we quantified mimetic resemblance from predators' perspective, which showed that female butterflies were better mimics than males. Mimetic resemblance in female-limited mimics was comparable to that in sexually monomorphic mimics, suggesting that intersexual genetic correlations did not constrain adaptive response to selection for female-limited mimicry. Mimetic resemblance on the ventral wing surface was better than that on the dorsal wing surface, implying stronger natural and sexual selection on ventral and dorsal surfaces, respectively. These results suggest that mimetic resemblance in butterfly mimicry rings has evolved under various selective pressures acting in a sex- and wing surface-specific manner. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

  14. Identification of novel small-molecule Ulex europaeus I mimetics for targeted drug delivery.

    PubMed

    Hamashin, Christa; Spindler, Lisa; Russell, Shannon; Schink, Amy; Lambkin, Imelda; O'Mahony, Daniel; Houghten, Richard; Pinilla, Clemencia

    2003-11-17

    Lectin mimetics have been identified that may have potential application towards targeted drug delivery. Synthetic multivalent polygalloyl constructs effectively competed with Ulex europaeus agglutinin I (UEA1) for binding to intestinal Caco-2 cell membranes.

  15. Comparison of sea turtle thrombocyte aggregation to human platelet aggregation in whole blood.

    PubMed

    Soslau, Gerald; Prest, Phillip J; Class, Reiner; George, Robert; Paladino, Frank; Violetta, Gary

    2005-11-01

    The endangered sea turtles are living "fossils" that afford us an opportunity to study the hemostatic process as it likely existed millions of years ago. There are essentially no data about turtle thrombocyte aggregation prior to our studies. Thrombocytes are nucleated cells that serve the same hemostatic functions as the anucleated mammalian platelet. Sea turtle thrombocytes aggregate in response to collagen and beta-thrombin. Ristocetin induces an agglutination/aggregation response indicating the presence of a von Willebrand-like receptor, GPIb, found in all mammalian platelets. Samples treated with alpha-thrombin plus gamma-thrombin followed by ristocetin results in a rapid, stronger response than ristocetin alone. These responses are inhibited by the RGDS peptide that blocks fibrinogen cross-linking of mammalian platelets via the fibrinogen receptor, GPIIb/IIIa. Three platelet-like proteins, GPIb, GPIIb/IIIa and P-selection are detected in sea turtle thrombocytes by fluorescence activated cell sorting. Turtle thrombocytes do not respond to ADP, epinephrine, serotonin, thromboxane A2 mimetic, U46619, trypsin, or alpha-thrombin and gamma-thrombin added alone. Comparison of hemostasis in sea turtles to other vertebrates could provide a framework for understanding the structure/function and evolution of these pathways and their individual components.

  16. Phenotypic and Genetic Divergence among Poison Frog Populations in a Mimetic Radiation

    PubMed Central

    Twomey, Evan; Yeager, Justin; Brown, Jason Lee; Morales, Victor; Cummings, Molly; Summers, Kyle

    2013-01-01

    The evolution of Müllerian mimicry is, paradoxically, associated with high levels of diversity in color and pattern. In a mimetic radiation, different populations of a species evolve to resemble different models, which can lead to speciation. Yet there are circumstances under which initial selection for divergence under mimicry may be reversed. Here we provide evidence for the evolution of extensive phenotypic divergence in a mimetic radiation in Ranitomeya imitator, the mimic poison frog, in Peru. Analyses of color hue (spectral reflectance) and pattern reveal substantial divergence between morphs. However, we also report that there is a “transition-zone” with mixed phenotypes. Analyses of genetic structure using microsatellite variation reveals some differentiation between populations, but this does not strictly correspond to color pattern divergence. Analyses of gene flow between populations suggest that, while historical levels of gene flow were low, recent levels are high in some cases, including substantial gene flow between some color pattern morphs. We discuss possible explanations for these observations. PMID:23405150

  17. A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models.

    PubMed

    Huang, Shiu-Wen; Kuo, Heng-Lan; Hsu, Ming-Tsung; Tseng, Yufeng Jane; Lin, Shu-Wha; Kuo, Sheng-Chu; Peng, Hui-Chin; Lien, Jin-Cherng; Huang, Tur-Fu

    2016-08-01

    A novel benzimidazole derivative, nstpbp5185, was discovered through in vitro and in vivo evaluations for antiplatelet activity. Thromaboxane receptor (TP) is important in vascular physiology, haemostasis and pathophysiological thrombosis. Nstpbp5185 concentration-dependently inhibited human platelet aggregation caused by collagen, arachidonic acid and U46619. Nstpbp5185 caused a right-shift of the concentration-response curve of U46619 and competitively inhibited the binding of 3H-SQ-29548 to TP receptor expressed on HEK-293 cells, with an IC50 of 0.1 µM, indicating that nstpbp5185 is a TP antagonist. In murine thrombosis models, nstpbp5185 significantly prolonged the latent period in triggering platelet plug formation in mesenteric and FeCl3-induced thrombi formation, and increased the survival rate in pulmonary embolism model with less bleeding than aspirin. This study suggests nstpbp5185, an orally selective anti-thrombotic agent, acting through blockade of TXA2 receptor, may be efficacious for prevention or treatment of pathologic thrombosis.

  18. The arbitrary order mixed mimetic finite difference method for the diffusion equation

    DOE PAGES

    Gyrya, Vitaliy; Lipnikov, Konstantin; Manzini, Gianmarco

    2016-05-01

    Here, we propose an arbitrary-order accurate mimetic finite difference (MFD) method for the approximation of diffusion problems in mixed form on unstructured polygonal and polyhedral meshes. As usual in the mimetic numerical technology, the method satisfies local consistency and stability conditions, which determines the accuracy and the well-posedness of the resulting approximation. The method also requires the definition of a high-order discrete divergence operator that is the discrete analog of the divergence operator and is acting on the degrees of freedom. The new family of mimetic methods is proved theoretically to be convergent and optimal error estimates for flux andmore » scalar variable are derived from the convergence analysis. A numerical experiment confirms the high-order accuracy of the method in solving diffusion problems with variable diffusion tensor. It is worth mentioning that the approximation of the scalar variable presents a superconvergence effect.« less

  19. Systematic Computation of Nonlinear Cellular and Molecular Dynamics with Low-Power CytoMimetic Circuits: A Simulation Study

    PubMed Central

    Papadimitriou, Konstantinos I.; Stan, Guy-Bart V.; Drakakis, Emmanuel M.

    2013-01-01

    This paper presents a novel method for the systematic implementation of low-power microelectronic circuits aimed at computing nonlinear cellular and molecular dynamics. The method proposed is based on the Nonlinear Bernoulli Cell Formalism (NBCF), an advanced mathematical framework stemming from the Bernoulli Cell Formalism (BCF) originally exploited for the modular synthesis and analysis of linear, time-invariant, high dynamic range, logarithmic filters. Our approach identifies and exploits the striking similarities existing between the NBCF and coupled nonlinear ordinary differential equations (ODEs) typically appearing in models of naturally encountered biochemical systems. The resulting continuous-time, continuous-value, low-power CytoMimetic electronic circuits succeed in simulating fast and with good accuracy cellular and molecular dynamics. The application of the method is illustrated by synthesising for the first time microelectronic CytoMimetic topologies which simulate successfully: 1) a nonlinear intracellular calcium oscillations model for several Hill coefficient values and 2) a gene-protein regulatory system model. The dynamic behaviours generated by the proposed CytoMimetic circuits are compared and found to be in very good agreement with their biological counterparts. The circuits exploit the exponential law codifying the low-power subthreshold operation regime and have been simulated with realistic parameters from a commercially available CMOS process. They occupy an area of a fraction of a square-millimetre, while consuming between 1 and 12 microwatts of power. Simulations of fabrication-related variability results are also presented. PMID:23393550

  20. Effect of Vanadyl Rosiglitazone, a New Insulin-Mimetic Vanadium Complexes, on Glucose Homeostasis of Diabetic Mice.

    PubMed

    Jiang, Pingzhe; Dong, Zhen; Ma, Baicheng; Ni, Zaizhong; Duan, Huikun; Li, Xiaodan; Wang, Bin; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Li, Minggang

    2016-11-01

    Diabetes has been cited as the most challenging health problem in the twenty-first century. Accordingly, it is urgent to develop a new type of efficient and low-toxic antidiabetic medication. Since vanadium compounds have insulin-mimetic and potential hypoglycemic activities for type 1 and type 2 diabetes, a new trend has been developed using vanadium and organic ligands to form a new compound in order to increase the intestinal absorption and reduce the toxicity of vanadium compound. In the current investigation, a new organic vanadium compounds, vanadyl rosiglitazone, was synthesized and determined by infrared spectra. Vanadyl rosiglitazone and three other organic vanadium compounds were administered to the diabetic mice through oral administration for 5 weeks. The results of mouse model test indicated that vanadyl rosiglitazone could regulate the blood glucose level and relieve the symptoms of polydipsia, polyphagia, polyuria, and weight loss without side effects and was more effective than the other three organic vanadium compounds including vanadyl trehalose, vanadyl metformin, and vanadyl quercetin. The study indicated that vanadyl rosiglitazone presents insulin-mimetic activities, and it will be a good potential candidate for the development of a new type of oral drug for type 2 diabetes.

  1. Comparative Allometric Growth of the Mimetic Ephippid Reef Fishes Chaetodipterus faber and Platax orbicularis.

    PubMed

    Barros, Breno; Sakai, Yoichi; Pereira, Pedro H C; Gasset, Eric; Buchet, Vincent; Maamaatuaiahutapu, Moana; Ready, Jonathan S; Oliveira, Yrlan; Giarrizzo, Tommaso; Vallinoto, Marcelo

    2015-01-01

    Mimesis is a relatively widespread phenomenon among reef fish, but the ontogenetic processes relevant for mimetic associations in fish are still poorly understood. In the present study, the allometric growth of two allopatric leaf-mimetic species of ephippid fishes, Chaetodipterus faber from the Atlantic and Platax orbicularis from the Indo-Pacific, was analyzed using ten morphological variables. The development of fins was considered owing to the importance of these structures for mimetic behaviors during early life stages. Despite the anatomical and behavioral similarities in both juvenile and adult stages, C. faber and P. orbicularis showed distinct patterns of growth. The overall shape of C. faber transforms from a rounded-shape in mimetic juveniles to a lengthened profile in adults, while in P. orbicularis, juveniles present an oblong profile including dorsal and anal fins, with relative fin size diminishing while the overall profile grows rounder in adults. Although the two species are closely-related, the present results suggest that growth patterns in C. faber and P. orbicularis are different, and are probably independent events in ephippids that have resulted from similar selective processes.

  2. Molecular building kit of fused-proline-derived peptide mimetics allowing specific adjustment of the dihedral Psi angle.

    PubMed

    Einsiedel, Juergen; Lanig, Harald; Waibel, Reiner; Gmeiner, Peter

    2007-11-23

    Proline-derived peptide mimetics have become an area of paramount importance in peptide and protein chemistry. Since protein crystal structures frequently display Psi angles of 140-170 degrees for prolyl moieties, our intention was to design a completely novel series of 2,3-fused-proline-derived lactams covering this particular conformational space. Extending our recently described toolset of spirocyclic reverse-turn mimetics, we synthesized pyrrolidinyl-fused seven-, eight-, and nine-membered unsaturated lactam model peptides taking advantage of Grubbs' ring-closing metathesis. Investigating the seven-membered lactam 3a by means of IR and NMR spectroscopy and semiempirical molecular dynamics simulations, we could not observe a U-turn conformation; however, increasing the ring size to give eight- and nine-membered congeners revealed moderate and high type IotaIota beta-turn inducing properties. Interestingly, the conformational properties of our model systems depend on both the ring size of the fused dehydro-Freidinger lactam and the position of the endocyclic double bond. Superior reverse-turn inducing properties could be observed for the fused azacyclononenone 3e. According to diagnostic transanular NOEs, a discrete folding principle of the lactam ring strongly deviating from the regioisomeric lactams 3c,f explains the conformational behavior. Hence, we were able to establish a molecular building kit that allows adjustments of a wide range of naturally occurring proline Psi angles and thus can be exploited to probe molecular recognition and functional properties of biological systems.

  3. A spectral mimetic least-squares method

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bochev, Pavel; Gerritsma, Marc

    We present a spectral mimetic least-squares method for a model diffusion–reaction problem, which preserves key conservation properties of the continuum problem. Casting the model problem into a first-order system for two scalar and two vector variables shifts material properties from the differential equations to a pair of constitutive relations. We also use this system to motivate a new least-squares functional involving all four fields and show that its minimizer satisfies the differential equations exactly. Discretization of the four-field least-squares functional by spectral spaces compatible with the differential operators leads to a least-squares method in which the differential equations are alsomore » satisfied exactly. Additionally, the latter are reduced to purely topological relationships for the degrees of freedom that can be satisfied without reference to basis functions. Furthermore, numerical experiments confirm the spectral accuracy of the method and its local conservation.« less

  4. A spectral mimetic least-squares method

    DOE PAGES

    Bochev, Pavel; Gerritsma, Marc

    2014-09-01

    We present a spectral mimetic least-squares method for a model diffusion–reaction problem, which preserves key conservation properties of the continuum problem. Casting the model problem into a first-order system for two scalar and two vector variables shifts material properties from the differential equations to a pair of constitutive relations. We also use this system to motivate a new least-squares functional involving all four fields and show that its minimizer satisfies the differential equations exactly. Discretization of the four-field least-squares functional by spectral spaces compatible with the differential operators leads to a least-squares method in which the differential equations are alsomore » satisfied exactly. Additionally, the latter are reduced to purely topological relationships for the degrees of freedom that can be satisfied without reference to basis functions. Furthermore, numerical experiments confirm the spectral accuracy of the method and its local conservation.« less

  5. Smac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines.

    PubMed

    Cekay, Michael John; Roesler, Stefanie; Frank, Tanja; Knuth, Anne-Kathrin; Eckhardt, Ines; Fulda, Simone

    2017-12-01

    Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)γ to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i.e. BV6, Birinapant), pointing to a broader relevance. Importantly, individual genetic knockdown of key components of necroptosis signaling, i.e. receptor-interacting protein (RIP) 1, RIP3 or mixed lineage kinase domain-like pseudokinase (MLKL), significantly protects from BV6/IFNγ-induced cell death. Similarly, pharmacological inhibitors of RIP1 (necrostatin-1(Nec-1)), RIP3 (GSK'872) or MLKL (necrosulfonamide (NSA)) significantly reduce BV6/IFNγ-stimulated cell death. Of note, IFN-regulatory factor (IRF)1 is required for BV6/IFNγ-mediated necroptosis, as IRF1 silencing provides protection from cell death. By comparison, antibodies blocking tumor necrosis factor (TNF)α, TNF-related apoptosis-inducing ligand (TRAIL) or CD95 ligand fail to inhibit BV6/IFNγ-induced cell death, pointing to a mechanism independently of death receptor ligands. This is the first report showing that Smac mimetics synergize with IFNγ to trigger necroptosis in apoptosis-resistant cancer cells with important implications for Smac mimetic-based strategies for the treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. GW627368X ((N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP4 receptor antagonist

    PubMed Central

    Wilson, Richard J; Giblin, Gerard M P; Roomans, Susan; Rhodes, Sharron A; Cartwright, Kerri-Ann; Shield, Vanessa J; Brown, Jason; Wise, Alan; Chowdhury, Jannatara; Pritchard, Sara; Coote, Jim; Noel, Lloyd S; Kenakin, Terry; Burns-Kurtis, Cynthia L; Morrison, Valerie; Gray, David W; Giles, Heather

    2006-01-01

    N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP4 receptors with additional human TP receptor affinity. At recombinant human prostanoid EP4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE2 concentration–effect (E/[A]) curves resulting in an affinity (pKb) estimate of 7.9±0.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used. In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30–300 nM) produced parallel rightward displacement of PGE2 E/[A] curves (pKb=9.2±0.2; slope=1). GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 μM) produced 100% inhibition of U-46619 (EC100)-induced aggregation (approximate pA2 ∼7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 μM) did not displace U-46619 E/[A] curves indicating an affinity of <5.0 for rabbit and guinea-pig prostanoid TP receptors. In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH2, EP2, EP3, IP and FP receptors. At prostanoid EP1 receptors, GW627368X was an antagonist with a pA2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP2 receptors the pA2 of GW627368X was <5.0. In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP4 and TP receptors (pKi=7.0±0.2 (n=10) and 6.8 (n=2), respectively). Affinity for all other human prostanoid receptors was <5.3. GW627368X will be a valuable tool to explore the role of the prostanoid EP4 receptor in many physiological and pathological settings. PMID:16604093

  7. C-glycoside mimetics inhibit glioma stem cell proliferation, migration, and invasion.

    PubMed

    Clarion, Ludovic; Jacquard, Carine; Sainte-Catherine, Odile; Decoux, Marc; Loiseau, Séverine; Rolland, Marc; Lecouvey, Marc; Hugnot, Jean-Philippe; Volle, Jean-Noël; Virieux, David; Pirat, Jean-Luc; Bakalara, Norbert

    2014-10-23

    This paper reports the design and synthesis of C-glycoside mimetics (d-glycero-d-talo- and d-glycero-d-galactopyranose analogues), a subset of the recently published phostines, belonging to the [1,2]oxaphosphinane core. Eighteen new compounds were tested against 11 cancer cell types belonging to six categories of tumor tissues and three different species. The hit compound 5.3d inhibited invasion and migration of both GBM stem cells (Gli7 and Gli4) and GBM cancer cell lines (C6, SNB75) on fibronectin, vitronectin, and laminin. Ki values for Gli7 and Gli4 migration inhibition on fibronectin were 16 and 31 nM respectively. Ki values for invasion inhibition in a 3D system were 46 nM for Gli7 and 290 nM for Gli4. These activities were associated with an antiproliferative effect on Gli4 (EC50 = 5.20 μM) and Gli7 (EC50 = 2.33 μM). In conclusion, the heptopyranose mimetic 5.3d, devoid of toxicity on astrocyte and cortical neuron cultures at concentrations below 100 μM, opens new therapeutic perspectives against glioblastoma.

  8. Low-cost endoscopic third ventriculostomy simulator with mimetic endoscope.

    PubMed

    Garling, Richard Justin; Jin, Xin; Yang, Jianzhong; Khasawneh, Ahmad H; Harris, Carolyn Anne

    2018-05-11

    OBJECTIVE Hydrocephalus affects approximately 1 in 500 people in the US, yet ventricular shunting, the gold standard of treatment, has a nearly 85% failure rate. Endoscopic third ventriculostomy (ETV) is an alternative surgical approach for a specific subset of hydrocephalic patients, but can be limited by the inability of neurosurgical residents to practice prior to patient contact. The goal of this study was to create an affordable ETV model and endoscope for resident training. METHODS Open-source software was used to isolate the skull and brain from the CT and MR images of a 2-year-old boy with hydrocephalus. A 3D printer created the skull and a 3D mold of the brain. A mixture of silicone and silicone tactile mutator was used to cast the brain mold prior to subsequent compression and shearing modulus testing. A mimetic endoscope was then created from basic supplies and a 3D printed frame. A small cohort of neurosurgical residents and attending physicians evaluated the ETV simulator with mimetic endoscope. RESULTS The authors successfully created a mimetic endoscope and ETV simulator. After compression and shearing modulus testing, a silicone/Slacker ratio between 10:6 and 10:7 was found to be similar to that of human brain parenchyma. Eighty-seven percent of participants strongly agreed that the simulator was useful for resident training, and 93% strongly agreed that the simulator helped them understand how to orient themselves with the endoscope. CONCLUSIONS The authors created an affordable (US$123, excluding 3D printer), easy-to-use ETV simulator with endoscope. Previous models have required expensive software and costly operative endoscopes that may not be available to most residents. Instead, this attempt takes advantage of open-source software for the manipulation and fabrication of a patient-specific mold. This model can assist with resident development, allowing them to safely practice use of the endoscope in ETV.

  9. Comparative Allometric Growth of the Mimetic Ephippid Reef Fishes Chaetodipterus faber and Platax orbicularis

    PubMed Central

    Barros, Breno; Sakai, Yoichi; Pereira, Pedro H. C.; Gasset, Eric; Buchet, Vincent; Maamaatuaiahutapu, Moana; Ready, Jonathan S.; Oliveira, Yrlan; Giarrizzo, Tommaso; Vallinoto, Marcelo

    2015-01-01

    Mimesis is a relatively widespread phenomenon among reef fish, but the ontogenetic processes relevant for mimetic associations in fish are still poorly understood. In the present study, the allometric growth of two allopatric leaf-mimetic species of ephippid fishes, Chaetodipterus faber from the Atlantic and Platax orbicularis from the Indo-Pacific, was analyzed using ten morphological variables. The development of fins was considered owing to the importance of these structures for mimetic behaviors during early life stages. Despite the anatomical and behavioral similarities in both juvenile and adult stages, C. faber and P. orbicularis showed distinct patterns of growth. The overall shape of C. faber transforms from a rounded-shape in mimetic juveniles to a lengthened profile in adults, while in P. orbicularis, juveniles present an oblong profile including dorsal and anal fins, with relative fin size diminishing while the overall profile grows rounder in adults. Although the two species are closely-related, the present results suggest that growth patterns in C. faber and P. orbicularis are different, and are probably independent events in ephippids that have resulted from similar selective processes. PMID:26630347

  10. The potent inhibition of vapiprost, a novel thromboxane A2 receptor antagonist, on the secondary aggregation and ATP release of human platelets.

    PubMed

    Horie, S; Yamada, M; Satoh, M; Noritake, S; Hiraishi, S; Kizaki, K; Kurusu, O; Nakahara, T; Ishii, H; Kazama, M

    1997-06-01

    The inhibitory effects of vapiprost hydrochloride (vapiprost), a novel thromboxane A2 receptor antagonist, on platelet aggregation and ATP release were studied using platelet rich plasma (PRP) of humans, guinea pigs, rabbits and rats. In in vitro experiments with human platelet, vapiprost inhibited the aggregation and ATP release stimulated with U-46619, collagen or arachidonic acid (AA) at an IC50 of less than 2.1 x 10(-8) M. Vapiprost did not inhibit the primary aggregation or ATP release of human platelets stimulated with adenosine 5'-diphosphate (ADP), epinephrine (Epi) or platelet activating factor (PAF), but inhibited the secondary aggregation stimulated with those agonists at an IC50 of less than 1.3 x 10(-7) M. The sensitivity of platelets in various species of animals to vapiprost was in the following order: human > or = guinea pigs > rats > rabbits. In ex vivo experiments with guinea pigs which received a single oral dose of vapiprost, the agent demonstrated strong inhibition of ATP release from platelets stimulated with U-46619, collagen or AA at an ID50 of less than 25.8 micrograms/kg. These inhibitory effects were observed within 30 min and sustained for 24 h at a single dosage of 5 mg/kg of vapiprost. In AA-induced pulmonary infarction models of mice, the sudden death rates decreased significantly with the oral administration of 10 mg/kg or more of vapiprost. These results indicate that vapiprost effectively inhibits the secondary aggregation and ATP release of human platelets stimulated with various agonists, and that guinea pig and human platelets are similar in response to vapiprost. Furthermore, it was demonstrated in ex vivo experiments with guinea pigs that the inhibitory action of vapiprost appears rapidly and lasts for long periods.

  11. Species differences in the effects of prostanoids on MAP kinase phosphorylation, myosin light chain phosphorylation and contraction in bovine and cat iris sphincter smooth muscle.

    PubMed

    Kaddour-Djebbar, I; Ansari, H R; Akhtar, R A; Abdel-Latif, A A

    2005-01-01

    There is evidence from our own laboratory and that of others that EP-receptor ligands are strong contractile agonists in bovine iris sphincter and that FP-receptor agonists are strong contractile agonists in cat iris sphincter. Here, we have investigated the effects of prostaglandin (PG) receptor agonists of the FP-, EP-, TP- and DP-class on myosin light chain (MLC) phosphorylation, p42/p44 MAP kinase phosphorylation and contraction in the iris sphincter of bovine and cat. Using three signal transduction mechanism assays, namely MLC phosphorylation, MAP kinase phosphorylation and contraction, we demonstrated that in bovine iris sphincter the rank order of potency of the PG agonists in the contractile and MLC phosphorylation assays is as follows: E2>U46619>F2alpha>D2, and in cat F2alpha>D2>E2>U46619. In the MAP kinase assay, in bovine iris sphincter the rank order of potency is E2>F2alpha and in cat F2alpha>E2. These conclusions are supported by the following findings: (1) In the contractile assay, in the bovine sphincter the EC50s for PGF2alpha, PGE2, U46619 and PGD2 were found to be 1.4x10(-7), 5.0x10(-9), 9.0x10(-9) and 1.3x10(-6)M, respectively, and the corresponding values in the cat were 1.9x10(-8), 2.3x10(-7), 1.5x10(-6) and 6.9x10(-8)M, respectively. (2) In the MLC phophorylation assay, in the bovine sphincter PGF2alpha, PGE2, U46619 and PGD2 increased MLC phophorylation by 118%, 165%, 153% and 72%, respectively, and the corresponding values in cat were 175%, 99%, 90% and 95%, respectively. (3) In the MAP kinase assay, in the bovine iris sphincter PGF2alpha and PGE2, increased MAP kinase phosphorylation by 276% and 328%, respectively, and the corresponding values in cat were 308% and 245%, respectively. The data presented demonstrate pronounced species differences in the effects of the prostanoids on the MLC kinase signaling pathway in bovine and cat irides and furthermore confirm the existence of FP-receptors in that of the bovine.

  12. A mimetic finite difference method for the Stokes problem with elected edge bubbles

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lipnikov, K; Berirao, L

    2009-01-01

    A new mimetic finite difference method for the Stokes problem is proposed and analyzed. The unstable P{sub 1}-P{sub 0} discretization is stabilized by adding a small number of bubble functions to selected mesh edges. A simple strategy for selecting such edges is proposed and verified with numerical experiments. The discretizations schemes for Stokes and Navier-Stokes equations must satisfy the celebrated inf-sup (or the LBB) stability condition. The stability condition implies a balance between discrete spaces for velocity and pressure. In finite elements, this balance is frequently achieved by adding bubble functions to the velocity space. The goal of this articlemore » is to show that the stabilizing edge bubble functions can be added only to a small set of mesh edges. This results in a smaller algebraic system and potentially in a faster calculations. We employ the mimetic finite difference (MFD) discretization technique that works for general polyhedral meshes and can accomodate non-uniform distribution of stabilizing bubbles.« less

  13. A Case of Mimetic Isomorphism: A Short-Cut to Increasing Loyalty to Academia

    ERIC Educational Resources Information Center

    Orkodashvili, Mariam

    2008-01-01

    The paper discusses the process of shortening career path to leadership positions in academia that could serve as an example of mimetic isomorphism, where university tries to apply business-like quick result-oriented strategies. This strategy incentivizes young faculty to stay in universities and keep loyalty to academia. This process could also…

  14. Compensatory and mimetic conditioned responses to effects of heroin in addicted persons.

    PubMed

    Trujillo, Humberto M; Oviedo-Joekes, Eugenia; Vargas, Cristina

    2006-02-01

    Study 1: The aim of this study was to analyze in persons detoxified of heroin, compensatory conditioned responses (CCRs) that are opposite to the unconditioned physiological, and subjective effects that are induced by this substance. The procedure consisted in presenting slides with images of neutral stimuli (NSs) and conditioned stimuli (CSs) of heroin to both non-addicted and detoxified addicted persons. The evaluated responses were heart rate (HR) and desire for heroin (DH). Study 2: The aim was to facilitate the emission of mimetic conditioned responses (MCRs) to the unconditioned physiological, and subjective effects of heroin in detoxified heroin addicts. Three different stimulus series were manipulated: SA, during which the participant remained alone; SB, administration of a needle prick given by the researcher; SC, performance of the "pump" ritual without drug by the participants. The responses measured were HR and DH. The results of both studies are considered, respectively, to be indicators of compensatory and mimetic conditioned responses.

  15. High-Density Lipoprotein-Targeted Therapy and Apolipoprotein A-I Mimetic Peptides.

    PubMed

    Uehara, Yoshinari; Chiesa, Giulia; Saku, Keijiro

    2015-01-01

    Numerous randomized clinical trials have established statins as the major standard therapy for atherosclerotic diseases because these molecules decrease the plasma level of low-density lipoprotein (LDL) cholesterol and moderately increase that of plasma high-density lipoprotein (HDL) cholesterol. The reverse cholesterol transport pathway, mediated by HDL particles, has a relevant antiatherogenic potential. An important approach to HDL-targeted therapy is optimization of the HDL-cholesterol level and enhanced removal of plasma cholesterol, together with the prevention and mitigation of inflammation related to atherosclerosis. Small-molecule inhibitors of cholesteryl ester transfer protein (CETP) increase the HDL-cholesterol level in subjects with normal or low HDL-cholesterol. However, CETP inhibitors do not seem to reduce the risk of atherosclerotic diseases. HDL therapies using reconstituted HDL, including apolipoprotein (Apo) A-I Milano, ApoA-I mimetics, or full-length ApoA-I, are dramatically effective in animal models. Of those, the ApoA-I-mimetic peptide called FAMP effectively removes cholesterol via the ABCA1 transporter and acts as an antiatherosclerotic agent by enhancing the biological functions of HDL without elevating the HDL-cholesterol level. Our review of the literature leads us to conclude that HDL-targeted therapies have significant atheroprotective potential and thus may effectively treat patients with cardiovascular diseases.

  16. Minimalist Antibodies and Mimetics: An Update and Recent Applications.

    PubMed

    Bruce, Virginia J; Ta, Angeline N; McNaughton, Brian R

    2016-10-17

    The immune system utilizes antibodies to recognize foreign or disease-relevant receptors, initiating an immune response to destroy unwelcomed guests. Because researchers can evolve antibodies to bind virtually any target, it is perhaps unsurprising that these reagents, and their small-molecule conjugates, are used extensively in clinical and basic research environments. However, virtues of antibodies are countered by significant challenges. Foremost among these is the need for expression in mammalian cells (largely due to often necessary post-translational modifications). In response to these challenges, researchers have developed an array of minimalist antibodies and mimetics, which are smaller, more stable, simpler to express in Escherichia coli, and amendable to laboratory evolution and protein engineering. Here we describe these scaffolds and discuss recent applications of minimalist antibodies and mimetics. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Involvement of connexin 43 phosphorylation and gap junctional communication between smooth muscle cells in vasopressin-induced ROCK-dependent vasoconstriction after hemorrhagic shock.

    PubMed

    Yang, Guangming; Peng, Xiaoyong; Wu, Yue; Li, Tao; Liu, Liangming

    2017-10-01

    We examined the roles played by gap junctions (GJs) and the GJ channel protein connexin 43 (Cx43) in arginine vasopressin (AVP)-induced vasoconstriction after hemorrhagic shock and their relationship to Rho kinase (ROCK) and protein kinase C (PKC). The results showed that AVP induced an endothelium-independent contraction in rat superior mesenteric arteries (SMAs). Blocking the GJs significantly decreased the contractile response of SMAs and vascular smooth muscle cells (VSMCs) to AVP after shock and hypoxia. The selective Cx43-mimetic peptide inhibited the vascular contractile effect of AVP after shock and hypoxia. AVP restored hypoxia-induced decrease of Cx43 phosphorylation at Ser 262 and gap junctional communication in VSMCs. Activation of RhoA with U-46619 increased the contractile effect of AVP. This effect was antagonized by the ROCK inhibitor Y27632 and the Cx43-mimetic peptide. In contrast, neither an agonist nor an inhibitor of PKC had significant effects on AVP-induced contraction after hemorrhagic shock. In addition, silencing of Cx43 with siRNA blocked the AVP-induced increase of ROCK activity in hypoxic VSMCs. In conclusion, AVP-mediated vascular contractile effects are endothelium and myoendothelial gap junction independent. Gap junctions between VSMCs, gap junctional communication, and Cx43 phosphorylation at Ser 262 play important roles in the vascular effects of AVP. RhoA/ROCK, but not PKC, is involved in this process. Copyright © 2017 the American Physiological Society.

  18. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes.

    PubMed

    Fulcher, G; Matthews, D R; Perkovic, V; de Zeeuw, D; Mahaffey, K W; Mathieu, C; Woo, V; Wysham, C; Capuano, G; Desai, M; Shaw, W; Vercruysse, F; Meininger, G; Neal, B

    2016-01-01

    To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist]. CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18. Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues. In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition. © 2015 John Wiley & Sons Ltd.

  19. Novel thrombopoietin mimetic peptides bind c-Mpl receptor: Synthesis, biological evaluation and molecular modeling.

    PubMed

    Liu, Yaquan; Tian, Fang; Zhi, Dejuan; Wang, Haiqing; Zhao, Chunyan; Li, Hongyu

    2017-02-01

    Thrombopoietin (TPO) acts in promoting the proliferation of hematopoietic stem cells and by initiating specific maturation events in megakaryocytes. Now, TPO-mimetic peptides with amino acid sequences unrelated to TPO are of considerable pharmaceutical interest. In the present paper, four new TPO mimetic peptides that bind and activate c-Mpl receptor have been identified, synthesized and tested by Dual-Luciferase reporter gene assay for biological activities. The molecular modeling research was also approached to understand key molecular mechanisms and structural features responsible for peptide binding with c-Mpl receptor. The results presented that three of four mimetic peptides showed significant activities. In addition, the molecular modeling approaches proved hydrophobic interactions were the driven positive forces for binding behavior between peptides and c-Mpl receptor. TPO peptide residues in P7, P13 and P7' positions were identified by the analysis of hydrogen bonds and energy decompositions as the key ones for benefiting better biological activities. Our data suggested the synthesized peptides have considerable potential for the future development of stable and highly active TPO mimetic peptides. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. DRP-1 is required for BH3 mimetic-mediated mitochondrial fragmentation and apoptosis

    PubMed Central

    Milani, Mateus; Byrne, Dominic P; Greaves, Georgia; Butterworth, Michael; Cohen, Gerald M; Eyers, Patrick A; Varadarajan, Shankar

    2017-01-01

    The concept of using BH3 mimetics as anticancer agents has been substantiated by the efficacy of selective drugs, such as Navitoclax and Venetoclax, in treating BCL-2-dependent haematological malignancies. However, most solid tumours depend on MCL-1 for survival, which is highly amplified in multiple cancers and a major factor determining chemoresistance. Most MCL-1 inhibitors that have been generated so far, while demonstrating early promise in vitro, fail to exhibit specificity and potency in a cellular context. To address the lack of standardised assays for benchmarking the in vitro binding of putative inhibitors before analysis of their cellular effects, we developed a rapid differential scanning fluorimetry (DSF)-based assay, and used it to screen a panel of BH3 mimetics. We next contrasted their binding signatures with their ability to induce apoptosis in a MCL-1 dependent cell line. Of all the MCL-1 inhibitors tested, only A-1210477 induced rapid, concentration-dependent apoptosis, which strongly correlated with a thermal protective effect on MCL-1 in the DSF assay. In cells that depend on both MCL-1 and BCL-XL, A-1210477 exhibited marked synergy with A-1331852, a BCL-XL specific inhibitor, to induce cell death. Despite this selectivity and potency, A-1210477 induced profound structural changes in the mitochondrial network in several cell lines that were not phenocopied following MCL-1 RNA interference or transcriptional repression, suggesting that A-1210477 induces mitochondrial fragmentation in an MCL-1-independent manner. However, A-1210477-induced mitochondrial fragmentation was dependent upon DRP-1, and silencing expression levels of DRP-1 diminished not just mitochondrial fragmentation but also BH3 mimetic-mediated apoptosis. These findings provide new insights into MCL-1 ligands, and the interplay between DRP-1 and the anti-apoptotic BCL-2 family members in the regulation of apoptosis. PMID:28079887

  1. Drug delivery vectors based on filamentous bacteriophages and phage-mimetic nanoparticles.

    PubMed

    Ju, Zhigang; Sun, Wei

    2017-11-01

    With the development of nanomedicine, a mass of nanocarriers have been exploited and utilized for targeted drug delivery, including liposomes, polymers, nanoparticles, viruses, and stem cells. Due to huge surface bearing capacity and flexible genetic engineering property, filamentous bacteriophage and phage-mimetic nanoparticles are attracting more and more attentions. As a rod-like bio-nanofiber without tropism to mammalian cells, filamentous phage can be easily loaded with drugs and directly delivered to the lesion location. In particular, chemical drugs can be conjugated on phage surface by chemical modification, and gene drugs can also be inserted into the genome of phage by recombinant DNA technology. Meanwhile, specific peptides/proteins displayed on the phage surface are able to conjugate with nanoparticles which will endow them specific-targeting and huge drug-loading capacity. Additionally, phage peptides/proteins can directly self-assemble into phage-mimetic nanoparticles which may be applied for self-navigating drug delivery nanovehicles. In this review, we summarize the production of phage particles, the identification of targeting peptides, and the recent applications of filamentous bacteriophages as well as their protein/peptide for targeting drug delivery in vitro and in vivo. The improvement of our understanding of filamentous bacteriophage and phage-mimetic nanoparticles will supply new tools for biotechnological approaches.

  2. The arbitrary order mimetic finite difference method for a diffusion equation with a non-symmetric diffusion tensor

    NASA Astrophysics Data System (ADS)

    Gyrya, V.; Lipnikov, K.

    2017-11-01

    We present the arbitrary order mimetic finite difference (MFD) discretization for the diffusion equation with non-symmetric tensorial diffusion coefficient in a mixed formulation on general polygonal meshes. The diffusion tensor is assumed to be positive definite. The asymmetry of the diffusion tensor requires changes to the standard MFD construction. We present new approach for the construction that guarantees positive definiteness of the non-symmetric mass matrix in the space of discrete velocities. The numerically observed convergence rate for the scalar quantity matches the predicted one in the case of the lowest order mimetic scheme. For higher orders schemes, we observed super-convergence by one order for the scalar variable which is consistent with the previously published result for a symmetric diffusion tensor. The new scheme was also tested on a time-dependent problem modeling the Hall effect in the resistive magnetohydrodynamics.

  3. Overcoming EMT-driven therapeutic resistance by BH3 mimetics.

    PubMed

    Keitel, Ulrike; Scheel, Christina; Dobbelstein, Matthias

    2014-01-01

    Epithelial-mesenchymal transition (EMT) contributes to the progression of cancer through enhanced invasion and stem-like properties of cancer cells. Additionally, EMT confers resistance towards many chemotherapeutics. We recently described a mechanism that mediates EMT-driven chemoresistance through augmented levels of Bcl-xL, an anti-apoptotic member of the Bcl-2 family (Keitel et al., Oncotarget, in press). Here, we elaborate on how these findings pertain to cancer cells dispersed in the tumor-adjacent stroma of breast cancer tissues, and how BH3-mimetics may provide a therapeutic strategy to eliminate cancer cell populations that have passed through an EMT.

  4. Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice

    PubMed Central

    Trapeaux, J; Busseuil, D; Shi, Y; Nobari, S; Shustik, D; Mecteau, M; El-Hamamsy, I; Lebel, M; Mongrain, R; Rhéaume, E; Tardif, J-C

    2013-01-01

    Background and Purpose We have shown that infusions of apolipoprotein A-I (ApoA-I) mimetic peptide induced regression of aortic valve stenosis (AVS) in rabbits. This study aimed at determining the effects of ApoA-I mimetic therapy in mice with calcific or fibrotic AVS. Experimental Approach Apolipoprotein E-deficient (ApoE−/−) mice and mice with Werner progeria gene deletion (WrnΔhel/Δhel) received high-fat diets for 20 weeks. After developing AVS, mice were randomized to receive saline (placebo group) or ApoA-I mimetic peptide infusions (ApoA-I treated groups, 100 mg·kg−1 for ApoE−/− mice; 50 mg·kg−1 for Wrn mice), three times per week for 4 weeks. We evaluated effects on AVS using serial echocardiograms and valve histology. Key Results Aortic valve area (AVA) increased in both ApoE−/− and Wrn mice treated with the ApoA-I mimetic compared with placebo. Maximal sinus wall thickness was lower in ApoA-I treated ApoE−/− mice. The type I/III collagen ratio was lower in the sinus wall of ApoA-I treated ApoE−/− mice compared with placebo. Total collagen content was reduced in aortic valves of ApoA-I treated Wrn mice. Our 3D computer model and numerical simulations confirmed that the reduction in aortic root wall thickness resulted in improved AVA. Conclusions and Implications ApoA-I mimetic treatment reduced AVS by decreasing remodelling and fibrosis of the aortic root and valve in mice. PMID:23638718

  5. Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate.

    PubMed

    Muzaffar, S; Shukla, N; Bond, M; Sala-Newby, G B; Newby, A C; Angelini, G D; Jeremy, J Y

    2008-11-01

    To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac(1) and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs). hVSMCs were incubated with xanthine-xanthine oxidase (X-XO; a superoxide generating system) or the thromboxane A(2) analogue, U46619 (+/-superoxide dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was assessed using Western blotting and superoxide measured. The role of Rac(1) in superoxide generation was assessed by overexpressing either the dominant-negative or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied. Following 16 h incubation, U46619 and X-XO promoted the expression of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over the same time course. X-XO and U46619 both promoted the formation of superoxide. Overexpression of dominant-negative Rac(1) or addition of iloprost, DETA-NONOate or Y27632 completely blocked both superoxide release and PDE5 protein expression and activity. These data demonstrate that superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions of NO.

  6. Geographic variation in mimetic precision among different species of coral snake mimics.

    PubMed

    Akcali, C K; Pfennig, D W

    2017-07-01

    Batesian mimicry is widespread, but whether and why different species of mimics vary geographically in resemblance to their model is unclear. We characterized geographic variation in mimetic precision among four Batesian mimics of coral snakes. Each mimic occurs where its model is abundant (i.e. in 'deep sympatry'), rare (i.e. at the sympatry/allopatry boundary or 'edge sympatry') and absent (i.e. in allopatry). Geographic variation in mimetic precision was qualitatively different among these mimics. In one mimic, the most precise individuals occurred in edge sympatry; in another, they occurred in deep sympatry; in the third, they occurred in allopatry; and in the fourth, precise mimics were not concentrated anywhere throughout their range. Mimicry was less precise in allopatry than in sympatry in only two mimics. We present several nonmutually exclusive hypotheses for these patterns. Generally, examining geographic variation in mimetic precision - within and among different mimics - offers novel insights into the causes and consequences of mimicry. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  7. HDL mimetic CER-001 targets atherosclerotic plaques in patients.

    PubMed

    Zheng, Kang He; van der Valk, Fleur M; Smits, Loek P; Sandberg, Mara; Dasseux, Jean-Louis; Baron, Rudi; Barbaras, Ronald; Keyserling, Constance; Coolen, Bram F; Nederveen, Aart J; Verberne, Hein J; Nell, Thijs E; Vugts, Danielle J; Duivenvoorden, Raphaël; Fayad, Zahi A; Mulder, Willem J M; van Dongen, Guus A M S; Stroes, Erik S G

    2016-08-01

    Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI. Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. Netherlands Trial Registry - NTR5178. http

  8. Functional Mimetics of the HIV-1 CCR5 Co-Receptor Displayed on the Surface of Magnetic Liposomes.

    PubMed

    Kuzmina, Alona; Vaknin, Karin; Gdalevsky, Garik; Vyazmensky, Maria; Marks, Robert S; Taube, Ran; Engel, Stanislav

    2015-01-01

    Chemokine G protein coupled receptors, principally CCR5 or CXCR4, function as co-receptors for HIV-1 entry into CD4+ T cells. Initial binding of the viral envelope glycoprotein (Env) gp120 subunit to the host CD4 receptor induces a cascade of structural conformational changes that lead to the formation of a high-affinity co-receptor-binding site on gp120. Interaction between gp120 and the co-receptor leads to the exposure of epitopes on the viral gp41 that mediates fusion between viral and cell membranes. Soluble CD4 (sCD4) mimetics can act as an activation-based inhibitor of HIV-1 entry in vitro, as it induces similar structural changes in gp120, leading to increased virus infectivity in the short term but to virus Env inactivation in the long term. Despite promising clinical implications, sCD4 displays low efficiency in vivo, and in multiple HIV strains, it does not inhibit viral infection. This has been attributed to the slow kinetics of the sCD4-induced HIV Env inactivation and to the failure to obtain sufficient sCD4 mimetic levels in the serum. Here we present uniquely structured CCR5 co-receptor mimetics. We hypothesized that such mimetics will enhance sCD4-induced HIV Env inactivation and inhibition of HIV entry. Co-receptor mimetics were derived from CCR5 gp120-binding epitopes and functionalized with a palmitoyl group, which mediated their display on the surface of lipid-coated magnetic beads. CCR5-peptidoliposome mimetics bound to soluble gp120 and inhibited HIV-1 infectivity in a sCD4-dependent manner. We concluded that CCR5-peptidoliposomes increase the efficiency of sCD4 to inhibit HIV infection by acting as bait for sCD4-primed virus, catalyzing the premature discharge of its fusion potential.

  9. Functional Mimetics of the HIV-1 CCR5 Co-Receptor Displayed on the Surface of Magnetic Liposomes

    PubMed Central

    Kuzmina, Alona; Vaknin, Karin; Gdalevsky, Garik; Vyazmensky, Maria; Marks, Robert S.; Taube, Ran

    2015-01-01

    Chemokine G protein coupled receptors, principally CCR5 or CXCR4, function as co-receptors for HIV-1 entry into CD4+ T cells. Initial binding of the viral envelope glycoprotein (Env) gp120 subunit to the host CD4 receptor induces a cascade of structural conformational changes that lead to the formation of a high-affinity co-receptor-binding site on gp120. Interaction between gp120 and the co-receptor leads to the exposure of epitopes on the viral gp41 that mediates fusion between viral and cell membranes. Soluble CD4 (sCD4) mimetics can act as an activation-based inhibitor of HIV-1 entry in vitro, as it induces similar structural changes in gp120, leading to increased virus infectivity in the short term but to virus Env inactivation in the long term. Despite promising clinical implications, sCD4 displays low efficiency in vivo, and in multiple HIV strains, it does not inhibit viral infection. This has been attributed to the slow kinetics of the sCD4-induced HIV Env inactivation and to the failure to obtain sufficient sCD4 mimetic levels in the serum. Here we present uniquely structured CCR5 co-receptor mimetics. We hypothesized that such mimetics will enhance sCD4-induced HIV Env inactivation and inhibition of HIV entry. Co-receptor mimetics were derived from CCR5 gp120-binding epitopes and functionalized with a palmitoyl group, which mediated their display on the surface of lipid-coated magnetic beads. CCR5-peptidoliposome mimetics bound to soluble gp120 and inhibited HIV-1 infectivity in a sCD4-dependent manner. We concluded that CCR5-peptidoliposomes increase the efficiency of sCD4 to inhibit HIV infection by acting as bait for sCD4-primed virus, catalyzing the premature discharge of its fusion potential. PMID:26629902

  10. The arbitrary order mimetic finite difference method for a diffusion equation with a non-symmetric diffusion tensor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gyrya, V.; Lipnikov, K.

    Here, we present the arbitrary order mimetic finite difference (MFD) discretization for the diffusion equation with non-symmetric tensorial diffusion coefficient in a mixed formulation on general polygonal meshes. The diffusion tensor is assumed to be positive definite. The asymmetry of the diffusion tensor requires changes to the standard MFD construction. We also present new approach for the construction that guarantees positive definiteness of the non-symmetric mass matrix in the space of discrete velocities. The numerically observed convergence rate for the scalar quantity matches the predicted one in the case of the lowest order mimetic scheme. For higher orders schemes, wemore » observed super-convergence by one order for the scalar variable which is consistent with the previously published result for a symmetric diffusion tensor. The new scheme was also tested on a time-dependent problem modeling the Hall effect in the resistive magnetohydrodynamics.« less

  11. The arbitrary order mimetic finite difference method for a diffusion equation with a non-symmetric diffusion tensor

    DOE PAGES

    Gyrya, V.; Lipnikov, K.

    2017-07-18

    Here, we present the arbitrary order mimetic finite difference (MFD) discretization for the diffusion equation with non-symmetric tensorial diffusion coefficient in a mixed formulation on general polygonal meshes. The diffusion tensor is assumed to be positive definite. The asymmetry of the diffusion tensor requires changes to the standard MFD construction. We also present new approach for the construction that guarantees positive definiteness of the non-symmetric mass matrix in the space of discrete velocities. The numerically observed convergence rate for the scalar quantity matches the predicted one in the case of the lowest order mimetic scheme. For higher orders schemes, wemore » observed super-convergence by one order for the scalar variable which is consistent with the previously published result for a symmetric diffusion tensor. The new scheme was also tested on a time-dependent problem modeling the Hall effect in the resistive magnetohydrodynamics.« less

  12. A safe lithium mimetic for bipolar disorder

    PubMed Central

    Singh, Nisha; Halliday, Amy C.; Thomas, Justyn M.; Kuznetsova, Olga; Baldwin, Rhiannon; Woon, Esther C. Y.; Aley, Parvinder K.; Antoniadou, Ivi; Sharp, Trevor; Vasudevan, Sridhar R.; Churchill, Grant C.

    2012-01-01

    Lithium is the most effective mood stabilizer for the treatment of bipolar disorder, but it is toxic at only twice the therapeutic dosage and has many undesirable side effects. It is likely that a small molecule could be found with lithium-like efficacy but without toxicity through target-based drug discovery; however, lithium’s therapeutic target remains equivocal. Inositol monophosphatase is a possible target but no bioavailable inhibitors exist. Here we report that the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behaviour, which are reversed with inositol, consistent with a mechanism involving inhibition of inositol recycling. Ebselen is part of the National Institutes of Health Clinical Collection, a chemical library of bioavailable drugs considered clinically safe but without proven use. Therefore, ebselen represents a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself. PMID:23299882

  13. Amylin structure–function relationships and receptor pharmacology: implications for amylin mimetic drug development

    PubMed Central

    Bower, Rebekah L

    2016-01-01

    Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin system is one worth developing is the FDA‐approved drug used in insulin‐requiring diabetic patients, pramlintide. However, certain characteristics of pramlintide pharmacokinetics and formulation leave considerable room for further development of amylin‐mimetic compounds. Given that amylin‐mimetic drug design and development is an active area of research, surprisingly little is known about the structure/function relationships of amylin. This is largely due to the unfavourable aggregative and solubility properties of the native peptide sequence, which are further complicated by the composition of amylin receptors. These are complexes of the calcitonin receptor with receptor activity‐modifying proteins. This review explores what is known of the structure–function relationships of amylin and provides insights that can be drawn from the closely related peptide, CGRP. We also describe how this information is aiding the development of more potent and stable amylin mimetics, including peptide hybrids. PMID:27061187

  14. Beyond dRGT as mimetic massive gravity

    NASA Astrophysics Data System (ADS)

    Golovnev, Alexey

    2018-04-01

    An interesting proposal has recently been made to extend massive gravity models beyond dRGT by a disformal transformation of the metric. In this Letter we want to note that it can be viewed as a mimetic extension of dRGT gravity which enormously simplifies the Hamiltonian analysis. In particular, pure gravity sector is equivalent to the usual dRGT gravity coupled to a constrained scalar field. And we also give some comments about possible matter couplings.

  15. Pancreatic cancer combination therapy using a BH3 mimetic and a synthetic tetracycline

    PubMed Central

    Quinn, Bridget A.; Dash, Rupesh; Sarkar, Siddik; Azab, Belal; Bhoopathi, Praveen; Das, Swadesh K.; Emdad, Luni; Wei, Jun; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B.

    2015-01-01

    Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small molecule BH3 mimetic, inhibits the function of anti-apoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with Minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3 rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that that the combination of Sabutoclax and Minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo. PMID:26032425

  16. A spectral mimetic least-squares method for the Stokes equations with no-slip boundary condition

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gerritsma, Marc; Bochev, Pavel

    Formulation of locally conservative least-squares finite element methods (LSFEMs) for the Stokes equations with the no-slip boundary condition has been a long standing problem. Existing LSFEMs that yield exactly divergence free velocities require non-standard boundary conditions (Bochev and Gunzburger, 2009 [3]), while methods that admit the no-slip condition satisfy the incompressibility equation only approximately (Bochev and Gunzburger, 2009 [4, Chapter 7]). Here we address this problem by proving a new non-standard stability bound for the velocity–vorticity–pressure Stokes system augmented with a no-slip boundary condition. This bound gives rise to a norm-equivalent least-squares functional in which the velocity can be approximatedmore » by div-conforming finite element spaces, thereby enabling a locally-conservative approximations of this variable. Here, we also provide a practical realization of the new LSFEM using high-order spectral mimetic finite element spaces (Kreeft et al., 2011) and report several numerical tests, which confirm its mimetic properties.« less

  17. A spectral mimetic least-squares method for the Stokes equations with no-slip boundary condition

    DOE PAGES

    Gerritsma, Marc; Bochev, Pavel

    2016-03-22

    Formulation of locally conservative least-squares finite element methods (LSFEMs) for the Stokes equations with the no-slip boundary condition has been a long standing problem. Existing LSFEMs that yield exactly divergence free velocities require non-standard boundary conditions (Bochev and Gunzburger, 2009 [3]), while methods that admit the no-slip condition satisfy the incompressibility equation only approximately (Bochev and Gunzburger, 2009 [4, Chapter 7]). Here we address this problem by proving a new non-standard stability bound for the velocity–vorticity–pressure Stokes system augmented with a no-slip boundary condition. This bound gives rise to a norm-equivalent least-squares functional in which the velocity can be approximatedmore » by div-conforming finite element spaces, thereby enabling a locally-conservative approximations of this variable. Here, we also provide a practical realization of the new LSFEM using high-order spectral mimetic finite element spaces (Kreeft et al., 2011) and report several numerical tests, which confirm its mimetic properties.« less

  18. The mimetic repertoire of the spotted bowerbird Ptilonorhynchus maculatus

    NASA Astrophysics Data System (ADS)

    Kelley, Laura A.; Healy, Susan D.

    2011-06-01

    Although vocal mimicry in songbirds is well documented, little is known about the function of such mimicry. One possibility is that the mimic produces the vocalisations of predatory or aggressive species to deter potential predators or competitors. Alternatively, these sounds may be learned in error as a result of their acoustic properties such as structural simplicity. We determined the mimetic repertoires of a population of male spotted bowerbirds Ptilonorhynchus maculatus, a species that mimics predatory and aggressive species. Although male mimetic repertoires contained an overabundance of vocalisations produced by species that were generally aggressive, there was also a marked prevalence of mimicry of sounds that are associated with alarm such as predator calls, alarm calls and mobbing calls, irrespective of whether the species being mimicked was aggressive or not. We propose that it may be the alarming context in which these sounds are first heard that may lead both to their acquisition and to their later reproduction. We suggest that enhanced learning capability during acute stress may explain vocal mimicry in many species that mimic sounds associated with alarm.

  19. A novel thromboxane A2 receptor N42S variant results in reduced surface expression and platelet dysfunction.

    PubMed

    Nisar, Shaista P; Lordkipanidzé, Marie; Jones, Matthew L; Dawood, Ban; Murden, Sherina; Cunningham, Margaret R; Mumford, Andrew D; Wilde, Jonathan T; Watson, Steve P; Mundell, Stuart J; Lowe, Gillian C

    2014-05-05

    A small number of thromboxane receptor variants have been described in patients with a bleeding history that result in platelet dysfunction. We have identified a patient with a history of significant bleeding, who expresses a novel heterozygous thromboxane receptor variant that predicts an asparagine to serine substitution (N42S). This asparagine is conserved across all class A GPCRs, suggesting a vital role for receptor structure and function.We investigated the functional consequences of the TP receptor heterozygous N42S substitution by performing platelet function studies on platelet-rich plasma taken from the patient and healthy controls. We investigated the N42S mutation by expressing the wild-type (WT) and mutant receptor in human embryonic kidney (HEK) cells. Aggregation studies showed an ablation of arachidonic acid responses in the patient, whilst there was right-ward shift of the U46619 concentration response curve (CRC). Thromboxane generation was unaffected. Calcium mobilisation studies in cells lines showed a rightward shift of the U46619 CRC in N42S-expressing cells compared to WT. Radioligand binding studies revealed a reduction in BMax in platelets taken from the patient and in N42S-expressing cells, whilst cell studies confirmed poor surface expression. We have identified a novel thromboxane receptor variant, N42S, which results in platelet dysfunction due to reduced surface expression. It is associated with a significant bleeding history in the patient in whom it was identified. This is the first description of a naturally occurring variant that results in the substitution of this highly conserved residue and confirms the importance of this residue for correct GPCR function.

  20. Ascorbate elevates perfusion pressure in the bovine extraocular long posterior ciliary artery: role of endothelium-derived hyperpolarizing factor (EDHF).

    PubMed

    Stirrat, Alison; Nelli, Silvia; McGuckin, Alicia; Ho, Vivian Wing Man; Wilson, William S; Martin, William

    2006-03-18

    Ascorbate blocks agonist-induced, endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation in the bovine perfused ciliary artery and this is associated with a rise in perfusion pressure. We now report the origins of this ascorbate-induced rise in perfusion pressure. In segments of ciliary artery perfused at 2.5 ml/min, the addition of ascorbate (10-150 microM) enhanced U46619-induced perfusion pressure. Ascorbate produced no enhancement in the absence of U46619, suggesting that its effects resulted not from a constrictor action but through removal of a tonic vasodilator influence. Experiments revealed the endothelial source of this vasodilator influence, and EDHF, but not nitric oxide or prostanoids, appeared to be involved. The ascorbate-induced enhancement of vasoconstrictor tone was not seen in a static myograph or in segments perfused at low rates of flow, but was seen at flow rates of 2.5 ml(-1) and above. We conclude that ascorbate augments vasoconstrictor tone through inhibition of flow-induced EDHF activity.

  1. Frequency-dependent variation in mimetic fidelity in an intraspecific mimicry system

    PubMed Central

    Iserbyt, Arne; Bots, Jessica; Van Dongen, Stefan; Ting, Janice J.; Van Gossum, Hans; Sherratt, Thomas N.

    2011-01-01

    Contemporary theory predicts that the degree of mimetic similarity of mimics towards their model should increase as the mimic/model ratio increases. Thus, when the mimic/model ratio is high, then the mimic has to resemble the model very closely to still gain protection from the signal receiver. To date, empirical evidence of this effect is limited to a single example where mimicry occurs between species. Here, for the first time, we test whether mimetic fidelity varies with mimic/model ratios in an intraspecific mimicry system, in which signal receivers are the same species as the mimics and models. To this end, we studied a polymorphic damselfly with a single male phenotype and two female morphs, in which one morph resembles the male phenotype while the other does not. Phenotypic similarity of males to both female morphs was quantified using morphometric data for multiple populations with varying mimic/model ratios repeated over a 3 year period. Our results demonstrate that male-like females were overall closer in size to males than the other female morph. Furthermore, the extent of morphological similarity between male-like females and males, measured as Mahalanobis distances, was frequency-dependent in the direction predicted. Hence, this study provides direct quantitative support for the prediction that the mimetic similarity of mimics to their models increases as the mimic/model ratio increases. We suggest that the phenomenon may be widespread in a range of mimicry systems. PMID:21367784

  2. Effects of low-dose aspirin on maternal blood pressure and vascular function in an experimental model of gestational hypertension.

    PubMed

    Osikoya, Oluwatobiloba; Jaini, Paresh A; Nguyen, An; Valdes, Melissa; Goulopoulou, Styliani

    2017-06-01

    Daily intake of low-dose aspirin after 12weeks of gestation is currently recommended as a preventative intervention in pregnancies in high risk of developing preeclampsia. This recommendation is based on epidemiological evidence, whereas experimental studies investigating the exact mechanisms of aspirin action during pregnancy are lacking. We previously showed that treating pregnant rats with a synthetic mimetic of unmethylated CpG DNA (bacterial DNA) caused preeclampsia-like characteristics such as maternal hypertension and increased cyclooxygenase (COX) expression and activity. In this study, we tested the hypothesis that daily maternal treatment with low-dose aspirin would prevent the development of maternal hypertension, reduce COX activity and thromboxane A 2 (TxA 2 ) production, and improve maternal vascular function in pregnant rats exposed to CpG ODN during gestation. Pregnant rats were treated with ODN2395 (synthetic CpG DNA) or saline (vehicle) on gestational days (GD) 14, 16, 18. Daily low-dose aspirin treatment (1.5mg/kgBW) started on GD10 and continued throughout gestation. Pregnant rats treated with ODN2395 had greater systolic blood pressure compared to controls (120±4mmHg vs. 100±5mmHg, p=0.03) and aspirin did not prevent this increase (p=0.86). Aspirin prevented ODN2395-induced increases of TxB 2 (TxA 2 metabolite) in serum and mesenteric arteries. ODN2395 increased expression of COX-1 and COX-2 in mesenteric and uterine arteries and aspirin abolished these effects. Aspirin reduced contractile responses to phenylephrine and U46619 (TxA 2 mimetic) in mesenteric arteries from control rats but not from ODN2395-treated rats. In conclusion, treatment with low-dose aspirin reduced systemic and vascular COX expression and activity but did not prevent the development of maternal hypertension induced by exposure to unmethylated CpG DNA (bacterial DNA). Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Non-Adrenergic, Tamsulosin-Insensitive Smooth Muscle Contraction is Sufficient to Replace α1 -Adrenergic Tension in the Human Prostate.

    PubMed

    Hennenberg, Martin; Acevedo, Alice; Wiemer, Nicolas; Kan, Aysenur; Tamalunas, Alexander; Wang, Yiming; Yu, Qingfeng; Rutz, Beata; Ciotkowska, Anna; Herlemann, Annika; Strittmatter, Frank; Stief, Christian G; Gratzke, Christian

    2017-05-01

    Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia may be caused by prostate smooth muscle contraction. Although α 1 -blockers may improve symptoms by prostate smooth muscle relaxation, their efficacy is limited. This may be explained by non-adrenergic mediators causing contraction in parallel to α 1 -adrenoceptors. However, little is known about the relevance and cooperative actions of non-adrenergic mediators in the prostate. Prostate tissues were obtained from radical prostatectomy (n = 127 patients). Contractile responses were studied in an organ bath. Endothelin-1 and noradrenaline induced contractions of similar magnitude (116 ± 23 and 117 ± 18% of KCl-induced contractions). Endothelin-2- and -3-induced maximum contractions of 63 ± 8.6 and 71 ± 19% of KCl, while contractions by the thromboxane analog U46619 amounted up to 63 ± 9.4%. Dopamine-induced contractions averaged to 22 ± 4.5% of KCl, while maximum contractions by serotonin, histamine, and carbachol stayed below 10% of KCl-induced. While noradrenaline-induced contractions were inhibited by tamsulosin (300 nM), endothelin-1-, -2-, or -3-induced contraction were not. No additive effects were observed if endothelins and noradrenaline were applied consecutively to the same samples. If endothelin-1 was applied after U46619, resulting tension (172 ± 43% of KCl) significantly exceeded noradrenaline-induced contraction. Tensions following combined application of endothelin-2 or -3 with U46619 stayed below noradrenaline-induced contractions. Tension following combined application of all three endothelins with U46619 resembled maximum noradrenaline-induced tone. Contractions following concomitant confrontation of human prostate tissue with noradrenaline and endothelin-1 are not additive. Endothelin-1 is sufficient to induce a smooth muscle tone resembling that of noradrenaline. This may replace lacking α 1 -adrenergic tone under therapy with

  4. Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

    PubMed Central

    Madani, Navid; Princiotto, Amy M.; Easterhoff, David; Bradley, Todd; Luo, Kan; Williams, Wilton B.; Liao, Hua-Xin; Moody, M. Anthony; Phad, Ganesh E.; Vázquez Bernat, Néstor; Melillo, Bruno; Santra, Sampa; Smith, Amos B.; Karlsson Hedestam, Gunilla B.; Haynes, Barton

    2016-01-01

    ABSTRACT The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. IMPORTANCE Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in

  5. Furoxans (1,2,5-Oxadiazole-N-Oxides) as Novel NO Mimetic Neuroprotective and Procognitive Agents

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Schiefer, Isaac T.; VandeVrede, Lawren; Fa

    2012-08-31

    Furoxans (1,2,5-oxadiazole-N-oxides) are thiol-bioactivated NO-mimetics that have not hitherto been studied in the CNS. Incorporation of varied substituents adjacent to the furoxan ring system led to modulation of reactivity toward bioactivation, studied by HPLC-MS/MS analysis of reaction products. Attenuated reactivity unmasked the cytoprotective actions of NO in contrast to the cytotoxic actions of higher NO fluxes reported previously for furoxans. Neuroprotection was observed in primary neuronal cell cultures following oxygen glucose deprivation (OGD). Neuroprotective activity was observed to correlate with thiol-dependent bioactivation to produce NO{sub 2}{sup -}, but not with depletion of free thiol itself. Neuroprotection was abrogated upon cotreatmentmore » with a sGC inhibitor, ODQ, thus supporting activation of the NO/sGC/CREB signaling cascade by furoxans. Long-term potentiation (LTP), essential for learning and memory, has been shown to be potentiated by NO signaling, therefore, a peptidomimetic furoxan was tested in hippocampal slices treated with oligomeric amyloid-{beta} peptide (A{beta}) and was shown to restore synaptic function. The novel observation of furoxan activity of potential therapeutic use in the CNS warrants further studies.« less

  6. Dual stimuli-sensitive dendrimers: Photothermogenic gold nanoparticle-loaded thermo-responsive elastin-mimetic dendrimers.

    PubMed

    Fukushima, Daichi; Sk, Ugir Hossain; Sakamoto, Yasuhiro; Nakase, Ikuhiko; Kojima, Chie

    2015-08-01

    Dendrimers are synthetic macromolecules with unique structures that can work as nanoplatforms for both photothermogenic gold nanoparticles (AuNPs) and thermosensitive elastin-like peptides (ELPs) with valine-proline-glycine-valine-glycine (VPGVG) repeats. In this study, photothermogenic AuNPs were loaded into thermo-responsive elastin-mimetic dendrimers (dendrimers conjugating ELPs at their periphery) to produce dual stimuli-sensitive nanoparticles. Polyamidoamine G4 dendrimers were modified with acetylated VPGVG and (VPGVG)2, and the resulting materials were named ELP1-den and ELP2-den, respectively. The AuNPs were prepared by the reduction of Au ions using a dendrimer-nanotemplated method. The AuNP-loaded elastin-mimetic dendrimers exhibited photothermal properties. ELP1-den and ELP2-den showed similar temperature-dependent changes in their conformations. Phase transitions were observed at around 55°C and 35°C for the AuNP-loaded ELP1-den and AuNP-loaded ELP2-den, respectively, but not for the corresponding PEGylated dendrimer. In contrast to the AuNP-loaded PEGylated dendrimer, AuNP-loaded ELP2-den readily associated with cells and induced efficient photocytotoxicity at 37°C. The cell association and the photocytotoxicity properties of AuNP-loaded ELP2-den could be controlled by temperature. These results therefore suggest that dual stimuli-sensitive dendrimer nanoparticles of this type could be used for photothermal therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Human Lactoferricin Is Partially Folded in Aqueous Solution and Is Better Stabilized in a Membrane Mimetic Solvent

    PubMed Central

    Hunter, Howard N.; Demcoe, A. Ross; Jenssen, Håvard; Gutteberg, Tore J.; Vogel, Hans J.

    2005-01-01

    Lactoferricins are highly basic bioactive peptides that are released in the stomach through proteolytic cleavage of various lactoferrin proteins. Here we have determined the solution structure of human lactoferricin (LfcinH) by conventional two-dimensional nuclear magnetic resonance methods in both aqueous solution and a membrane mimetic solvent. Unlike the 25-residue bovine lactoferricin (LfcinB), which adopts a somewhat distorted antiparallel β sheet, the longer LfcinH peptide shows a helical content from Gln14 to Lys29 in the membrane mimetic solvent but a nonexistent β-sheet character in either the N- or C-terminal regions of the peptide. The helical characteristic of the LfcinH peptide resembles the conformation that this region adopts in the crystal structure of the intact protein. The LfcinH structure determined in aqueous solution displays a nascent helix in the form of a coiled conformation in the region from Gln14 to Lys29. Numerous hydrophobic interactions create the basis for the better-defined overall structure observed in the membrane mimetic solvent. The 49-residue LfcinH peptide isolated for these studies was found to be slightly longer than previously reported peptide preparations and was found to have an intact peptide bond between residues Ala11 and Val12. The distinct solution structures of LfcinH and LfcinB represent a novel difference in the physical properties of these two peptides, which contributes to their unique physiological activities. PMID:16048952

  8. Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate

    PubMed Central

    Muzaffar, S; Shukla, N; Bond, M; Sala-Newby, G B; Newby, A C; Angelini, G D; Jeremy, J Y

    2008-01-01

    Background and purpose: To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac1 and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs). Experimental approach: hVSMCs were incubated with xanthine–xanthine oxidase (X-XO; a superoxide generating system) or the thromboxane A2 analogue, U46619 (±superoxide dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was assessed using Western blotting and superoxide measured. The role of Rac1 in superoxide generation was assessed by overexpressing either the dominant-negative or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied. Key results: Following 16 h incubation, U46619 and X-XO promoted the expression of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over the same time course. X-XO and U46619 both promoted the formation of superoxide. Overexpression of dominant-negative Rac1 or addition of iloprost, DETA-NONOate or Y27632 completely blocked both superoxide release and PDE5 protein expression and activity. Conclusions and implications: These data demonstrate that superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions of NO. PMID:18660830

  9. d-Allulose, a stereoisomer of d-fructose, extends Caenorhabditis elegans lifespan through a dietary restriction mechanism: A new candidate dietary restriction mimetic.

    PubMed

    Shintani, Tomoya; Sakoguchi, Hirofumi; Yoshihara, Akihide; Izumori, Ken; Sato, Masashi

    2017-12-02

    Dietary restriction (DR) is an effective intervention known to increase lifespan in a wide variety of organisms. DR also delays the onset of aging-associated diseases. DR mimetics, compounds that can mimic the effects of DR, have been intensively explored. d-Allulose (d-Alu), the C3-epimer of d-fructose, is a rare sugar that has various health benefits, including anti-hyperglycemia and anti-obesity effects. Here, we report that d-Alu increased the lifespan of Caenorhabditis elegans both under monoxenic and axenic culture conditions. d-Alu did not further extend the lifespan of the long-lived DR model eat-2 mutant, strongly indicating that the effect is related to DR. However, d-Alu did not reduce the food intake of wild-type C. elegans. To explore the mechanisms of the d-Alu longevity effect, we examined the lifespan of d-Alu-treated mutants deficient for nutrient sensing pathway-related genes daf-16, sir-2.1, aak-2, and skn-1. As a result, d-Alu increased the lifespan of the daf-16, sir-2.1, and skn-1 mutants, but not the aak-2 mutant, indicating that the lifespan extension was dependent on the energy sensor, AMP-activated protein kinase (AMPK). d-Alu also enhanced the mRNA expression and enzyme activities of superoxide dismutase (SOD) and catalase. From these findings, we conclude that d-Alu extends lifespan by increasing oxidative stress resistance through a DR mechanism, making it a candidate DR mimetic. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation.

    PubMed

    Zhao, Jing; Zhang, Lei; Mu, Xiaodong; Doebelin, Christelle; Nguyen, William; Wallace, Callen; Reay, Daniel P; McGowan, Sara J; Corbo, Lana; Clemens, Paula R; Wilson, Gabriela Mustata; Watkins, Simon C; Solt, Laura A; Cameron, Michael D; Huard, Johnny; Niedernhofer, Laura J; Kamenecka, Theodore M; Robbins, Paul D

    2018-06-11

    Nuclear factor κB (NF-κB) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-κB and its upstream regulator IκB kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11-amino acid peptide containing the NF-κB essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of β subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKKβ and the IKKγ subunit NEMO. A structure-based pharmacophore model was developed to identify NBD mimetics by in silico screening. Two optimized lead NBD mimetics, SR12343 and SR12460, inhibited tumor necrosis factor α (TNF-α)- and lipopolysaccharide (LPS)-induced NF-κB activation by blocking the interaction between IKKβ and NEMO and suppressed LPS-induced acute pulmonary inflammation in mice. Chronic treatment of a mouse model of Duchenne muscular dystrophy (DMD) with SR12343 and SR12460 attenuated inflammatory infiltration, necrosis and muscle degeneration, demonstrating that these small-molecule NBD mimetics are potential therapeutics for inflammatory and degenerative diseases.

  11. Tetra(p-tolyl)borate-functionalized solvent polymeric membrane: a facile and sensitive sensing platform for peroxidase and peroxidase mimetics.

    PubMed

    Wang, Xuewei; Qin, Wei

    2013-07-22

    The determination of peroxidase activities is the basis for enzyme-labeled bioaffinity assays, peroxidase-mimicking DNAzymes- and nanoparticles-based assays, and characterization of the catalytic functions of peroxidase mimetics. Here, a facile, sensitive, and cost-effective solvent polymeric membrane-based peroxidase detection platform is described that utilizes reaction intermediates with different pKa values from those of substrates and final products. Several key but long-debated intermediates in the peroxidative oxidation of o-phenylenediamine (o-PD) have been identified and their charge states have been estimated. By using a solvent polymeric membrane functionalized by an appropriate substituted tetraphenylborate as a receptor, those cationic intermediates could be transferred into the membrane from the aqueous phase to induce a large cationic potential response. Thus, the potentiometric indication of the o-PD oxidation catalyzed by peroxidase or its mimetics can be fulfilled. Horseradish peroxidase has been detected with a detection limit at least two orders of magnitude lower than those obtained by spectrophotometric techniques and traditional membrane-based methods. As an example of peroxidase mimetics, G-quadruplex DNAzymes were probed by the intermediate-sensitive membrane and a label-free thrombin detection protocol was developed based on the catalytic activity of the thrombin-binding G-quadruplex aptamer. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Modulation of stress-induced neurobehavioral changes and brain oxidative injury by nitric oxide (NO) mimetics in rats.

    PubMed

    Gulati, Kavita; Chakraborti, Ayanabha; Ray, Arunabha

    2007-11-02

    The present study evaluated the effects of NO mimetics on stress-induced neurobehavioral changes and the possible involvement of ROS-RNS interactions in rats. Restraint stress (RS) suppressed both percent open arm entries and time spent in the open arms in the elevated plus maze (EPM) test. These RS-induced changes in EPM activity were attenuated by the NO mimetics, l-arginine, isosorbide dinitrate and molsidomine, in a differential manner. RS-exposed rats showed (a) increased lipid peroxidation (MDA) and (b) lowered reduced glutathione (GSH) and NO metabolites (NOx), in brain homogenates of these animals. Pretreatment with the NO mimetics also differentially influenced RS-induced changes in brain oxidative stress markers. The results suggest that NO may protect against stress-induced anxiogenic behavior and oxidative injury in the brain and highlight the significance of ROS-RNS interactions.

  13. Mimetic Muscles in a Despotic Macaque (Macaca mulatta) Differ from Those in a Closely Related Tolerant Macaque (M. nigra).

    PubMed

    Burrows, Anne M; Waller, Bridget M; Micheletta, Jérôme

    2016-10-01

    Facial displays (or expressions) are a primary means of visual communication among conspecifics in many mammalian orders. Macaques are an ideal model among primates for investigating the co-evolution of facial musculature, facial displays, and social group size/behavior under the umbrella of "ecomorphology". While all macaque species share some social behaviors, dietary, and ecological parameters, they display a range of social dominance styles from despotic to tolerant. A previous study found a larger repertoire of facial displays in tolerant macaque species relative to despotic species. The present study was designed to further explore this finding by comparing the gross morphological features of mimetic muscles between the Sulawesi macaque (Macaca nigra), a tolerant species, and the rhesus macaque (M. mulatta), a despotic species. Five adult M. nigra heads were dissected and mimetic musculature was compared to those from M. mulatta. Results showed that there was general similarity in muscle presence/absence between the species as well as muscle form except for musculature around the external ear. M. mulatta had more musculature around the external ear than M. nigra. In addition, M. nigra lacked a zygomaticus minor while M. mulatta is reported to have one. These morphological differences match behavioral observations documenting a limited range of ear movements used by M. nigra during facial displays. Future studies focusing on a wider phylogenetic range of macaques with varying dominance styles may further elucidate the roles of phylogeny, ecology, and social variables in the evolution of mimetic muscles within Macaca Anat Rec, 299:1317-1324, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  14. Analysis of Arg-Gly-Asp mimetics and soluble receptor of tumour necrosis factor as therapeutic modalities for concanavalin A induced hepatitis in mice.

    PubMed Central

    Bruck, R; Shirin, H; Hershkoviz, R; Lider, O; Kenet, G; Aeed, H; Matas, Z; Zaidel, L; Halpern, Z

    1997-01-01

    BACKGROUND/AIMS: It has been shown that synthetic non-peptidic analogues of Arg-Gly-Asp, a major cell adhesive ligand of extracellular matrix, prevented an increase in serum aminotransferase activity, as a manifestation of concanavalin A induced liver damage in mice. This study examined the effects of an Arg-Gly-Asp mimetic on liver histology and cytokine release in response to concanavalin A administration, and the efficacy of soluble receptor of tumour necrosis factor (TNF) alpha in preventing hepatitis in this model of liver injury. METHODS: Mice were pretreated with either the Arg-Gly-Asp mimetic SF-6,5 or recombinant soluble receptor of TNF alpha before their inoculation with 10 mg/kg concanavalin A. Liver enzymes, histology, and the serum values of TNF alpha and interleukin (IL)6 were examined. RESULTS: The histopathological damage in the liver, and the concanavalin A induced release of TNF alpha and IL6 were significantly inhibited by the synthetic Arg-Gly-Asp mimetic (p < 0.001). Liver injury, manifested by the increase in serum aminotransferase and cytokines, as well as by histological manifestations of hepatic damage, was effectively prevented by pretreatment of the mice with the soluble TNF receptor (p < 0.001). CONCLUSIONS: This study confirms the efficacy of a synthetic Arg-Gly-Asp mimetic and soluble TNF receptor in the prevention of immune mediated liver damage in mice. Images PMID:9155591

  15. The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma

    PubMed Central

    Lieber, Justus; Armeanu-Ebinger, Sorin; Fuchs, Jörg

    2015-01-01

    Pediatric hepatoblastoma (HB) is commonly treated by neoadjuvant chemotherapy and surgical tumor resection according to international multicenter trial protocols. Complete tumor resection is essential and survival rates up to 95% have now been achieved in those tumors classified as standard-risk HB. Drug resistance and occurrence of metastases remain the major challenges in the treatment of HB, especially in high-risk tumors. These conditions urgently require the development of alternative therapeutic strategies. One of those alternatives is the modulation of apoptosis in HB cells. HBs regularly overexpress anti-apoptotic proteins of the Bcl-family in comparison to healthy liver tissue. This fact may contribute to the development of chemoresistance of HB cells. Synthetic small inhibitory molecules with BH3-mimetic effects, such as ABT-737 and obatoclax, enhance the susceptibility of tumor cells to different cytotoxic drugs and thereby affect initiator proteins of the apoptosis cascade via the intrinsic pathway. Besides additive effects on HB cell viability when used in combination with cytotoxic drugs, BH3-mimetics also play a role in preventing metastasation by reducing adhesion and inhibiting cell migration abilities. Presumably, including additive BH3-mimetic drugs into existing therapeutic regimens in HB patients might allow dose reduction of established cytotoxic drugs and thereby associated immanent side effects, while maintaining the antitumor activity. Furthermore, reduction of tumor growth and inhibition of tumor cell dissemination may facilitate complete surgical tumor resection, which is mandatory in this tumor type resulting in improved survival rates in high-risk HB. Currently, there are phase I and phase II clinical trials in several cancer entities using this potential target. This paper reviews the available literature regarding the use of BH3-mimetic drugs as single agents or in combination with chemotherapy in various malignancies and focuses on

  16. The <u>Be>rkeley <u>A>tmospheric <u>C>O2 <u>O>bservation <u>N>etwork (BEACON): Measuring Greenhouse Gases and Criteria Pollutants within the Urban Dome

    NASA Astrophysics Data System (ADS)

    Teige, V. E.; Weichsel, K.; Hooker, A.; Wooldridge, P. J.; Cohen, R. C.

    2012-12-01

    Efforts to curb greenhouse gas emissions, while global in their impacts, often focus on local and regional scales for execution and are dependent on the actions of communities and individuals. Evaluating the effectiveness of local policies requires observations with much higher spatial resolution than are currently available---kilometer scale. The <u>Be>rkeley <u>A>tmospheric <u>C>O2 <u>O>bservation <u>N>etwork (BEACON):, launched at the end of 2011, aims to provide measurements of urban-scale concentrations of CO2, temperature, pressure, relative humidity, O3, CO, and NO2 with sufficient spatial and temporal resolution to characterize the sources of CO2 within cities. Our initial deployment in Oakland, California uses ~40 sensor packages at a roughly 2 km spacing throughout the city. We will present an initial analysis of the vertical gradients and other spatial patterns observed to date.

  17. Modular protein switches derived from antibody mimetic proteins.

    PubMed

    Nicholes, N; Date, A; Beaujean, P; Hauk, P; Kanwar, M; Ostermeier, M

    2016-02-01

    Protein switches have potential applications as biosensors and selective protein therapeutics. Protein switches built by fusion of proteins with the prerequisite input and output functions are currently developed using an ad hoc process. A modular switch platform in which existing switches could be readily adapted to respond to any ligand would be advantageous. We investigated the feasibility of a modular protein switch platform based on fusions of the enzyme TEM-1 β-lactamase (BLA) with two different antibody mimetic proteins: designed ankyrin repeat proteins (DARPins) and monobodies. We created libraries of random insertions of the gene encoding BLA into genes encoding a DARPin or a monobody designed to bind maltose-binding protein (MBP). From these libraries, we used a genetic selection system for β-lactamase activity to identify genes that conferred MBP-dependent ampicillin resistance to Escherichia coli. Some of these selected genes encoded switch proteins whose enzymatic activity increased up to 14-fold in the presence of MBP. We next introduced mutations into the antibody mimetic domain of these switches that were known to cause binding to different ligands. To different degrees, introduction of the mutations resulted in switches with the desired specificity, illustrating the potential modularity of these platforms. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Interfacial Cavity Filling To Optimize CD4-Mimetic Miniprotein Interactions with HIV-1 Surface Glycoprotein

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Morellato-Castillo, Laurence; Acharya, Priyamvada; Combes, Olivier

    Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface glycoprotein (gp120) and cluster of differentiation 4 (CD4) receptor extends beyond residue phenylalanine 43 of CD4 and cannot be fully accessed by natural amino acids. To increase HIV-1 gp120 affinity for a family of CD4-mimetic miniproteins (miniCD4s), we targeted the gp120 Phe43 cavity with 11 non-natural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative, named M48U12 (13), bound HIV-1 YU2 gp120 with 8 pM affinity and showed potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine, and its cocrystalmore » structure with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and the aniline nitrogen potentially providing a focus for further improvement. Altogether, the results provide a framework for filling the interfacial Phe43 cavity to enhance miniCD4 affinity.« less

  19. Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic.

    PubMed

    Sarkar, Siddik; Quinn, Bridget A; Shen, Xue-Ning; Dash, Rupesh; Das, Swadesh K; Emdad, Luni; Klibanov, Alexander L; Wang, Xiang-Yang; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B

    2015-05-10

    Despite recent advances, treatment options for advanced prostate cancer (CaP) remain limited. We are pioneering approaches to treat advanced CaP that employ conditionally replication-competent oncolytic adenoviruses that simultaneously produce a systemically active cancer-specific therapeutic cytokine, mda-7/IL-24, Cancer Terminator Viruses (CTV). A truncated version of the CCN1/CYR61 gene promoter, tCCN1-Prom, was more active than progression elevated gene-3 promoter (PEG-Prom) in regulating transformation-selective transgene expression in CaP and oncogene-transformed rat embryo cells. Accordingly, we developed a new CTV, Ad.tCCN1-CTV-m7, which displayed dose-dependent killing of CaP without harming normal prostate epithelial cells in vitro with significant anti-cancer activity in vivo in both nude mouse CaP xenograft and transgenic Hi-Myc mice (using ultrasound-targeted microbubble (MB)-destruction, UTMD, with decorated MBs). Resistance to mda-7/IL-24-induced cell death correlated with overexpression of Bcl-2 family proteins. Inhibiting Mcl-1 using an enhanced BH3 mimetic, BI-97D6, sensitized CaP cell lines to mda-7/IL-24-induced apoptosis. Combining BI-97D6 with Ads expressing mda-7/IL-24 promoted ER stress, decreased anti-apoptotic Mcl-1 expression and enhanced mda-7/IL-24 expression through mRNA stabilization selectively in CaP cells. In Hi-myc mice, the combination induced enhanced apoptosis and tumor growth suppression. These studies highlight therapeutic efficacy of combining a BH3 mimetic with a novel CTV, supporting potential clinical applications for treating advanced CaP.

  20. Virus-mimetic nanovesicles as a versatile antigen-delivery system

    PubMed Central

    Zhang, Pengfei; Chen, Yixin; Zeng, Yun; Shen, Chenguang; Li, Rui; Guo, Zhide; Li, Shaowei; Zheng, Qingbing; Chu, Chengchao; Wang, Zhantong; Zheng, Zizheng; Tian, Rui; Ge, Shengxiang; Zhang, Xianzhong; Xia, Ning-Shao; Liu, Gang; Chen, Xiaoyuan

    2015-01-01

    It is a critically important challenge to rapidly design effective vaccines to reduce the morbidity and mortality of unexpected pandemics. Inspired from the way that most enveloped viruses hijack a host cell membrane and subsequently release by a budding process that requires cell membrane scission, we genetically engineered viral antigen to harbor into cell membrane, then form uniform spherical virus-mimetic nanovesicles (VMVs) that resemble natural virus in size, shape, and specific immunogenicity with the help of surfactants. Incubation of major cell membrane vesicles with surfactants generates a large amount of nano-sized uniform VMVs displaying the native conformational epitopes. With the diverse display of epitopes and viral envelope glycoproteins that can be functionally anchored onto VMVs, we demonstrate VMVs to be straightforward, robust and tunable nanobiotechnology platforms for fabricating antigen delivery systems against a wide range of enveloped viruses. PMID:26504197

  1. Modeling of Arylamide Helix Mimetics in the p53 Peptide Binding Site of hDM2 Suggests Parallel and Anti-Parallel Conformations Are Both Stable

    PubMed Central

    Fuller, Jonathan C.; Jackson, Richard M.; Edwards, Thomas A.; Wilson, Andrew J.; Shirts, Michael R.

    2012-01-01

    The design of novel α-helix mimetic inhibitors of protein-protein interactions is of interest to pharmaceuticals and chemical genetics researchers as these inhibitors provide a chemical scaffold presenting side chains in the same geometry as an α-helix. This conformational arrangement allows the design of high affinity inhibitors mimicking known peptide sequences binding specific protein substrates. We show that GAFF and AutoDock potentials do not properly capture the conformational preferences of α-helix mimetics based on arylamide oligomers and identify alternate parameters matching solution NMR data and suitable for molecular dynamics simulation of arylamide compounds. Results from both docking and molecular dynamics simulations are consistent with the arylamides binding in the p53 peptide binding pocket. Simulations of arylamides in the p53 binding pocket of hDM2 are consistent with binding, exhibiting similar structural dynamics in the pocket as simulations of known hDM2 binders Nutlin-2 and a benzodiazepinedione compound. Arylamide conformations converge towards the same region of the binding pocket on the 20 ns time scale, and most, though not all dihedrals in the binding pocket are well sampled on this timescale. We show that there are two putative classes of binding modes for arylamide compounds supported equally by the modeling evidence. In the first, the arylamide compound lies parallel to the observed p53 helix. In the second class, not previously identified or proposed, the arylamide compound lies anti-parallel to the p53 helix. PMID:22916232

  2. Escherichia coli tRNA 2-selenouridine synthase (SelU) converts S2U-RNA to Se2U-RNA via S-geranylated-intermediate.

    PubMed

    Sierant, Malgorzata; Leszczynska, Grazyna; Sadowska, Klaudia; Komar, Patrycja; Radzikowska-Cieciura, Ewa; Sochacka, Elzbieta; Nawrot, Barbara

    2018-06-04

    To date the only tRNAs containing nucleosides modified with a selenium (5-carboxymethylaminomethyl-2-selenouridine and 5-methylaminomethyl-2-selenouridine) have been found in bacteria. By using tRNA anticodon-stem-loop fragments containing S2U, Se2U, or geS2U, we found that in vitro tRNA 2-selenouridine synthase (SelU) converts S2U-RNA to Se2U-RNA in a two-step process involving S2U-RNA geranylation (with ppGe) and subsequent selenation of the resulting geS2U-RNA (with SePO 3 3- ). No 'direct' S2U-RNA→Se2U-RNA replacement is observed in the presence of SelU/SePO 3 3- only (without ppGe). These results suggest that the in vivo S2U→Se2U and S2U→geS2U transformations in tRNA, so far claimed to be the elementary reactions occurring independently in the same domain of the SelU enzyme, should be considered a combination of two consecutive events - geranylation (S2U→geS2U) and selenation (geS2U→Se2U). © 2018 Federation of European Biochemical Societies.

  3. The Representation of Reality in Teaching: A "Mimetic Didactic" Perspective on Examples in Plenary Talk

    ERIC Educational Resources Information Center

    Willbergh, Ilmi

    2017-01-01

    Using an observation study in Norwegian lower-secondary school classrooms this paper explores how subject matter and students' real-world experiences are linked within the use of examples in teaching. The theory of "mimetic didactics" claims that giving students the possibility to interpret examples as both subject matter and something…

  4. Interleukin-1beta-induced hyperresponsiveness to [Sar9,Met(O2)11]substance P in isolated human bronchi.

    PubMed

    Barchasz, E; Naline, E; Molimard, M; Moreau, J; Georges, O; Emonds-Alt, X; Advenier, C

    1999-08-20

    Interleukin-1beta has been reported to induce airway hyperresponsiveness in several animal models. In this study, we have investigated whether interleukin-1beta was able to potentiate the contractions of human isolated small bronchi (internal diameter < or = 1 mm) provoked by a specific tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P. Pre-incubation of human isolated small bronchi with interleukin-1beta (10 ng/ml, in Krebs-Henseleit solution, at 21 degrees C for 15 h) potentiated the contractile response to [Sar9,Met(O2)11]substance P. It also increased the [Sar9,Met(O2)11]substance P-induced release of thromboxane B2, the stable metabolite of thromboxane A2. Indomethacin (10(-6) M), a non-specific cyclooxygenase inhibitor, or GR 32191 ((1R-(1alpha(Z)),2beta,3beta,5alpha))-(+)-7-(5-(((1,1' -biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-hept enoic acid, hydrochloride) (10(-6) M), a prostanoid TP-receptor antagonist, blocked the contractions induced by [Sar9,Met(O2)11]substance P both in control experiments and after interleukin-1beta pre-treatment, indicating that prostanoids and thromboxane receptors are directly implicated in the [Sar9,Met(O2)11]substance P-induced contractile response. The thromboxane mimetic U-46619 (10(-8)-10(-6) M) (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F2alpha)-induced contractions of human isolated small bronchi were not enhanced by interleukin-1beta pre-treatment, suggesting that no up-regulation of thromboxane receptors occurred. Furthermore, the cyclooxygenase-2 inhibitor CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanon e) (10(-6) M) had no direct effect on [Sar9,Met(O2)11]substance P-provoked contractions, but inhibited the interleukin-1beta-induced potentiation of [Sar9,Met(O2)11]substance P response. In conclusion, our results show that interleukin-1beta pre-treatment is able to potentiate the contractions of isolated human small bronchi provoked by [Sar9,Met(O2

  5. Bioinspired Hydroxyapatite/Poly(methyl methacrylate) Composite with a Nacre-Mimetic Architecture by a Bidirectional Freezing Method.

    PubMed

    Bai, Hao; Walsh, Flynn; Gludovatz, Bernd; Delattre, Benjamin; Huang, Caili; Chen, Yuan; Tomsia, Antoni P; Ritchie, Robert O

    2016-01-06

    Using a bidirectional freezing technique, combined with uniaxial pressing and in situ polymerization, "nacre-mimetic" hydroxyapatite/poly(methyl methacrylate) (PMMA) composites are developed by processing large-scale aligned lamellar ceramic scaffolds. Structural and mechanical characterization shows "brick-and-mortar" structures, akin to nacre, with interesting combinations of strength, stiffness, and work of fracture, which provide a pathway to making strong and tough lightweight materials. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Spaceflight on the Bion-M1 biosatellite alters cerebral artery vasomotor and mechanical properties in mice

    PubMed Central

    Sofronova, Svetlana I.; Tarasova, Olga S.; Gaynullina, Dina; Borzykh, Anna A.; Behnke, Bradley J.; Stabley, John N.; McCullough, Danielle J.; Maraj, Joshua J.; Hanna, Mina; Muller-Delp, Judy M.; Vinogradova, Olga L.

    2015-01-01

    Conditions during spaceflight, such as the loss of the head-to-foot gravity vector, are thought to potentially alter cerebral blood flow and vascular resistance. The purpose of the present study was to determine the effects of long-term spaceflight on the functional, mechanical, and structural properties of cerebral arteries. Male C57BL/6N mice were flown 30 days in a Bion-M1 biosatellite. Basilar arteries isolated from spaceflight (SF) (n = 6), habitat control (HC) (n = 6), and vivarium control (VC) (n = 16) mice were used for in vitro functional and mechanical testing and histological structural analysis. The results demonstrate that vasoconstriction elicited through a voltage-gated Ca2+ mechanism (30–80 mM KCl) and thromboxane A2 receptors (10−8 − 3 × 10−5 M U46619) are lower in cerebral arteries from SF mice. Inhibition of Rho-kinase activity (1 μM Y27632) abolished group differences in U46619-evoked contractions. Endothelium-dependent vasodilation elicited by acetylcholine (10 μM, 2 μM U46619 preconstriction) was virtually absent in cerebral arteries from SF mice. The pressure-diameter relation was lower in arteries from SF mice relative to that in HC mice, which was not related to differences in the extracellular matrix protein elastin or collagen content or the elastin/collagen ratio in the basilar arteries. Diameter, medial wall thickness, and medial cross-sectional area of unpressurized basilar arteries were not different among groups. These results suggest that the microgravity-induced attenuation of both vasoconstrictor and vasodilator properties may limit the range of vascular control of cerebral perfusion or impair the distribution of brain blood flow during periods of stress. PMID:25593287

  7. Antibody-Mimetic Peptoid Nanosheet for Label-Free Serum-Based Diagnosis of Alzheimer's Disease.

    PubMed

    Zhu, Ling; Zhao, Zijian; Cheng, Peng; He, Zhaohui; Cheng, Zhiqiang; Peng, Jiaxi; Wang, Huayi; Wang, Chen; Yang, Yanlian; Hu, Zhiyuan

    2017-08-01

    Alzheimer's disease (AD) is the most common form of dementia characterized by progressive cognitive decline. Current diagnosis of AD is based on symptoms, neuropsychological tests, and neuroimaging, and is usually evident years after the pathological process. Early assessment at the preclinical or prodromal stage is in a great demand since treatment after the onset can hardly stop or reverse the disease progress. However, early diagnosis of AD is challenging due to the lack of reliable noninvasive approaches. Here, an antibody-mimetic self-assembling peptoid nanosheet containing surface-exposed Aβ42-recognizing loops is constructed, and a label-free sensor for the detection of AD serum is developed. The loop-displaying peptoid nanosheet is demonstrated to have high affinity to serum Aβ42, and to be able to identify AD sera with high sensitivity. The dense distribution of molecular recognition loops on the robust peptoid nanosheet scaffold not only mimics the architecture of antibodies, but also reduces the nonspecific binding in detecting multicomponent samples. This antibody-mimetic 2D material holds great potential toward the blood-based diagnosis of AD, and meanwhile provides novel insights into the antibody alternative engineering and the universal application in biological and chemical sensors. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Type I Collagen and Collagen Mimetics as Angiogenesis Promoting Superpolymers

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Twardowski, T.; Fertala, A.; Orgel, J.P.R.O.

    Angiogenesis, the development of blood vessels from the pre-existing vasculature, is a key component of embryogenesis and tissue regeneration. Angiogenesis also drives pathologies such as tumor growth and metastasis, and hemangioma development in newborns. On the other hand, promotion of angiogenesis is needed in tissues with vascular insufficiencies, and in bioengineering, to endow tissue substitutes with appropriate microvasculatures. Therefore, much research has focused on defining mechanisms of angiogenesis, and identifying pro- and anti-angiogenic molecules. Type I collagen, the most abundant protein in humans, potently stimulates angiogenesis in vitro and in vivo. Crucial to its angiogenic activity appears to be ligationmore » and possibly clustering of endothelial cell (EC) surface {alpha}1{beta}1/{alpha}2{beta}1 integrin receptors by the GFPGER502-507 sequence of the collagen fibril. However, additional aspects of collagen structure and function that may modulate its angiogenic properties are discussed. Moreover, type I collagen and fibrin, another angiogenic polymer, share several structural features. These observations suggest strategies for creating 'angiogenic superpolymers', including: modifying type I collagen to influence its biological half-life, immunogenicity, and integrin binding capacity; genetically engineering fibrillar collagens to include additional integrin binding sites or angiogenic determinants, and remove unnecessary or deleterious sequences without compromising fibril integrity; and exploring the suitability of poly(ortho ester), PEG-lysine copolymer, tubulin, and cholesteric cuticle as collagen mimetics, and suggesting means of modifying them to display ideal angiogenic properties. The collagenous and collagen mimetic angiogenic superpolymers described here may someday prove useful for many applications in tissue engineering and human medicine.« less

  9. Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice

    PubMed Central

    Aslam, Mohamad F.; Frazer, David M.; Faria, Nuno; Bruggraber, Sylvaine F. A.; Wilkins, Sarah J.; Mirciov, Cornel; Powell, Jonathan J.; Anderson, Greg J.; Pereira, Dora I. A.

    2014-01-01

    The ferritin core is composed of fine nanoparticulate Fe3+ oxohydroxide, and we have developed a synthetic mimetic, nanoparticulate Fe3+ polyoxohydroxide (nanoFe3+). The aim of this study was to determine how dietary iron derived in this fashion is absorbed in the duodenum. Following a 4 wk run-in on an Fe-deficient diet, mice with intestinal-specific disruption of the Fpn-1 gene (Fpn-KO), or littermate wild-type (WT) controls, were supplemented with Fe2+ sulfate (FeSO4), nanoFe3+, or no added Fe for a further 4 wk. A control group was Fe sufficient throughout. Direct intestinal absorption of nanoFe3+ was investigated using isolated duodenal loops. Our data show that FeSO4 and nanoFe3+ are equally bioavailable in WT mice, and at wk 8 the mean ± sem hemoglobin increase was 18 ± 7 g/L in the FeSO4 group and 30 ± 5 g/L in the nanoFe3+ group. Oral iron failed to be utilized by Fpn-KO mice and was retained in enterocytes, irrespective of the iron source. In summary, although nanoFe3+ is taken up directly by the duodenum its homeostasis is under the normal regulatory control of dietary iron absorption, namely via ferroportin-dependent efflux from enterocytes, and thus offers potential as a novel oral iron supplement.—Aslam, M. F., Frazer, D. M., Faria, N., Bruggraber, S. F. A., Wilkins, S. J., Mirciov, C., Powell, J. J., Anderson, G. J., Pereira, D. I. A. Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice. PMID:24776745

  10. Amarogentin, a Secoiridoid Glycoside, Abrogates Platelet Activation through PLCγ2-PKC and MAPK Pathways

    PubMed Central

    Yen, Ting-Lin; Lu, Wan-Jung; Lien, Li-Ming; Thomas, Philip Aloysius; Lee, Tzu-Yin; Chiu, Hou-Chang; Sheu, Joen-Rong

    2014-01-01

    Amarogentin, an active principle of Gentiana lutea, possess antitumorigenic, antidiabetic, and antioxidative properties. Activation of platelets is associated with intravascular thrombosis and cardiovascular diseases. The present study examined the effects of amarogentin on platelet activation. Amarogentin treatment (15~60 μM) inhibited platelet aggregation induced by collagen, but not thrombin, arachidonic acid, and U46619. Amarogentin inhibited collagen-induced phosphorylation of phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). It also inhibits in vivo thrombus formation in mice. In addition, neither the guanylate cyclase inhibitor ODQ nor the adenylate cyclase inhibitor SQ22536 affected the amarogentin-mediated inhibition of platelet aggregation, which suggests that amarogentin does not regulate the levels of cyclic AMP and cyclic GMP. In conclusion, amarogentin prevents platelet activation through the inhibition of PLCγ2-PKC cascade and MAPK pathway. Our findings suggest that amarogentin may offer therapeutic potential for preventing or treating thromboembolic disorders. PMID:24868545

  11. Apolipoprotein E-mimetics inhibit neurodegeneration and restore cognitive functions in a transgenic Drosophila model of Alzheimer's disease.

    PubMed

    Sarantseva, Svetlana; Timoshenko, Svetlana; Bolshakova, Olga; Karaseva, Eugenia; Rodin, Dmitry; Schwarzman, Alexander L; Vitek, Michael P

    2009-12-07

    Mutations of the amyloid precursor protein gene (APP) are found in familial forms of Alzheimer's disease (AD) and some lead to the elevated production of amyloid-beta-protein (Abeta). While Abeta has been implicated in the causation of AD, the exact role played by Abeta and its APP precursor are still unclear. In our study, Drosophila melanogaster transgenics were established as a model to analyze AD-like pathology caused by APP overexpression. We demonstrated that age related changes in the levels and pattern of synaptic proteins accompanied progressive neurodegeneration and impairment of cognitive functions in APP transgenic flies, but that these changes may be independent from the generation of Abeta. Using novel peptide mimetics of Apolipoprotein-E, COG112 or COG133 proved to be neuroprotective and significantly improved the learning and memory of APP transgenic flies. The development of neurodegeneration and cognitive deficits was corrected by injections of COG112 or COG133, novel mimetics of apolipoprotein-E (apoE) with neuroprotective activities.

  12. Polyketide mimetics yield structural and mechanistic insights into product template domain function in nonreducing polyketide synthases

    PubMed Central

    Barajas, Jesus F.; Shakya, Gaurav; Moreno, Gabriel; Rivera, Heriberto; Jackson, David R.; Topper, Caitlyn L.; Vagstad, Anna L.; La Clair, James J.; Townsend, Craig A.; Burkart, Michael D.; Tsai, Shiou-Chuan

    2017-01-01

    Product template (PT) domains from fungal nonreducing polyketide synthases (NR-PKSs) are responsible for controlling the aldol cyclizations of poly-β-ketone intermediates assembled during the catalytic cycle. Our ability to understand the high regioselective control that PT domains exert is hindered by the inaccessibility of intrinsically unstable poly-β-ketones for in vitro studies. We describe here the crystallographic application of “atom replacement” mimetics in which isoxazole rings linked by thioethers mimic the alternating sites of carbonyls in the poly-β-ketone intermediates. We report the 1.8-Å cocrystal structure of the PksA PT domain from aflatoxin biosynthesis with a heptaketide mimetic tethered to a stably modified 4′-phosphopantetheine, which provides important empirical evidence for a previously proposed mechanism of PT-catalyzed cyclization. Key observations support the proposed deprotonation at C4 of the nascent polyketide by the catalytic His1345 and the role of a protein-coordinated water network to selectively activate the C9 carbonyl for nucleophilic addition. The importance of the 4′-phosphate at the distal end of the pantetheine arm is demonstrated to both facilitate delivery of the heptaketide mimetic deep into the PT active site and anchor one end of this linear array to precisely meter C4 into close proximity to the catalytic His1345. Additional structural features, docking simulations, and mutational experiments characterize protein–substrate mimic interactions, which likely play roles in orienting and stabilizing interactions during the native multistep catalytic cycle. These findings afford a view of a polyketide “atom-replaced” mimetic in a NR-PKS active site that could prove general for other PKS domains. PMID:28484029

  13. Effect of fat level on the perception of five flavor chemicals in ice cream with or without fat mimetics by using a descriptive test.

    PubMed

    Liou, B K; Grün, I U

    2007-10-01

    Fat mimetics are commonly used in the manufacture of low-fat and fat-free ice creams. However, the use of fat mimetics affects flavor and texture characteristics of ice cream, which results in decreased overall acceptability by consumers. The initial objective of this study was to investigate the release behavior of 5 strawberry flavor compounds in ice creams with Simplesse((R)), Litesse((R)), and Litesse((R))/Simplesse((R)) mixes using descriptive analysis. Fat mimetics and flavor formulation significantly influenced the perception of Furaneoltrade mark (cooked sugar flavor), alpha-ionone (violet flavor), and gamma-undecalactone (peach flavor), but there was no interaction between ice cream type and flavor formulation for the 3 flavors. Furaneol and ethyl-3-methyl-3-phenylglycidate (candy flavor) were perceived more strongly in full-fat ice cream, while cis-3-hexen-1-ol (grassy flavor), alpha-ionone, and gamma-undecalactone were perceived more strongly in low-fat ice cream. Ice creams with Simplesse and full-fat ice cream had similar sensory characteristics, while ice creams with Litesse were similar to low-fat ice creams in flavor characteristics, and ice creams with Litesse/Simplesse mixes were closer in flavor profile to low-fat ice cream but had similar texture properties to those of full-fat ice cream. Simplesse was found to be a better fat mimetic for duplicating the flavor profiles and mouthfeel of full-fat ice cream.

  14. Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

    PubMed Central

    Ryan, Lisa K.; Freeman, Katie B.; Masso-Silva, Jorge A.; Falkovsky, Klaudia; Aloyouny, Ashwag; Markowitz, Kenneth; Hise, Amy G.; Fatahzadeh, Mahnaz; Scott, Richard W.

    2014-01-01

    There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis. PMID:24752272

  15. Perylene Diimide as a Precise Graphene-like Superoxide Dismutase Mimetic

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jalilov, Almaz S.; Nilewski, Lizanne G.; Berka, Vladimir

    Here we show that the active portion of a graphitic nanoparticle can be mimicked by a perylene diimide (PDI) to explain the otherwise elusive biological and electrocatalytic activity of the nanoparticle construct. Development of molecular analogues that mimic the antioxidant properties of oxidized graphenes, in this case the poly(ethylene glycolated) hydrophilic carbon clusters (PEG–HCCs), will afford important insights into the highly efficient activity of PEG–HCCs and their graphitic analogues. PEGylated perylene diimides (PEGn–PDI) serve as well-defined molecular analogues of PEG–HCCs and oxidized graphenes in general, and their antioxidant and superoxide dismutase-like (SOD-like) properties were studied. PEGn–PDIs have two reversible reductionmore » peaks, which are more positive than the oxidation peak of superoxide (O2•–). This is similar to the reduction peak of the HCCs. Thus, as with PEG–HCCs, PEGn–PDIs are also strong single-electron oxidants of O2•–. Furthermore, reduced PEGn–PDI, PEGn–PDI•–, in the presence of protons, was shown to reduce O2•– to H2O2 to complete the catalytic cycle in this SOD analogue. The kinetics of the conversion of O2•– to O2 and H2O2 by PEG8–PDI was measured using freeze-trap EPR experiments to provide a turnover number of 133 s–1; the similarity in kinetics further supports that PEG8–PDI is a true SOD mimetic. Finally, PDIs can be used as catalysts in the electrochemical oxygen reduction reaction in water, which proceeds by a two-electron process with the production of H2O2, mimicking graphene oxide nanoparticles that are otherwise difficult to study spectroscopically.« less

  16. The reconstruction of f(ϕ)R and mimetic gravity from viable slow-roll inflation

    NASA Astrophysics Data System (ADS)

    Odintsov, S. D.; Oikonomou, V. K.

    2018-04-01

    In this work, we extend the bottom-up reconstruction framework of F (R) gravity to other modified gravities, and in particular for f (ϕ) R and mimetic F (R) gravities. We investigate which are the important conditions in order for the method to work, and we study several viable cosmological evolutions, focusing on the inflationary era. Particularly, for the f (ϕ) R theory case, we specify the functional form of the Hubble rate and of the scalar-to-tensor ratio as a function of the e-foldings number and accordingly, the rest of the physical quantities and also the slow-roll and the corresponding observational indices can be calculated. The same method is applied in the mimetic F (R) gravity case, and in both cases we thoroughly analyze the resulting free parameter space, in order to show that the viability of the models presented is guaranteed and secondly that there is a wide range of values of the free parameters for which the viability of the models occurs. In addition, the reconstruction method is also studied in the context of mimetic F (R) = R gravity. As we demonstrate, the resulting theory is viable, and also in this case, only the scalar-to-tensor ratio needs to be specified, since the rest follow from this condition. Finally, we discuss in brief how the reconstruction method could function for other modified gravities.

  17. Student-Driven Design of Peptide Mimetics: Microwave-Assisted Synthesis of Peptoid Oligomers

    ERIC Educational Resources Information Center

    Pohl, Nicola L. B.; Kirshenbaum, Kent; Yoo, Barney; Schulz, Nathan; Zea, Corbin J.; Streff, Jennifer M.; Schwarz, Kimberly L.

    2011-01-01

    An experiment for the undergraduate organic laboratory is described in which peptide mimetic oligomers called "peptoids" are built stepwise on a solid-phase resin. Students employ two modern strategies to facilitate rapid multistep syntheses: solid-phase techniques to obviate the need for intermediate purifications and microwave irradiation to…

  18. Amarogentin, a secoiridoid glycoside, abrogates platelet activation through PLC γ 2-PKC and MAPK pathways.

    PubMed

    Yen, Ting-Lin; Lu, Wan-Jung; Lien, Li-Ming; Thomas, Philip Aloysius; Lee, Tzu-Yin; Chiu, Hou-Chang; Sheu, Joen-Rong; Lin, Kuan-Hung

    2014-01-01

    Amarogentin, an active principle of Gentiana lutea, possess antitumorigenic, antidiabetic, and antioxidative properties. Activation of platelets is associated with intravascular thrombosis and cardiovascular diseases. The present study examined the effects of amarogentin on platelet activation. Amarogentin treatment (15~60  μM) inhibited platelet aggregation induced by collagen, but not thrombin, arachidonic acid, and U46619. Amarogentin inhibited collagen-induced phosphorylation of phospholipase C (PLC) γ2, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). It also inhibits in vivo thrombus formation in mice. In addition, neither the guanylate cyclase inhibitor ODQ nor the adenylate cyclase inhibitor SQ22536 affected the amarogentin-mediated inhibition of platelet aggregation, which suggests that amarogentin does not regulate the levels of cyclic AMP and cyclic GMP. In conclusion, amarogentin prevents platelet activation through the inhibition of PLC γ2-PKC cascade and MAPK pathway. Our findings suggest that amarogentin may offer therapeutic potential for preventing or treating thromboembolic disorders.

  19. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis.

    PubMed

    Li, Ning; Feng, Lin; Han, Hui-Qiong; Yuan, Jing; Qi, Xue-Kang; Lian, Yi-Fan; Kuang, Bo-Hua; Zhang, Yu-Chen; Deng, Cheng-Cheng; Zhang, Hao-Jiong; Yao, You-Yuan; Xu, Miao; He, Gui-Ping; Zhao, Bing-Chun; Gao, Ling; Feng, Qi-Sheng; Chen, Li-Zhen; Yang, Lu; Yang, Dajun; Zeng, Yi-Xin

    2016-10-10

    Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC. Copyright © 2016. Published by Elsevier Ireland Ltd.

  20. Nacre-mimetic clay/xyloglucan bionanocomposites: a chemical modification route for hygromechanical performance at high humidity.

    PubMed

    Kochumalayil, Joby J; Morimune, Seira; Nishino, Takashi; Ikkala, Olli; Walther, Andreas; Berglund, Lars A

    2013-11-11

    Nacre-mimetic bionanocomposites of high montmorillonite (MTM) clay content, prepared from hydrocolloidal suspensions, suffer from reduced strength and stiffness at high relative humidity. We address this problem by chemical modification of xyloglucan in (XG)/MTM nacre-mimetic nanocomposites, by subjecting the XG to regioselective periodate oxidation of side chains to enable it to form covalent cross-links to hydroxyl groups in neighboring XG chains or to the MTM surface. The resulting materials are analyzed by FTIR spectroscopy, thermogravimetric analysis, carbohydrate analysis, calorimetry, X-ray diffraction, scanning electron microscopy, tensile tests, and oxygen barrier properties. We compare the resulting mechanical properties at low and high relative humidity. The periodate oxidation leads to a strong increase in modulus and strength of the materials. A modulus of 30 GPa for cross-linked composite at 50% relative humidity compared with 13.7 GPa for neat XG/MTM demonstrates that periodate oxidation of the XG side chains leads to crucially improved stress transfer at the XG/MTM interface, possibly through covalent bond formation. This enhanced interfacial adhesion and internal cross-linking of the matrix moreover preserves the mechanical properties at high humidity condition and leads to a Young's modulus of 21 GPa at 90%RH.

  1. A modular synthesis of teraryl-based α-helix mimetics, part 1: Synthesis of core fragments with two electronically differentiated leaving groups.

    PubMed

    Peters, Martin; Trobe, Melanie; Tan, Hao; Kleineweischede, Rolf; Breinbauer, Rolf

    2013-02-11

    Teraryl-based α-helix mimetics have proven to be useful compounds for the inhibition of protein-protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl-based α-helix mimetics. Central to our strategy is the use of a benzene core unit featuring two leaving groups of differentiated reactivity in the Pd-catalyzed cross-coupling used for terphenyl assembly. With the halogen/diazonium route and the halogen/triflate route, two strategies have successfully been established. The synthesis of core building blocks with aliphatic (Ala, Val, Leu, Ile), aromatic (Phe), polar (Cys, Lys), hydrophilic (Ser, Gln), and acidic (Glu) amino acid side chains are reported. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Superstretchable Nacre-Mimetic Graphene/Poly(vinyl alcohol) Composite Film Based on Interfacial Architectural Engineering.

    PubMed

    Zhao, Nifang; Yang, Miao; Zhao, Qian; Gao, Weiwei; Xie, Tao; Bai, Hao

    2017-05-23

    Through designing hierarchical structures, particularly optimizing the chemical and architectural interactions at its inorganic/organic interface, nacre has achieved an excellent combination of contradictory mechanical properties such as strength and toughness, which is highly demanded yet difficult to achieve by most synthetic materials. Most techniques applied to develop nacre-mimetic composites have been focused on mimicking the "brick-and-mortar" structure, but the interfacial architectural features, especially the asperities and mineral bridges of "bricks", have been rarely concerned, which are of equal importance for enhancing mechanical properties of nacre. Here, we used a modified bidirectional freezing method followed by uniaxial pressing and chemical reduction to assemble a nacre-mimetic graphene/poly(vinyl alcohol) composite film, with both asperities and bridges introduced in addition to the lamellar layers to mimic the interfacial architectural interactions found in nacre. As such, we have developed a composite film that is not only strong (up to ∼150.9 MPa), but also tough (up to ∼8.50 MJ/m 3 ), and highly stretchable (up to ∼10.44%), difficult to obtain by other methods. This was all achieved by only interfacial architectural engineering within the traditional "brick-and-mortar" structure, without introducing a third component or employing chemical cross-linker as in some other nacre-mimetic systems. More importantly, we believe that the design principles and processing strategies reported here can also be applied to other material systems to develop strong and stretchable materials.

  3. Effects of canola and corn oil mimetic on Jurkat cells

    PubMed Central

    2011-01-01

    Background The Western diet is high in omega-6 fatty acids and low in omega-3 fatty acids. Canola oil contains a healthier omega 3 to omega 6 ratio than corn oil. Jurkat T leukemia cells were treated with free fatty acids mixtures in ratios mimicking that found in commercially available canola oil (7% α-linolenic, 30% linoleic, 54% oleic) or corn oil (59% linoleic, 24% oleic) to determine the cell survival or cell death and changes in expression levels of inflammatory cytokines and receptors following oil treatment. Methods Fatty acid uptake was assessed by gas chromatography. Cell survival and cell death were evaluated by cell cycle analyses, propidium-iodide staining, trypan blue exclusion and phosphatidylserine externalization. mRNA levels of inflammatory cytokines and receptors were assessed by RT-PCR. Results There was a significant difference in the lipid profiles of the cells after treatment. Differential action of the oils on inflammatory molecules, following treatment at non-cytotoxic levels, indicated that canola oil mimetic was anti-inflammatory whereas corn oil mimetic was pro-inflammatory. Significance These results indicate that use of canola oil in the diet instead of corn oil might be beneficial for diseases promoted by inflammation. PMID:21631947

  4. Age-related decrease in the mitochondrial sirtuin deacetylase Sirt3 expression associated with ROS accumulation in the auditory cortex of the mimetic aging rat model.

    PubMed

    Zeng, Lingling; Yang, Yang; Hu, Yujuan; Sun, Yu; Du, Zhengde; Xie, Zhen; Zhou, Tao; Kong, Weijia

    2014-01-01

    Age-related dysfunction of the central auditory system, also known as central presbycusis, can affect speech perception and sound localization. Understanding the pathogenesis of central presbycusis will help to develop novel approaches to prevent or treat this disease. In this study, the mechanisms of central presbycusis were investigated using a mimetic aging rat model induced by chronic injection of D-galactose (D-Gal). We showed that malondialdehyde (MDA) levels were increased and manganese superoxide dismutase (SOD2) activity was reduced in the auditory cortex in natural aging and D-Gal-induced mimetic aging rats. Furthermore, mitochondrial DNA (mtDNA) 4834 bp deletion, abnormal ultrastructure and cell apoptosis in the auditory cortex were also found in natural aging and D-Gal mimetic aging rats. Sirt3, a mitochondrial NAD+-dependent deacetylase, has been shown to play a crucial role in controlling cellular reactive oxygen species (ROS) homeostasis. However, the role of Sirt3 in the pathogenesis of age-related central auditory cortex deterioration is still unclear. Here, we showed that decreased Sirt3 expression might be associated with increased SOD2 acetylation, which negatively regulates SOD2 activity. Oxidative stress accumulation was likely the result of low SOD2 activity and a decline in ROS clearance. Our findings indicate that Sirt3 might play an essential role, via the mediation of SOD2, in central presbycusis and that manipulation of Sirt3 expression might provide a new approach to combat aging and oxidative stress-related diseases.

  5. Bicontinuous microemulsions as a biomembrane mimetic system for melittin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hayes, Douglas G.; Ye, Ran; Dunlap, Rachel N.

    Antimicrobial peptides effectively kill antibiotic-resistant bacteria by forming pores in prokaryotes' biomembranes via penetration into the biomembranes' interior. Bicontinuous microemulsions, consisting of interdispersed oil and water nanodomains separated by flexible surfactant monolayers, are potentially valuable for hosting membrane-associated peptides and proteins due to their thermodynamic stability, optical transparency, low viscosity, and high interfacial area. Here, we show that bicontinuous microemulsions formed by negatively-charged surfactants are a robust biomembrane mimetic system for the antimicrobial peptide melittin. When encapsulated in bicontinuous microemulsions formed using three-phase (Winsor-III) systems, melittin's helicity increases greatly due to penetration into the surfactant monolayers, mimicking its behavior inmore » biomembranes. But, the threshold melittin concentration required to achieve these trends is lower for the microemulsions. The extent of penetration was decreased when the interfacial fluidity of the microemulsions was increased. In conclusion, these results suggest the utility of bicontinuous microemulsions for isolation, purification, delivery, and host systems for antimicrobial peptides.« less

  6. Bicontinuous microemulsions as a biomembrane mimetic system for melittin

    DOE PAGES

    Hayes, Douglas G.; Ye, Ran; Dunlap, Rachel N.; ...

    2017-11-12

    Antimicrobial peptides effectively kill antibiotic-resistant bacteria by forming pores in prokaryotes' biomembranes via penetration into the biomembranes' interior. Bicontinuous microemulsions, consisting of interdispersed oil and water nanodomains separated by flexible surfactant monolayers, are potentially valuable for hosting membrane-associated peptides and proteins due to their thermodynamic stability, optical transparency, low viscosity, and high interfacial area. Here, we show that bicontinuous microemulsions formed by negatively-charged surfactants are a robust biomembrane mimetic system for the antimicrobial peptide melittin. When encapsulated in bicontinuous microemulsions formed using three-phase (Winsor-III) systems, melittin's helicity increases greatly due to penetration into the surfactant monolayers, mimicking its behavior inmore » biomembranes. But, the threshold melittin concentration required to achieve these trends is lower for the microemulsions. The extent of penetration was decreased when the interfacial fluidity of the microemulsions was increased. In conclusion, these results suggest the utility of bicontinuous microemulsions for isolation, purification, delivery, and host systems for antimicrobial peptides.« less

  7. Mimetic Theory and the evolutionary paradox of schizophrenia: The archetypal scapegoat hypothesis.

    PubMed

    Riordan, Daniel Vincent

    2017-10-01

    Schizophrenia poses an evolutionary paradox, being genetically mediated yet associated with reduced fecundity. Numerous hypotheses have attempted to address this, but few describe how the schizophrenic phenotype itself might constitute an evolutionary adaptation. This paper draws on René Girard's theory on human origins, which claims that humans evolved a tendency to mimic both the desires and the behaviours of each other (mimetic theory). This would have promoted social cohesion and co-operation, but at the cost of intra-group rivalry and conflict. The mimetic dynamic would have escalated such conflicts into reciprocal internecine violence, threatening the survival of the entire group. Girard theorised that the "scapegoat mechanism" emerged, by which means such violence was curtailed by the unanimity of "all against one", thus allowing the mimetic impulse to safely evolve further, making language and complex social behaviours possible. Whereas scapegoating may have emerged in the entire population, and any member of a community could be scapegoated if necessary, this paper proposes that the scapegoat mechanism would have worked better in groups containing members who exhibited traits, recognised by all others, which singled them out as victims. Schizophrenia may be a functional adaptation, similar in evolutionary terms to altruism, in that it may have increased inclusive fitness, by providing scapegoat victims, the choice of whom was likely to be agreed upon unanimously, even during internecine conflict, thus restoring order and protecting the group from self-destruction. This evolutionary hypothesis, uses Girardian anthropology to combine the concept of the schizophrenic as religious shaman with that of the schizophrenic as scapegoat. It may help to reconcile divergent philosophical concepts of mental illness, and also help us to better understand, and thus counter, social exclusion and stigmatisation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its D,L-polylactide microparticle formulation.

    PubMed

    Bartolini, D; Piroddi, M; Tidei, C; Giovagnoli, S; Pietrella, D; Manevich, Y; Tew, K D; Giustarini, D; Rossi, R; Townsend, D M; Santi, C; Galli, F

    2015-01-01

    Catalytic properties and cellular effects of the glutathione peroxidase (GPx)-mimetic compound PhSeZnCl or its d,l-lactide polymer microencapsulation form (M-PhSeZnCl) were investigated and compared with the prototypical Se-organic compounds ebselen and diselenide (PhSe)2. PhSeZnCl was confirmed to catalyze the ping-pong reaction of GPx with higher Vmax than ebselen and (PhSe)2, but the catalytic efficiency calculated for the cosubstrates glutathione (GSH) and H2O2, and particularly the high reactivity against thiols (lowest KM for GSH in the series of test molecules), suggested poor biological applicability of PhSeZnCl as a GPx mimetic. Cytotoxicity of PhSeZnCl was demonstrated in various cancer cell lines via increased reactive oxygen species (ROS) generation, depletion of intracellular thiols, and induction of apoptosis. Experiments carried out in GSH S-transferase P (GSTP)-overexpressing K562 human erythroleukemia cells and in GSTP1-1-knockout murine embryonic fibroblasts (MEFs) demonstrated that this cytosolic enzyme represents a preferential target of the redox disturbances produced by this Se-compound with a key role in controlling H2O2 generation and the perturbation of stress/survival kinase signaling. Microencapsulation was adopted as a strategy to control the thiol reactivity and oxidative stress effects of PhSeZnCl, then assessing applications alternative to anticancer. The uptake of this "depowered" GPx-mimetic formulation, which occurred through an endocytosis-like mechanism, resulted in a marked reduction of cytotoxicity. In MCF-7 cells transfected with different allelic variants of GSTP, M-PhSeZnCl lowered the burst of cellular ROS induced by the exposure to extracellular H2O2, and the extent of this effect changed between the GSTP variants. Microencapsulation is a straightforward strategy to mitigate the toxicity of thiol-reactive Se-organic drugs that enhanced the antioxidant and cellular protective effects of PhSeZnCl. A mechanistic linkage of

  9. Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its d,l-polylactide microparticle formulation

    PubMed Central

    Bartolini, D.; Piroddi, M.; Tidei, C.; Giovagnoli, S.; Pietrella, D.; Manevich, Y.; Tew, K.D.; Giustarini, D.; Rossi, R.; Townsend, D.M.; Santi, C.; Galli, F.

    2015-01-01

    Catalytic properties and cellular effects of the glutathione peroxidase (GPx)-mimetic compound PhSeZnCl or its d,l-lactide polymer microencapsulation form (M-PhSeZnCl) were investigated and compared with the prototypical Se-organic compounds ebselen and diselenide (PhSe)2. PhSeZnCl was confirmed to catalyze the ping-pong reaction of GPx with higher Vmax than ebselen and (PhSe)2, but the catalytic efficiency calculated for the cosubstrates glutathione (GSH) and H2O2, and particularly the high reactivity against thiols (lowest KM for GSH in the series of test molecules), suggested poor biological applicability of PhSeZnCl as a GPx mimetic. Cytotoxicity of PhSeZnCl was demonstrated in various cancer cell lines via increased reactive oxygen species (ROS) generation, depletion of intracellular thiols, and induction of apoptosis. Experiments carried out in GSH S-transferase P (GSTP)-overexpressing K562 human erythroleukemia cells and in GSTP1-1-knockout murine embryonic fibroblasts (MEFs) demonstrated that this cytosolic enzyme represents a preferential target of the redox disturbances produced by this Se-compound with a key role in controlling H2O2 generation and the perturbation of stress/survival kinase signaling. Microencapsulation was adopted as a strategy to control the thiol reactivity and oxidative stress effects of PhSeZnCl, then assessing applications alternative to anticancer. The uptake of this “depowered” GPx-mimetic formulation, which occurred through an endocytosis-like mechanism, resulted in a marked reduction of cytotoxicity. In MCF-7 cells transfected with different allelic variants of GSTP, M-PhSeZnCl lowered the burst of cellular ROS induced by the exposure to extracellular H2O2, and the extent of this effect changed between the GSTP variants. Microencapsulation is a straightforward strategy to mitigate the toxicity of thiol-reactive Se-organic drugs that enhanced the antioxidant and cellular protective effects of PhSeZnCl. A mechanistic linkage

  10. Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-α but not through TRAIL and FasL.

    PubMed

    Jinesh G, Goodwin; Chunduru, Srinivas; Kamat, Ashish M

    2012-07-01

    BCG, the current gold standard immunotherapy for bladder cancer, exerts its activity via recruitment of neutrophils to the tumor microenvironment. Many patients do not respond to BCG therapy, indicating the need to understand the mechanism of action of BCG-stimulated neutrophils and to identify ways to overcome resistance to BCG therapy. Using isolated human neutrophils stimulated with BCG, we found that TNF-α is the key mediator secreted by BCG-stimulated neutrophils. RT4v6 human bladder cancer cells, which express TNFR1, CD95/Fas, CD95 ligand/FasL, DR4, and DR5, were resistant to BCG-stimulated neutrophil conditioned medium but effectively killed by the combination of conditioned medium and Smac mimetic. rhTNF-α and rhFasL, but not rhTRAIL, in combination with Smac mimetic, generated signature molecular events similar to those produced by BCG-stimulated neutrophils in combination with Smac mimetic. However, experiments using neutralizing antibodies to these death ligands showed that TNF-α secreted from BCG-stimulated neutrophils was the key mediator of anticancer action. These findings explain the mechanism of action of BCG and identified Smac mimetics as potential combination therapeutic agents for bladder cancer.

  11. Activity of antimicrobial peptide mimetics in the oral cavity: II. Activity against periopathogenic biofilms and anti-inflammatory activity

    PubMed Central

    Hua, J; Scott, R.W.; Diamond, G

    2011-01-01

    Whereas periodontal disease is ultimately of bacterial etiology, from multispecies biofilms of gram-negative anaerobic microorganisms, much of the deleterious effects are caused by the resultant epithelial inflammatory response. Hence, development of a treatment that combines anti-biofilm antibiotic activity with anti-inflammatory activity would be of great utility. Antimicrobial peptides (AMPs) such as defensins are naturally occurring peptides that exhibit broad-spectrum activity as well as a variety of immunomodulatory activities. Furthermore, bacteria do not readily develop resistance to these agents. However, clinical studies have suggested that they do not represent optimal candidates for exogenous therapeutic agents. Small-molecule mimetics of these AMPs exhibit similar activities to the parent peptides, in addition to having low toxicity, high stability and low cost. To determine whether AMP mimetics have the potential for treatment of periodontal disease, we examined the activity of one mimetic, mPE, against biofilm cultures of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Metabolic assays as well as culture and biomass measurement assays demonstrated that mPE exhibits potent activity against biofilm cultures of both species. Furthermore, as little as 2 µg ml−1 mPE was sufficient to inhibit interleukin-1β-induced secretion of interleukin-8 in both gingival epithelial cells and THP-1 cells. This anti-inflammatory activity is associated with a reduction in activation of nuclear factor-κB, suggesting that mPE can act both as an anti-biofilm agent in an anaerobic environment and as an anti-inflammatory agent in infected tissues. PMID:21040516

  12. Anti-endotoxic activity and structural basis for human MD-2·TLR4 antagonism of tetraacylated lipid A mimetics based on βGlcN(1↔1)αGlcN scaffold

    PubMed Central

    Garate, Jose Antonio; Stöckl, Johannes; del Carmen Fernández-Alonso, María; Artner, Daniel; Haegman, Mira; Oostenbrink, Chris; Jiménez-Barbero, Jesús; Beyaert, Rudi; Heine, Holger; Kosma, Paul

    2015-01-01

    Interfering with LPS binding by the co-receptor protein myeloid differentiation factor 2 (MD-2) represents a useful approach for down-regulation of MD-2·TLR4-mediated innate immune signaling, which is implicated in the pathogenesis of a variety of human diseases, including sepsis syndrome. The antagonistic activity of a series of novel synthetic tetraacylated bis-phosphorylated glycolipids based on the βGlcN(1↔1)αGlcN scaffold was assessed in human monocytic macrophage-like cell line THP-1, dendritic cells and human epithelial cells. Two compounds were shown to inhibit efficiently the LPS-induced inflammatory signaling by down-regulation of the expression of TNF-α, IL-6, IL-8, IL-10 and IL-12 to background levels. The binding of the tetraacylated by (R)-3-hydroxy-fatty acids (2 × C12, 2 × C14), 4,4′-bisphosphorylated βGlcN(1↔1)αGlcN-based lipid A mimetic DA193 to human MD-2 was calculated to be 20-fold stronger than that of Escherichia coli lipid A. Potent antagonistic activity was related to a specific molecular shape induced by the β,α(1↔1)-diglucosamine backbone. ‘Co-planar’ relative arrangement of the GlcN rings was inflicted by the double exo-anomeric conformation around both glycosidic torsions in the rigid β,α(1↔1) linkage, which was ascertained using NOESY NMR experiments and confirmed by molecular dynamics simulation. In contrast to the native lipid A ligands, the binding affinity of βGlcN(1↔1)αGlcN-based lipid A mimetics to human MD-2 was independent on the orientation of the diglucosamine backbone of the synthetic antagonist within the binding pocket of hMD-2 (rotation by 180°) allowing for two equally efficient binding modes as shown by molecular dynamics simulation. PMID:25394365

  13. Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols

    PubMed Central

    Pitt, Jason; Thorner, Michael; Brautigan, David; Larner, Joseph; Klein, William L.

    2013-01-01

    Alzheimer's disease (AD) is a progressive dementia that correlates highly with synapse loss. This loss appears due to the synaptic accumulation of toxic Aβ oligomers (ADDLs), which damages synapse structure and function. Although it has been reported that oligomer binding and toxicity can be prevented by stimulation of neuronal insulin signaling with PPARγ agonists, these agonists have problematic side effects. We therefore investigated the therapeutic potential of chiro-inositols, insulin-sensitizing compounds safe for human consumption. Chiro-inositols have been studied extensively for treatment of diseases associated with peripheral insulin resistance, but their insulin mimetic function in memory-relevant central nervous system (CNS) cells is unknown. Here we demonstrate that mature cultures of hippocampal neurons respond to d-chiro-inositol (DCI), pinitol (3-O-methyl DCI), and the inositol glycan INS-2 (pinitol β-1-4 galactosamine) with increased phosphorylation in key upstream components in the insulin-signaling pathway (insulin receptor, insulin receptor substrate-1, and Akt). Consistent with insulin stimulation, DCI treatment promotes rapid withdrawal of dendritic insulin receptors. With respect to neuroprotection, DCI greatly enhances the ability of insulin to prevent ADDL-induced synapse damage (EC50 of 90 nM). The mechanism comprises inhibition of oligomer binding at synapses and requires insulin/IGF signaling. DCI showed no effects on Aβ oligomerization. We propose that inositol glycans and DCI, a compound already established as safe for human consumption, have potential as AD therapeutics by protecting CNS synapses against Aβ oligomers through their insulin mimetic activity.—Pitt, J., Thorner, M., Brautigan, D., Larner, J., Klein, W. L. Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols. PMID:23073831

  14. The BH3 Mimetic Obatoclax Accumulates in Lysosomes and Causes Their Alkalinization.

    PubMed

    Stamelos, Vasileios A; Fisher, Natalie; Bamrah, Harnoor; Voisey, Carolyn; Price, Joshua C; Farrell, William E; Redman, Charles W; Richardson, Alan

    2016-01-01

    Obatoclax belongs to a class of compounds known as BH3 mimetics which function as antagonists of Bcl-2 family apoptosis regulators. It has undergone extensive preclinical and clinical evaluation as a cancer therapeutic. Despite this, it is clear that obatoclax has additional pharmacological effects that contribute to its cytotoxic activity. It has been claimed that obatoclax, either alone or in combination with other molecularly targeted therapeutics, induces an autophagic form of cell death. In addition, obatoclax has been shown to inhibit lysosomal function, but the mechanism of this has not been elucidated. We have evaluated the mechanism of action of obatoclax in eight ovarian cancer cell lines. Consistent with its function as a BH3 mimetic, obatoclax induced apoptosis in three cell lines. However, in the remaining cell lines another form of cell death was evident because caspase activation and PARP cleavage were not observed. Obatoclax also failed to show synergy with carboplatin and paclitaxel, chemotherapeutic agents which we have previously shown to be synergistic with authentic Bcl-2 family antagonists. Obatoclax induced a profound accumulation of LC-3 but knockdown of Atg-5 or beclin had only minor effects on the activity of obatoclax in cell growth assays suggesting that the inhibition of lysosomal function rather than stimulation of autophagy may play a more prominent role in these cells. To evaluate how obatoclax inhibits lysosomal function, confocal microscopy studies were conducted which demonstrated that obatoclax, which contains two basic pyrrole groups, accumulates in lysosomes. Studies using pH sensitive dyes demonstrated that obatoclax induced lysosomal alkalinization. Furthermore, obatoclax was synergistic in cell growth/survival assays with bafilomycin and chloroquine, two other drugs which cause lysosomal alkalinization. These studies explain, for the first time, how obatoclax inhibits lysosomal function and suggest that lysosomal

  15. A hydroxychalcone derived from cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes.

    PubMed

    Jarvill-Taylor, K J; Anderson, R A; Graves, D J

    2001-08-01

    These studies investigated the ability of a hydroxychalcone from cinnamon to function as an insulin mimetic in 3T3-LI adipocytes. Comparative experiments were performed with the cinnamon methylhydroxychalcone polymer and insulin with regard to glucose uptake, glycogen synthesis. phosphatidylinositol-3-kinase dependency, glycogen synthase activation and glycogen synthase kinase-3beta activity. The phosphorylation state of the insulin receptor was also investigated. MHCP treatment stimulated glucose uptake and glycogen synthesis to a similar level as insulin. Glycogen synthesis was inhibited by both wortmannin and LY294002, inhibitors directed against the PI-3-kinase. In addition, MHCP treatment activated glycogen synthase and inhibited glycogen synthase kinase-3beta activities, known effects of insulin treatment. Analysis of the insulin receptor demonstrated that the receptor was phosphorylated upon exposure to the MHCP. This supports that the insulin cascade was triggered by MHCP. Along with comparing MHCP to insulin, experiments were done with MHCP and insulin combined. The responses observed using the dual treatment were greater than additive, indicating synergism between the two compounds. Together, these results demonstrate that the MHCP is an effective mimetic of insulin. MHCP may be useful in the treatment of insulin resistance and in the study of the pathways leading to glucose utilization in cells.

  16. Synthesis and evaluation of di- and trimeric hydroxylamine-based β-(1→3)-glucan mimetics.

    PubMed

    Ferry, Angélique; Malik, Gaëlle; Guinchard, Xavier; Vĕtvička, Václav; Crich, David

    2014-10-22

    Di- and trimeric hydroxylamine-based mimetics of β-(1→3)-glucans have been accessed by an asymmetric synthesis route featuring an iterative double ring-closing reductive amination reaction. These oligomeric hydroxylamines are demonstrated to inhibit the staining of human neutrophils and of mouse macrophages by fluorescent anti-CR3 and anti-dectin-1 antibodies, respectively, and to stimulate phagocytosis, all in a linkage-dependent manner suggestive of binding to the lectin domains of complement receptor 3 (CR3) and dectin-1. The ability of these relatively short mimetics to bind to CR3 and dectin-1, as compared to the greater degree of polymerization required in β-(1→3)-glucans, is discussed in terms of the increased hydrophobicity of the α-face on replacement of the glycosidic bond by the hydroxylamine linkage.

  17. Determination of superoxide dismutase mimetic activity in common culinary herbs.

    PubMed

    Chohan, Magali; Naughton, Declan P; Opara, Elizabeth I

    2014-01-01

    Under conditions of oxidative stress, the removal of superoxide, a free radical associated with chronic inflammation, is catalysed by superoxide dismutase (SOD). Thus in addition to acting as an antioxidant, SOD may also be utilized as an anti-inflammatory agent. Some plant derived foods have been shown to have SOD mimetic (SODm) activity however it is not known if this activity is possessed by culinary herbs which have previously been shown to possess both antioxidant and anti-inflammatory properties. The aim of the study was to ascertain if the culinary herbs rosemary, sage and thyme possess SODm activity, and to investigate the influence of cooking and digestion on this activity. Transition metal ion content was also determined to establish if it could likely contribute to any SODm activity detected. All extracts of uncooked (U), cooked (C) and cooked and digested (C&D) herbs were shown to possess SODm activity, which was significantly correlated with previously determined antioxidant and anti-inflammatory activities of these herbs. SODm activity was significantly increased following (C) and (C&D) for rosemary and sage only. The impact of (C) and (C&D) on the SODm for thyme may have been influenced by its transition metal ion content. SODm activity may contribute to the herbs' antioxidant and anti-inflammatory activities however the source and significance of this activity need to be established.

  18. Mg2+ ion effect on conformational equilibrium of poly A . 2 poly U and poly A poly U in aqueous solutions.

    PubMed

    Sorokin, Victor A; Valeev, Vladimir A; Gladchenko, Galina O; Degtiar, Marina V; Karachevtsev, Victor A; Blagoi, Yuri P

    2003-01-15

    Differential UV spectroscopy and thermal denaturation were used to study the Mg(2+) ion effect on the conformational equilibrium in poly A.2 poly U (A2U) and poly A . poly U (AU) solutions at low (0.01 M Na(+)) and high (0.1 M Na(+)) ionic strengths. Four complete phase diagrams were obtained for Mg(2+)-polynucleotide complexes in ranges of temperatures 20-96 degrees C and concentrations (10(-5)-10(-2)) M Mg(2+). Three of them have a 'critical' point at which the type of the conformational transition changes. The value of the 'critical' concentration ([Mg(t)(2+)](cr)=(4.5+/-1.0) x 10(-5) M) is nearly independent of the initial conformation of polynucleotides (AU, A2U) and of Na(+) contents in the solution. Such a value is observed for Ni(2+) ions too. The phase diagram of the (A2U+Mg(2+)) complex with 0.01 M Na(+) has no 'critical' point: temperatures of (3-->2) and (2-->1) transitions increase in the whole Mg(2+) range. In (AU+Mg(2+)) phase diagram at 0.01 M Na(+) the temperature interval in which triple helices are formed and destroyed is several times larger than at 0.1 M Na(+). Using the ligand theory, a qualitative thermodynamic analysis of the phase diagrams was performed.

  19. A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome

    PubMed Central

    Kron, Miriam; Lang, Min; Adams, Ian T.; Sceniak, Michael; Longo, Frank; Katz, David M.

    2014-01-01

    Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal

  20. EPOR-Based Purification and Analysis of Erythropoietin Mimetic Peptides from Human Urine by Cys-Specific Cleavage and LC/MS/MS

    NASA Astrophysics Data System (ADS)

    Vogel, Matthias; Thomas, Andreas; Schänzer, Wilhelm; Thevis, Mario

    2015-09-01

    The development of a new class of erythropoietin mimetic agents (EMA) for treating anemic conditions has been initiated with the discovery of oligopeptides capable of dimerizing the erythropoietin (EPO) receptor and thus stimulating erythropoiesis. The most promising amino acid sequences have been mounted on various different polymeric structures or carrier molecules to obtain highly active EPO-like drugs exhibiting beneficial and desirable pharmacokinetic profiles. Concomitant with creating new therapeutic options, erythropoietin mimetic peptide (EMP)-based drug candidates represent means to artificially enhance endurance performance and necessitate coverage by sports drug testing methods. Therefore, the aim of the present study was to develop a strategy for the comprehensive detection of EMPs in doping controls, which can be used complementary to existing protocols. Three model EMPs were used to provide proof-of-concept data. Following EPO receptor-facilitated purification of target analytes from human urine, the common presence of the cysteine-flanked core structure of EMPs was exploited to generate diagnostic peptides with the aid of a nonenzymatic cleavage procedure. Sensitive detection was accomplished by targeted-SIM/data-dependent MS2 analysis. Method characterization was conducted for the EMP-based drug peginesatide concerning specificity, linearity, precision, recovery, stability, ion suppression/enhancement, and limit of detection (LOD, 0.25 ng/mL). Additionally, first data for the identification of the erythropoietin mimetic peptides EMP1 and BB68 were generated, demonstrating the multi-analyte testing capability of the presented approach.

  1. Stick–slip friction of gecko-mimetic flaps on smooth and rough surfaces

    PubMed Central

    Das, Saurabh; Cadirov, Nicholas; Chary, Sathya; Kaufman, Yair; Hogan, Jack; Turner, Kimberly L.; Israelachvili, Jacob N.

    2015-01-01

    The discovery and understanding of gecko ‘frictional-adhesion’ adhering and climbing mechanism has allowed researchers to mimic and create gecko-inspired adhesives. A few experimental and theoretical approaches have been taken to understand the effect of surface roughness on synthetic adhesive performance, and the implications of stick–slip friction during shearing. This work extends previous studies by using a modified surface forces apparatus to quantitatively measure and model frictional forces between arrays of polydimethylsiloxane gecko footpad-mimetic tilted microflaps against smooth and rough glass surfaces. Constant attachments and detachments occur between the surfaces during shearing, as described by an avalanche model. These detachments ultimately result in failure of the adhesion interface and have been characterized in this study. Stick–slip friction disappears with increasing velocity when the flaps are sheared against a smooth silica surface; however, stick–slip was always present at all velocities and loads tested when shearing the flaps against rough glass surfaces. These results demonstrate the significance of pre-load, shearing velocity, shearing distances, commensurability and shearing direction of gecko-mimetic adhesives and provide us a simple model for analysing and/or designing such systems. PMID:25589569

  2. Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIb/β3 integrin

    PubMed Central

    Rasmussen, Mark; Zhu, Jieqing; Aster, Richard H.

    2012-01-01

    Arginine-glycine-aspartic acid (RGD)–mimetic platelet inhibitors act by occupying the RGD recognition site of αIIb/β3 integrin (GPIIb/IIIa), thereby preventing the activated integrin from reacting with fibrinogen. Thrombocytopenia is a well-known side effect of treatment with this class of drugs and is caused by Abs, often naturally occurring, that recognize αIIb/β3 in a complex with the drug being administered. RGD peptide and RGD-mimetic drugs are known to induce epitopes (ligand-induced binding sites [LIBS]) in αIIb/β3 that are recognized by certain mAbs. It has been speculated, but not shown experimentally, that Abs from patients who develop thrombocytopenia when treated with an RGD-mimetic inhibitor similarly recognize LIBS determinants. We addressed this question by comparing the reactions of patient Abs and LIBS-specific mAbs against αIIb/β3 in a complex with RGD and RGD-mimetic drugs, and by examining the ability of selected non-LIBS mAbs to block binding of patient Abs to the liganded integrin. Findings made provide evidence that the patient Abs recognize subtle, drug-induced structural changes in the integrin head region that are clustered about the RGD recognition site. The target epitopes differ from classic LIBS determinants, however, both in their location and by virtue of being largely drug-specific. PMID:22490676

  3. Solving Navier-Stokes' equation using Castillo-Grone's mimetic difference operators on GPUs

    NASA Astrophysics Data System (ADS)

    Abouali, Mohammad; Castillo, Jose

    2012-11-01

    This paper discusses the performance and the accuracy of Castillo-Grone's (CG) mimetic difference operator in solving the Navier-Stokes' equation in order to simulate oceanic and atmospheric flows. The implementation is further adapted to harness the power of the many computing cores available on the Graphics Processing Units (GPUs) and the speedup is discussed.

  4. Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes

    PubMed Central

    Delmastro-Greenwood, Meghan M.; Marré, Meghan L.; O’Connor, Erin C.; Novak, Elizabeth A.; Vincent, Garret; Mollen, Kevin P.; Lee, Sojin; Dong, H. Henry; Piganelli, Jon D.

    2017-01-01

    Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity. PMID:29104232

  5. Light-Adaptive Supramolecular Nacre-Mimetic Nanocomposites.

    PubMed

    Zhu, Baolei; Noack, Manuel; Merindol, Remi; Barner-Kowollik, Christopher; Walther, Andreas

    2016-08-10

    Nature provides design paradigms for adaptive, self-healing, and synergistic high-performance structural materials. Nacre's brick-and-mortar architecture is renowned for combining stiffness, toughness, strength, and lightweightness. Although elaborate approaches exist to mimic its static structure and performance, and to incorporate functionalities for the engineering world, there is a profound gap in addressing adaptable mechanical properties, particularly using remote, quick, and spatiotemporal triggers. Here, we demonstrate a generic approach to control the mechanical properties of nacre-inspired nanocomposites by designing a photothermal energy cascade using colloidal graphene as light-harvesting unit and coupling it to molecularly designed, thermoreversible, supramolecular bonds in the nanoconfined soft phase of polymer/nanoclay nacre-mimetics. The light intensity leads to adaptive steady-states balancing energy uptake and dissipation. It programs the mechanical properties and switches the materials from high stiffness/strength to higher toughness within seconds under spatiotemporal control. We envisage possibilities beyond mechanical materials, for example, light-controlled (re)shaping or actuation in highly reinforced nanocomposites.

  6. Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques

    PubMed Central

    Bogers, Willy M.; Yates, Nicole L.; Ferrari, Guido; Dey, Antu K.; Williams, William T.; Jaeger, Frederick H.; Wiehe, Kevin; Sawant, Sheetal; Alam, S. Munir; LaBranche, Celia C.; Montefiori, David C.; Martin, Loic; Srivastava, Indresh; Heeney, Jonathan; Barnett, Susan W.

    2017-01-01

    ABSTRACT Evaluation of the epitope specificities, locations (systemic or mucosal), and effector functions of antibodies elicited by novel HIV-1 immunogens engineered to improve exposure of specific epitopes is critical for HIV-1 vaccine development. Utilizing an array of humoral assays, we evaluated the magnitudes, epitope specificities, avidities, and functions of systemic and mucosal immune responses elicited by a vaccine regimen containing Env cross-linked to a CD4-mimetic miniprotein (gp140-M64U1) in rhesus macaques. Cross-linking of gp140 Env to M64U1 resulted in earlier increases of both the magnitude and avidity of the IgG binding response than those with Env protein alone. Notably, IgG binding responses at an early time point correlated with antibody-dependent cellular cytotoxicity (ADCC) function at the peak immunity time point, which was higher for the cross-linked Env group than for the Env group. In addition, the cross-linked Env group developed higher IgG responses against a linear epitope in the gp120 C1 region of the HIV-1 envelope glycoprotein. These data demonstrate that structural modification of the HIV-1 envelope immunogen by cross-linking of gp140 with the CD4-mimetic M64U1 elicited an earlier increase of binding antibody responses and altered the specificity of the IgG responses, correlating with the rise of subsequent antibody-mediated antiviral functions. IMPORTANCE The development of an efficacious HIV-1 vaccine remains a global priority to prevent new cases of HIV-1 infection. Of the six HIV-1 efficacy trials to date, only one has demonstrated partial efficacy, and immune correlate analysis of that trial revealed a role for binding antibodies and antibody Fc-mediated effector functions. New HIV-1 envelope immunogens are being engineered to selectively expose the most vulnerable and conserved sites on the HIV-1 envelope, with the goal of eliciting antiviral antibodies. Evaluation of the humoral responses elicited by these novel immunogen

  7. Sidedness of interfacial arginine residues and anti-atherogenicity of apolipoprotein A-I mimetic peptides

    PubMed Central

    Nayyar, Gaurav; Mishra, Vinod K.; Handattu, Shaila P.; Palgunachari, Mayakonda N.; Shin, Ronald; McPherson, David T.; Deivanayagam, Champion C. S.; Garber, David W.; Segrest, Jere P.; Anantharamaiah, G. M.

    2012-01-01

    To test the hypothesis that sidedness of interfacial arginine (Arg) in apoA-I mimetic peptides, similar to that observed in apoA-I (Bashtovyy, D. et al. 2011. Sequence conservation of apolipoprotein A-I affords novel insights into HDL structure-function. J. Lipid Res. 52: 435–450.), may be important for biological activity, we compared properties of 4F and analogs, [K4,15>R]4F and [K9,13>R]4F, with Lys>Arg substitutions on the right and left side, respectively, of the 4F amphipathic helix. Intraperitoneal administration of these peptides into female apoE null mice (n = 13 in each group) reduced en face lesions significantly compared with controls; 4F and [K4,15>R]4F were equally effective whereas [K9,13>R]4F was less effective. Turnover experiments indicated that [K4,15>R]4F reached the highest, whereas [K9,13>R]4F had the lowest, plasma peak levels with a similar half life as the [K4,15>R]4F analog. The half life of 4F was two times longer than the other two peptides. The order in their abilities to associate with HDL in human plasma, generation of apoA-I particles with pre-β mobility from isolated HDL, lipid associating ability, and sensitivity of lipid complexes to trypsin digestion was: 4F>[K4,15,>R]4F>[K9,13>R]4F. These studies support our hypothesis that the sidedness of interfacial Arg residues in the polar face of apoA-I mimetics results in differential biological properties. PMID:22377531

  8. Ancient homology underlies adaptive mimetic diversity across butterflies

    PubMed Central

    Gallant, Jason R.; Imhoff, Vance E.; Martin, Arnaud; Savage, Wesley K.; Chamberlain, Nicola L.; Pote, Ben L.; Peterson, Chelsea; Smith, Gabriella E.; Evans, Benjamin; Reed, Robert D.; Kronforst, Marcus R.; Mullen, Sean P.

    2014-01-01

    Convergent evolution provides a rare, natural experiment with which to test the predictability of adaptation at the molecular level. Little is known about the molecular basis of convergence over macro-evolutionary timescales. Here we use a combination of positional cloning, population genomic resequencing, association mapping and developmental data to demonstrate that positionally orthologous nucleotide variants in the upstream region of the same gene, WntA, are responsible for parallel mimetic variation in two butterfly lineages that diverged >65 million years ago. Furthermore, characterization of spatial patterns of WntA expression during development suggests that alternative regulatory mechanisms underlie wing pattern variation in each system. Taken together, our results reveal a strikingly predictable molecular basis for phenotypic convergence over deep evolutionary time. PMID:25198507

  9. Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies

    PubMed Central

    Huang, DCS

    2016-01-01

    The intracellular protein B‐cell‐lymphoma‐2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti‐apoptotic) in the late 1980s. However, the challenges of targeting a protein‐protein interaction delayed the discovery of fit‐for‐purpose molecules until the mid‐2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so‐called BH3‐mimetics, have been developed. Venetoclax (formerly ABT‐199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B‐cell malignancies that highly express BCL2. PMID:27806433

  10. Antifreeze Protein Mimetic Metallohelices with Potent Ice Recrystallization Inhibition Activity.

    PubMed

    Mitchell, Daniel E; Clarkson, Guy; Fox, David J; Vipond, Rebecca A; Scott, Peter; Gibson, Matthew I

    2017-07-26

    Antifreeze proteins are produced by extremophile species to control ice formation and growth, and they have potential applications in many fields. There are few examples of synthetic materials which can reproduce their potent ice recrystallization inhibition property. We report that self-assembled enantiomerically pure, amphipathic metallohelicies inhibited ice growth at just 20 μM. Structure-property relationships and calculations support the hypothesis that amphipathicity is the key motif for activity. This opens up a new field of metallo-organic antifreeze protein mimetics and provides insight into the origins of ice-growth inhibition.

  11. Facial mimetic, cosmetic, and functional standardized assessment of the facial artery musculomucosal (FAMM) flap.

    PubMed

    Jowett, Nathan; Hadlock, Tessa A; Sela, Eyal; Toth, Miklos; Knecht, Rainald; Lörincz, Balazs B

    2017-04-01

    To objectively assess donor site morbidity after harvesting the facial artery musculomucosal flap. Use of the FAMM-flap in oral cavity reconstruction remains sporadic. This case series describes our newly developed standardized assessment of this flap in a floor of mouth (FOM) reconstructive setting. Standardized postoperative assessment of the FAMM flap for donor site wound complications, functional, facial mimetic and oncologic outcomes. There were no wound complications. Oral competence remained intact, tongue mobility was good to excellent, average word articulation score was 98%, and mimetic function excellent in all patients. Three patients experienced ipsilateral upper lip anesthesia, and five patients were noted to have slight dysfunction of the orbicularis oris resulting in a loss of lip height at rest. The FAMM flap is a reliable option for reconstruction of ablative defects of the FOM, and should be considered a workhorse flap for oral cavity defects. Unlike the submental island flap, a complete level I dissection may be concurrently performed without compromising the vascular supply to the FAMM flap. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Nacre-mimetic bulk lamellar composites reinforced with high aspect ratio glass flakes.

    PubMed

    Guner, Selen N Gurbuz; Dericioglu, Arcan F

    2016-12-05

    Nacre-mimetic epoxy matrix composites reinforced with readily available micron-sized high aspect ratio C-glass flakes were fabricated by a relatively simple, single-step, scalable, time, cost and man-power effective processing strategy: hot-press assisted slip casting (HASC). HASC enables the fabrication of preferentially oriented two-dimensional inorganic reinforcement-polymer matrix bulk lamellar composites with a micro-scale structure resembling the brick-and-mortar architecture of nacre. By applying the micro-scale design guideline found in nacre and optimizing the relative volume fractions of the reinforcement and the matrix as well as by anchoring the brick-and-mortar architecture, and tailoring the interface between reinforcements and the matrix via silane coupling agents, strong, stiff and tough bio-inspired nacre-mimetic bulk composites were fabricated. As a result of high shear stress transfer lengths and effective stress transfer at the interface achieved through surface functionalization of the reinforcements, fabricated bulk composites exhibited enhanced mechanical performance as compared to neat epoxy. Furthermore, governed flake pull-out mode along with a highly torturous crack path, which resulted from extensive deflection and meandering of the advancing crack around well-aligned high aspect ratio C-glass flakes, have led to high work-of-fracture values similar to nacre.

  13. Apo A1 Mimetic Rescues the Diabetic Phenotype of HO-2 Knockout Mice via an Increase in HO-1 Adiponectin and LKBI Signaling Pathway

    PubMed Central

    Cao, Jian; Puri, Nitin; Sodhi, Komal; Bellner, Lars; Abraham, Nader G.; Kappas, Attallah

    2012-01-01

    Insulin resistance, with adipose tissue dysfunction, is one of the hallmarks of metabolic syndrome. We have reported a metabolic syndrome-like phenotype in heme oxygenase (HO)-2 knockout mice, which presented with concurrent HO-1 deficiency and were amenable to rescue by an EET analog. Apo A-I mimetic peptides, such as L-4F, have been shown to induce HO-1 expression and decrease oxidative stress and adiposity. In this study we aimed to characterize alleviatory effects of HO-1 induction (if any) on metabolic imbalance observed in HO-2 KO mice. In this regard, HO-2(−/−) mice were injected with 2 mg/kg/day L-4F, or vehicle, i.p., for 6 weeks. As before, compared to WT animals, the HO-2 null mice were obese, displayed insulin resistance, and had elevated blood pressure. These changes were accompanied by enhanced tissue (hepatic) oxidative stress along with attenuation of HO-1 expression and activity and reduced adiponectin, pAMPK, and LKB1 expression. Treatment with L-4F restored HO-1 expression and activity and increased adiponectin, LKB1, and pAMPK in the HO-2(−/−) mice. These alterations resulted in a decrease in blood pressure, insulin resistance, blood glucose, and adiposity. Taken together, our results show that a deficient HO-1 response, in a state with reduced HO-2 basal levels, is accompanied by disruption of metabolic homeostasis which is successfully restored by an HO-1 inducer. PMID:22577519

  14. A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on HBV-positive hepatocellular carcinoma with high expression of cIAP2 by inducing apoptosis and enhancing innate anti-tumor immunity.

    PubMed

    Pan, Wentao; Luo, Qiuyun; Yan, Xianglei; Yuan, Luping; Yi, Hanjie; Zhang, Lin; Li, Baoxia; Zhang, Yuxin; Sun, Jian; Qiu, Miao-Zhen; Yang, Da-Jun

    2018-04-18

    Check point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, Second mitochondria-derived activator of caspases (SMAC) mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs). In our study, firstly, we found that HCC patients with copy number alteration of cIAP1, cIAP2, and XIAP had a dismal prognosis. Then, we discovered that APG-1387 alone could induce apoptosis of PLC/PRF/5 which was HBV positive both in-vitro and in-vivo. Furthermore, we found that APG-1387 significantly up-regulated the expression of calreticulin and HLA-DR in PLC/PRF/5 via activating non-classic NF-κB pathway. Also, compared to vehicle group, APG-1387 increased NK cell counts by 5 folds in PLC/PRF/5 xenograft model. In-vitro, APG-1387 positively regulated T cells by reducing Treg differentiation and down-regulating PD1 expression in CD4 T cell. Moreover, APG-1387 had no impact on memory T cells. Consequently, our results suggest that APG1387 could be a good candidate to combine with anti-PD1 antibody treatment to overcome low responds of check point inhibitors in HBV positive HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Collagen-binding VEGF mimetic peptide: Structure, matrix interaction, and endothelial cell activation

    NASA Astrophysics Data System (ADS)

    Chan, Tania R.

    Long term survival of artificial tissue constructs depends greatly on proper vascularization. In nature, differentiation of endothelial cells and formation of vasculature are directed by dynamic spatio-temporal cues in the extracellular matrix that are difficult to reproduce in vitro. In this dissertation, we present a novel bifunctional peptide that mimics matrix-bound vascular endothelial growth factor (VEGF), which can be used to encode spatially controlled angiogenic signals in collagen-based scaffolds. The peptide, QKCMP, contains a collagen mimetic domain (CMP) that binds to type I collagen by a unique triple helix hybridization mechanism and a VEGF mimetic domain (QK) with pro-angiogenic activity. We demonstrate QKCMP's ability to hybridize with native and heat denatured collagens through a series of binding studies on collagen and gelatin substrates. Circular dichroism experiments show that the peptide retains the triple helical structure vital for collagen binding, and surface plasmon resonance study confirms the molecular interaction between the peptide and collagen strands. Cell culture studies demonstrate QKCMP's ability to induce endothelial cell morphogenesis and network formation as a matrix-bound factor in 2D and 3D collagen scaffolds. We also show that the peptide can be used to spatially modify collagen-based substrates to promote localized endothelial cell activation and network formation. To probe the biological events that govern these angiogenic cellular responses, we investigated the cell signaling pathways activated by collagen-bound QKCMP and determined short and long-term endothelial cell response profiles for p38, ERK1/2, and Akt signal transduction cascades. Finally, we present our efforts to translate the peptide's in vitro bioactivity to an in vivo burn injury animal model. When implanted at the wound site, QKCMP functionalized biodegradable hydrogels induce enhanced neovascularization in the granulation tissue. The results show QKCMP

  16. The pulmonary pharmacology of [4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide] (2NTX-99), an anti-atherotrombotic compound with therapeutic potential in pathological conditions that target lung vasculature.

    PubMed

    Brivio, I; Buccellati, C; Fumagalli, F; Hodge, J; Casagrande, C; Folco, G C; Sala, A

    2012-08-01

    The pharmacological activity of 2NTX-99 ([4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide]) was investigated in vitro in the intact, rat pulmonary vasculature and in guinea pig airways. Rat lungs were perfused at constant flow and changes in vascular tone recorded. Challenge with the TXA₂ analogue 9,11-dideoxy-9α11α-methanoepoxy ProstaglandinF₂ (U46619, 0.5 μM) increased vessel tone (32.48±1.5 vs 13.13±0.56 mmHg; n=12). 2NTX-99 (0.1-100 μM; n=5), caused a concentration-dependent relaxation, prevented by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 μM, n=4), an inhibitor of soluble guanylate cyclase. Acetylcholine (0.1-10 μM; n=3) and a reference NO-donor, isosorbide-5-mononitrate (5-100 μM; n=4), were ineffective. Intraluminal perfusion of washed human platelets (2 × 10⁸ cells/ml) increased intravascular pressure after challenge with arachidonic acid (AA, 2 μM; n=5), an increase abolished by acetylsalicylic acid and significantly reduced by 2NTX-99 (40 μM; n=5). TXB₂ in the lung perfusate was detected after platelet activation, 2NTX-99 inhibited TXA₂ synthesis (6.45±0.6 and 1.10±0.2 ng/ml, respectively). 2NTX-99 did not alter central or peripheral airway responsiveness to Histamine (0.001-300 μM; n=6), U46619 (0.001-3 μM, n=3) or LTD₄ (1 pM-1 μM; n=6). 2NTX-99 vasodilates the pulmonary vasculature via the release of nitric oxide (NO) and reduces intraluminal, AA-induced, TXA₂ formation. The combined activity of 2NTX-99 as an NO-donor and a TXA₂-synthesis inhibitor provides strong support for its potential therapeutic use in pathologies of the pulmonary vascular bed (e.g. pulmonary hypertension). Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic)

    PubMed Central

    Yan, Ji-Geng; Zhang, Lin-ling; Agresti, Michael; Yan, Yuhui; LoGiudice, John; Sanger, James R.; Matloub, Hani S.; Pritchard, Kirkwood A.; Jaradeh, Safwan S.; Havlik, Robert

    2017-01-01

    Background Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. Methods A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. Results Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. Conclusions The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning. PMID:26433438

  18. Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic).

    PubMed

    Yan, Ji-Geng; Zhang, Lin-ling; Agresti, Michael; Yan, Yuhui; LoGiudice, John; Sanger, James R; Matloub, Hani S; Pritchard, Kirkwood A; Jaradeh, Safwan S; Havlik, Robert

    2015-12-01

    Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning. Copyright © 2015 National Stroke Association. All rights reserved.

  19. ^2^3^8U/^2^3^5U Ratios of Anagrams: Angrites and Granites

    NASA Astrophysics Data System (ADS)

    Tissot, F. L. H.; Dauphas, N.

    2012-03-01

    We report ^2^3^8U/^2^3^5U ratios of five angrites and give the corresponding Pb-Pb ages of D'Orbigny and Angra Dos Reis. The U-isotopic composition of terrestrial granites (I, S, and A types) is also assessed to determine the influence of the protolith.

  20. Caloric restriction mimetic 2-deoxyglucose maintains cytoarchitecture and reduces tau phosphorylation in primary culture of mouse hippocampal pyramidal neurons.

    PubMed

    Bele, M S; Gajare, K A; Deshmukh, A A

    2015-06-01

    Typical form of neurons is crucially important for their functions. This is maintained by microtubules and associated proteins like tau. Hyperphosphorylation of tau is a major concern in neurodegenerative diseases. Glycogen synthase kinase3β (GSK3β) and cyclin-dependent protein kinase 5 (Cdk5) are the enzymes that govern tau phosphorylation. Currently, efforts are being made to target GSK3β and Cdk5 as possible therapeutic avenues to control tau phosphorylation and treat neurodegenerative diseases related to taupathies. In a number of studies, caloric restriction mimetic 2-deoxyglucose (C6H12O5) was found to be beneficial in improving the brain functions. However, no reports are available on the effect of 2-deoxyglucose 2-DG on tau phosphorylation. In the present study, hippocampal pyramidal neurons from E17 mouse embryos were isolated and cultured on poly-L-lysine-coated coverslips. Neurons from the experimental group were treated with 10 mM 2-deoxyglucose. The treatment of 2-DG resulted in healthier neuronal morphology in terms of significantly lower number of cytoplasmic vacuoles, little or no membrane blebbings, maintained axon hillock and intact neurites. There were decreased immunofluorescence signals for GSK3β, pTau at Ser262, Cdk5 and pTau at Ser235 suggesting decreased tau phosphorylation, which was further confirmed by Western blotting. The results indicate the beneficial effects of 2-DG in controlling the tau phosphorylation and maintaining the healthy neuronal cytoarchitecture.

  1. Mimetic discretization of the Abelian Chern-Simons theory and link invariants

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Di Bartolo, Cayetano; Grau, Javier; Leal, Lorenzo

    A mimetic discretization of the Abelian Chern-Simons theory is presented. The study relies on the formulation of a theory of differential forms in the lattice, including a consistent definition of the Hodge duality operation. Explicit expressions for the Gauss Linking Number in the lattice, which correspond to their continuum counterparts are given. A discussion of the discretization of metric structures in the space of transverse vector densities is presented. The study of these metrics could serve to obtain explicit formulae for knot an link invariants in the lattice.

  2. Mimetic discretization of the Abelian Chern-Simons theory and link invariants

    NASA Astrophysics Data System (ADS)

    Di Bartolo, Cayetano; Grau, Javier; Leal, Lorenzo

    2013-12-01

    A mimetic discretization of the Abelian Chern-Simons theory is presented. The study relies on the formulation of a theory of differential forms in the lattice, including a consistent definition of the Hodge duality operation. Explicit expressions for the Gauss Linking Number in the lattice, which correspond to their continuum counterparts are given. A discussion of the discretization of metric structures in the space of transverse vector densities is presented. The study of these metrics could serve to obtain explicit formulae for knot an link invariants in the lattice.

  3. Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers.

    PubMed Central

    Bennett, A.; Hensby, C. N.; Sanger, G. J.; Stamford, I. F.

    1981-01-01

    1. Gas chromatography-mass spectrometry demonstrated the presence of arachidonic acid (AA), 6-keto-prostaglandin F1 alpha and thromboxane B2 (TxB2) in all extracts of homogenized muscle or mucosa from human stomach, terminal ileum or sigmoid colon. Prostaglandin D2 (PGD2), PGE2 or PGF2 alpha were usually found more often in the mucosal extracts. The 12-hydroxy-derivative of AA (12-HETE) was detected in all extracts of the colon but in only some of the other tissues. 2. Most prostanoids tested contracted the longitudinal muscle, the order of potency being U-46619 (an epoxymethano analogue of PGH2) greater than PGE2 greater than PGF2 alpha greater than PGD2; PGI2 usually caused relaxation, whereas its breakdown products or TxB2 had weak and variable effects. 3. U-46619 or, less potently, PGF2 alpha contracted the circular muscle, whereas PGI2 and usually PGE2 caused relaxation. PGD2, 6-keto-PGF1 alpha, 6,15-diketo-PGF1 alpha or TxB2 usually had little or no effect. 4. PGI2 antagonized contractions to some excitatory prostanoids, without greatly affecting contractions to acetylcholine. 5. For both muscle layers there was a gradient in sensitivity to prostanoids along the gastrointestinal tract. The sensitivities were stomach greater than distal ileum greater than sigmoid colon. 6. The results are discussed in relation to gastrointestinal physiology and pathophysiology. PMID:7317691

  4. Calorie restriction (CR) and CR mimetics for the prevention and treatment of age-related eye disorders.

    PubMed

    Kawashima, Motoko; Ozawa, Yoko; Shinmura, Ken; Inaba, Takaaki; Nakamura, Shigeru; Kawakita, Tetsuya; Watanabe, Mitsuhiro; Tsubota, Kazuo

    2013-10-01

    The morbidity of ocular diseases, including macular degeneration, diabetic retinopathy, and dry eye disease, has been gradually increasing worldwide. Because these diseases develop from age-associated ocular dysfunctions, interventions against the aging process itself may be a promising strategy for their management. Among the several approaches to interrupt aging processes, calorie restriction (CR) has been shown to recover and/or slow age-related functional declines in various organs, including the eye. Here, we review interventions against the aging process as potential therapeutic approaches to age-related ocular diseases. The effects of CR and CR mimetics in animal models of age-related eye diseases are explored. Furthermore, we discuss the possibilities of expanding this research to prospective studies to elucidate the molecular mechanisms by which CR and/or CR mimetics preserve ocular functions. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Molecular Design, Structures, and Activity of Antimicrobial Peptide-Mimetic Polymers

    PubMed Central

    Takahashi, Haruko; Palermo, Edmund F.; Yasuhara, Kazuma; Caputo, Gregory A.

    2014-01-01

    There is an urgent need for new antibiotics which are effective against drug-resistant bacteria without contributing to resistance development. We have designed and developed antimicrobial copolymers with cationic amphiphilic structures based on the mimicry of naturally occurring antimicrobial peptides. These copolymers exhibit potent antimicrobial activity against a broad spectrum of bacteria including methicillin-resistant Staphylococcus aureus with no adverse hemolytic activity. Notably, these polymers also did not result in any measurable resistance development in E. coli. The peptide-mimetic design principle offers significant flexibility and diversity in the creation of new antimicrobial materials and their potential biomedical applications. PMID:23832766

  6. A charge-optimized many-body potential for the U-UO2-O2 system

    NASA Astrophysics Data System (ADS)

    Li, Yangzhong; Liang, Tao; Sinnott, Susan B.; Phillpot, Simon R.

    2013-12-01

    Building on previous charge-optimized many-body (COMB) potentials for metallic α-U and gaseous O2, we have developed a new potential for UO2, which also allows the simulation of U-UO2-O2 systems. The UO2 lattice parameter, elastic constants and formation energies of stoichiometric and non-stoichiometric intrinsic defects are well reproduced. Moreover, this is the first rigid-ion potential that produces the correct deviation of the Cauchy relation, as well as the first classical interatomic potential that is able to determine the defect energies of non-stoichiometric intrinsic point defects in UO2 with an appropriate reference state. The oxygen molecule interstitial in the α-U structure is shown to decompose, with some U-O bonds approaching the natural bond length of perfect UO2. Finally, we demonstrate the capability of this COMB potential to simulate a complex system by performing a simulation of the α-U + O2 → UO2 phase transformation. We also identify a possible mechanism for uranium oxidation and the orientation of the resulting fluorite UO2 structure relative to the coordinate system of orthorhombic α-U.

  7. Basal Lamina Mimetic Nanofibrous Peptide Networks for Skeletal Myogenesis

    NASA Astrophysics Data System (ADS)

    Yasa, I. Ceren; Gunduz, Nuray; Kilinc, Murat; Guler, Mustafa O.; Tekinay, Ayse B.

    2015-11-01

    Extracellular matrix (ECM) is crucial for the coordination and regulation of cell adhesion, recruitment, differentiation and death. Therefore, equilibrium between cell-cell and cell-matrix interactions and matrix-associated signals are important for the normal functioning of cells, as well as for regeneration. In this work, we describe importance of adhesive signals for myoblast cells’ growth and differentiation by generating a novel ECM mimetic peptide nanofiber scaffold system. We show that not only structure but also composition of bioactive signals are important for cell adhesion, growth and differentiation by mimicking the compositional and structural properties of native skeletal muscle basal lamina. We conjugated laminin-derived integrin binding peptide sequence, “IKVAV”, and fibronectin-derived well known adhesive sequence, “RGD”, into peptide nanostructures to provide adhesive and myogenic cues on a nanofibrous morphology. The myogenic and adhesive signals exhibited a synergistic effect on model myoblasts, C2C12 cells. Our results showed that self-assembled peptide nanofibers presenting laminin derived epitopes support adhesion, growth and proliferation of the cells and significantly promote the expression of skeletal muscle-specific marker genes. The functional peptide nanofibers used in this study present a biocompatible and biodegradable microenvironment, which is capable of supporting the growth and differentiation of C2C12 myoblasts into myotubes.

  8. Basal Lamina Mimetic Nanofibrous Peptide Networks for Skeletal Myogenesis

    PubMed Central

    Yasa, I. Ceren; Gunduz, Nuray; Kilinc, Murat; Guler, Mustafa O.; Tekinay, Ayse B.

    2015-01-01

    Extracellular matrix (ECM) is crucial for the coordination and regulation of cell adhesion, recruitment, differentiation and death. Therefore, equilibrium between cell-cell and cell-matrix interactions and matrix-associated signals are important for the normal functioning of cells, as well as for regeneration. In this work, we describe importance of adhesive signals for myoblast cells’ growth and differentiation by generating a novel ECM mimetic peptide nanofiber scaffold system. We show that not only structure but also composition of bioactive signals are important for cell adhesion, growth and differentiation by mimicking the compositional and structural properties of native skeletal muscle basal lamina. We conjugated laminin-derived integrin binding peptide sequence, “IKVAV”, and fibronectin-derived well known adhesive sequence, “RGD”, into peptide nanostructures to provide adhesive and myogenic cues on a nanofibrous morphology. The myogenic and adhesive signals exhibited a synergistic effect on model myoblasts, C2C12 cells. Our results showed that self-assembled peptide nanofibers presenting laminin derived epitopes support adhesion, growth and proliferation of the cells and significantly promote the expression of skeletal muscle-specific marker genes. The functional peptide nanofibers used in this study present a biocompatible and biodegradable microenvironment, which is capable of supporting the growth and differentiation of C2C12 myoblasts into myotubes. PMID:26555958

  9. Davalintide (AC2307), a Novel Amylin Mimetic Peptide: Enhanced Pharmacological Properties over Native Amylin to Reduce Food Intake and Body Weight

    USDA-ARS?s Scientific Manuscript database

    Objective: These studies describe the in vivo metabolic actions of the novel amylin mimetic peptide davalintide (AC2307) in rodents, and compare these effects to those of the native peptide. Research Design and Methods: The anti-obesity effects of davalintide were examined following intraperitoneal ...

  10. Alignment effect of N2(Au+) in the energy transfer reaction of aligned N2(Au+) + NO(X2Π) → NO(A2Σ+) + N2(X1Σg+).

    PubMed

    Ohoyama, H; Maruyama, S

    2012-06-28

    Steric effect in the energy transfer reaction of N(2)(A(3)Σ(u)(+)) + NO(X(2)Π) → NO(A(2)Σ(+)) + N(2)(X(1)Σ(g)(+)) has been studied under crossed beam conditions at a collision energy of ~0.07 eV by using an aligned N(2)(A(3)Σ(u)(+)) beam prepared by a magnetic hexapole. The emission intensity of NO(A(2)Σ(+)) has been measured as a function of the magnetic orientation field direction (i.e., alignment of N(2)(A(3)Σ(u)(+))) in the collision frame. A significant alignment effect on the energy transfer probability is observed. The shape of the steric opacity function turns out to be most reactive at the oblique configuration of N(2)(A(3)Σ(u)(+)) with an orientation angle of γ(v(R)) ~ 45° with respect to the relative velocity vector (v(R)), which has a good correlation with the spatial distribution of the 2pπ(g)* molecular orbital of N(2)(A(3)Σ(u)(+)). We propose the electron exchange mechanism in which the energy transfer probability is dominantly controlled by the orbital overlap between N(2)(2pπ(g)*) and NO(6σ).

  11. Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies.

    PubMed

    Roberts, A W; Huang, Dcs

    2017-01-01

    The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed. Venetoclax (formerly ABT-199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B-cell malignancies that highly express BCL2. © 2016 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  12. Designing ECM-mimetic Materials Using Protein Engineering

    PubMed Central

    Cai, Lei; Heilshorn, Sarah C.

    2014-01-01

    The natural extracellular matrix (ECM), with its multitude of evolved cell-instructive and cell-responsive properties, provides inspiration and guidelines for the design of engineered biomaterials. One strategy to create ECM-mimetic materials is the modular design of protein-based engineered ECM (eECM) scaffolds. This modular design strategy involves combining multiple protein domains with different functionalities into a single, modular polymer sequence, resulting in a multifunctional matrix with independent tunability of the individual domain functions. These eECMs often enable decoupled control over multiple material properties for fundamental studies of cell-matrix interactions. In addition, since the eECMs are frequently composed entirely of bioresorbable amino acids, these matrices have immense clinical potential for a variety of regenerative medicine applications. This brief review demonstrates how fundamental knowledge gained from structure-function studies of native proteins can be exploited in the design of novel protein-engineered biomaterials. While the field of protein-engineered biomaterials has existed for over 20 years, the community is only now beginning to fully explore the diversity of functional peptide modules that can be incorporated into these materials. We have chosen to highlight recent examples that either (1) demonstrate exemplary use as matrices with cell-instructive and cell-responsive properties or (2) demonstrate outstanding creativity in terms of novel molecular-level design and macro-level functionality. PMID:24365704

  13. Scaling mimesis: Morphometric and ecomorphological similarities in three sympatric plant-mimetic fish of the family Carangidae (Teleostei).

    PubMed

    Queiroz, Alexya Cunha de; Vallinoto, Marcelo; Sakai, Yoichi; Giarrizzo, Tommaso; Barros, Breno

    2018-01-01

    The mimetic juveniles of a number of carangid fish species resemble plant parts floating near the water surface, such as leaves, seeds and other plant debris. The present study is the first to verify the morphological similarities and ecomorphological relationships between three carangids (Oligoplites saurus, Oligoplites palometa and Trachinotus falcatus) and their associated plant models. Behavioral observations were conducted in the estuary of Curuçá River, in northeastern Pará (Brazil) between August 2015 and July 2016. Individual fishes and associated floating objects (models) were sampled for comparative analysis using both geometric and morphometric approaches. While the mimetic fish and their models retain their own distinct, intrinsic morphological features, a high degree of morphological similarity was found between each fish species and its model. The morphometric analyses revealed a general tendency of isometric development in all three fish species, probably related to their pelagic habitats, during all ontogenetic stages.

  14. Thioredoxin-mimetic peptide CB3 lowers MAPKinase activity in the Zucker rat brain☆

    PubMed Central

    Cohen-Kutner, Moshe; Khomsky, Lena; Trus, Michael; Ben-Yehuda, Hila; Lenhard, James M.; Liang, Yin; Martin, Tonya; Atlas, Daphne

    2014-01-01

    Diabetes is a high risk factor for dementia. High glucose may be a risk factor for dementia even among persons without diabetes, and in transgenic animals it has been shown to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the activation of mitogen-activated kinsase (MAPKs), c-jun NH2-terminal kinase (JNK), p38 MAP kinases (p38MAPK), and extracellular activating kinsae1/2 (ERK1/2) and the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats and human neuroblastoma SH-SY5Y cells. Daily i.p. injection of CB3 to ZDF rats inhibited the phosphorylation of JNK and p38MAPK, and prevented the expression of thioredoxin-interacting-protein (TXNIP/TBP-2) in ZDF rat brain. Although plasma glucose/insulin remained high, CB3 also increased the phosphorylation of AMP-ribose activating kinase (AMPK) and inhibited p70S6K kinase in the brain. Both CB3 and CB4 reversed apoptosis induced by inhibiting thioredoxin reductase as monitored by decreasing caspase 3 cleavage and PARP dissociation in SH-SY5Y cells. The decrease in JNK and p38MAPK activity in the absence of a change in plasma glucose implies a decrease in oxidative or neuroinflammatory stress in the ZDF rat brain. CB3 not only attenuated MAPK phosphorylation and activated AMPK in the brain, but it also diminished apoptotic markers, most likely acting via the MAPK–AMPK–mTOR pathway. These results were correlated with CB3 and CB4 inhibiting inflammation progression and protection from oxidative stress induced apoptosis in human neuronal cells. We suggest that by attenuating neuro-inflammatory processes in the brain Trx1 mimetic peptides could become beneficial for preventing neurological

  15. Modulating Mimetic Preference with Theta Burst Stimulation of the Inferior Parietal Cortex

    PubMed Central

    Ticini, Luca F.; Urgesi, Cosimo; Kotz, Sonja A.

    2017-01-01

    We like an object more when we see someone else reaching for it. To what extent is action observation causally linked to object valuation? In this study, we set out to answer to this question by applying continuous theta burst stimulation (cTBS) over the left inferior parietal lobule (IPL). Previous studies pointed to this region as critical in the representation of others' actions and in tool manipulation. However, it is unclear to what extent IPL's involvement simply reflects action observation, rather than a casual role in objects' valuation. To clarify this issue, we measured cTBS-dependent modulations of participants' “mimetic preference ratings”, i.e., the difference between the ratings of pairs of familiar objects that were (vs. were not) reached out for by other individuals. Our result shows that cTBS increased mimetic preference ratings for tools, when compared to a control condition without stimulation. This effect was selective for items that were reached for or manipulated by another individual, whilst it was not detected in non-tool objects. Although preliminary, this finding suggests that the automatic and covert simulation of an observed action, even when there is no intention to act on an object, influences explicit affective judgments for objects. This work supports embodied cognition theories by substantiating that our subjective preference is grounded in action. PMID:29250021

  16. Aging-associated oxidative stress leads to decrease in IAS tone via RhoA/ROCK downregulation.

    PubMed

    Singh, Jagmohan; Kumar, Sumit; Krishna, Chadalavada Vijay; Rattan, Satish

    2014-06-01

    Internal anal sphincter (IAS) tone plays an important role in rectoanal incontinence (RI). IAS tone may be compromised during aging, leading to RI in certain patients. We examined the influence of oxidative stress in the aging-associated decrease in IAS tone (AADI). Using adult (4-6 mo old) and aging (24-30 mo old) rats, we determined the effect of oxidative stress on IAS tone and the regulatory RhoA/ROCK signal transduction cascade. We determined the effect of the oxidative stress inducer LY83583, which produces superoxide anions (O2 (·-)), on basal and stimulated IAS tone before and after treatment of intact smooth muscle strips and smooth muscle cells with the O2 (·-) scavenger SOD. Our data showed that AADI was associated with a decrease in RhoA/ROCK expression at the transcriptional and translational levels. Oxidative stress with a LY83583-mediated decrease in IAS tone and relaxation of IAS smooth muscle cells was associated with a decrease in RhoA/ROCK signal transduction, which was reversible by SOD. In addition, LY83583 caused a significant decrease in IAS contraction produced by the RhoA activator and a known RhoA/ROCK agonist, U46619, that was also reversible by SOD. The inhibitory effects of LY83583 and the ROCK inhibitor Y27632 on the U46619-induced increase in IAS tone were similar. We conclude that an increase in oxidative stress plays an important role in AADI in the elderly and may be one of the underlying mechanisms of RI in certain aging patients. Copyright © 2014 the American Physiological Society.

  17. Aging-associated oxidative stress leads to decrease in IAS tone via RhoA/ROCK downregulation

    PubMed Central

    Singh, Jagmohan; Kumar, Sumit; Krishna, Chadalavada Vijay

    2014-01-01

    Internal anal sphincter (IAS) tone plays an important role in rectoanal incontinence (RI). IAS tone may be compromised during aging, leading to RI in certain patients. We examined the influence of oxidative stress in the aging-associated decrease in IAS tone (AADI). Using adult (4–6 mo old) and aging (24–30 mo old) rats, we determined the effect of oxidative stress on IAS tone and the regulatory RhoA/ROCK signal transduction cascade. We determined the effect of the oxidative stress inducer LY83583, which produces superoxide anions (O2·−), on basal and stimulated IAS tone before and after treatment of intact smooth muscle strips and smooth muscle cells with the O2·− scavenger SOD. Our data showed that AADI was associated with a decrease in RhoA/ROCK expression at the transcriptional and translational levels. Oxidative stress with a LY83583-mediated decrease in IAS tone and relaxation of IAS smooth muscle cells was associated with a decrease in RhoA/ROCK signal transduction, which was reversible by SOD. In addition, LY83583 caused a significant decrease in IAS contraction produced by the RhoA activator and a known RhoA/ROCK agonist, U46619, that was also reversible by SOD. The inhibitory effects of LY83583 and the ROCK inhibitor Y27632 on the U46619-induced increase in IAS tone were similar. We conclude that an increase in oxidative stress plays an important role in AADI in the elderly and may be one of the underlying mechanisms of RI in certain aging patients. PMID:24742984

  18. A comment on the thermal conductivity of (U,Pu)O 2 and (U,Th)O 2 by molecular dynamics with adjustment for phonon-spin scattering

    DOE PAGES

    Cooper, Michael William D.; Liu, Xiang -Yang; Stanek, Christopher Richard; ...

    2016-07-15

    In this study, a new approach for adjusting molecular dynamics results on UO 2 thermal conductivity to include phonon-spin scattering has been used to improve calculations on U x Pu 1–x O 2 and U xTh 1xO 2. We demonstrate that by including spin scattering a strong asymmetry as a function of uranium actinide fraction, x, is obtained. Greater degradation is shown for U xTh 1–xO 2 than U xPu 1-xO 2. Minimum thermal conductivities are predicted at U 0.97Pu 0.03O 2 and U 0.58Th 0.42O 2, although the degradation in U xPu 1–xO 2 is negligible relative to puremore » UO 2.« less

  19. In Situ Enzymatically Generated Photoswitchable Oxidase Mimetics and Their Application for Colorimetric Detection of Glucose Oxidase.

    PubMed

    Cao, Gen-Xia; Wu, Xiu-Ming; Dong, Yu-Ming; Li, Zai-Jun; Wang, Guang-Li

    2016-07-09

    In this study, a simple and amplified colorimetric assay is developed for the detection of the enzymatic activity of glucose oxidase (GOx) based on in situ formation of a photoswitchable oxidase mimetic of PO₄(3-)-capped CdS quantum dots (QDs). GOx catalyzes the oxidation of 1-thio-β-d-glucose to give 1-thio-β-d-gluconic acid which spontaneously hydrolyzes to β-d-gluconic acid and H₂S; the generated H₂S instantly reacts with Cd(2+) in the presence of Na₃PO₄ to give PO₄(3-)-stabilized CdS QDs in situ. Under visible-light (λ ≥ 400 nm) stimulation, the PO₄(3-)-capped CdS QDs are a new style of oxidase mimic derived by producing some active species, such as h⁺, (•)OH, O₂(•-) and a little H₂O₂, which can oxidize the typical substrate (3,3,5,5-tetramethylbenzydine (TMB)) with a color change. Based on the GOx-triggered growth of the oxidase mimetics of PO₄(3-)-capped CdS QDs in situ, we developed a simple and amplified colorimetric assay to probe the enzymatic activity of GOx. The proposed method allowed the detection of the enzymatic activity of GOx over the range from 25 μg/L to 50 mg/L with a low detection limit of 6.6 μg/L. We believe the PO₄(3-)-capped CdS QDs generated in situ with photo-stimulated enzyme-mimicking activity may find wide potential applications in biosensors.

  20. Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics.

    PubMed

    Cragg, Mark S; Harris, Claire; Strasser, Andreas; Scott, Clare L

    2009-05-01

    Therapeutic targeting of tumours on the basis of molecular analysis is a new paradigm for cancer treatment but has yet to fulfil expectations. For many solid tumours, targeted therapeutics, such as inhibitors of oncogenic kinase pathways, elicit predominantly disease-stabilizing, cytostatic responses, rather than tumour regression. Combining oncogenic kinase inhibitors with direct activators of the apoptosis machinery, such as the BH3 mimetic ABT-737, may unlock potent anti-tumour potential to produce durable clinical responses with less collateral damage.

  1. Characterization of Phospho-(Tyrosine)-Mimetic Calmodulin Mutants

    PubMed Central

    Stateva, Silviya R.; Salas, Valentina; Benaim, Gustavo; Menéndez, Margarita; Solís, Dolores; Villalobo, Antonio

    2015-01-01

    Calmodulin (CaM) phosphorylated at different serine/threonine and tyrosine residues is known to exert differential regulatory effects on a variety of CaM-binding enzymes as compared to non-phosphorylated CaM. In this report we describe the preparation and characterization of a series of phospho-(Y)-mimetic CaM mutants in which either one or the two tyrosine residues present in CaM (Y99 and Y138) were substituted to aspartic acid or glutamic acid. It was expected that the negative charge of the respective carboxyl group of these amino acids mimics the negative charge of phosphate and reproduce the effects that distinct phospho-(Y)-CaM species may have on target proteins. We describe some physicochemical properties of these CaM mutants as compared to wild type CaM, after their expression in Escherichia coli and purification to homogeneity, including: i) changes in their electrophoretic mobility in the absence and presence of Ca2+; ii) ultraviolet (UV) light absorption spectra, far- and near-UV circular dichroism data; iii) thermal stability in the absence and presence of Ca2+; and iv) Tb3+-emitted fluorescence upon tyrosine excitation. We also describe some biochemical properties of these CaM mutants, such as their differential phosphorylation by the tyrosine kinase c-Src, and their action as compared to wild type CaM, on the activity of two CaM-dependent enzymes: cyclic nucleotide phosphodiesterase 1 (PDE1) and endothelial nitric oxide synthase (eNOS) assayed in vitro. PMID:25830911

  2. Heparin-mimetic polyurethane hydrogels with anticoagulant, tunable mechanical property and controllable drug releasing behavior.

    PubMed

    Chen, Yuan; Wang, Rui; Wang, Yonghui; Zhao, Weifeng; Sun, Shudong; Zhao, Changsheng

    2017-05-01

    In the present study, novel heparin-mimetic polyurethane hydrogels were prepared by introducing chemical crosslinked sulfated konjac glucomannan (SKGM). Scanning electron microscopy (SEM) results indicated that the introduction of SKGM and the increase of the molecular weight of diol segments could enlarge the pore sizes of the hydrogels. The swelling behavior corresponded with the SEM results, and the hydrogels could absorb more water after the modification. The modification also led to an improvement in the mechanical property. Meanwhile, the SKGM and the modified polyurethane hydrogels showed excellent hemocompatibility. The thromboplastin time of SKGM could reach up to 182.9s. Gentamycin sulfate (GS) was used as a model drug to be loaded into the hydrogels, and the loading amount was increased ca. 50% after the introduction of SKGM, thus resulting in high bactericidal efficiency. The results indicated that the introduction of SKGM and the alternation in the diol's molecular weight bestowed polyurethane hydrogels with promising properties of integrated blood-compatibility, mechanical properties and drug loading-releasing behavior. Therefore, the heparin-mimetic multifunctional polyurethane hydrogels have great potential to be used in biomedical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus.

    PubMed

    Venkova, Kalina; Mann, William; Nelson, Richard; Greenwood-Van Meerveld, Beverley

    2009-06-01

    Ghrelin and ghrelin mimetics stimulate appetite and enhance gastric motility. The present study investigates whether ipamorelin, a selective growth hormone secretagogue and agonist of the ghrelin receptor, would accelerate gastrointestinal transit and ameliorate the symptoms in a rodent model of postoperative ileus (POI). Fasted male rats were subjected to laparotomy and intestinal manipulation. At the end of surgery, a dye marker was infused in the proximal colon to evaluate postsurgical colonic transit time, which was the time to the first bowel movement. In addition, fecal pellet output, food intake, and body weight were monitored regularly for 48 h. Ipamorelin (0.01-1 mg/kg), growth hormone-releasing peptide (GHRP)-6 (20 microg/kg), or vehicle (saline) were administered via intravenous bolus infusion after a single dosing or a 2-day repetitive dosing regimen (four doses a day at 3-h intervals). Compared with the vehicle, a single dose of ipamorelin (1 mg/kg) or GHRP-6 (20 microg/kg) decreased the time to the first bowel movement but had no effect on cumulative fecal output, food intake, or body weight gain measured 48 h after the surgery. In contrast, repetitive dosing of ipamorelin (0.1 or 1 mg/kg) significantly increased the cumulative fecal pellet output, food intake, and body weight gain. The results suggest that postsurgical intravenous infusions of ipamorelin may ameliorate the symptoms in patients with POI.

  4. Scaling mimesis: Morphometric and ecomorphological similarities in three sympatric plant-mimetic fish of the family Carangidae (Teleostei)

    PubMed Central

    de Queiroz, Alexya Cunha; Vallinoto, Marcelo; Sakai, Yoichi; Giarrizzo, Tommaso

    2018-01-01

    The mimetic juveniles of a number of carangid fish species resemble plant parts floating near the water surface, such as leaves, seeds and other plant debris. The present study is the first to verify the morphological similarities and ecomorphological relationships between three carangids (Oligoplites saurus, Oligoplites palometa and Trachinotus falcatus) and their associated plant models. Behavioral observations were conducted in the estuary of Curuçá River, in northeastern Pará (Brazil) between August 2015 and July 2016. Individual fishes and associated floating objects (models) were sampled for comparative analysis using both geometric and morphometric approaches. While the mimetic fish and their models retain their own distinct, intrinsic morphological features, a high degree of morphological similarity was found between each fish species and its model. The morphometric analyses revealed a general tendency of isometric development in all three fish species, probably related to their pelagic habitats, during all ontogenetic stages. PMID:29558476

  5. N-acetylcysteine enhances endothelium-dependent vasorelaxation in the isolated rat mesenteric artery.

    PubMed

    Lopez, B L; Snyder, J W; Birenbaum, D S; Ma, X I

    1998-10-01

    Previous studies have suggested that N-acetylcysteine (NAC) may confer additional protection in acetaminophen (APAP) overdose by improving hepatic microcirculation. We hypothesize that NAC enhances release of nitric oxide (NO) from the vasculature. Sprague-Dawley rat superior mesenteric artery rings were suspended in oxygenated Krebs-Henseleit tissue baths and contracted with U-46619 (a thromboxane A2-mimetic). In part 1, the effect of NAC on endothelial cell (EC) release of NO was assessed by measurement of vasorelaxation induced by acetylcholine (ACh, an EC-dependent vasorelaxor) in the presence and absence of NAC. In part 2, the effect of glutathione (a major component of NAC hepatoprotection) was examined by measuring ACh-induced vasorelaxation in rings from rats treated with L-buthionine sulfoxamine (BSO, a glutathione synthesis inhibitor). Data were analyzed by repeated-measures ANOVA. Addition of 15 to 30 mmol/L NAC after ring contraction had no direct vasodilatory effect. By contrast, pretreatment of rings with NAC (15 mmol/L) enhanced vasorelaxation induced by ACh (95.0% +/- 7.9% versus 62.3% +/- 7.6% for control; ACh dose, 1 mumol/L; P < .001) or by A23187, a receptor-independent, NO-mediated vasodilator (91.6% +/- 9.6% versus 68.3% +/- 12.1% for control; A23187 dose, 1 mumol/L; P < .001). In rings from BSO-treated rats, NAC also enhanced vasorelaxation (76.5% +/- 7.1%; P < .001 versus control), but to a lesser degree than in nontreated rats. NAC enhances endothelium-dependent vasodilation in an isolated rat mesenteric artery ring preparation. In addition to its antioxidant effects, NAC may decrease APAP hepatotoxicity by stimulating NO production and improving microvascular circulation.

  6. Potential for control of detrusor smooth muscle spontaneous rhythmic contraction by cyclooxygenase products released by interstitial cells of Cajal

    PubMed Central

    Collins, Clinton; Klausner, Adam P; Herrick, Benjamin; Koo, Harry P; Miner, Amy S; Henderson, Scott C; Ratz, Paul H

    2009-01-01

    Interstitial cells of Cajal (ICCs) have been identified as pacemaker cells in the upper urinary tract and urethra, but the role of ICCs in the bladder remains to be determined. We tested the hypotheses that ICCs express cyclooxygenase (COX), and that COX products (prostaglandins), are the cause of spontaneous rhythmic contraction (SRC) of isolated strips of rabbit bladder free of urothelium. SRC was abolished by 10 μM indomethacin and ibuprofen (non-selective COX inhibitors). SRC was concentration-dependently inhibited by selective COX-1 (SC-560 and FR-122047) and COX-2 inhibitors (NS-398 and LM-1685), and by SC-51089, a selective antagonist for the PGE-2 receptor (EP) and ICI-192,605 and SQ-29,548, selective antagonists for thromboxane receptors (TP). The partial agonist/antagonist of the PGF-2α receptor (FP), AL-8810, inhibited SRC by ∼50%. Maximum inhibition was ∼90% by SC-51089, ∼80–85% by the COX inhibitors and ∼70% by TP receptor antagonists. In the presence of ibuprofen to abolish SRC, PGE-2, sulprostone, misoprostol, PGF-2α and U-46619 (thromboxane mimetic) caused rhythmic contractions that mimicked SRC. Fluorescence immunohistochemistry coupled with confocal laser scanning microscopy revealed that c-Kit and vimentin co-localized to interstitial cells surrounding detrusor smooth muscle bundles, indicating the presence of extensive ICCs in rabbit bladder. Co-localization of COX-1 and vimentin, and COX-2 and vimentin by ICCs supports the hypothesis that ICCs were the predominant cell type in rabbit bladder expressing both COX isoforms. These data together suggest that ICCs appear to be an important source of prostaglandins that likely play a role in regulation of SRC. Additional studies on prostaglandin-dependent SRC may generate opportunities for the application of novel treatments for disorders leading to overactive bladder. PMID:19243470

  7. Insight into the mechanism revealing the peroxidase mimetic catalytic activity of quaternary CuZnFeS nanocrystals: colorimetric biosensing of hydrogen peroxide and glucose

    NASA Astrophysics Data System (ADS)

    Dalui, Amit; Pradhan, Bapi; Thupakula, Umamahesh; Khan, Ali Hossain; Kumar, Gundam Sandeep; Ghosh, Tanmay; Satpati, Biswarup; Acharya, Somobrata

    2015-05-01

    Artificial enzyme mimetics have attracted immense interest recently because natural enzymes undergo easy denaturation under environmental conditions restricting practical usefulness. We report for the first time chalcopyrite CuZnFeS (CZIS) alloyed nanocrystals (NCs) as novel biomimetic catalysts with efficient intrinsic peroxidase-like activity. Novel peroxidase activities of CZIS NCs have been evaluated by catalytic oxidation of the peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2). CZIS NCs demonstrate the synergistic effect of elemental composition and photoactivity towards peroxidase-like activity. The quaternary CZIS NCs show enhanced intrinsic peroxidase-like activity compared to the binary NCs with the same constituent elements. Intrinsic peroxidase-like activity has been correlated with the energy band position of CZIS NCs extracted using scanning tunneling spectroscopy and ultraviolet photoelectron spectroscopy. Kinetic analyses indicate Michaelis-Menten enzyme kinetic model catalytic behavior describing the rate of the enzymatic reaction by correlating the reaction rate with substrate concentration. Typical color reactions arising from the catalytic oxidation of TMB over CZIS NCs with H2O2 have been utilized to establish a simple and sensitive colorimetric assay for detection of H2O2 and glucose. CZIS NCs are recyclable catalysts showing high efficiency in multiple uses. Our study may open up the possibility of designing new photoactive multi-component alloyed NCs as enzyme mimetics in biotechnology applications.Artificial enzyme mimetics have attracted immense interest recently because natural enzymes undergo easy denaturation under environmental conditions restricting practical usefulness. We report for the first time chalcopyrite CuZnFeS (CZIS) alloyed nanocrystals (NCs) as novel biomimetic catalysts with efficient intrinsic peroxidase-like activity. Novel peroxidase activities of CZIS NCs have been

  8. Effect of thromboxane antagonists on ozone-induced airway responses in dogs

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jones, G.L.; Lane, C.G.; O'Byrne, P.M.

    1990-09-01

    Airway hyperresponsiveness after inhaled ozone in dogs may occur as a result of thromboxane release in the airway. In this study, two thromboxane receptor antagonists, L-655,240 and L-670,596, were used in doses that inhibit the response to an inhaled thromboxane mimetic, U-46619, to determine further the role of thromboxane in ozone-induced airway hyperresponsiveness. Dogs were studied on 2 days separated by 1 wk. On each day, the dogs inhaled ozone (3 ppm) for 30 min. On one randomly assigned day, 10 dogs received an infusion of L-655,240 (5 mg.kg-1.h-1) and 5 dogs received an infusion of L-670,596 (1 mg.kg-1.h-1); onmore » the other day dogs received a control infusion. Airway responses to doubling doses of acetylcholine were measured before and after inhalation of ozone and were expressed as the concentration of acetylcholine giving a rise in resistance of 5 cmH2O.l-1.s from baseline (acetylcholine provocation concentration). The development of airway hyperresponsiveness after ozone was not inhibited by the thromboxane antagonists. The mean log difference in the acetylcholine provocative concentration before and after ozone on the L-655,240 treatment day was 0.62 +/- 0.12 (SE) and on the control day was 0.71 +/- 0.12 (P = 0.48); on the L-670,596 treatment day the mean log difference was 0.68 +/- 0.15 (SE) and on the control day it was 0.75 +/- 0.19 (P = 0.45). These results do not support an important role for thromboxane in causing ozone-induced airway hyperresponsiveness.« less

  9. Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes.

    PubMed

    Lee, Erinna F; Clarke, Oliver B; Evangelista, Marco; Feng, Zhiping; Speed, Terence P; Tchoubrieva, Elissaveta B; Strasser, Andreas; Kalinna, Bernd H; Colman, Peter M; Fairlie, W Douglas

    2011-04-26

    Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2-like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with "BH3 mimetic" drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.

  10. Knockdown of BAG3 sensitizes bladder cancer cells to treatment with the BH3 mimetic ABT-737.

    PubMed

    Mani, Jens; Antonietti, Patrick; Rakel, Stefanie; Blaheta, Roman; Bartsch, Georg; Haferkamp, Axel; Kögel, Donat

    2016-02-01

    BAG3 is overexpressed in several malignancies and mediates a non-canonical, selective form of (macro)autophagy. By stabilizing pro-survival Bcl-2 proteins in complex with HSP70, BAG3 can also exert an apoptosis-antagonizing function. ABT-737 is a high affinity Bcl-2 inhibitor that fails to target Mcl-1. This failure may confer resistance in various cancers. Urothelial cancer cells were treated with the BH3 mimetics ABT-737 and (-)-gossypol, a pan-Bcl-2 inhibitor which inhibits also Mcl-1. To clarify the importance of the core autophagy regulator ATG5 and BAG3 in ABT-737 treatment, cell lines carrying a stable lentiviral knockdown of ATG5 and BAG3 were created. The synergistic effect of ABT-737 and pharmaceutical inhibition of BAG3 with the HSF1 inhibitor KRIBB11 or sorafenib was also evaluated. Total cell death and apoptosis were quantified by FACS analysis of propidium iodide, annexin. Target protein analysis was conducted by Western blotting. Knockdown of BAG3 significantly downregulated Mcl-1 protein levels and sensitized urothelial cancer cells to apoptotic cell death induced by ABT-737, while inhibition of bulk autophagy through depletion of ATG5 had no discernible effect on cell death. Similar to knockdown of BAG3, pharmacological targeting of the BAG3/Mcl-1 pathway with KRIBB11 was capable to sensitize both cell lines to treatment with ABT-737. Our results show that BAG3, but not bulk autophagy has a major role in the response of bladder cancer cells to BH3 mimetics. They also suggest that BAG3 is a suitable target for combined therapies aimed at synergistically inducing apoptosis in bladder cancer.

  11. Identification of U2AF(35)-dependent exons by RNA-Seq reveals a link between 3′ splice-site organization and activity of U2AF-related proteins

    PubMed Central

    Kralovicova, Jana; Knut, Marcin; Cross, Nicholas C. P.; Vorechovsky, Igor

    2015-01-01

    The auxiliary factor of U2 small nuclear RNA (U2AF) is a heterodimer consisting of 65- and 35-kD proteins that bind the polypyrimidine tract (PPT) and AG dinucleotides at the 3′ splice site (3′ss). The gene encoding U2AF35 (U2AF1) is alternatively spliced, giving rise to two isoforms U2AF35a and U2AF35b. Here, we knocked down U2AF35 and each isoform and characterized transcriptomes of HEK293 cells with varying U2AF35/U2AF65 and U2AF35a/b ratios. Depletion of both isoforms preferentially modified alternative RNA processing events without widespread failure to recognize 3′ss or constitutive exons. Over a third of differentially used exons were terminal, resulting largely from the use of known alternative polyadenylation (APA) sites. Intronic APA sites activated in depleted cultures were mostly proximal whereas tandem 3′UTR APA was biased toward distal sites. Exons upregulated in depleted cells were preceded by longer AG exclusion zones and PPTs than downregulated or control exons and were largely activated by PUF60 and repressed by CAPERα. The U2AF(35) repression and activation was associated with a significant interchange in the average probabilities to form single-stranded RNA in the optimal PPT and branch site locations and sequences further upstream. Although most differentially used exons were responsive to both U2AF subunits and their inclusion correlated with U2AF levels, a small number of transcripts exhibited distinct responses to U2AF35a and U2AF35b, supporting the existence of isoform-specific interactions. These results provide new insights into function of U2AF and U2AF35 in alternative RNA processing. PMID:25779042

  12. Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor.

    PubMed

    Miao, Yinglong; McCammon, J Andrew

    2018-03-20

    Protein-protein binding is key in cellular signaling processes. Molecular dynamics (MD) simulations of protein-protein binding, however, are challenging due to limited timescales. In particular, binding of the medically important G-protein-coupled receptors (GPCRs) with intracellular signaling proteins has not been simulated with MD to date. Here, we report a successful simulation of the binding of a G-protein mimetic nanobody to the M 2 muscarinic GPCR using the robust Gaussian accelerated MD (GaMD) method. Through long-timescale GaMD simulations over 4,500 ns, the nanobody was observed to bind the receptor intracellular G-protein-coupling site, with a minimum rmsd of 2.48 Å in the nanobody core domain compared with the X-ray structure. Binding of the nanobody allosterically closed the orthosteric ligand-binding pocket, being consistent with the recent experimental finding. In the absence of nanobody binding, the receptor orthosteric pocket sampled open and fully open conformations. The GaMD simulations revealed two low-energy intermediate states during nanobody binding to the M 2 receptor. The flexible receptor intracellular loops contribute remarkable electrostatic, polar, and hydrophobic residue interactions in recognition and binding of the nanobody. These simulations provided important insights into the mechanism of GPCR-nanobody binding and demonstrated the applicability of GaMD in modeling dynamic protein-protein interactions.

  13. Lower neurocognitive function in U-2 pilots

    PubMed Central

    Tate, David F.; Wood, Joe; Sladky, John H.; McDonald, Kent; Sherman, Paul M.; Kawano, Elaine S.; Rowland, Laura M.; Patel, Beenish; Wright, Susan N.; Hong, Elliot; Rasmussen, Jennifer; Willis, Adam M.; Kochunov, Peter V.

    2014-01-01

    Objective: Determine whether United States Air Force (USAF) U-2 pilots (U2Ps) with occupational exposure to repeated hypobaria had lower neurocognitive performance compared to pilots without repeated hypobaric exposure and whether U2P neurocognitive performance correlated with white matter hyperintensity (WMH) burden. Methods: We collected Multidimensional Aptitude Battery–II (MAB-II) and MicroCog: Assessment of Cognitive Functioning (MicroCog) neurocognitive data on USAF U2Ps with a history of repeated occupational exposure to hypobaria and compared these with control data collected from USAF pilots (AFPs) without repeated hypobaric exposure (U2Ps/AFPs MAB-II 87/83; MicroCog 93/80). Additional comparisons were performed between U2Ps with high vs low WMH burden. Results: U2Ps with repeated hypobaric exposure had significantly lower scores than control pilots on reasoning/calculation (U2Ps/AFPs 99.4/106.5), memory (105.5/110.9), information processing accuracy (102.1/105.8), and general cognitive functioning (103.5/108.5). In addition, U2Ps with high whole-brain WMH count showed significantly lower scores on reasoning/calculation (high/low 96.8/104.1), memory (102.9/110.2), general cognitive functioning (101.5/107.2), and general cognitive proficiency (103.6/108.8) than U2Ps with low WMH burden (high/low WMH mean volume 0.213/0.003 cm3 and mean count 14.2/0.4). Conclusion: In these otherwise healthy, highly functioning individuals, pilots with occupational exposure to repeated hypobaria demonstrated lower neurocognitive performance, albeit demonstrable on only some tests, than pilots without repeated exposure. Furthermore, within the U2P population, higher WMH burden was associated with lower neurocognitive test performance. Hypobaric exposure may be a risk factor for subtle changes in neurocognition. PMID:25008397

  14. Elicitation of Neutralizing Antibodies Directed against CD4-Induced Epitope(s) Using a CD4 Mimetic Cross-Linked to a HIV-1 Envelope Glycoprotein

    PubMed Central

    Dey, Antu K.; Burke, Brian; Sun, Yide; Sirokman, Klara; Nandi, Avishek; Hartog, Karin; Lian, Ying; Geonnotti, Anthony R.; Montefiori, David; Franti, Michael; Martin, Grégoire; Carfi, Andrea; Kessler, Pascal; Martin, Loïc; Srivastava, Indresh K.; Barnett, Susan W.

    2012-01-01

    The identification of HIV-1 envelope glycoprotein (Env) structures that can generate broadly neutralizing antibodies (BNAbs) is pivotal to the development of a successful vaccine against HIV-1 aimed at eliciting effective humoral immune responses. To that end, the production of novel Env structure(s) that might induce BNAbs by presentation of conserved epitopes, which are otherwise occluded, is critical. Here, we focus on a structure that stabilizes Env in a conformation representative of its primary (CD4) receptor-bound state, thereby exposing highly conserved “CD4 induced” (CD4i) epitope(s) known to be important for co-receptor binding and subsequent virus infection. A CD4-mimetic miniprotein, miniCD4 (M64U1-SH), was produced and covalently complexed to recombinant, trimeric gp140 envelope glycoprotein (gp140) using site-specific disulfide linkages. The resulting gp140-miniCD4 (gp140-S-S-M64U1) complex was recognized by CD4i antibodies and the HIV-1 co-receptor, CCR5. The gp140-miniCD4 complex elicited the highest titers of CD4i binding antibodies as well as enhanced neutralizing antibodies against Tier 1 viruses as compared to gp140 protein alone following immunization of rabbits. Neutralization against HIV-27312/V434M and additional serum mapping confirm the specific elicitation of antibodies directed to the CD4i epitope(s). These results demonstrate the utility of structure-based approach in improving immunogenic response against specific region, such as the CD4i epitope(s) here, and its potential role in vaccine application. PMID:22291921

  15. An investigation of the mimetic enzyme activity of two-dimensional Pd-based nanostructures

    NASA Astrophysics Data System (ADS)

    Wei, Jingping; Chen, Xiaolan; Shi, Saige; Mo, Shiguang; Zheng, Nanfeng

    2015-11-01

    In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis.In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis. Electronic supplementary information (ESI) available: TEM images, EDX and dispersion stability of Pd-based nanomaterials

  16. A pH-responsive interface derived from resilin-mimetic protein Rec1-resilin.

    PubMed

    Truong, My Y; Dutta, Naba K; Choudhury, Namita R; Kim, Misook; Elvin, Christopher M; Hill, Anita J; Thierry, Benjamin; Vasilev, Krasimir

    2010-05-01

    In this investigation, for the first time we report the effects of pH on the molecular orientation, packing density, structural properties, adsorption characteristics and viscoelastic behaviour of resilin-mimetic protein rec1-resilin at the solid-liquid interface using quartz crystal microbalance with dissipation monitoring (QCM-D) and surface plasmon resonance (SPR) spectroscopy. QCM-D and SPR data confirm that the binding ability of rec1-resilin on a substrate is strongly pH-dependent the protein packing density on a gold surface is calculated to be 4.45 x 10(13) per cm(2) at the isoelectric point (IEP approximately 4.9), 8.79 x 10(11) per cm(2) at pH 2 and 9.90 x 10(11) per cm(2) at pH 12, respectively. Our findings based on the thickness, dissipation and viscoelasticity of the rec1-resilin adlayer also indicate that it is adsorbed onto the gold substrate with different orientation depending on pH, such as back-on adsorption at acidic pH of 2, compact end-on bilayer adsorption at the IEP and side-on at high alkaline pH of 12. When rec1-resilin is 'pinned' to the substrate at IEP and subsequently exposed to an electrolyte solution adjusted to different pH, it switches from a compact globular conformation of the bio-macromolecule at the IEP to a coil conformation at pH between IEP to IED (IED = pKa value of tyrosine amino acid residue) and an extended coil conformation at pH > IED. This transformation from globule to coil to extended coil conformation is kinetically fast, robust and completely reversible. Such responsive surfaces created using 'smart' biomimetic rec1-resilin have the potential to find applications in many areas including biotechnology, medicine, sensors, controlled drug delivery systems and engineering. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  17. Characterisation of a novel, high affinity and selective αvβ6 integrin RGD-mimetic radioligand.

    PubMed

    Hall, Eleanor R; Bibby, Lloyd I; Slack, Robert J

    2016-10-01

    The alpha-v beta-6 (αvβ6) integrin has been identified as playing a key role in the activation of transforming growth factor-β (TGFβ) that is hypothesised to be pivotal in the development of cancer and fibrotic diseases. Therefore, the αvβ6 integrin is an attractive therapeutic target for these debilitating diseases and a drug discovery programme to identify small molecule αvβ6 selective arginyl-glycinyl-aspartic acid (RGD)-mimetics was initiated within GlaxoSmithKline. The primary aim of this study was to pharmacologically characterise the binding to αvβ6 of a novel clinical candidate, compound 1, using a radiolabelled form. Radioligand binding studies were completed with [(3)H]compound 1 against the human and mouse soluble protein forms of αvβ6 to determine accurate affinity estimates and binding kinetics. The selectivity of compound 1 for the RGD integrin family was also determined using saturation binding studies (αvβ1, αvβ3, αvβ5, αvβ8, α5β1 and α8β1 integrins) and fibrinogen-induced platelet aggregation (αIIbβ3 integrin). In addition, the relationship between divalent metal cation type and concentration and αvβ6 RGD site binding was also investigated. Compound 1 has been demonstrated to bind with extremely high affinity and selectivity for the αvβ6 integrin and has the potential as a clinical tool and therapeutic for investigating the role of αvβ6 in a range of disease states both pre-clinically and clinically. In addition, this is the first study that has successfully applied radioligand binding to the RGD integrin field to accurately determine the affinity and selectivity profile of a small molecule RGD-mimetic. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Separation of uranium from (U, Th)O 2 and (U, Pu)O 2 by solid state reactions route

    NASA Astrophysics Data System (ADS)

    Keskar, Meera; Mudher, K. D. Singh; Venugopal, V.

    2005-01-01

    Solid state reactions of UO 2, ThO 2, PuO 2 and their mixed oxides (U, Th)O 2 and (U, Pu)O 2 were carried out with sodium nitrate upto 900 °C, to study the formation of various phases at different temperatures, which are amenable for easy dissolution and separation of the actinide elements in dilute acid. Products formed by reacting unsintered as well as sintered UO 2 with NaNO 3 above 500 °C were readily soluble in 2 M HNO 3, whereas ThO 2 and PuO 2 did not react with NaNO 3 to form any soluble products. Thus reactions of mixed oxides (U, Th)O 2 and (U, Pu)O 2 with NaNO 3 were carried out to study the quantitative separation of U from (U, Th)O 2 and (U, Pu)O 2. X-ray diffraction, X-ray fluorescence, thermal analysis and chemical analysis techniques were used for the characterization of the products formed during the reactions.

  19. Decreased contraction induced by endothelium-derived contracting factor in prolonged treatment of rat renal artery with endoplasmic reticulum stress inducer.

    PubMed

    Ando, Makoto; Matsumoto, Takayuki; Taguchi, Kumiko; Kobayashi, Tsuneo

    2018-05-04

    Recent evidence suggests that endoplasmic reticulum (ER) stress is involved in the regulation of various physiological functions, including those of the vascular system. However, the relationship between ER stress and vascular function is poorly understood. The endothelial cells control the vascular tone by releasing endothelium-derived relaxing factors and contracting factors (EDCFs). We hypothesized that tunicamycin, an inducer of ER stress, modifies endothelium-dependent contraction and prostaglandins (PGs), a major class of EDCFs, induced contractions in the rat renal artery in rats. An organ-culture technique was used to purely investigate the effects of ER stress on the vascular tissue. We observed that tunicamycin treatment (20 μg/mL for 23 ± 1 h) did not affect acetylcholine (ACh)-induced relaxation and decreased EDCF-mediated contractions under nitric oxide synthase (NOS) inhibition induced by ACh, ATP, or A23187 (a calcium ionophore) in the renal arteries. Under NOS inhibition, U46619 (a thromboxane A 2 mimetic)- and beraprost (a prostacyclin analog)-induced contractions were also decreased in the renal arteries of the tunicamycin-treated group (vs. vehicle), while PGE 2 - and PGF 2α -induced contractions were similar between the groups. Tunicamycin treatment slightly enhanced the contractions induced by phenylephrine, an α 1 adrenoceptor ligand. Isotonic high-K + -induced contractions were similar between the vehicle- and tunicamycin-treated groups. Another ER stress inducer, thapsigargin (4 μmol/L for 23 ± 1 h), also caused substantial reduction of ACh-induced EDCF-mediated contraction (vs. vehicle-treated group). In the cultured renal arteries, tunicamycin and thapsigargin increased the expression of binding immunoglobulin protein (BiP), an ER stress marker. In conclusion, ER stress induction directly affects renal arterial function, especially in reducing EDCF-mediated contractions.

  20. Non-stoichiometry in U 3Si 2

    DOE PAGES

    Middleburgh, Simon C.; Grimes, Robin W.; Lahoda, Ed J.; ...

    2016-10-08

    Uranium silicides, in particular U 3Si 2, are being explored as an advanced nuclear fuel with increased accident tolerance as well as competitive economics compared to the baseline UO 2 fuel. Here we use density functional theory calculations and thermochemical analysis to assess the stability of U 3Si 2 with respect to non-stoichiometry reactions in both the hypo- and hyper-stoichiometric regimes. We find that the degree of non-stoichiometry in U 3Si 2 is much smaller than in UO 2 and at most reaches a few percent at high temperature. Non-stoichiometry impacts fuel performance by determining whether the loss of uraniummore » due to fission leads to a non-stoichiometric U 3Si 2±x phase or precipitation of a second U-Si phase. Lastly, we also investigate the U 5Si 4 phase as a candidate for the equilibrium phase diagram.« less

  1. Glycosides from Stevia rebaudiana Bertoni Possess Insulin-Mimetic and Antioxidant Activities in Rat Cardiac Fibroblasts

    PubMed Central

    Prata, Cecilia; Zambonin, Laura; Rizzo, Benedetta; Vieceli Dalla Sega, Francesco

    2017-01-01

    Stevia rebaudiana Bertoni is a shrub having a high content of sweet diterpenoid glycosides in its leaves, mainly stevioside and rebaudioside A, which are used as noncaloric, natural sweeteners. The aim of this study was to deepen the knowledge about the insulin-mimetic effect exerted by four different mixtures of steviol glycosides, rich in stevioside and rebaudioside A, in neonatal rat cardiac fibroblasts. The potential antioxidant activity of these steviol glycosides was also assessed, as oxidative stress is associated with diabetes. Likewise the insulin effect, steviol glycosides caused an increase in glucose uptake into rat fibroblasts by activating the PI3K/Akt pathway, thus inducing Glut4 translocation to the plasma membrane. The presence of S961, an insulin antagonist, completely abolished these effects, allowing to hypothesize that steviol glycosides could act as ligands of the same receptor engaged by insulin. Moreover, steviol glycosides counteracted oxidative stress by increasing reduced glutathione intracellular levels and upregulating expression and activity of the two antioxidant enzymes superoxide dismutase and catalase. The present work unravels the insulin-mimetic effect and the antioxidant property exerted by steviol glycosides, suggesting their potential beneficial role in the cotreatment of diabetes and in health maintenance. PMID:28947927

  2. Local U(2,2) symmetry in relativistic quantum mechanics

    NASA Astrophysics Data System (ADS)

    Finster, Felix

    1998-12-01

    Local gauge freedom in relativistic quantum mechanics is derived from a measurement principle for space and time. For the Dirac equation, one obtains local U(2,2) gauge transformations acting on the spinor index of the wave functions. This local U(2,2) symmetry allows a unified description of electrodynamics and general relativity as a classical gauge theory.

  3. A mimetic, semi-implicit, forward-in-time, finite volume shallow water model: comparison of hexagonal-icosahedral and cubed sphere grids

    NASA Astrophysics Data System (ADS)

    Thuburn, J.; Cotter, C. J.; Dubos, T.

    2013-12-01

    A new algorithm is presented for the solution of the shallow water equations on quasi-uniform spherical grids. It combines a mimetic finite volume spatial discretization with a Crank-Nicolson time discretization of fast waves and an accurate and conservative forward-in-time advection scheme for mass and potential vorticity (PV). The algorithm is implemented and tested on two families of grids: hexagonal-icosahedral Voronoi grids, and modified equiangular cubed-sphere grids. Results of a variety of tests are presented, including convergence of the discrete scalar Laplacian and Coriolis operators, advection, solid body rotation, flow over an isolated mountain, and a barotropically unstable jet. The results confirm a number of desirable properties for which the scheme was designed: exact mass conservation, very good available energy and potential enstrophy conservation, consistent mass, PV and tracer transport, and good preservation of balance including vanishing ∇ × ∇, steady geostrophic modes, and accurate PV advection. The scheme is stable for large wave Courant numbers and advective Courant numbers up to about 1. In the most idealized tests the overall accuracy of the scheme appears to be limited by the accuracy of the Coriolis and other mimetic spatial operators, particularly on the cubed sphere grid. On the hexagonal grid there is no evidence for damaging effects of computational Rossby modes, despite attempts to force them explicitly.

  4. A mimetic, semi-implicit, forward-in-time, finite volume shallow water model: comparison of hexagonal-icosahedral and cubed-sphere grids

    NASA Astrophysics Data System (ADS)

    Thuburn, J.; Cotter, C. J.; Dubos, T.

    2014-05-01

    A new algorithm is presented for the solution of the shallow water equations on quasi-uniform spherical grids. It combines a mimetic finite volume spatial discretization with a Crank-Nicolson time discretization of fast waves and an accurate and conservative forward-in-time advection scheme for mass and potential vorticity (PV). The algorithm is implemented and tested on two families of grids: hexagonal-icosahedral Voronoi grids, and modified equiangular cubed-sphere grids. Results of a variety of tests are presented, including convergence of the discrete scalar Laplacian and Coriolis operators, advection, solid body rotation, flow over an isolated mountain, and a barotropically unstable jet. The results confirm a number of desirable properties for which the scheme was designed: exact mass conservation, very good available energy and potential enstrophy conservation, consistent mass, PV and tracer transport, and good preservation of balance including vanishing ∇ × ∇, steady geostrophic modes, and accurate PV advection. The scheme is stable for large wave Courant numbers and advective Courant numbers up to about 1. In the most idealized tests the overall accuracy of the scheme appears to be limited by the accuracy of the Coriolis and other mimetic spatial operators, particularly on the cubed-sphere grid. On the hexagonal grid there is no evidence for damaging effects of computational Rossby modes, despite attempts to force them explicitly.

  5. Chemomics-based marker compounds mining and mimetic processing for exploring chemical mechanisms in traditional processing of herbal medicines, a continuous study on Rehmanniae Radix.

    PubMed

    Zhou, Li; Xu, Jin-Di; Zhou, Shan-Shan; Shen, Hong; Mao, Qian; Kong, Ming; Zou, Ye-Ting; Xu, Ya-Yun; Xu, Jun; Li, Song-Lin

    2017-12-29

    Exploring processing chemistry, in particular the chemical transformation mechanisms involved, is a key step to elucidate the scientific basis in traditional processing of herbal medicines. Previously, taking Rehmanniae Radix (RR) as a case study, the holistic chemome (secondary metabolome and glycome) difference between raw and processed RR was revealed by integrating hyphenated chromatographic techniques-based targeted glycomics and untargeted metabolomics. Nevertheless, the complex chemical transformation mechanisms underpinning the holistic chemome variation in RR processing remain to be extensively clarified. As a continuous study, here a novel strategy by combining chemomics-based marker compounds mining and mimetic processing is proposed for further exploring the chemical mechanisms involved in herbal processing. First, the differential marker compounds between raw and processed herbs were rapidly discovered by untargeted chemomics-based mining approach through multivariate statistical analysis of the chemome data obtained by integrated metabolomics and glycomics analysis. Second, the marker compounds were mimetically processed under the simulated physicochemical conditions as in the herb processing, and the final reaction products were chemically characterized by targeted chemomics-based mining approach. Third, the main chemical transformation mechanisms involved were clarified by linking up the original marker compounds and their mimetic processing products. Using this strategy, a set of differential marker compounds including saccharides, glycosides and furfurals in raw and processed RR was rapidly found, and the major chemical mechanisms involved in RR processing were elucidated as stepwise transformations of saccharides (polysaccharides, oligosaccharides and monosaccharides) and glycosides (iridoid glycosides and phenethylalcohol glycosides) into furfurals (glycosylated/non-glycosylated hydroxymethylfurfurals) by deglycosylation and/or dehydration. The

  6. Discovering the enzyme mimetic activity of metal-organic framework (MOF) for label-free and colorimetric sensing of biomolecules.

    PubMed

    Wang, Ying; Zhu, Yingjing; Binyam, Atsebeha; Liu, Misha; Wu, Yinan; Li, Fengting

    2016-12-15

    A label-free sensing strategy based on the enzyme-mimicking activity of MOF was demonstrated for colorimetric detection of biomolecules. Firstly obvious blue color was observed due to the high efficiency of peroxidase-like catalytic activity of Fe-MIL-88A (an ion-based MOF material) toward 3,3',5,5'-tetramethylbenzidine (TMB). Then in the presence of target biomolecule and corresponding aptamer, the mimetic activity of Fe-MIL-88A can be strongly inhibited and used directly to realize the colorimetric detection. On the basis of the interesting findings, we designed a straightforward, label-free and sensitive colorimetric method for biomolecule detection by using the enzyme mimetic property of MOF coupling with molecular recognition element. Compared with the existed publications, our work breaks the routine way by setting up an inorganic-organic MOF-aptamer hybrid platform for colorimetric determination of biomolecules, expanding the targets scope from H2O2 or glucose to biomolecules. As a proof of concept, thrombin and thrombin aptamer was used as a model analyte. The limit of detection of 10nM can be achieved with naked eyes and ultrahigh selectivity of thrombin toward numerous interfering substances with 10-fold concentration was demonstrated significantly. Of note, the method was further applied for the detection of thrombin in human serum samples, showing the results in agreement with those values obtained in an immobilization buffer by the colorimetric method. This inorganic-organic MOF-aptamer sensing strategy may in principle be universally applicable for the detection of a range of environmental or biomedical molecules of interests. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. U2 8 + -intensity record applying a H2 -gas stripper cell

    NASA Astrophysics Data System (ADS)

    Barth, Winfried; Adonin, Aleksey; Düllmann, Christoph E.; Heilmann, Manuel; Hollinger, Ralph; Jäger, Egon; Khuyagbaatar, Jadambaa; Krier, Joerg; Scharrer, Paul; Vormann, Hartmut; Yakushev, Alexander

    2015-04-01

    To meet the Facility for Antiproton and Ion Research science requirements higher beam intensity has to be achieved in the present GSI-accelerator complex. For this an advanced upgrade program for the UNILAC is ongoing. Stripping is a key technology for all heavy ion accelerators. For this an extensive research and development program was carried out to optimize for high brilliance heavy ion operation. After upgrade of the supersonic N2 -gas jet (2007), implementation of high current foil stripping (2011) and preliminary investigation of H2 -gas jet operation (2012), recently (2014) a new H2 -gas cell using a pulsed gas regime synchronized with arrival of the beam pulse has been developed. An obviously enhanced stripper gas density as well as a simultaneously reduced gas load for the pumping system result in an increased stripping efficiency, while the beam emittance remains the same. A new record intensity (7.8 emA) for 238U2 8 + beams at 1.4 MeV /u has been achieved applying the pulsed high density H2 stripper target to a high intensity 238U4 + beam from the VARIS ion source with a newly developed extraction system. The experimental results are presented in detail.

  8. The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide

    PubMed Central

    Barnett, A H

    2012-01-01

    In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM—exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m2, and patients with a BMI <35 kg/m2 who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m2) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. PMID:22051096

  9. Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice.

    PubMed

    Gu, Zhen; Li, Fengqiao; Zhang, Yi Ping; Shields, Lisa B E; Hu, Xiaoling; Zheng, Yiyan; Yu, Panpan; Zhang, Yongjie; Cai, Jun; Vitek, Michael P; Shields, Christopher B

    2013-04-01

    Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice. A focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords. Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days. The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment. The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs). The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method. The area of demyelination in the spinal cord was significantly reduced in the COG112 group. EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter. Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls. TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses. The apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and associated functional recovery in animal model

  10. A Contribution to the Kinetic Study of the Metatectic Reaction U+U$sub 3$Si$sub 2$$Yields$U$sub 3$Si; CONTRIBUTION AL ESTUDIO CINETICO DE LA REACCION METATECTICA U+U$sub 3$Si$sub 2$$Yields$U$sub 3$Si

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ruiperez, J.A.; Hernandez, J.A.E.

    1962-01-01

    An experimental study was made to decide upon the advantages and drawbacks of the different methods and reagents employed in the metallography of U-Si alloys. It has been observed that all samples thermally treated to the epsilon-phase undergo a coalescence of the U/sub 3/Si/sub 2/ particles. The coalescence decreases the surface available for reaction and consequently the reaction rate. The growth of the U/sub 3/Si/sub 2/ phase particles was determined as a function of time and temperature. To obtain samples with nuclei sufficiently isolated so that the U/sub 3/Si rings will not interfere their respective growth, the conditions that regulatemore » coalescence, Si content and thermal treatment, were determined. Data rel1tive to the growth of the U/sub 3/ Si phase-rings were obtained. Curves relating growth, time, and temperature are presented. The parameters that define the diffusion regulated reaction can be deduced from these curves. (auth)« less

  11. Unobtrusive Software and System Health Management with R2U2 on a Parallel MIMD Coprocessor

    NASA Technical Reports Server (NTRS)

    Schumann, Johann; Moosbrugger, Patrick

    2017-01-01

    Dynamic monitoring of software and system health of a complex cyber-physical system requires observers that continuously monitor variables of the embedded software in order to detect anomalies and reason about root causes. There exists a variety of techniques for code instrumentation, but instrumentation might change runtime behavior and could require costly software re-certification. In this paper, we present R2U2E, a novel realization of our real-time, Realizable, Responsive, and Unobtrusive Unit (R2U2). The R2U2E observers are executed in parallel on a dedicated 16-core EPIPHANY co-processor, thereby avoiding additional computational overhead to the system under observation. A DMA-based shared memory access architecture allows R2U2E to operate without any code instrumentation or program interference.

  12. Arbitrary Order Mixed Mimetic Finite Differences Method with Nodal Degrees of Freedom

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Iaroshenko, Oleksandr; Gyrya, Vitaliy; Manzini, Gianmarco

    2016-09-01

    In this work we consider a modification to an arbitrary order mixed mimetic finite difference method (MFD) for a diffusion equation on general polygonal meshes [1]. The modification is based on moving some degrees of freedom (DoF) for a flux variable from edges to vertices. We showed that for a non-degenerate element this transformation is locally equivalent, i.e. there is a one-to-one map between the new and the old DoF. Globally, on the other hand, this transformation leads to a reduction of the total number of degrees of freedom (by up to 40%) and additional continuity of the discrete flux.

  13. Solid state reactions of CeO 2, PuO 2, (U,Ce)O 2 and (U,Pu)O 2 with K 2S 2O 8

    NASA Astrophysics Data System (ADS)

    Keskar, Meera; Kasar, U. M.; Mudher, K. D. Singh; Venugopal, V.

    2004-09-01

    Solid state reactions of CeO 2, PuO 2 and mixed oxides (U,Ce)O 2 and (U,Pu)O 2 containing different mol.% of Ce and Pu, were carried out with K 2S 2O 8 at different temperatures to identify the formation of various products and to investigate their dissolution behaviour. X-ray, chemical and thermal analysis methods were used to characterise the products formed at various temperatures. The products obtained by heating two moles of K 2S 2O 8 with one mole each of CeO 2, PuO 2, (U,Ce)O 2 and (U,Pu)O 2 at 400 °C were identified as K 4Ce(SO 4) 4, K 4Pu(SO 4) 4, K 4(U,Ce)(SO 4) 4 and K 4(U,Pu)(SO 4) 4, respectively. K 4Ce(SO 4) 4 further decomposed to form K 4Ce(SO 4) 3.5 at 600 °C and mixture of K 2SO 4 and CeO 2 at 950 °C. Thus the products formed during the reaction of 2K 2S 2O 8 + CeO 2 show that cerium undergoes changes in oxidation state from +4 to +3 and again to +4. XRD data of K 4Ce(SO 4) 4 and K 4Ce(SO 4) 3.5 were indexed on triclinic and monoclinic system, respectively. PuO 2 + 2K 2S 2O 8 reacts at 400 °C to form K 4Pu(SO 4) 4 which was stable upto 750 °C and further decomposes to form K 2SO 4 + PuO 2 at 1000 °C. The products formed at 400 °C during the reactions of the oxides and mixed oxides were found to be readily soluble in 1-2 M HNO 3.

  14. Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination.

    PubMed

    Hoekstra, R; de Vos, F Y F L; Eskens, F A L M; de Vries, E G E; Uges, D R A; Knight, R; Carr, R A; Humerickhouse, R; Verweij, J; Gietema, J A

    2006-03-01

    We performed a phase I study with the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 combined with 5-fluorouracil and leucovorin (5-FU/LV) to determine safety profile and assess pharmacokinetic interactions. Patients with advanced solid malignancies received LV 20 mg/m(2) followed by 5-FU 425 mg/m(2) both administered intravenously in 15 min daily for 5 days every 4 weeks. ABT-510 was administered subcutaneously twice daily continuously from day 2 onwards. Blood and urine samples for pharmacokinetic analyses were collected at days 1, 5 and 22. Twelve patients received a total of 45 cycles of 5-FU/LV combined with ABT-510. ABT-510 dose levels studied were 50 and 100 mg. The combination was well tolerated, with a toxicity profile comparable to that of 5-FU/LV alone. At the dose levels studied no significant pharmacokinetic interactions were observed. These data indicate that ABT-510 administered twice daily subcutaneously can be safely combined with 5-FU/LV administered daily for 5 days, every 4 weeks.

  15. Targeting BCL-2-like Proteins to Kill Cancer Cells.

    PubMed

    Cory, Suzanne; Roberts, Andrew W; Colman, Peter M; Adams, Jerry M

    2016-08-01

    Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies. Moreover, preclinical studies herald the potential of emerging BH3 mimetics targeting other BCL-2 pro-survival members, particularly myeloid cell leukemia (MCL)-1, for multiple cancer types. Thus, BH3 mimetics seem destined to become powerful new weapons in the arsenal against cancer. This review sketches the discovery of the BCL-2 family and its impact on cancer development and therapy; describes how interactions of family members trigger apoptosis; outlines the development of BH3 mimetic drugs; and discusses their potential to advance cancer therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. The effect of a diiodothyronine mimetic on insulin sensitivity in male cardiometabolic patients: a double-blind randomized controlled trial.

    PubMed

    van der Valk, Fleur; Hassing, Carlijne; Visser, Maartje; Thakkar, Purav; Mohanan, Anookh; Pathak, Kaushal; Dutt, Chaitanya; Chauthaiwale, Vijay; Ackermans, Mariette; Nederveen, Aart; Serlie, Mireille; Nieuwdorp, Max; Stroes, Erik

    2014-01-01

    Obesity and its associated cardiometabolic co-morbidities are increasing worldwide. Since thyroid hormone mimetics are capable of uncoupling the beneficial metabolic effects of thyroid hormones from their deleterious effects on heart, bone and muscle, this class of drug is considered as adjacent therapeutics to weight-lowering strategies. This study investigated the safety and efficacy of TRC150094, a thyroid hormone mimetic. This 4-week, randomized, placebo-controlled, double-blind trial was conducted in India and The Netherlands. Forty subjects were randomized at a 1:1 ratio to receive either TRC150094 dosed at 50 mg or placebo once daily for 4 weeks. Hyperinsulinemic euglycemic clamp and (1)H-Magnetic Resonance Spectroscopy (MRS) were performed before and after treatment. At baseline, subjects were characterized by markedly impaired hepatic and peripheral insulin sensitivity. TRC150094 dosed 50 mg once daily was safe and well tolerated. Hepatic nor peripheral insulin sensitivity improved after TRC150094 treatment, expressed as the suppression of Endogenous Glucose Production from 59.5 to 62.1%; p = 0.477, and the rate of glucose disappearance from 28.8 to 26.4 µmol kg(-1)min(-1), p = 0.185. TRC150094 administration did not result in differences in fasting plasma free fatty acids from 0.51 to 0.51 mmol/L, p = 0.887 or in insulin-mediated suppression of lipolysis from 57 to 54%, p = 0.102. Also, intrahepatic triglyceride content was unaltered. Collectively, these data show that, in contrast to the potent metabolic effects in experimental models, TRC150094 at a dose of 50 mg daily does not improve the metabolic homeostasis in subjects at an increased cardiometabolic risk. Further studies are needed to evaluate whether TRC150094 has beneficial effects in patients with more severe metabolic derangement, such as overt diabetes mellitus and hypertriglyceridemia. clinicaltrials.gov NCT01408667.

  17. Influence of Block Copolymerization on the Antifreeze Protein Mimetic Ice Recrystallization Inhibition Activity of Poly(vinyl alcohol).

    PubMed

    Congdon, Thomas R; Notman, Rebecca; Gibson, Matthew I

    2016-09-12

    Antifreeze (glyco) proteins are produced by many cold-acclimatized species to enable them to survive subzero temperatures. These proteins have multiple macroscopic effects on ice crystal growth which makes them appealing for low-temperature applications-from cellular cryopreservation to food storage. Poly(vinyl alcohol) has remarkable ice recrystallization inhibition activity, but its mode of action is uncertain as is the extent at which it can be incorporated into other high-order structures. Here the synthesis and characterization of well-defined block copolymers containing poly(vinyl alcohol) and poly(vinylpyrrolidone) by RAFT/MADIX polymerization is reported, as new antifreeze protein mimetics. The effect of adding a large second hydrophilic block is studied across a range of compositions, and it is found to be a passive component in ice recrystallization inhibition assays, enabling retention of all activity. In the extreme case, a block copolymer with only 10% poly(vinyl alcohol) was found to retain all activity, where statistical copolymers of PVA lose all activity with very minor changes to composition. These findings present a new method to increase the complexity of antifreeze protein mimetic materials, while retaining activity, and also to help understand the underlying mechanisms of action.

  18. Influence of Block Copolymerization on the Antifreeze Protein Mimetic Ice Recrystallization Inhibition Activity of Poly(vinyl alcohol)

    PubMed Central

    2016-01-01

    Antifreeze (glyco) proteins are produced by many cold-acclimatized species to enable them to survive subzero temperatures. These proteins have multiple macroscopic effects on ice crystal growth which makes them appealing for low-temperature applications—from cellular cryopreservation to food storage. Poly(vinyl alcohol) has remarkable ice recrystallization inhibition activity, but its mode of action is uncertain as is the extent at which it can be incorporated into other high-order structures. Here the synthesis and characterization of well-defined block copolymers containing poly(vinyl alcohol) and poly(vinylpyrrolidone) by RAFT/MADIX polymerization is reported, as new antifreeze protein mimetics. The effect of adding a large second hydrophilic block is studied across a range of compositions, and it is found to be a passive component in ice recrystallization inhibition assays, enabling retention of all activity. In the extreme case, a block copolymer with only 10% poly(vinyl alcohol) was found to retain all activity, where statistical copolymers of PVA lose all activity with very minor changes to composition. These findings present a new method to increase the complexity of antifreeze protein mimetic materials, while retaining activity, and also to help understand the underlying mechanisms of action. PMID:27476873

  19. The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic

    PubMed Central

    Bieghs, Liesbeth; Lub, Susanne; Fostier, Karel; Maes, Ken; Van Valckenborgh, Els; Menu, Eline; Johnsen, Hans E.; Overgaard, Michael T.; Larsson, Olle; Axelson, Magnus; Nyegaard, Mette; Schots, Rik; Jernberg-Wiklund, Helena

    2014-01-01

    The ABT-analogous 737, 263 and 199 are BH3 mimetics showing potent anti-myeloma (MM) activity, but only on defined molecular subgroups of MM patients presenting a Bcl-2high/Mcl-1low profile. IGF-1 is a major survival factor in MM regulating the expression of Bcl-2 proteins and might therefore be a resistance factor to these ABT-analogous. We first show that IGF-1 protected human MM cell lines (HMCLs) against ABT-737. Concurrently, the IGF-1 receptor inhibitor picropodophyllin (PPP) synergistically sensitized HMCL, primary human MM and murine 5T33MM cells to ABT-737 and ABT-199 by further decreasing cell viability and enhancing apoptosis. Knockdown of Bcl-2 by shRNA protected MM cells to ABT-737, while Mcl-1 shRNA sensitized the cells. PPP overcame the Bcl-2 dependency of ABT-737, but failed to completely overcome the protective effect of Mcl-1. In vivo, co-treatment of 5T33MM bearing mice significantly decreased tumor burden and prolonged overall survival both in a prophylactic and therapeutic setting. Interestingly, proteasome inhibitor resistant CD138− 5T33MM cells were more sensitive to ABT-737, whereas PPP alone targeted the CD138+ cells more effectively. After co-treatment, both subpopulations were targeted equally. Together, the combination of an IGF-1R inhibitor and an ABT-analogue displays synergistic anti-myeloma activity providing the rational for further (pre)clinical testing. PMID:25008202

  20. Vector correlation between the alignment of reactant N2 (Au+) and the alignment of product NO (A 2Σ+) rotation in the energy transfer reaction of aligned N2 (Au+) + NO (X 2Π) → NO (A 2Σ+) + N2 (X 1Σg+).

    PubMed

    Ohoyama, H

    2013-12-21

    The vector correlation between the alignment of reactant N2 (A (3)Σu(+)) and the alignment of product NO (A (2)Σ(+)) rotation has been studied in the energy transfer reaction of aligned N2 (A (3)Σu(+)) + NO (X (2)Π) → NO (A (2)Σ(+)) + N2 (X (1)Σg(+)) under the crossed beam condition at a collision energy of ~0.07 eV. NO (A (2)Σ(+)) emission in the two linear polarization directions (i.e., parallel and perpendicular with respect to the relative velocity vector v(R)) has been measured as a function of the alignment of N2 (A (3)Σu(+)) along its molecular axis in the collision frame. The degree of polarization of NO (A (2)Σ(+)) emission is found to depend on the alignment angle (θ(v(R))) of N2 (A (3)Σu(+)) in the collision frame. The shape of the steric opacity function at the two polarization conditions turns out to be extremely different from each other: The steric opacity function at the parallel polarization condition is more favorable for the oblique configuration of N2 (A (3)Σu(+)) at an alignment angle of θ(v(R)) ~ 45° as compared with that at the perpendicular polarization condition. The alignment of N2 (A (3)Σu(+)) is found to give a significant effect on the alignment of NO (A (2)Σ(+)) rotation in the collision frame: The N2 (A (3)Σu(+)) configuration at an oblique alignment angle θ(v(R)) ~ 45° leads to a parallel alignment of NO (A (2)Σ(+)) rotation (J-vector) with respect to v(R), while the axial and sideways configurations of N2 (A (3)Σu(+)) lead to a perpendicular alignment of NO (A (2)Σ(+)) rotation with respect to vR. These stereocorrelated alignments of the product rotation have a good correlation with the stereocorrelated reactivity observed in the multi-dimensional steric opacity function [H. Ohoyama and S. Maruyama, J. Chem. Phys. 137, 064311 (2012)].

  1. Inhibition of bacterial DD-peptidases (penicillin-binding proteins) in membranes and in vivo by peptidoglycan-mimetic boronic acids.

    PubMed

    Dzhekieva, Liudmila; Kumar, Ish; Pratt, R F

    2012-04-03

    The DD-peptidases or penicillin-binding proteins (PBPs) catalyze the final steps of bacterial peptidoglycan biosynthesis and are inhibited by the β-lactam antibiotics. There is at present a question of whether the active site structure and activity of these enzymes is the same in the solubilized (truncated) DD-peptidase constructs employed in crystallographic and kinetics studies as in membrane-bound holoenzymes. Recent experiments with peptidoglycan-mimetic boronic acids have suggested that these transition state analogue-generating inhibitors may be able to induce reactive conformations of these enzymes and thus inhibit strongly. We have now, therefore, measured the dissociation constants of peptidoglycan-mimetic boronic acids from Escherichia coli and Bacillus subtilis PBPs in membrane preparations and, in the former case, in vivo, by means of competition experiments with the fluorescent penicillin Bocillin Fl. The experiments showed that the boronic acids bound measurably (K(i) < 1 mM) to the low-molecular mass PBPs but not to the high-molecular mass enzymes, both in membrane preparations and in whole cells. In two cases, E. coli PBP2 and PBP5, the dissociation constants obtained were very similar to those obtained with the pure enzymes in homogeneous solution. The boronic acids, therefore, are unable to induce tightly binding conformations of these enzymes in vivo. There is no evidence from these experiments that DD-peptidase inhibitors are more or less effective in vivo than in homogeneous solution.

  2. Structure and Orientation of Bovine Lactoferrampin in the Mimetic Bacterial Membrane as Revealed by Solid-State NMR and Molecular Dynamics Simulation

    PubMed Central

    Tsutsumi, Atsushi; Javkhlantugs, Namsrai; Kira, Atsushi; Umeyama, Masako; Kawamura, Izuru; Nishimura, Katsuyuki; Ueda, Kazuyoshi; Naito, Akira

    2012-01-01

    Bovine lactoferrampin (LFampinB) is a newly discovered antimicrobial peptide found in the N1-domain of bovine lactoferrin (268–284), and consists of 17 amino-acid residues. It is important to determine the orientation and structure of LFampinB in bacterial membranes to reveal the antimicrobial mechanism. We therefore performed 13C and 31P NMR, 13C-31P rotational echo double resonance (REDOR), potassium ion-selective electrode, and quartz-crystal microbalance measurements for LFampinB with mimetic bacterial membrane and molecular-dynamics simulation in acidic membrane. 31P NMR results indicated that LFampinB caused a defect in mimetic bacterial membranes. Ion-selective electrode measurements showed that ion leakage occurred for the mimetic bacterial membrane containing cardiolipin. Quartz-crystal microbalance measurements revealed that LFampinB had greater affinity to acidic phospholipids than that to neutral phospholipids. 13C DD-MAS and static NMR spectra showed that LFampinB formed an α-helix in the N-terminus region and tilted 45° to the bilayer normal. REDOR dephasing patterns between carbonyl carbon nucleus in LFampinB and phosphorus nuclei in lipid phosphate groups were measured by 13C-31P REDOR and the results revealed that LFampinB is located in the interfacial region of the membrane. Molecular-dynamics simulation showed the tilt angle to be 42° and the rotation angle to be 92.5° for Leu3, which are in excellent agreement with the experimental values. PMID:23083717

  3. L-Eye to Me: The Combined Role of Need for Cognition and Facial Trustworthiness in Mimetic Desires

    ERIC Educational Resources Information Center

    Treinen, Evelyne; Corneille, Olivier; Luypaert, Gaylord

    2012-01-01

    Recent studies showed that stimuli are evaluated more favourably when they are perceived to capture others' attention, an effect coined "mimetic desire". The aim of the present research was to examine the combined role of Need for Cognition and target's facial trustworthiness in this effect. Participants saw movie excerpts of trustworthy and…

  4. Inhibition of agonist-induced smooth muscle contraction by picotamide in the male human lower urinary tract outflow region.

    PubMed

    Hennenberg, Martin; Tamalunas, Alexander; Wang, Yiming; Keller, Patrick; Schott, Melanie; Strittmatter, Frank; Herlemann, Annika; Yu, Qingfeng; Rutz, Beata; Ciotkowska, Anna; Stief, Christian G; Gratzke, Christian

    2017-05-15

    Male lower urinary tract symptoms (LUTS) due to bladder outlet obstruction are characterized by abnormal smooth muscle contractions in the lower urinary tract. Alpha 1 -adrenoceptor antagonists may induce smooth muscle relaxation in the outflow region and represent the current gold standard of medical treatment. However, results may be unsatisfactory or inadequate. Apart from α 1 -adrenoceptor agonists, smooth muscle contraction in the outflow region may be induced by thromboxane A 2 (TXA 2 ), endothelins, or muscarinic receptor agonists. Here, we studied effects of the thromboxane A 2 receptor (TP receptor) antagonist picotamide on contraction in the human male bladder trigone and prostate. Carbachol, the α 1 -adrenoceptor agonist phenylephrine, the thromboxane A 2 analog U46619, and electric field stimulation (EFS) induced concentration- or frequency-dependent contractions of trigone tissues in an organ bath. Picotamide (300µM) inhibited carbachol-, phenylephrine-, U46619-, and EFS-induced contractions. Endothelins 1-3 induced concentration-dependent contractions of prostate tissues, which were inhibited by picotamide. Analyses using real time polymerase chain reaction and antibodies suggested expression of thromboxane A 2 receptors and synthase in trigone smooth muscle cells. Thromboxane B 2 (the stable metabolite of thromboxane A 2 ) was detectable by enzyme immune assay in trigone samples, with most values ranging between 50 and 150pg/mg trigone protein. Picotamide inhibits contractions induced by different stimuli in the human lower urinary tract, including cholinergic, adrenergic, thromboxane A 2 - and endothelin-induced, and neurogenic contractions in different locations of the outflow region. This distinguishes picotamide from current medical treatments for LUTS, and suggests that picotamide may induce urodynamic effects in vivo. Copyright © 2017. Published by Elsevier B.V.

  5. Substrate-Independent Robust and Heparin-Mimetic Hydrogel Thin Film Coating via Combined LbL Self-Assembly and Mussel-Inspired Post-Cross-linking.

    PubMed

    Ma, Lang; Cheng, Chong; He, Chao; Nie, Chuanxiong; Deng, Jie; Sun, Shudong; Zhao, Changsheng

    2015-12-02

    In this work, we designed a robust and heparin-mimetic hydrogel thin film coating via combined layer-by-layer (LbL) self-assembly and mussel-inspired post-cross-linking. Dopamine-grafted heparin-like/-mimetic polymers (DA-g-HepLP) with abundant carboxylic and sulfonic groups were synthesized by the conjugation of adhesive molecule, DA, which exhibited substrate-independent adhesive affinity to various solid surfaces because of the formation of irreversible covalent bonds. The hydrogel thin film coated substrates were prepared by a three-step reaction: First, the substrates were coated with DA-g-HepLP to generate negatively charged surfaces. Then, multilayers were obtained via LbL coating of chitosan and the DA-g-HepLP. Finally, the noncovalent multilayers were oxidatively cross-linked by NaIO4. Surface ATR-FTIR and XPS spectra confirmed the successful fabrication of the hydrogel thin film coatings onto membrane substrates; SEM images revealed that the substrate-independent coatings owned 3D porous morphology. The soaking tests in highly alkaline, acid, and concentrated salt solutions indicated that the cross-linked hydrogel thin film coatings owned high chemical resistance. In comparison, the soaking tests in physiological solution indicated that the cross-linked hydrogel coatings owned excellent long-term stability. The live/dead cell staining and morphology observations of the adhered cells revealed that the heparin-mimetic hydrogel thin film coated substrates had low cell toxicity and high promotion ability for cell proliferation. Furthermore, systematic in vitro investigations of protein adsorption, platelet adhesion, blood clotting, and blood-related complement activation confirmed that the hydrogel film coated substrates showed excellent hemocompatibility. Both the results of inhibition zone and bactericidal activity indicated that the gentamycin sulfate loaded hydrogel thin films had significant inhibition capability toward both Escherichia coli and

  6. The mimetic transition: a simulation study of the evolution of learning by imitation.

    PubMed

    Higgs, P G

    2000-07-07

    Culturally transmitted ideas or memes must have had a large effect on the survival and fecundity of early humans. Those with better techniques of obtaining food and making tools, clothing and shelters would have had a substantial advantage. It has been proposed that memes can explain why our species has an unusually large brain and high cognitive ability: the brain evolved because of selection for the ability to imitate. This article presents an evolutionary model of a population in which culturally transmitted memes can have both positive and negative effects on the fitness of individuals. It is found that genes for increased imitative ability are selectively favoured. The model predicts that imitative ability increases slowly until a mimetic transition occurs where memes become able to spread like an epidemic. At this point there is a dramatic increase in the imitative ability, the number of memes known per individual and the mean fitness of the population. Selection for increased imitative ability is able to overcome substantial selection against increased brain size in some cases.

  7. The mimetic transition: a simulation study of the evolution of learning by imitation.

    PubMed Central

    Higgs, P G

    2000-01-01

    Culturally transmitted ideas or memes must have had a large effect on the survival and fecundity of early humans. Those with better techniques of obtaining food and making tools, clothing and shelters would have had a substantial advantage. It has been proposed that memes can explain why our species has an unusually large brain and high cognitive ability: the brain evolved because of selection for the ability to imitate. This article presents an evolutionary model of a population in which culturally transmitted memes can have both positive and negative effects on the fitness of individuals. It is found that genes for increased imitative ability are selectively favoured. The model predicts that imitative ability increases slowly until a mimetic transition occurs where memes become able to spread like an epidemic. At this point there is a dramatic increase in the imitative ability, the number of memes known per individual and the mean fitness of the population. Selection for increased imitative ability is able to overcome substantial selection against increased brain size in some cases. PMID:10972132

  8. Reversible electropermeabilisation of human and rat blood platelets: evaluation of morphological and functional integrity 'in vitro' and 'in vivo'.

    PubMed

    Hughes, K; Crawford, N

    1989-06-06

    A high-voltage discharge procedure has been developed for permeabilising the plasma membranes of both human and rat blood platelets. The cells can be resealed by incubation at 37 degrees C, show less than 4% loss of lactate dehydrogenase (LDH) implying minimal cell lysis and also have well maintained morphological and functional integrity. The prototype apparatus used at field strengths between 6 and 8 kV/cm produces membrane pores which allow free diffusion of low molecular weight substances such as adenine nucleotides, inositol phosphate and fluorescent dyes. Two properties, namely Ca2+-induced secretion of granule stored 5-hydroxytryptamine (5HT) and inositol 1,4,5-trisphosphate (IP3)-induced release of intracellularly sequestered 45Ca, which are both well expressed immediately after permeabilisation, are essentially abolished after resealing. The efficiency of permeabilisation and resealing can be simply monitored by shifts in 'apparent platelet volume' using a resistive particle counter (Coulter). Permeabilised platelets show a shift in modal volumes from a control range 4-7 fl to 10-15 fl. Resealing restores these modal volumes to the original control range. Encapsulation of the fluorochrome, Lucifer yellow (Mr 550), during permeabilisation revealed that after resealing greater than 85% of rat platelets, and close to 100% human platelets, contained the encapsulated dye. The initial rates and % aggregation responses of both human and rat platelets to collagen, thrombin and the thromboxane A2-mimetic U46619 remained essentially normal after permeabilisation and resealing further illustrating the maintenance of functional competence following treatment. Resealed rat platelets reinfused into the circulation after labelling with [111In]indium oxine gave survival curves similar to those of control platelets. Therefore, this reversible permeabilisation procedure may allow the use of autologous or heterologous platelets as carrier vehicles for the delivery of drugs

  9. RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death

    PubMed Central

    Dächert, Jasmin; Schoeneberger, Hannah; Rohde, Katharina; Fulda, Simone

    2016-01-01

    Redox mechanisms play an important role in the control of various signaling pathways. Here, we report that Second mitochondrial activator of caspases (Smac) mimetic-induced cell death is regulated by redox signaling. We show that RSL3, a glutathione (GSH) peroxidase (GPX) 4 inhibitor, or Erastin, an inhibitor of the cystine/glutamate antiporter, cooperate with the Smac mimetic BV6 to induce reactive oxygen species (ROS)-dependent cell death in acute lymphoblastic leukemia (ALL) cells. Addition of the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) fails to rescue ROS-induced cell death, demonstrating that RSL3/BV6- or Erastin/BV6-induced cell death occurs in a caspase-independent manner. Interestingly, the iron chelator Deferoxamine (DFO) significantly inhibits RSL3/BV6-induced cell death, whereas it is unable to rescue cell death by Erastin/BV6, showing that RSL3/BV6-, but not Erastin/BV6-mediated cell death depends on iron. ROS production is required for both RSL3/BV6- and Erastin/BV6-induced cell death, since the ROS scavenger α-tocopherol (α-Toc) rescues RSL3/BV6- and Erastin/BV6-induced cell death. By comparison, genetic or pharmacological inhibition of lipid peroxidation by GPX4 overexpression or ferrostatin (Fer)-1 significantly decreases RSL3/BV6-, but not Erastin/BV6-induced cell death, despite inhibition of lipid peroxidation upon exposure to RSL3/BV6 or Erastin/BV6. Of note, inhibition of lipid peroxidation by Fer-1 protects from RSL3/BV6-, but not from Erastin/BV6-stimulated ROS production, indicating that other forms of ROS besides lipophilic ROS occur during Erastin/BV6-induced cell death. Taken together, RSL3/BV6 and Erastin/BV6 differentially regulate redox signaling and cell death in ALL cells. While RSL3/BV6 cotreatment induces ferroptotic cell death, Erastin/BV6 stimulates oxidative cell death independently of iron. These findings have important implications for the therapeutic targeting of redox signaling to

  10. RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death.

    PubMed

    Dächert, Jasmin; Schoeneberger, Hannah; Rohde, Katharina; Fulda, Simone

    2016-09-27

    Redox mechanisms play an important role in the control of various signaling pathways. Here, we report that Second mitochondrial activator of caspases (Smac) mimetic-induced cell death is regulated by redox signaling. We show that RSL3, a glutathione (GSH) peroxidase (GPX) 4 inhibitor, or Erastin, an inhibitor of the cystine/glutamate antiporter, cooperate with the Smac mimetic BV6 to induce reactive oxygen species (ROS)-dependent cell death in acute lymphoblastic leukemia (ALL) cells. Addition of the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) fails to rescue ROS-induced cell death, demonstrating that RSL3/BV6- or Erastin/BV6-induced cell death occurs in a caspase-independent manner. Interestingly, the iron chelator Deferoxamine (DFO) significantly inhibits RSL3/BV6-induced cell death, whereas it is unable to rescue cell death by Erastin/BV6, showing that RSL3/BV6-, but not Erastin/BV6-mediated cell death depends on iron. ROS production is required for both RSL3/BV6- and Erastin/BV6-induced cell death, since the ROS scavenger α-tocopherol (α-Toc) rescues RSL3/BV6- and Erastin/BV6-induced cell death. By comparison, genetic or pharmacological inhibition of lipid peroxidation by GPX4 overexpression or ferrostatin (Fer)-1 significantly decreases RSL3/BV6-, but not Erastin/BV6-induced cell death, despite inhibition of lipid peroxidation upon exposure to RSL3/BV6 or Erastin/BV6. Of note, inhibition of lipid peroxidation by Fer-1 protects from RSL3/BV6-, but not from Erastin/BV6-stimulated ROS production, indicating that other forms of ROS besides lipophilic ROS occur during Erastin/BV6-induced cell death. Taken together, RSL3/BV6 and Erastin/BV6 differentially regulate redox signaling and cell death in ALL cells. While RSL3/BV6 cotreatment induces ferroptotic cell death, Erastin/BV6 stimulates oxidative cell death independently of iron. These findings have important implications for the therapeutic targeting of redox signaling to

  11. Microwave-assisted synthesis of triple-helical, collagen-mimetic lipopeptides

    PubMed Central

    Banerjee, Jayati; Hanson, Andrea J; Muhonen, Wallace W; Shabb, John B; Mallik, Sanku

    2018-01-01

    Collagen-mimetic peptides and lipopeptides are widely used as substrates for matrix degrading enzymes, as new biomaterials for tissue engineering, as drug delivery systems and so on. However, the preparation and subsequent purification of these peptides and their fatty-acid conjugates are really challenging. Herein, we report a rapid microwave-assisted, solid-phase synthetic protocol to prepare the fatty-acid conjugated, triple-helical peptides containing the cleavage site for the enzyme matrix metalloproteinase-9 (MMP-9). We employed a PEG-based resin as the solid support and the amino acids were protected with Fmoc- and tert-butyl groups. The amino acids were coupled at 50 °C (25 W of microwave power) for 5 min. The deprotection reactions were carried out at 75 °C (35 W of microwave power) for 3 min. Using this protocol, a peptide containing 23 amino acids was synthesized and then conjugated to stearic acid in 14 h. PMID:20057380

  12. Compact toroid injection into C-2U

    NASA Astrophysics Data System (ADS)

    Roche, Thomas; Gota, H.; Garate, E.; Asai, T.; Matsumoto, T.; Sekiguchi, J.; Putvinski, S.; Allfrey, I.; Beall, M.; Cordero, M.; Granstedt, E.; Kinley, J.; Morehouse, M.; Sheftman, D.; Valentine, T.; Waggoner, W.; the TAE Team

    2015-11-01

    Sustainment of an advanced neutral beam-driven FRC for a period in excess of 5 ms is the primary goal of the C-2U machine at Tri Alpha Energy. In addition, a criteria for long-term global sustainment of any magnetically confined fusion reactor is particle refueling. To this end, a magnetized coaxial plasma-gun has been developed. Compact toroids (CT) are to be injected perpendicular to the axial magnetic field of C-2U. To simulate this environment, an experimental test-stand has been constructed. A transverse magnetic field of B ~ 1 kG is established (comparable to the C-2U axial field) and CTs are fired across it. As a minimal requirement, the CT must have energy density greater than that of the magnetic field it is to penetrate, i.e., 1/2 ρv2 >=B2 / 2μ0 . This criteria is easily met and indeed the CTs traverse the test-stand field. A preliminary experiment on C-2U shows the CT also capable of penetrating into FRC plasmas and refueling is observed resulting in a 20 - 30% increase in total particle number per single-pulsed CT injection. Results from test-stand and C-2U experiments will be presented.

  13. A Fock space coupled cluster study on the electronic structure of the UO(2), UO(2) (+), U(4+), and U(5+) species.

    PubMed

    Infante, Ivan; Eliav, Ephraim; Vilkas, Marius J; Ishikawa, Yasuyuki; Kaldor, Uzi; Visscher, Lucas

    2007-09-28

    The ground and excited states of the UO(2) molecule have been studied using a Dirac-Coulomb intermediate Hamiltonian Fock-space coupled cluster approach (DC-IHFSCC). This method is unique in describing dynamic and nondynamic correlation energies at relatively low computational cost. Spin-orbit coupling effects have been fully included by utilizing the four-component Dirac-Coulomb Hamiltonian from the outset. Complementary calculations on the ionized systems UO(2) (+) and UO(2) (2+) as well as on the ions U(4+) and U(5+) were performed to assess the accuracy of this method. The latter calculations improve upon previously published theoretical work. Our calculations confirm the assignment of the ground state of the UO(2) molecule as a (3)Phi(2u) state that arises from the 5f(1)7s(1) configuration. The first state from the 5f(2) configuration is found above 10,000 cm(-1), whereas the first state from the 5f(1)6d(1) configuration is found at 5,047 cm(-1).

  14. U2 small nuclear ribonucleoprotein particle (snRNP) auxiliary factor of 65 kDa, U2AF65, can promote U1 snRNP recruitment to 5' splice sites.

    PubMed Central

    Förch, Patrik; Merendino, Livia; Martínez, Concepción; Valcárcel, Juan

    2003-01-01

    The splicing factor U2AF(65), U2 small nuclear ribonucleoprotein particle (snRNP) auxillary factor of 65 kDa, binds to pyrimidine-rich sequences at 3' splice sites to recruit U2 snRNP to pre-mRNAs. We report that U2AF(65) can also promote the recruitment of U1 snRNP to weak 5' splice sites that are followed by uridine-rich sequences. The arginine- and serine-rich domain of U2AF(65) is critical for U1 recruitment, and we discuss the role of its RNA-RNA annealing activity in this novel function of U2AF(65). PMID:12558503

  15. The mimetic finite difference method for the Landau–Lifshitz equation

    DOE PAGES

    Kim, Eugenia Hail; Lipnikov, Konstantin Nikolayevich

    2017-01-01

    The Landau–Lifshitz equation describes the dynamics of the magnetization inside ferromagnetic materials. This equation is highly nonlinear and has a non-convex constraint (the magnitude of the magnetization is constant) which poses interesting challenges in developing numerical methods. We develop and analyze explicit and implicit mimetic finite difference schemes for this equation. These schemes work on general polytopal meshes which provide enormous flexibility to model magnetic devices with various shapes. A projection on the unit sphere is used to preserve the magnitude of the magnetization. We also provide a proof that shows the exchange energy is decreasing in certain conditions. Themore » developed schemes are tested on general meshes that include distorted and randomized meshes. As a result, the numerical experiments include a test proposed by the National Institute of Standard and Technology and a test showing formation of domain wall structures in a thin film.« less

  16. The mimetic finite difference method for the Landau–Lifshitz equation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Eugenia Hail; Lipnikov, Konstantin Nikolayevich

    The Landau–Lifshitz equation describes the dynamics of the magnetization inside ferromagnetic materials. This equation is highly nonlinear and has a non-convex constraint (the magnitude of the magnetization is constant) which poses interesting challenges in developing numerical methods. We develop and analyze explicit and implicit mimetic finite difference schemes for this equation. These schemes work on general polytopal meshes which provide enormous flexibility to model magnetic devices with various shapes. A projection on the unit sphere is used to preserve the magnitude of the magnetization. We also provide a proof that shows the exchange energy is decreasing in certain conditions. Themore » developed schemes are tested on general meshes that include distorted and randomized meshes. As a result, the numerical experiments include a test proposed by the National Institute of Standard and Technology and a test showing formation of domain wall structures in a thin film.« less

  17. A Special Extract of Bacopa monnieri (CDRI-08)-Restored Memory in CoCl2-Hypoxia Mimetic Mice Is Associated with Upregulation of Fmr-1 Gene Expression in Hippocampus

    PubMed Central

    Rani, Anupama; Prasad, S.

    2015-01-01

    Fragile X mental retardation protein (FMRP) is a neuronal translational repressor and has been implicated in learning, memory, and cognition. However, the role of Bacopa monnieri extract (CDRI-08) in enhancing cognitive abilities in hypoxia-induced memory impairment via Fmr-1 gene expression is not known. Here, we have studied effects of CDRI-08 on the expression of Fmr-1 gene in the hippocampus of well validated cobalt chloride (CoCl2)-induced hypoxia mimetic mice and analyzed the data with alterations in spatial memory. Results obtained from Morris water maze test suggest that CoCl2 treatment causes severe loss of spatial memory and CDRI-08 is capable of reversing it towards that in the normal control mice. Our semiquantitative RT-PCR, Western blot, and immunofluorescence microscopic data reveal that CoCl2-induced hypoxia significantly upregulates the expression of Hif-1α and downregulates the Fmr-1 expression in the hippocampus, respectively. Further, CDRI-08 administration reverses the memory loss and this is correlated with significant downregulation of Hif-1α and upregulation of Fmr-1 expression. Our data are novel and may provide mechanisms of hypoxia-induced impairments in the spatial memory and action of CDRI-08 in the recovery of hypoxia led memory impairment involving Fmr-1 gene encoded protein called FMRP. PMID:26413121

  18. Density functional theory calculations of UO2 oxidation: evolution of UO(2+x), U4O(9-y), U3O7, and U3O8.

    PubMed

    Andersson, D A; Baldinozzi, G; Desgranges, L; Conradson, D R; Conradson, S D

    2013-03-04

    Formation of hyperstoichiometric uranium dioxide, UO2+x, derived from the fluorite structure was investigated by means of density functional theory (DFT) calculations. Oxidation was modeled by adding oxygen atoms to UO2 fluorite supercells. For each compound ab initio molecular dynamics simulations were performed to allow the ions to optimize their local geometry. A similar approach was used for studying the reduction of U3O8. In agreement with the experimental phase diagram we identify stable line compounds at the U4O9-y and U3O7 stoichiometries. Although the transition from fluorite to the layered U3O8 structure occurs at U3O7 (UO2.333) or U3O7.333 (UO2.444), our calculated low temperature phase diagram indicates that the fluorite derived compounds are favored up to UO2.5, that is, as long as the charge-compensation for adding oxygen atoms occurs via formation of U(5+) ions, after which the U3O8-y phase becomes more stable. The most stable fluorite UO2+x phases at low temperature (0 K) are based on ordering of split quad-interstitial oxygen clusters. Most existing crystallographic models of U4O9 and U3O7, however, apply the cuboctahedral cluster. To better understand these discrepancies, the new structural models are analyzed in terms of existing neutron diffraction data. DFT calculations were also performed on the experimental cuboctahedral based U4O9-y structure, which enable comparisons between the properties of this phase with the quad-interstitial ones in detail.

  19. Modulation of Platelet Activation and Thrombus Formation Using a Pan-PI3K Inhibitor S14161

    PubMed Central

    Ren, Lijie; Liu, Xiaohui; Wang, Qi; He, Sudan; Wu, Qingyu; Hu, Hu; Mao, Xinliang; Zhu, Li

    2014-01-01

    The phosphatidylinositol 3–kinase (PI3K) signaling pathway is critical in modulating platelet functions. In the present study, we evaluated the effect of S14161, a recently identified pan-class I PI3K inhibitor, on platelet activation and thrombus formation. Results showed that S14161 inhibited human platelet aggregation induced by collagen, thrombin, U46619, and ADP in a dose-dependent manner. Flow cytometric studies showed that S14161 inhibited convulxin- or thrombin-induced P-selectin expression and fibrinogen binding of single platelet. S14161 also inhibited platelet spreading on fibrinogen and clot retraction, processes mediated by outside-in signaling. Using a microfluidic chamber we demonstrated that S14161 decreased platelet adhesion on collagen-coated surface by about 80%. Western blot showed that S14161 inhibited phosphorylation of Akt at both Ser473 and Thr308 sites, and GSK3β at Ser9 in response to collagen, thrombin, or U46619. Comparable studies showed that S14161 has a higher potential bioavailability than LY294002, a prototypical inhibitor of pan-class I PI3K. Finally, the effects of S14161 on thrombus formation in vivo were measured using a ferric chloride-induced carotid artery injury model in mice. The intraperitoneal injection of S14161 (2 mg/kg) to male C57BL/6 mice significantly extended the first occlusion time (5.05±0.99 min, n = 9) compared to the vehicle controls (3.72±0.95 min, n = 8) (P<0.05), but did not prolong the bleeding time (P>0.05). Taken together, our data showed that S14161 inhibits platelet activation and thrombus formation without significant bleeding tendency and toxicity, and considering its potential higher bioavailability, it may be developed as a novel therapeutic agent for the prevention of thrombotic disorders. PMID:25115838

  20. The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide.

    PubMed

    Barnett, A H

    2012-04-01

    In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM-exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m(2) , and patients with a BMI <35 kg/m(2) who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m(2) ) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. © 2011 Blackwell Publishing Ltd.

  1. Mechanism of endothelium-dependent relaxation induced by substance P in the coronary artery of the pig.

    PubMed Central

    Kuroiwa, M.; Aoki, H.; Kobayashi, S.; Nishimura, J.; Kanaide, H.

    1995-01-01

    1. Using front-surface fluorometry of fura-2-loaded porcine coronary arterial strips with the endothelium intact, we investigated the mechanisms of vasorelaxation induced by substance P (SP). Fura-2 fluorescence signals which indicated the cytosolic Ca2+-concentration ([Ca2+]i), were observed to arise exclusively from teh smooth muscle cells in these strips. 2. During the contractions induced by U46619 (100 nM), a thromboxane A2 analogue, an SP-induced endothelium-dependent, biphasic vasorelaxation was observed, which consisted of an initial rapid relaxation phase followed by a sustained phase, with a transient decrease in [Ca2+]i. Pretreatment with indomethacin (Ind) had no effect on the SP-induced relaxation; however, pretreatment with NG-nitro-L-arginine (L-NOARG) partially, but significantly inhibited the decrease in both the [Ca2+]i and tension abolished. Thus, part of the relaxation was considered to be mediated by L-NOARG-sensitive relaxing factor (endothelium-derived relaxing factor: EDRF). 3. During the 40 mM K+-depolarization-induced contraction which may eliminate the effects of endothelium-derived hyperpolarizing factor (EDRF), the vasorelaxation reduced by SP was completely inhibited by L-NOARG. 4. During the vasorelaxation induced SP, the [Ca2+]i-tension relationships shifted to the right of the contractions induced by either U46619 or high K+-depolarization. 5. Using front-surface fluorometry of fura-2 loaded porcine aortic valvular strips, we examined the effects of SP on [Ca2+]i in endothelial cells in situ. SP induced a rapid increase in [Ca2+]i of endothelial cells in situ followed by a small sustained phase in normal PSS (5.9 mM K+). The increase in extracellular K+ had no apparent effect on the SP-induced [Ca2+]i elevation of endothelial cells. Images Figure 1 PMID:8640343

  2. Assessing Hubbard-corrected AM05+ U and PBEsol+ U density functionals for strongly correlated oxides CeO 2 and Ce 2O 3

    DOE PAGES

    Weck, Philippe F.; Kim, Eunja

    2016-09-12

    The structure–property relationships of bulk CeO 2 and Ce 2O 3 have been investigated using AM05 and PBEsol exchange–correlation functionals within the frameworks of Hubbard-corrected density functional theory (DFT+ U) and density functional perturbation theory (DFPT+ U). Compared with conventional PBE+ U, RPBE+ U, PW91+ U and LDA+ U functionals, AM05+ U and PBEsol+ U describe experimental crystalline parameters and properties of CeO 2 and Ce 2O 3 with superior accuracy, especially when + U is chosen close to its value derived by the linear-response approach. Lastly, the present findings call for a reexamination of some of the problematic oxidemore » materials featuring strong f- and d-electron correlation using AM05+ U and PBEsol+ U.« less

  3. Assessing Hubbard-corrected AM05+ U and PBEsol+ U density functionals for strongly correlated oxides CeO 2 and Ce 2O 3

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Weck, Philippe F.; Kim, Eunja

    The structure–property relationships of bulk CeO 2 and Ce 2O 3 have been investigated using AM05 and PBEsol exchange–correlation functionals within the frameworks of Hubbard-corrected density functional theory (DFT+ U) and density functional perturbation theory (DFPT+ U). Compared with conventional PBE+ U, RPBE+ U, PW91+ U and LDA+ U functionals, AM05+ U and PBEsol+ U describe experimental crystalline parameters and properties of CeO 2 and Ce 2O 3 with superior accuracy, especially when + U is chosen close to its value derived by the linear-response approach. Lastly, the present findings call for a reexamination of some of the problematic oxidemore » materials featuring strong f- and d-electron correlation using AM05+ U and PBEsol+ U.« less

  4. The progestin levonorgestrel induces endothelium-independent relaxation of rabbit jugular vein via inhibition of calcium entry and protein kinase C: role of cyclic AMP

    PubMed Central

    Herkert, Olaf; Kuhl, Herbert; Busse, Rudi; Schini-Kerth, Valérie B

    2000-01-01

    The progestin and oestrogen component of oral contraceptives have been involved in the development of venous thromboembolic events in women. In the present study we determined the vasoactive effects of sex steroids used in oral contraceptives in isolated preconstricted rabbit jugular veins in the presence of diclofenac and examined the underlying mechanisms.The natural hormone progesterone, the synthetic progestins levonorgestrel, 3-keto-desogestrel, gestodene and chlormadinone acetate, and the synthetic estrogen 17 α-ethinyloestradiol induced concentration-dependent relaxations of endothelium-intact veins constricted with U46619. Levonorgestrel also inhibited constrictions evoked by either a high potassium (K+) solution or phorbol myristate acetate (PMA) in the absence and presence of extracellular calcium (Ca2+). In addition, levonorgestrel depressed contractions evoked by Ca2+ and reduced 45Ca2+ influx in depolarized veins.Relaxations to levonorgestrel in U46619-constricted veins were neither affected by the presence of the endothelium nor by the inhibitor of soluble guanylyl cyclase, NS2028, but were significantly improved either by the selective cyclic AMP phosphodiesterase inhibitor rolipram or in the absence of diclofenac, and decreased by the protein kinase A inhibitor, Rp-8-CPT-cAMPS. Rolipram also potentiated relaxations to levonorgestrel in PMA-constricted veins in the presence, but not in the absence of extracellular Ca2+. Levonorgestrel increased levels of cyclic AMP and inhibited PMA-induced activation of protein kinase C in veins.These findings indicate that levonorgestrel caused endothelium-independent relaxations of jugular veins via inhibition of Ca2+ entry and of protein kinase C activation. In addition, the cyclic AMP effector pathway contributes to the levonorgestrel-induced relaxation possibly by depressing Ca2+ entry. PMID:10952682

  5. Fusion protein of CDR mimetic peptide with Fc inhibit TNF-alpha induced cytotoxicity.

    PubMed

    Qin, Weisong; Feng, Jiannan; Li, Yan; Lin, Zhou; Shen, Beifen

    2006-02-01

    The variable regions of antibodies play central roles in the binding with antigens. Based on the model of a tumour necrosis factor-alpha (TNF-alpha) neutralizing monoclonal antibody (named as Z12) with TNF-alpha, heavy chain CDR2 (HCDR2) and light chain CDR3 (LCDR3) of Z12 were found to be the most responsible to bind with TNF-alpha. A mimetic peptide (PT) was designed based on the sequence derived from HCDR2 and LCDR3. Fusion protein PT-Fc was constructed by linking PT with Fc of human IgG1 through a flexible linker (GGGGGS). The primary structural characteristics of Fc and PT-Fc were analyzed, including the flexibility, hydrophilicity and epitopes. It was demonstrated that PT and Fc in the fusion protein possessed bio-function properly and non-interfering with each other. Furthermore, PT-Fc was expressed in Escherichia coli by fusion with thioredoxin (Trx). After trx-PT-Fc was cleaved with recombinant enterokinase, PT-Fc was obtained. The results of in vitro cytotoxic assays showed that both PT and PT-Fc could efficiently inhibit TNF-alpha induced apoptosis on L929 cells. At the same micromole concentration, the inhibition activity of PT-Fc was significantly higher than PT.

  6. N-octanoyl-dopamine is a potent inhibitor of platelet function.

    PubMed

    Ait-Hsiko, Lamia; Kraaij, Tineke; Wedel, Johannes; Theisinger, Bastian; Theisinger, Sonja; Yard, Benito; Bugert, Peter; Schedel, Angelika

    2013-01-01

    Dopamine (DA) is a co-agonist for platelet activation; yet, donor DA treatment is associated with improved transplantation outcome in renal and heart recipients. Recently, N-octanoyl-dopamine (NOD) was developed which displays superior effects compared to DA in terms of graft protecting properties. Whereas DA is a known platelet co-agonist, the effect of NOD on platelet function is unknown. This is a hypothesis generating study with the aim to assess the effects and molecular mechanisms of NOD and NOD-like compounds on platelet function. The influence of DA, NOD, and NOD-like compounds on platelet responses to classical agonists (adenosine 5'-diphosphate (ADP), U46619) was investigated in six healthy donors by applying whole blood aggregometry (Multiplate®) and flow cytometry for Pac-1, CD62P, and CD63 expression. Changes in platelet cAMP concentrations were assessed by ELISA. While DA showed synergy in platelet activation by ADP and U46619, NOD caused significant inhibition of platelet function both in whole blood aggregometry and flow cytometry. The inhibitory effect of NOD was not mediated via cAMP levels. The nonredox-active NOD-analog N-octanoyl-tyramine had no effects on platelet function. Acetylated NOD conferred to NOD by intracellular esterases showed similar inhibitory effects as NOD. In contrast to DA, NOD is a potent inhibitor of platelet function most likely through intracellular redox-active processes. This adds to the overall protective effect of NOD on pre-transplantation injury and makes NOD an attractive candidate compound for donor or organ conditioning prior to transplantation.

  7. U-2 Aircraft at the Lewis Research Center

    NASA Image and Video Library

    1973-09-21

    A National Aeronautics and Space Administration (NASA) Lockheed U-2 aircraft on display at the 1973 Inspection of the Lewis Research Center in Cleveland, Ohio. Lockheed developed the U-2 as a high-altitude reconnaissance aircraft in the early 1950s before satellites were available. The U-2 could cruise over enemy territory at 70,000 feet and remain impervious to ground fire, interceptor aircraft, and even radar. An advanced camera system was designed specifically for the aircraft. The pilot is required to use a pressure suit similar to those worn by astronauts. NASA’s Ames Research Center received two U-2 aircraft in April 1971 to conduct high-altitude research. They were used to study and monitor various Earth resources, celestial bodies, atmospheric chemistry, and oceanic processes. NASA replaced its U-2s with ER-2 aircraft in 1981 and 1989. The ER-2s were designed to carry up to 2600 pounds of scientific equipment. The ER-2 program was transferred to Dryden Flight Research Center in 1997. Since the inaugural flight for this program on August 31, 1971, NASA’s U-2 and ER-2 aircraft have flown more than 4500 data missions and test flights for NASA, other federal agencies, states, universities, and the private sector.

  8. Towards natural mimetics of metformin and rapamycin.

    PubMed

    Aliper, Alexander; Jellen, Leslie; Cortese, Franco; Artemov, Artem; Karpinsky-Semper, Darla; Moskalev, Alexey; Swick, Andrew G; Zhavoronkov, Alex

    2017-11-15

    Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.

  9. U-PuO2, U-PuC, U-PuN cermet fuel for fast reactor

    NASA Astrophysics Data System (ADS)

    Mishra, Sudhir; Kaity, Santu; Banerjee, Joydipta; Nandi, Chiranjeet; Dey, G. K.; Khan, K. B.

    2018-02-01

    Cermet fuel combines beneficial properties of both ceramic and metal and attracts global interest for research as a candidate fuel for nuclear reactors. In the present study, U matrix PuC/PuN/PuO2 cermet for fast reactor have been fabricated on laboratory scale by the powder metallurgy route. Characterization of the fuel has been carried out using Dilatometer, Differential Thermal analysis (DTA), X-ray diffractometer and Optical microscope. X ray diffraction study of the fuel reveals presence of different phases. The PuN dispersed cermet was observed to have high solidus temperature as compared to PuC and PuO2 dispersed cermet. Swelling was observed in U matrix PuO2 cermet which also showed higher thermal expansion. Among the three cermets studied, U matrix PuC cermet showed maximum thermal conductivity.

  10. Structural Insight into Inhibitor of Apoptosis Proteins Recognition by a Potent Divalent Smac-Mimetic

    PubMed Central

    Vachette, Patrice; Malvezzi, Francesca; Grassi, Serena; Lecis, Daniele; Delia, Domenico; Drago, Carmelo; Seneci, Pierfausto; Bolognesi, Martino; Mastrangelo, Eloise

    2012-01-01

    Genetic alterations enhancing cell survival and suppressing apoptosis are hallmarks of cancer that significantly reduce the efficacy of chemotherapy or radiotherapy. The Inhibitor of Apoptosis Protein (IAP) family hosts conserved proteins in the apoptotic pathway whose over-expression, frequently found in tumours, potentiates survival and resistance to anticancer agents. In humans, IAPs comprise eight members hosting one or more structural Baculoviral IAP Repeat (BIR) domains. Cellular IAPs (cIAP1 and 2) indirectly inhibit caspase-8 activation, and regulate both the canonical and the non-canonical NF-κB signaling pathways. In contrast to cIAPs, XIAP (X chromosome-linked Inhibitor of Apoptosis Protein) inhibits directly the effector caspases-3 and -7 through its BIR2 domain, and initiator caspase-9 through its BIR3 domain; molecular docking studies suggested that Smac/DIABLO antagonizes XIAP by simultaneously targeting both BIR2 and BIR3 domains. Here we report analytical gel filtration, crystallographic and SAXS experiments on cIAP1-BIR3, XIAP-BIR3 and XIAP-BIR2BIR3 domains, alone and in the presence of compound 9a, a divalent homodimeric Smac mimetic. 9a is shown to bind two BIR domains inter- (in the case of two BIR3) and intra-molecularly (in the case of XIAP-BIR2BIR3), with higher affinity for cIAP1-BIR3, relative to XIAP-BIR3. Despite the different crystal lattice packing, 9a maintains a right handed helical conformation in both cIAP1-BIR3 and XIAP-BIR3 crystals, that is likely conserved in solution as shown by SAXS data. Our structural results demonstrate that the 9a linker length, its conformational degrees of freedom and its hydrophobicity, warrant an overall compact structure with optimal solvent exposure of its two active moieties for IAPs binding. Our results show that 9a is a good candidate for pre-clinical and clinical studies, worth of further investigations in the field of cancer therapy. PMID:23166698

  11. Modelling the thermal conductivity of (U xTh 1-x)O 2 and (U xPu 1-x)O 2

    DOE PAGES

    Cooper, M. W. D.; Middleburgh, S. C.; Grimes, R. W.

    2015-07-15

    The degradation of thermal conductivity due to the non-uniform cation lattice of (U xTh 1-x)O 2 and (U xPu 1-x)O 2 solid solutions has been investigated by molecular dynamics, using the non-equilibrium method, from 300 to 2000 K. Degradation of thermal conductivity is predicted in (U xTh 1-x)O 2 and (U xPu 1-x)O 2 as compositions deviate from the pure end members: UO 2, PuO 2 and ThO 2. The reduction in thermal conductivity is most apparent at low temperatures where phonon-defect scattering dominates over phonon-phonon interactions. The effect is greater for (U xTh 1-x)O 2 than U xPu 1-x)Omore » 2 due to the greater mismatch in cation size. Parameters for an analytical expressions have been developed that describe the predicted thermal conductivities over the full temperature and compositional ranges. Finally, these expressions may be used in higher level fuel performance codes.« less

  12. A magnetic nanoscale Fe₃O₄/Pβ-CD composite as an efficient peroxidase mimetic for glucose detection.

    PubMed

    Shi, Yun; Huang, Jun; Wang, Jiangning; Su, Ping; Yang, Yi

    2015-10-01

    Magnetic polymer particles with different surface functionalizations were prepared by a simple one-pot solvothermal method and characterized as peroxidase mimetics. The fluorescence enhancement obtained by attaching a β-cyclodextrin polymer (Pβ(-CD)) to the surfaces of Fe3O4 magnetic microspheres (Fe3O4 MMs) to generate a Fe3O4/P(β-CD) composite allowed the rapid, sensitive and selective analysis of glucose. The catalytic activity of the Fe3O4/P(β-CD) composite was evaluated with regard to the effects of catalyst particle size and species, pH value, level of catalyst, benzoic acid concentration and reaction time. Detection limits of 0.015 μM for H2O2 and 0.03 μM for glucose were determined when measuring at the 10-min mark. The presence of other saccharides, ion species, amino acids and proteins, had little effect on the results, and this technique was found to allow the analysis of glucose in human serum with high accuracy. The reusability of the Fe3O4/P(β-CD) composite was also investigated after 10 successive runs. A possible mechanism is proposed in which Fe3O4 plays a significant role in inducing fluorescence and P(β-CD) enhances the fluorescence signal, acting as both a stabilizer and a phase transfer agent. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Dramatic nano-fluidic properties of carbon nanotube membranes as a platform for protein channel mimetics

    NASA Astrophysics Data System (ADS)

    Hinds, Bruce

    2013-03-01

    Carbon nanotubes have three key attributes that make them of great interest for novel membrane applications: 1) atomically flat graphite surface allows for ideal fluid slip boundary conditions and extremely fast flow rates 2) the cutting process to open CNTs inherently places functional chemistry at CNT core entrance for chemical selectivity and 3) CNT are electrically conductive allowing for electrochemical reactions and application of electric fields gradients at CNT tips. Pressure driven flux of a variety of solvents (H2O, hexane, decane ethanol, methanol) are 4-5 orders of magnitude higher than conventional Newtonian flow [Nature 2005, 438, 44] due to atomically flat graphite planes inducing nearly ideal slip conditions. However this is eliminated with selective chemical functionalization [ACS Nano 2011 5(5) 3867-3877] needed to give chemical selectivity. These unique properties allow us to explore the hypothesis of producing ``Gatekeeper'' membranes that mimic natural protein channels to actively pump through rapid nm-scale channels. With anionic tip functionality strong electroosmotic flow is induced by unimpeded cation flow with similar 10,000 fold enhancements [Nature Nano 2012 7(2) 133-39]. With enhanced power efficiency, carbon nanotube membranes were employed as the active element of a switchable transdermal drug delivery device that can facilitate more effective treatments of drug abuse and addiction. Recently methods to deposit Pt monolayers on CNT surface have been developed making for highly efficient catalytic platforms. Discussed are other applications of CNT protein channel mimetics, for large area robust engineering platforms, including water purification, flow battery energy storage, and biochemical/biomass separations. DOE EPSCoR (DE-FG02-07ER46375) and DARPA, W911NF-09-1-0267

  14. 7 CFR 51.3197 - U.S. No. 2.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false U.S. No. 2. 51.3197 Section 51.3197 Agriculture... Standards for Grades of Bermuda-Granex-Grano Type Onions Grades § 51.3197 U.S. No. 2. U.S. No. 2 consists of...) Free from serious damage caused by: (1) Seedstems; (2) Dry sunken areas; (3) Sprouting; (4) Staining...

  15. 7 CFR 51.3197 - U.S. No. 2.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 2 2011-01-01 2011-01-01 false U.S. No. 2. 51.3197 Section 51.3197 Agriculture... Standards for Grades of Bermuda-Granex-Grano Type Onions Grades § 51.3197 U.S. No. 2. U.S. No. 2 consists of...) Free from serious damage caused by: (1) Seedstems; (2) Dry sunken areas; (3) Sprouting; (4) Staining...

  16. 7 CFR 51.3197 - U.S. No. 2.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 2 2012-01-01 2012-01-01 false U.S. No. 2. 51.3197 Section 51.3197 Agriculture... Standards for Grades of Bermuda-Granex-Grano Type Onions Grades § 51.3197 U.S. No. 2. U.S. No. 2 consists of...) Free from serious damage caused by: (1) Seedstems; (2) Dry sunken areas; (3) Sprouting; (4) Staining...

  17. Superoxide Dismutase Mimetic GC4419 Enhances the Oxidation of Pharmacological Ascorbate and Its Anticancer Effects in an H₂O₂-Dependent Manner.

    PubMed

    Heer, Collin D; Davis, Andrew B; Riffe, David B; Wagner, Brett A; Falls, Kelly C; Allen, Bryan G; Buettner, Garry R; Beardsley, Robert A; Riley, Dennis P; Spitz, Douglas R

    2018-01-19

    Lung cancer, together with head and neck cancer, accounts for more than one-fourth of cancer deaths worldwide. New, non-toxic therapeutic approaches are needed. High-dose IV vitamin C (aka, pharmacological ascorbate; P-AscH - ) represents a promising adjuvant to radiochemotherapy that exerts its anti-cancer effects via metal-catalyzed oxidation to form H₂O₂. Mn(III)-porphyrins possessing superoxide dismutase (SOD) mimetic activity have been shown to increase the rate of oxidation of AscH - , enhancing the anti-tumor effects of AscH - in several cancer types. The current study demonstrates that the Mn(II)-containing pentaazamacrocyclic selective SOD mimetic GC4419 may serve as an AscH - /O₂ •- oxidoreductase as evidenced by the increased rate of oxygen consumption, steady-state concentrations of ascorbate radical, and H₂O₂ production in complete cell culture media. GC4419, but not CuZnSOD, was shown to significantly enhance the toxicity of AscH - in H1299, SCC25, SQ20B, and Cal27 cancer cell lines. This enhanced cancer cell killing was dependent upon the catalytic activity of the SOD mimetic and the generation of H₂O₂, as determined using conditional overexpression of catalase in H1299T cells. GC4419 combined with AscH - was also capable of enhancing radiation-induced cancer cell killing. Currently, AscH - and GC4419 are each being tested separately in clinical trials in combination with radiation therapy. Data presented here support the hypothesis that the combination of GC4419 and AscH - may provide an effective means by which to further enhance radiation therapy responses.

  18. A study of a new TSM bio-mimetic sensor using a molecularly imprinted polymer coating and its application for the determination of nicotine in human serum and urine.

    PubMed

    Tan, Y; Yin, J; Liang, C; Peng, H; Nie, L; Yao, S

    2001-03-01

    A new bio-mimetic quartz crystal thickness-shear-mode (TSM) sensor, using an imprinted polymer coating as the sensitive material, has been fabricated and applied to the determination of nicotine (NIC) in human serum and urine. The molecularly imprinted polymer (MIP) was synthesized using NIC as the template molecule and methacrylic acid (MAA) as the functional monomer. The sensor showed high selectivity and a sensitive response to NIC in aqueous system. The linear response range of the sensor was between 5.0 x 10(-8) and 1.0 x 10(-4) M with a detection limit of 2.5 x 10(-8) M. The viscoelasticity of the coating in the air and in liquid has been studied by the impedance spectrum. The MIP sensor was stable and exhibited effective reproducibility. Satisfactory results were achieved in the detection of the real samples.

  19. Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL.

    PubMed

    McComb, Scott; Aguadé-Gorgorió, Júlia; Harder, Lena; Marovca, Blerim; Cario, Gunnar; Eckert, Cornelia; Schrappe, Martin; Stanulla, Martin; von Stackelberg, Arend; Bourquin, Jean-Pierre; Bornhauser, Beat C

    2016-05-18

    More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice. Antileukemic activity was dependent on simultaneous execution of apoptosis and necroptosis, as demonstrated by functional genomic dissection with a multicolored lentiCRISPR approach to simultaneously disrupt multiple genes in patient-derived ALL. SM specifically targeted receptor-interacting protein kinase 1 (RIP1)-dependent death, and CRISPR-mediated disruption of RIP1 completely blocked SM-induced death yet had no impact on the response to standard antileukemic agents. Thus, SM compounds such as birinapant circumvent escape from apoptosis in leukemia by activating a potent dual RIP1-dependent apoptotic and necroptotic cell death, which is not exploited by current therapy. Ex vivo drug activity profiling could provide important functional diagnostic information to identify patients who may benefit from targeted treatment with birinapant in early clinical trials. Copyright © 2016, American Association for the Advancement of Science.

  20. 7 CFR 51.2835 - U.S. No. 2.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... areas; (8) Disease; (9) Freezing; (10) Insects; and, (11) Other means. (d) For tolerances see § 51.2837... 7 Agriculture 2 2013-01-01 2013-01-01 false U.S. No. 2. 51.2835 Section 51.2835 Agriculture... Creole Types) Grades § 51.2835 U.S. No. 2. U.S. No. 2 consists of onions which meet the following...

  1. 7 CFR 51.1575 - U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large. 51.1575 Section 51.1575 Agriculture Regulations of the Department of... Potatoes Grades § 51.1575 U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade...

  2. 7 CFR 51.1575 - U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 2 2012-01-01 2012-01-01 false U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large. 51.1575 Section 51.1575 Agriculture Regulations of the Department of... Potatoes Grades § 51.1575 U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade...

  3. 7 CFR 51.1575 - U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 2 2011-01-01 2011-01-01 false U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large. 51.1575 Section 51.1575 Agriculture Regulations of the Department of... Potatoes Grades § 51.1575 U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade...

  4. Synthesis and properties of ApU analogues containing 2'-halo-2'-deoxyadenosines. Effects of 2' substituents on oligonucleotide conformation.

    PubMed

    Uesugi, S; Kaneyasu, T; Ikehara, M

    1982-11-09

    Five A-U analogues containing deoxyadenosine or 2'-halo-2'-deoxyadenosines, which are known to have widely different C3'-endo conformer populations according to their electronegativities of the halogen substituents, dAfl-U, dAcl-U, dAbr-U, dAio-U, and dA-U, were synthesized chemically. Characterization of these dimers has been performed by UV absorption, circular dichroism, and proton nuclear magnetic resonance spectroscopy. The results show that the dimers containing 2'-halo-2'-deoxyadenosines have stacked conformations with a geometry similar to that of A-U and the degree of stacking decreases in the order dAfl-U greater than dAcl-U greater than dAbr-U greater than dAio-U. dAcl-U is assumed to have the same degree of stacking as A-U. dA-U takes a more stacked conformation than does dAio-U, but the mode of stacking is different from those of the other dimers. The effects of the 2' substituents on dimer conformation are discussed in terms of electronegativity, molecular size, and hydrophobicity.

  5. BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

    PubMed Central

    Prévost, Jérémie; von Bredow, Benjamin; Ding, Shilei; Brassard, Nathalie; Medjahed, Halima; Coutu, Mathieu; Melillo, Bruno; Bibollet-Ruche, Frédéric; Hahn, Beatrice H.; Kaufmann, Daniel E.; Smith, Amos B.; Sodroski, Joseph; Sauter, Daniel; Kirchhoff, Frank; Gee, Katrina; Neil, Stuart J.; Evans, David T.

    2017-01-01

    ABSTRACT Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV-positive (HIV+) sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4 mimetics (CD4mc) that are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. However, HIV-1 developed additional mechanisms to avoid ADCC, including Vpu-mediated BST-2 antagonism, which decreases the overall amount of Env present at the cell surface. Accordingly, BST-2 upregulation in response to alpha interferon (IFN-α) was shown to increase the susceptibility of HIV-1-infected cells to ADCC despite the activity of Vpu. Here we show that BST-2 upregulation by IFN-β and interleukin-27 (IL-27) also increases the surface expression of Env and thus boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from HIV-1-infected individuals. IMPORTANCE HIV-1 evolved sophisticated strategies to conceal Env epitopes from ADCC-mediating antibodies present in HIV+ sera. Vpu-mediated BST-2 downregulation was shown to decrease ADCC responses by limiting the amount of Env present at the cell surface. This effect of Vpu was shown to be attenuated by IFN-α treatment. Here we show that in addition to IFN-α, IFN-β and IL-27 also affect Vpu-mediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-infected cells in the presence of CD4mc. These findings may inform strategies aimed at HIV prevention and eradication. PMID:28331088

  6. Vascular targets for cannabinoids: animal and human studies

    PubMed Central

    Stanley, Christopher; O'Sullivan, Saoirse E

    2014-01-01

    Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the result is vasorelaxation, although vasoconstrictor responses are also observed. Cannabinoids also modulate the actions of vasoactive compounds including acetylcholine, methoxamine, angiotensin II and U46619 (thromboxane mimetic). Numerous mechanisms of action have been proposed including receptor activation, potassium channel activation, calcium channel inhibition and the production of vasoactive mediators such as calcitonin gene-related peptide, prostanoids, NO, endothelial-derived hyperpolarizing factor and hydrogen peroxide. The purpose of this review is to examine the evidence for the range of receptors now known to be activated by cannabinoids. Direct activation by cannabinoids of CB1, CBe, TRPV1 (and potentially other TRP channels) and PPARs in the vasculature has been observed. A potential role for CB2, GPR55 and 5-HT1A has also been identified in some studies. Indirectly, activation of prostanoid receptors (TP, IP, EP1 and EP4) and the CGRP receptor is involved in the vascular responses to cannabinoids. The majority of this evidence has been obtained through animal research, but recent work has confirmed some of these targets in human arteries. Vascular responses to cannabinoids are enhanced in hypertension and cirrhosis, but are reduced in obesity and diabetes, both due to changes in the target sites of action. Much further work is required to establish the extent of vascular actions of cannabinoids and the application of this research in physiological and pathophysiological situations. Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6 PMID:24329566

  7. 7 CFR 51.1575 - U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 2 2014-01-01 2014-01-01 false U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large. 51.1575 Section 51.1575 Agriculture Regulations of the Department of...) United States Consumer Standards for Potatoes Grades § 51.1575 U.S. Grade A Small; U.S. Grade A Medium; U...

  8. 7 CFR 51.1575 - U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 2 2013-01-01 2013-01-01 false U.S. Grade A Small; U.S. Grade A Medium; U.S. Grade A Medium to Large; U.S. Grade A Large. 51.1575 Section 51.1575 Agriculture Regulations of the Department of...) United States Consumer Standards for Potatoes Grades § 51.1575 U.S. Grade A Small; U.S. Grade A Medium; U...

  9. Infrared radiative decay dynamics from the γ 1u (3P2), H 1u (3P1), and 1u (1D2) ion-pair states of I2 observed by a perturbation facilitated optical-optical double resonance technique

    NASA Astrophysics Data System (ADS)

    Hoshino, Shoma; Araki, Mitsunori; Nakano, Yukio; Ishiwata, Takashi; Tsukiyama, Koichi

    2016-01-01

    We report the spectroscopic and temporal analyses on the amplified spontaneous emission (ASE) from the single rovibrational levels of the Ω = 1u ion-pair series, γ 1u (3P2), H 1u (3P1), and 1u (1D2), of I2 by using a perturbation facilitated optical-optical double resonance technique through the c 1 Π g ˜ B 3 Π ( 0u + ) hyperfine mixed valence state as the intermediate state. The ASE detected in the infrared region was assigned to the parallel transitions from the Ω = 1u ion-pair states down to the nearby Ω = 1g ion-pair states. The subsequent ultraviolet (UV) fluorescence from the Ω = 1g states was also observed and the relative vibrational populations in the Ω = 1g states were derived through the Franck-Condon simulation of the intensity pattern of the vibrational progression. In the temporal profiles of the UV fluorescence, an obvious delay in the onset of the fluorescence was recognized after the excitation laser pulse. These results revealed that ASE is a dominant energy relaxation process between the Ω = 1u and 1g ion-pair states of I2. Finally, the lifetimes of the relevant ion-pair states were evaluated by temporal analyses of the UV fluorescence. The propensity was found which was the longer lifetime in the upper level of the ASE transitions tends to give intense ASE.

  10. A Novel Apolipoprotein C-II Mimetic Peptide That Activates Lipoprotein Lipase and Decreases Serum Triglycerides in Apolipoprotein E–Knockout Mice

    PubMed Central

    Sakurai, Toshihiro; Sakurai-Ikuta, Akiko; Sviridov, Denis; Freeman, Lita; Ahsan, Lusana; Remaley, Alan T.

    2015-01-01

    Apolipoprotein A-I (apoA-I) mimetic peptides are currently being developed as possible new agents for the treatment of cardiovascular disease based on their ability to promote cholesterol efflux and their other beneficial antiatherogenic properties. Many of these peptides, however, have been reported to cause transient hypertriglyceridemia due to inhibition of lipolysis by lipoprotein lipase (LPL). We describe a novel bihelical amphipathic peptide (C-II-a) that contains an amphipathic helix (18A) for binding to lipoproteins and stimulating cholesterol efflux as well as a motif based on the last helix of apolipoprotein C-II (apoC-II) that activates lipolysis by LPL. The C-II-a peptide promoted cholesterol efflux from ATP-binding cassette transporter ABCA1-transfected BHK cells similar to apoA-I mimetic peptides. Furthermore, it was shown in vitro to be comparable to the full-length apoC-II protein in activating lipolysis by LPL. When added to serum from a patient with apoC-II deficiency, it restored normal levels of LPL-induced lipolysis and also enhanced lipolysis in serum from patients with type IV and V hypertriglyceridemia. Intravenous injection of C-II-a (30 mg/kg) in apolipoprotein E–knockout mice resulted in a significant reduction of plasma cholesterol and triglycerides of 38 ± 6% and 85 ± 7%, respectively, at 4 hours. When coinjected with the 5A peptide (60 mg/kg), the C-II-a (30 mg/kg) peptide was found to completely block the hypertriglyceridemic effect of the 5A peptide in C57Bl/6 mice. In summary, C-II-a is a novel peptide based on apoC-II, which promotes cholesterol efflux and lipolysis and may therefore be useful for the treatment of apoC-II deficiency and other forms of hypertriglyceridemia. PMID:25395590

  11. Facile CO Cleavage by a Multimetallic CsU2 Nitride Complex.

    PubMed

    Falcone, Marta; Kefalidis, Christos E; Scopelliti, Rosario; Maron, Laurent; Mazzanti, Marinella

    2016-09-26

    Uranium nitrides are important materials with potential for application as fuels for nuclear power generation, and as highly active catalysts. Molecular nitride compounds could provide important insight into the nature of the uranium-nitride bond, but currently little is known about their reactivity. In this study, we found that a complex containing a nitride bridging two uranium centers and a cesium cation readily cleaved the C≡O bond (one of the strongest bonds in nature) under ambient conditions. The product formed has a [CsU2 (μ-CN)(μ-O)] core, thus indicating that the three cations cooperate to cleave CO. Moreover, the addition of MeOTf to the nitride complex led to an exceptional valence disproportionation of the CsU(IV) -N-U(IV) core to yield CsU(III) (OTf) and [MeN=U(V) ] fragments. The important role of multimetallic cooperativity in both reactions is illustrated by the computed reaction mechanisms. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Membrane mimetic surface functionalization of nanoparticles: Methods and applications

    PubMed Central

    Weingart, Jacob; Vabbilisetty, Pratima; Sun, Xue-Long

    2013-01-01

    Nanoparticles (NPs), due to their size-dependent physical and chemical properties, have shown remarkable potential for a wide range of applications over the past decades. Particularly, the biological compatibilities and functions of NPs have been extensively studied for expanding their potential in areas of biomedical application such as bioimaging, biosensing, and drug delivery. In doing so, surface functionalization of NPs by introducing synthetic ligands and/or natural biomolecules has become a critical component in regards to the overall performance of the NP system for its intended use. Among known examples of surface functionalization, the construction of an artificial cell membrane structure, based on phospholipids, has proven effective in enhancing biocompatibility and has become a viable alternative to more traditional modifications, such as direct polymer conjugation. Furthermore, certain bioactive molecules can be immobilized onto the surface of phospholipid platforms to generate displays more reminiscent of cellular surface components. Thus, NPs with membrane-mimetic displays have found use in a range of bioimaging, biosensing, and drug delivery applications. This review herein describes recent advances in the preparations and characterization of integrated functional NPs covered by artificial cell membrane structures and their use in various biomedical applications. PMID:23688632

  13. Oxidation/reduction studies on Zr yU 1-yO 2+x and delineation of a new orthorhombic phase in U-Zr-O system

    NASA Astrophysics Data System (ADS)

    Sali, S. K.; Kulkarni, N. K.; Krishnan, K.; Achary, S. N.; Tyagi, A. K.

    2008-08-01

    In this communication, we report the oxidation and reduction behavior of fluorite type solid solutions in U-Zr-O. The maximum solubility of ZrO 2 in UO 2 lattice could be achieved with a mild oxidizing followed by reducing conditions. The role of valency state of U is more dominating in controlling the unit cell parameters than the incorporated interstitial oxygen in the fluorite lattice. The controlled oxidation studies on U-Zr-O solid solutions led to the delineation of a new distorted fluorite lattice at the U:Zr=2:1 composition. The detailed crystal structure analysis of this ordered composition Zr 0.33U 0.67O 2.33 (ZrU 2O 7) has been carried from the powder XRD data. This phase crystallizes in an orthorhombically distorted fluorite type lattice with unit cell parameters: a=5.1678(2), b=5.4848(2), c=5.5557(2) Å and V=157.47(1) Å 3 (Space group: Cmcm, No. 63). The metal ions have distorted cubical polyhedra with anion similar to the fluorite structure. The excess anions are occupied in the interstitial (empty cubes) of the fluorite unit cell. The crystal structure and chemical analyses suggest approximately equal fractions of U 4+ and U 6+ in this compound. The details of the thermal stability as well as kinetics of formation and oxidation of ZrU 2O 7 are also studied using thermogravimetry.

  14. Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival

    PubMed Central

    Fei, Dennis Liang; Motowski, Hayley; Chatrikhi, Rakesh; Gao, Shaojian; Kielkopf, Clara L.; Varmus, Harold

    2016-01-01

    We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation. A human lung epithelial cell line was genetically modified so that U2AF1S34F is expressed from one of the two endogenous U2AF1 loci. By altering levels of mutant or wild-type U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F-associated changes in alternative splicing are proportional to the ratio of S34F:wild-type gene products and not to absolute levels of either the mutant or wild-type factor. Preferential recognition of specific 3′ splice sites in S34F-expressing cells is largely explained by differential in vitro RNA-binding affinities of mutant versus wild-type U2AF1 for those same 3′ splice sites. Finally, we show that lung adenocarcinoma cell lines bearing U2AF1 mutations do not require the mutant protein for growth in vitro or in vivo. In contrast, wild-type U2AF1 is required for survival, regardless of whether cells carry the U2AF1S34F allele. Our results provide mechanistic explanations of the magnitude of splicing changes observed in U2AF1-mutant cells and why tumors harboring U2AF1 mutations always retain an expressed copy of the wild-type allele. PMID:27776121

  15. Non-Covalent Photo-Patterning of Gelatin Matrices Using Caged Collagen Mimetic Peptides

    PubMed Central

    Li, Yang; Hoa San, Boi; L. Kessler, Julian; Hwan Kim, Jin; Xu, Qingguo; Hanes, Justin; Yu, Seungju Michael

    2015-01-01

    Advancements in photolithography have enabled us to spatially encode biochemical cues in biocompatible platforms such as synthetic hydrogels. Conventional patterning works through photo-activated chemical reactions on inert polymer networks. However, these techniques cannot be directly applied to protein hydrogels without chemically altering the protein scaffolds. To this end, we developed a non-covalent photo-patterning strategy for gelatin (denatured collagen) hydrogels utilizing a caged collagen mimetic peptide (caged CMP) which binds to gelatin strands through UV activated, triple helix hybridization. Here we present 2D and 3D photo-patterning of gelatin hydrogels enabled by the caged CMPs as well as creation of concentration gradients of CMPs. We show that photo-patterning of PEG-conjugated caged CMPs can be used to spatially control cell adhesion on gelatin films. CMP’s specificity for binding to gelatin allows patterning of almost any synthetic or natural gelatin-containing matrix, such as zymograms, gelatin-methacrylate hydrogels, and even a corneal tissue. Since the CMP is a chemically and biologically inert peptide which is proven to be an ideal carrier for bioactive molecules, our patterning method provides a radically new tool for immobilizing drugs to natural tissues and for functionalizing scaffolds for complex tissue formation. PMID:25476588

  16. Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX).

    PubMed

    Keller, T C Stevenson; Butcher, Joshua T; Broseghini-Filho, Gilson Brás; Marziano, Corina; DeLalio, Leon J; Rogers, Stephen; Ning, Bo; Martin, Jennifer N; Chechova, Sylvia; Cabot, Maya; Shu, Xiahong; Best, Angela K; Good, Miranda E; Simão Padilha, Alessandra; Purdy, Michael; Yeager, Mark; Peirce, Shayn M; Hu, Song; Doctor, Allan; Barrett, Eugene; Le, Thu H; Columbus, Linda; Isakson, Brant E

    2016-12-01

    The ability of hemoglobin to scavenge the potent vasodilator nitric oxide (NO) in the blood has been well established as a mechanism of vascular tone homeostasis. In endothelial cells, the alpha chain of hemoglobin (hereafter, alpha globin) and endothelial NO synthase form a macromolecular complex, providing a sink for NO directly adjacent to the production source. We have developed an alpha globin mimetic peptide (named HbαX) that displaces endogenous alpha globin and increases bioavailable NO for vasodilation. Here we show that, in vivo, HbαX administration increases capillary oxygenation and blood flow in arterioles acutely and produces a sustained decrease in systolic blood pressure in normal and angiotensin II-induced hypertensive states. HbαX acts with high specificity and affinity to endothelial NO synthase, without toxicity to liver and kidney and no effect on p50 of O 2 binding in red blood cells. In human vasculature, HbαX blunts vasoconstrictive response to cumulative doses of phenylephrine, a potent constricting agent. By binding to endothelial NO synthase and displacing endogenous alpha globin, HbαX modulates important metrics of vascular function, increasing vasodilation and flow in the resistance vasculature. © 2016 American Heart Association, Inc.

  17. Free fatty acid effects on myokine production in combination with exercise mimetics.

    PubMed

    Sánchez, Juana; Nozhenko, Yuriy; Palou, Andreu; Rodríguez, Ana M

    2013-08-01

    We aimed to study the effects of free fatty acids (FFAs) alone and combined with the exercise mimetics adrenaline and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) in the production of IL6, IL15 and Irisin in muscle cells, using a time-sequential model. Differentiated C2C12 myotubes were treated with FFA, adrenaline or AICAR alone for 0, 1, 3, 8, 12 and 24 h and with double or triple combinations for 0, 3 and 24 h. Levels of mRNA in cells and protein in the medium were measured. Adrenaline, AICAR and FFA showed no significant effects on Irisin expression, while the presence in the culture of adrenaline and/or AICAR decreased IL15 mRNA expression. On contrary, the three signals showed a deep, rapid impact on the IL6 induction, especially when both AICAR and FFA were present. The different response in IL6 versus IL15 regulation may be explained by their different energy-activating versus muscle-cell-hypertrophy suggested roles, considering that adrenaline and AMPK are involved in the activation of energy-generating pathways. Moreover, the results suggest FFAs are components that may regulate IL6 production and may have a role in muscle-adipose tissue crosstalk. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Hydrogen absorption-desorption properties of U 2Ti

    NASA Astrophysics Data System (ADS)

    Takuya, Yamamoto; Satoru, Tanaka; Michio, Yamawaki

    1990-02-01

    Hydrogen absorption-desorption properties of U 2Ti intermetallic compound was examined over the temperature range of 298 to 973 K and at hydrogen pressures below 10 5 Pa. It absorbs hydrogen up to 7.6 atoms per F.U. (formula unit) by two step reactions and hence each desorption isotherm is separated into two plateau regions. In the first plateau, a newly-found ternary hydride is formed, where the hydrogen concentration, cH, reaches 2.4 H atoms/F.U. In the second plateau, UH 3 is formed and cH reaches 7.6 H atoms/F.U. The specimen is disintegrated into fine powder in the second plateau, while in the first plateau the ternary hydride which was identified to be UTi 2H x, ( x = 4.8 to 6.2) showed high durability against powdering. It is predicted that UTi 2 can be suitable material for tritium storage.

  19. Complexes of Neutralizing and Non-Neutralizing Affinity Matured Fabs with a Mimetic of the Internal Trimeric Coiled-Coil of HIV-1 gp41

    PubMed Central

    Gustchina, Elena; Li, Mi; Ghirlando, Rodolfo; Schuck, Peter; Louis, John M.; Pierson, Jason; Rao, Prashant; Subramaniam, Sriram; Gustchina, Alla; Clore, G. Marius; Wlodawer, Alexander

    2013-01-01

    A series of mini-antibodies (monovalent and bivalent Fabs) targeting the conserved internal trimeric coiled-coil of the N-heptad repeat (N-HR) of HIV-1 gp41 has been previously constructed and reported. Crystal structures of two closely related monovalent Fabs, one (Fab 8066) broadly neutralizing across a wide panel of HIV-1 subtype B and C viruses, and the other (Fab 8062) non-neutralizing, representing the extremes of this series, were previously solved as complexes with 5-Helix, a gp41 pre-hairpin intermediate mimetic. Binding of these Fabs to covalently stabilized chimeric trimers of N-peptides of HIV-1 gp41 (named (CCIZN36)3 or 3-H) has now been investigated using X-ray crystallography, cryo-electron microscopy, and a variety of biophysical methods. Crystal structures of the complexes between 3-H and Fab 8066 and Fab 8062 were determined at 2.8 and 3.0 Å resolution, respectively. Although the structures of the complexes with the neutralizing Fab 8066 and its non-neutralizing counterpart Fab 8062 were generally similar, small differences between them could be correlated with the biological properties of these antibodies. The conformations of the corresponding CDRs of each antibody in the complexes with 3-H and 5-Helix are very similar. The adaptation to a different target upon complex formation is predominantly achieved by changes in the structure of the trimer of N-HR helices, as well as by adjustment of the orientation of the Fab molecule relative to the N-HR in the complex, via rigid-body movement. The structural data presented here indicate that binding of three Fabs 8062 with high affinity requires more significant changes in the structure of the N-HR trimer compared to binding of Fab 8066. A comparative analysis of the structures of Fabs complexed to different gp41 intermediate mimetics allows further evaluation of biological relevance for generation of neutralizing antibodies, as well as provides novel structural insights into immunogen design. PMID

  20. Superoxide differentially controls pulmonary and systemic vascular tone through multiple signalling pathways

    PubMed Central

    Snetkov, Vladimir A.; Smirnov, Sergey V.; Kua, Justin; Aaronson, Philip I.; Ward, Jeremy P.T.; Knock, Greg A.

    2011-01-01

    Aims The aim of this study was to determine the relative importance of Ca2+ sensitization, ion channels, and intracellular Ca2+ ([Ca2+]i) in the mixed constrictor/relaxation actions of superoxide anion on systemic and pulmonary arteries. Methods and results Pulmonary and mesenteric arteries were obtained from rat. Superoxide was generated in arteries and cells with 6-anilino-5,8-quinolinequinone (LY83583). Following pre-constriction with U46619, 10 μmol/L LY83583 caused constriction in pulmonary and relaxation in mesenteric arteries. Both constrictor and relaxant actions of LY83583 were inhibited by superoxide dismutase and catalase. LY83583 caused Rho-kinase-dependent constriction in α-toxin-permeabilized pulmonary but not mesenteric arteries. Phosphorylation of myosin phosphatase-targeting subunit-1 (MYPT-1; as determined by western blot), was enhanced by LY83583 in pulmonary artery only. However, in both artery types, changes in tension were closely correlated with changes in phosphorylation of the 20 kDa myosin light chain as well as changes in [Ca2+]i (as measured with Fura PE-3), with LY83583 causing increases in pulmonary and decreases in mesenteric arteries. When U46619 was replaced by 30 mmol/L K+, all changes in [Ca2+]i were abolished and LY83583 constricted both artery types. The KV channel inhibitor 4-aminopyridine abolished the LY83583-induced relaxation in mesenteric artery without affecting constriction in pulmonary artery. However, LY83583 caused a similar hyperpolarizing shift in the steady-state activation of KV current in isolated smooth muscle cells of both artery types. Conclusions Superoxide only causes Rho-kinase-dependent Ca2+ sensitization in pulmonary artery, resulting in constriction, and whilst it opens KV channels in both artery types, this only results in relaxation in mesenteric. PMID:20805095

  1. R2U2: Monitoring and Diagnosis of Security Threats for Unmanned Aerial Systems

    NASA Technical Reports Server (NTRS)

    Schumann, Johann; Moosbruger, Patrick; Rozier, Kristin Y.

    2015-01-01

    We present R2U2, a novel framework for runtime monitoring of security properties and diagnosing of security threats on-board Unmanned Aerial Systems (UAS). R2U2, implemented in FPGA hardware, is a real-time, REALIZABLE, RESPONSIVE, UNOBTRUSIVE Unit for security threat detection. R2U2 is designed to continuously monitor inputs from the GPS and the ground control station, sensor readings, actuator outputs, and flight software status. By simultaneously monitoring and performing statistical reasoning, attack patterns and post-attack discrepancies in the UAS behavior can be detected. R2U2 uses runtime observer pairs for linear and metric temporal logics for property monitoring and Bayesian networks for diagnosis of security threats. We discuss the design and implementation that now enables R2U2 to handle security threats and present simulation results of several attack scenarios on the NASA DragonEye UAS.

  2. Incorporating beta-turns and a turn mimetic out of context in loop 1 of the WW domain affords cooperatively folded beta-sheets.

    PubMed

    Kaul, R; Angeles, A R; Jäger, M; Powers, E T; Kelly, J W

    2001-06-06

    To probe the conformational requirements of loop 1 in the Pin1 WW domain, the residues at the i + 2 and i + 3 positions of a beta-turn within this loop were replaced by dPro-Gly and Asn-Gly, which are known to prefer the conformations required at the i + 1 and i + 2 positions of type II' and type I' beta-turns. Conformational specificity or lack thereof was further examined by incorporating into the i + 2 and i + 3 positions a non-alpha-amino acid-based beta-turn mimetic (4-(2'-aminoethyl)-6-dibenzofuran propionic acid residue, 1), which was designed to replace the i + 1 and i + 2 positions of beta-turns. All these Pin WW variants are monomeric and folded as discerned by analytical ultracentrifugation, NMR, and CD. They exhibit cooperative two-state transitions and display thermodynamic stability within 0.5 kcal/mol of the wild-type WW domain, demonstrating that the acquisition of native structure and stability does not require a specific sequence and, by extension, conformation within loop 1. However, it could be that these loop 1 mutations alter the kinetics of antiparallel beta-sheet folding, which will be addressed by subsequent kinetic studies.

  3. Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins.

    PubMed

    Colin, Didier J; Hain, Karolina O; Allan, Lindsey A; Clarke, Paul R

    2015-03-01

    Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-xL by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

  4. Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain-barrier and impairs iron-dependent hippocampal neuron dendrite development

    PubMed Central

    Bastian, Thomas W.; Duck, Kari A.; Michalopoulos, George C.; Chen, Michael J.; Liu, Zhi-Jian; Connor, James R.; Lanier, Lorene M.; Sola-Visner, Martha C.; Georgieff, Michael K.

    2017-01-01

    Background Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g., eltrombopag (ELT)) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling, and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective Determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7 days in vitro (DIV) through 14DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6 μM ELT increased Tfr1 and Slc11a2 (iron-responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6 μM ELT, but not 2 μM ELT, decreased BdnfVI, Camk2a, and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length was reduced in 6 μM ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions ELT treatment during development may impair neuronal structure due to neuronal ID. Pre-clinical in vivo studies are warranted to assess ELT safety during periods of rapid brain development. PMID:28005311

  5. The Mimetic Finite Element Method and the Virtual Element Method for elliptic problems with arbitrary regularity.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Manzini, Gianmarco

    2012-07-13

    We develop and analyze a new family of virtual element methods on unstructured polygonal meshes for the diffusion problem in primal form, that use arbitrarily regular discrete spaces V{sub h} {contained_in} C{sup {alpha}} {element_of} N. The degrees of freedom are (a) solution and derivative values of various degree at suitable nodes and (b) solution moments inside polygons. The convergence of the method is proven theoretically and an optimal error estimate is derived. The connection with the Mimetic Finite Difference method is also discussed. Numerical experiments confirm the convergence rate that is expected from the theory.

  6. Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex.

    PubMed

    Roll, Patrice; Vernes, Sonja C; Bruneau, Nadine; Cillario, Jennifer; Ponsole-Lenfant, Magali; Massacrier, Annick; Rudolf, Gabrielle; Khalife, Manal; Hirsch, Edouard; Fisher, Simon E; Szepetowski, Pierre

    2010-12-15

    It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.

  7. Microfluidic strategies for understanding the mechanics of cells and cell-mimetic systems

    PubMed Central

    Dahl, Joanna B.; Lin, Jung-Ming G.; Muller, Susan J.; Kumar, Sanjay

    2016-01-01

    Microfluidic systems are attracting increasing interest for the high-throughput measurement of cellular biophysical properties and for the creation of engineered cellular microenvironments. Here we review recent applications of microfluidic technologies to the mechanics of living cells and synthetic cell-mimetic systems. We begin by discussing the use of microfluidic devices to dissect the mechanics of cellular mimics such as capsules and vesicles. We then explore applications to circulating cells, including erythrocytes and other normal blood cells, and rare populations with potential disease diagnostic value, such as circulating tumor cells. We conclude by discussing how microfluidic devices have been used to investigate the mechanics, chemotaxis, and invasive migration of adherent cells. In these ways, microfluidic technologies represent an increasingly important toolbox for investigating cellular mechanics and motility at high throughput and in a format that lends itself to clinical translation. PMID:26134738

  8. 7 CFR 51.1147 - U.S. No. 2 Bright.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...) Internal quality: Lots meeting the internal requirements for “U.S. Grade AA Juice (Double A)” or “U.S... 7 Agriculture 2 2010-01-01 2010-01-01 false U.S. No. 2 Bright. 51.1147 Section 51.1147 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing...

  9. Promotion of hair growth by newly synthesized ceramide mimetic compound.

    PubMed

    Park, Bu-Mahn; Bak, Soon-Sun; Shin, Kyung-Oh; Kim, Minhee; Kim, Daehwan; Jung, Sang-Hun; Jeong, Sekyoo; Sung, Young Kwan; Kim, Hyun Jung

    2017-09-09

    Based on the crucial roles of ceramides in skin barrier function, use of ceramides or their structural mimetic compounds, pseudoceramides, as cosmetic ingredients are getting more popular. While currently used pseudoceramides are intended to substitute the structural roles of ceramides in stratum corneum, development of bioactive pseudoceramides has been repeatedly reported. In this study, based on the potential involvement of sphingolipids in hair cycle regulation, we investigated the effects of newly synthesized pseudoceramide, bis-oleamido isopropyl alcohol (BOI), on hair growth using cultured human hair follicles and animal models. BOI treatment promoted hair growth in cultured human hair follicles ex vivo and induced earlier conversion of telogen into anagen. Although we did not find a significant enhancement of growth factor expression and follicular cell proliferation, BOI treatment resulted in an increased sphinganine and sphingosine contents as well as increased ceramides contents in cultured dermal papilla (DP) cells. Taken together, our data strongly suggest that biologically active pseudoceramide promotes hair growth by stimulating do novo synthesis of sphingolipids in DP cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Performance of U3Si2 Fuel in a Reactivity Insertion Accident

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cheng, Lap Y.; Cuadra, Arantxa; Todosow, Michael

    In this study we examined the performance of the U3Si2 fuel cladded with Zircaloy (Zr) in a reactivity insertion accident (RIA) in a PWR core. The power excursion as a result of a $1 reactivity insertion was calculated by a TRACE PWR plant model using point-kinetics, for alternative cores with UO2 and U3Si2 fuel assemblies. The point-kinetics parameters (feedback coefficients, prompt-neutron lifetime and group constants for six delayed-neutron groups) were obtained from beginning-of-cycle equilibrium full core calculations with PARCS. In the PARCS core calculations, the few-group parameters were developed utilizing the TRITON/NEWT tools in the SCALE package. In order tomore » assess the fuel response in finer detail (e.g. the maximum fuel temperature) the power shape and thermal boundary conditions from the TRACE/PARCS calculations were used to drive a BISON model of a fuel pin with U3Si2 and UO2 respectively. For a $1 reactivity transient both TRACE and BISON predicted a higher maximum fuel temperature for the UO2 fuel than the U3Si2 fuel. Furthermore, BISON is noted to calculate a narrower gap and a higher gap heat transfer coefficient than TRACE. This resulted in BISON predicting consistently lower fuel temperatures than TRACE. This study also provides a systematic comparison between TRACE and BISON using consistent transient boundary conditions. The TRACE analysis of the RIA only reflects the core-wide response in power. A refinement to the analysis would be to predict the local peaking in a three-dimensional core as a result of control rod ejection.« less

  11. Single crystal structures and theoretical calculations of uranium endohedral metallofullerenes (U@C2n , 2n = 74, 82) show cage isomer dependent oxidation states for U.

    PubMed

    Cai, Wenting; Morales-Martínez, Roser; Zhang, Xingxing; Najera, Daniel; Romero, Elkin L; Metta-Magaña, Alejandro; Rodríguez-Fortea, Antonio; Fortier, Skye; Chen, Ning; Poblet, Josep M; Echegoyen, Luis

    2017-08-01

    Charge transfer is a general phenomenon observed for all endohedral mono-metallofullerenes. Since the detection of the first endohedral metallofullerene (EMF), La@C 82 , in 1991, it has always been observed that the oxidation state of a given encapsulated metal is always the same, regardless of the cage size. No crystallographic data exist for any early actinide endohedrals and little is known about the oxidation states for the few compounds that have been reported. Here we report the X-ray structures of three uranium metallofullerenes, U@ D 3h -C 74 , U@ C 2 (5)-C 82 and U@ C 2v (9)-C 82 , and provide theoretical evidence for cage isomer dependent charge transfer states for U. Results from DFT calculations show that U@ D 3h -C 74 and U@ C 2 (5)-C 82 have tetravalent electronic configurations corresponding to U 4+ @ D 3h -C 74 4- and U 4+ @ C 2 (5)-C 82 4- . Surprisingly, the isomeric U@ C 2v (9)-C 82 has a trivalent electronic configuration corresponding to U 3+ @ C 2v (9)-C 82 3- . These are the first X-ray crystallographic structures of uranium EMFs and this is first observation of metal oxidation state dependence on carbon cage isomerism for mono-EMFs.

  12. 7 CFR 51.2078 - U.S. No. 2 Mixed.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 2 2012-01-01 2012-01-01 false U.S. No. 2 Mixed. 51.2078 Section 51.2078 Agriculture... Standards for Grades of Almonds in the Shell Grades § 51.2078 U.S. No. 2 Mixed. “U.S. No. 2 Mixed” consists... varieties of sweet almonds are mixed. Application of Tolerances ...

  13. 7 CFR 51.2078 - U.S. No. 2 Mixed.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 2 2014-01-01 2014-01-01 false U.S. No. 2 Mixed. 51.2078 Section 51.2078 Agriculture.... No. 2 Mixed. “U.S. No. 2 Mixed” consists of almonds in the shell which meet the requirements of U.S. No. 2 grade, except that two or more varieties of sweet almonds are mixed. Application of Tolerances ...

  14. 7 CFR 51.2078 - U.S. No. 2 Mixed.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 2 2013-01-01 2013-01-01 false U.S. No. 2 Mixed. 51.2078 Section 51.2078 Agriculture.... No. 2 Mixed. “U.S. No. 2 Mixed” consists of almonds in the shell which meet the requirements of U.S. No. 2 grade, except that two or more varieties of sweet almonds are mixed. Application of Tolerances ...

  15. Conformation-Based Design and Synthesis of Apratoxin A Mimetics Modified at the α,β-Unsaturated Thiazoline Moiety.

    PubMed

    Onda, Yuichi; Masuda, Yuichi; Yoshida, Masahito; Doi, Takayuki

    2017-08-10

    We have demonstrated design, synthesis, and biological evaluation of apratoxin A mimetics. In the first generation, the moCys moiety was replaced with seven simple amino acids as their 3D structures can be similar to that of apratoxin A. Apratoxins M1-M7 were synthesized using solid-phase peptide synthesis and solution-phase macrolactamization. Apratoxin M7, which contains a piperidinecarboxylic acid moiety, exhibited potent cytotoxicity against HCT-116 cells. In the second generation, substitution of each amino acid residue in the tripeptide Tyr(Me)-MeAla-MeIle moiety in apratoxin M7 led to the development of the highly potent apratoxin M16 possessing biphenylalanine (Bph) instead of Tyr(Me), which exhibited an IC 50 value of 1.1 nM against HCT-116 cells. Moreover, compared to apratoxin A, apratoxin M16 exhibited a similarly high level of growth inhibitory activity against various cancer cell lines. The results indicate that apratoxin M16 could be a potential candidate as an anticancer agent.

  16. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L).

    PubMed

    Maiuri, Maria Chiara; Criollo, Alfredo; Tasdemir, Ezgi; Vicencio, José Miguel; Tajeddine, Nicolas; Hickman, John A; Geneste, Olivier; Kroemer, Guido

    2007-01-01

    Beclin 1 has recently been identified as novel BH3-only protein, meaning that it carries one Bcl-2-homology-3 (BH3) domain. As other BH3-only proteins, Beclin 1 interacts with anti-apoptotic multidomain proteins of the Bcl-2 family (in particular Bcl-2 and its homologue Bcl-X(L)) by virtue of its BH3 domain, an amphipathic alpha-helix that binds to the hydrophobic cleft of Bcl-2/Bcl-X(L). The BH3 domains of other BH3-only proteins such as Bad, as well as BH3-mimetic compounds such as ABT737, competitively disrupt the inhibitory interaction between Beclin 1 and Bcl-2/Bcl-X(L). This causes autophagy of mitochondria (mitophagy) but not of the endoplasmic reticulum (reticulophagy). Only ER-targeted (not mitochondrion-targeted) Bcl-2/Bcl-X(L) can inhibit autophagy induced by Beclin 1, and only Beclin 1-Bcl-2/Bcl-X(L) complexes present in the ER (but not those present on heavy membrane fractions enriched in mitochondria) are disrupted by ABT737. These findings suggest that the Beclin 1-Bcl-2/Bcl-X(L) complexes that normally inhibit autophagy are specifically located in the ER and point to an organelle-specific regulation of autophagy. Furthermore, these data suggest a spatial organization of autophagy and apoptosis control in which BH3-only proteins exert two independent functions. On the one hand, they can induce apoptosis, by (directly or indirectly) activating the mitochondrion-permeabilizing function of pro-apoptotic multidomain proteins from the Bcl-2 family. On the other hand, they can activate autophagy by liberating Beclin 1 from its inhibition by Bcl-2/Bcl-X(L) at the level of the endoplasmic reticulum.

  17. 7 CFR 51.2732 - U.S. No. 2 Spanish.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false U.S. No. 2 Spanish. 51.2732 Section 51.2732... STANDARDS) United States Standards for Grades of Shelled Spanish Type Peanuts Grades § 51.2732 U.S. No. 2 Spanish. “U.S. No. 2 Spanish” consists of shelled Spanish type peanut kernels which may be split or broken...

  18. VizieR Online Data Catalog: H2, D2, and HD c3Πu;

    NASA Astrophysics Data System (ADS)

    Liu, X.; Shemansky, D. E.; Yoshii, J.; Liu, M. J.; Johnson, P. V.; Malone, C. P.; Khakoo, M. A.

    2017-11-01

    The c3{Pi}u state of the hydrogen molecule has the triplet-state excitation cross-section, and plays an important role in the heating of the upper thermospheres of outer planets by electron excitation. Precise energies of the H2, D2, and HD c3{Pi}u-(v,N) levels are calculated from highly accurate ab initio potential energy curves that include relativistic, radiative, and empirical non-adiabatic corrections. The emission yields are determined from predissociation rates and refined radiative transition probabilities. The excitation function and excitation cross-section of the c3{Pi}u state are extracted from previous theoretical calculations and experimental measurements. The emission cross-section is determined from the calculated emission yield and the extracted excitation cross-section. The kinetic energy (Ek) distributions of H atoms produced via the predissociation of the c3{Pi}u state, the c3{Pi}u--b3{Sigma}u+ dissociative emission by the magnetic dipole and electric quadrupole, and the c3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ cascade dissociative emission by the electric dipole are obtained. The predissociation of the c3{Pi}u+ and c3{Pi}u- states both produce H(1s) atoms with an average Ek of ~4.1eV/atom, while the c3{Pi}u--b3{Sigma}u+ dissociative emissions by the magnetic dipole and electric quadrupole give an average Ek of ~1.0 and ~0.8eV/atom, respectively. The c3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ cascade and dissociative emission gives an average Ek of ~1.3 eV/atom. On average, each H2 excited to the c3{Pi}u state in an H2-dominated atmosphere deposits ~7.1eV into the atmosphere while each H2 directly excited to the a3{Sigma}g+ and d3{Pi}u states contribute ~2.3 and ~3.3eV, respectively, to the atmosphere. The spectral distribution of the calculated continuum emission arising from the X1{Sigma}g+-c3{Pi}u excitation is significantly different from that of direct a3{Sigma}g+ or d3{Pi}u excitations. (5 data files).

  19. 7 CFR 51.341 - U.S. No. 2.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., CERTIFICATION, AND STANDARDS) United States Standards for Grades of Apples for Processing Grades § 51.341 U.S. No. 2. “U.S. No. 2” consists of apples of one variety, unless designated as mixed varieties, which... preparation for use will cause a loss of more than 12 percent, by weight, of the apple. ...

  20. 7 CFR 51.341 - U.S. No. 2.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., CERTIFICATION, AND STANDARDS) United States Standards for Grades of Apples for Processing Grades § 51.341 U.S. No. 2. “U.S. No. 2” consists of apples of one variety, unless designated as mixed varieties, which... preparation for use will cause a loss of more than 12 percent, by weight, of the apple. ...

  1. Physiological adaptations following Roux-en-Y gastric bypass and the identification of targets for bariatric mimetic pharmacotherapy.

    PubMed

    Docherty, Neil G; Le Roux, Carel W

    2015-12-01

    The present opinion article provides an overview of the key improvements in metabolic and cardiovascular health following Roux-en-Y Gastric Bypass (RYGB). Some clinically important long-term complications of RYGB are also briefly described to contextualise the potential value of finding selective non-surgical means of replicating only the beneficial aspects of RYGB. Three biological responses linked to changes in gastrointestinal tract structure and function post-RYGB, that are implicated in the clinical efficacy of RYGB and that have actual or potential applications as non-surgical mimetic based approaches are addressed. These are (1) exaggerated post-prandial gut hormone responses; (2) local increases in undiluted bile in the gut lumen and augmented circulating bile acid and FGF19 concentrations and (3) compositional changes in the gut microbiota. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. GROMOS polarizable charge-on-spring models for liquid urea: COS/U and COS/U2

    NASA Astrophysics Data System (ADS)

    Lin, Zhixiong; Bachmann, Stephan J.; van Gunsteren, Wilfred F.

    2015-03-01

    Two one-site polarizable urea models, COS/U and COS/U2, based on the charge-on-spring model are proposed. The models are parametrized against thermodynamic properties of urea-water mixtures in combination with the polarizable COS/G2 and COS/D2 models for liquid water, respectively, and have the same functional form of the inter-atomic interaction function and are based on the same parameter calibration procedure and type of experimental data as used to develop the GROMOS biomolecular force field. Thermodynamic, dielectric, and dynamic properties of urea-water mixtures simulated using the polarizable models are closer to experimental data than using the non-polarizable models. The COS/U and COS/U2 models may be used in biomolecular simulations of protein denaturation.

  3. Useful to Usable (U2U): Transforming climate information into usable tools to support Midwestern agricultural production

    NASA Astrophysics Data System (ADS)

    Prokopy, L. S.; Widhalm, M.

    2014-12-01

    There is a close connection between weather and climate patterns and successful agricultural production. Therefore, incorporating climate information into farm management is likely to reduce the risk of economic losses and increase profitability. While weather and climate information is becoming ever more abundant and accessible, the use of such information in the agricultural community remains limited. Useful to Usable (U2U): Transforming Climate Variability and Change Information for Cereal Crop Producers is a USDA-NIFA funded research and extension project focused on improving the use of climate information for agricultural production in the Midwestern United States by developing user-driven decision tools and training resources. The U2U team is a diverse and uniquely qualified group of climatologists, crop modelers, agronomists, and social scientists from 9 Midwestern universities and two NOAA Regional Climate Centers. Together, we strive to help producers make better long-term plans on what, when and where to plant and also how to manage crops for maximum yields and minimum environmental damage. To ensure relevance and usability of U2U products, our social science team is using a number of techniques including surveys and focus groups to integrate stakeholder interests, needs, and concerns into all aspects of U2U research. It is through this coupling of physical and social science disciplines that we strive to transform existing climate information into actionable knowledge.

  4. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats

    PubMed Central

    Hoelmkjaer, Kirsten M.; Wewer Albrechtsen, Nicolai J.; Holst, Jens J.; Cronin, Anna M.; Nielsen, Dorte H.; Mandrup-Poulsen, Thomas; Bjornvad, Charlotte R.

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats. PMID:27136422

  5. 7 CFR 51.341 - U.S. No. 2.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... FRESH FRUITS, VEGETABLES AND OTHER PRODUCTS 1,2 (INSPECTION, CERTIFICATION, AND STANDARDS) United States Standards for Grades of Apples for Processing Grades § 51.341 U.S. No. 2. “U.S. No. 2” consists of apples of... 12 percent, by weight, of the apple. ...

  6. Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier: Role of the VEGF/uPAR Pathway

    PubMed Central

    El-Remessy, Azza B.; Franklin, Telina; Ghaley, Nagla; Yang, Jinling; Brands, Michael W.; Caldwell, Ruth B.; Behzadian, Mohamed Ali

    2013-01-01

    Diabetes-induced breakdown of the blood-retinal barrier (BRB) has been linked to hyperglycemia-induced expression of vascular endothelial growth factor (VEGF) and is likely mediated by an increase in oxidative stress. We have shown that VEGF increases permeability of retinal endothelial cells (REC) by inducing expression of urokinase plasminogen activator receptor (uPAR). The purpose of this study was to define the role of superoxide anion in VEGF/uPAR expression and BRB breakdown in diabetes. Studies were performed in streptozotocin diabetic rats and mice and high glucose (HG) treated REC. The superoxide dismutase (SOD) mimetic tempol blocked diabetes-induced permeability and uPAR expression in rats and the cell permeable SOD inhibited HG-induced expression of uPAR and VEGF in REC. Inhibiting VEGFR blocked HG-induced expression of VEGF and uPAR and GSK-3β phosphorylation in REC. HG caused β-catenin translocation from the plasma membrane into the cytosol and nucleus. Treatment with HG-conditioned media increased REC paracellular permeability that was blocked by anti-uPA or anti-uPAR antibodies. Moreover, deletion of uPAR blocked diabetes-induced BRB breakdown and activation of MMP-9 in mice. Together, these data indicate that diabetes-induced oxidative stress triggers BRB breakdown by a mechanism involving uPAR expression through VEGF-induced activation of the GSK3β/β-catenin signaling pathway. PMID:23951261

  7. An overview on antidiabetic medicinal plants having insulin mimetic property

    PubMed Central

    Patel, DK; Prasad, SK; Kumar, R; Hemalatha, S

    2012-01-01

    Diabetes mellitus is one of the common metabolic disorders acquiring around 2.8% of the world's population and is anticipated to cross 5.4% by the year 2025. Since long back herbal medicines have been the highly esteemed source of medicine therefore, they have become a growing part of modern, high-tech medicine. In view of the above aspects the present review provides profiles of plants (65 species) with hypoglycaemic properties, available through literature source from various database with proper categorization according to the parts used, mode of reduction in blood glucose (insulinomimetic or insulin secretagogues activity) and active phytoconstituents having insulin mimetics activity. From the review it was suggested that, plant showing hypoglycemic potential mainly belongs to the family Leguminoseae, Lamiaceae, Liliaceae, Cucurbitaceae, Asteraceae, Moraceae, Rosaceae and Araliaceae. The most active plants are Allium sativum, Gymnema sylvestre, Citrullus colocynthis, Trigonella foenum greacum, Momordica charantia and Ficus bengalensis. The review describes some new bioactive drugs and isolated compounds from plants such as roseoside, epigallocatechin gallate, beta-pyrazol-1-ylalanine, cinchonain Ib, leucocyandin 3-O-beta-d-galactosyl cellobioside, leucopelargonidin-3- O-alpha-L rhamnoside, glycyrrhetinic acid, dehydrotrametenolic acid, strictinin, isostrictinin, pedunculagin, epicatechin and christinin-A showing significant insulinomimetic and antidiabetic activity with more efficacy than conventional hypoglycaemic agents. Thus, from the review majorly, the antidiabetic activity of medicinal plants is attributed to the presence of polyphenols, flavonoids, terpenoids, coumarins and other constituents which show reduction in blood glucose levels. The review also discusses the management aspect of diabetes mellitus using these plants and their active principles. PMID:23569923

  8. 7 CFR 51.2077 - U.S. No. 2.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Standards for Grades of Almonds in the Shell Grades § 51.2077 U.S. No. 2. “U.S. No. 2” consists of almonds... 20 percent shall be allowed for almonds with shells damaged by discoloration. ...

  9. Age-related decline of the cytochrome c oxidase subunit expression in the auditory cortex of the mimetic aging rat model associated with the common deletion.

    PubMed

    Zhong, Yi; Hu, Yujuan; Peng, Wei; Sun, Yu; Yang, Yang; Zhao, Xueyan; Huang, Xiang; Zhang, Honglian; Kong, Weijia

    2012-12-01

    The age-related deterioration in the central auditory system is well known to impair the abilities of sound localization and speech perception. However, the mechanisms involved in the age-related central auditory deficiency remain unclear. Previous studies have demonstrated that mitochondrial DNA (mtDNA) deletions accumulated with age in the auditory system. Also, a cytochrome c oxidase (CcO) deficiency has been proposed to be a causal factor in the age-related decline in mitochondrial respiratory activity. This study was designed to explore the changes of CcO activity and to investigate the possible relationship between the mtDNA common deletion (CD) and CcO activity as well as the mRNA expression of CcO subunits in the auditory cortex of D-galactose (D-gal)-induced mimetic aging rats at different ages. Moreover, we explored whether peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) were involved in the changes of nuclear- and mitochondrial-encoded CcO subunits in the auditory cortex during aging. Our data demonstrated that d-gal-induced mimetic aging rats exhibited an accelerated accumulation of the CD and a gradual decline in the CcO activity in the auditory cortex during the aging process. The reduction in the CcO activity was correlated with the level of CD load in the auditory cortex. The mRNA expression of CcO subunit III was reduced significantly with age in the d-gal-induced mimetic aging rats. In contrast, the decline in the mRNA expression of subunits I and IV was relatively minor. Additionally, significant increases in the mRNA and protein levels of PGC-1α, NRF-1 and TFAM were observed in the auditory cortex of D-gal-induced mimetic aging rats with aging. These findings suggested that the accelerated accumulation of the CD in the auditory cortex may induce a substantial decline in CcO subunit III and lead to a significant decline in the Cc

  10. Morphometric comparisons of plant-mimetic juvenile fish associated with plant debris observed in the coastal subtropical waters around Kuchierabu-jima Island, southern Japan

    PubMed Central

    2016-01-01

    The general morphological shape of plant-resembling fish and plant parts were compared using a geometric morphometrics approach. Three plant-mimetic fish species, Lobotes surinamensis (Lobotidae), Platax orbicularis (Ephippidae) and Canthidermis maculata (Balistidae), were compared during their early developmental stages with accompanying plant debris (i.e., leaves of several taxa) in the coastal subtropical waters around Kuchierabu-jima Island, closely facing the Kuroshio Current. The degree of similarity shared between the plant parts and co-occurring fish species was quantified, however fish remained morphologically distinct from their plant models. Such similarities were corroborated by analysis of covariance and linear discriminant analysis, in which relative body areas of fish were strongly related to plant models. Our results strengthen the paradigm that morphological clues can lead to ecological evidence to allow predictions of behavioural and habitat choice by mimetic fish, according to the degree of similarity shared with their respective models. The resemblance to plant parts detected in the three fish species may provide fitness advantages via convergent evolutionary effects. PMID:27547571

  11. Mussel-mimetic, bioadhesive polymers from plant-derived materials.

    PubMed

    Hiraishi, Noriko; Kaneko, Daisaku; Taira, Shu; Wang, Siqian; Otsuki, Masayuki; Tagami, Junji

    2015-02-01

    Mussel-mimetic, bioadhesive polymers are synthesized from plant-derived sources. The strong adhesive action is caused by interactions between the catechol groups at the end of the polymer terminal chains and the substrate surface. Here, we present a preliminary study of the adhesion properties and a discussion of the adhesion mechanism. Two bioadhesive polymers were synthesized from natural plant-derived monomers by the transesterification of: (a) caffeic acid (3,4-dihydroxycinnamic acid; DHCA) and p-coumaric acid (4-hydroxycinnamic acid; 4HCA) to produce poly(DHCA-co-4HCA); and (b) 4-dihydroxyhydrocinnamic acid (DHHCA) and 3-(3-hydroxyphenyl) propionic acid (3HPPA) to produce poly(DHHCA-co-3HPPA). Thermoplastic poly(DHCA-co-4HCA) or poly(DHHCA-co-3HPPA) was placed between glass, carbon, steel, or bovine dentin substrates, and a lap shear adhesion test was conducted to compare them using conventional cyanoacrylate glue and epoxy resin. The greatest adhesion for all tested substrates was exhibited by poly(DHHCA-co-3HPPA), followed by epoxy resin adhesive, poly(DHCA-co-4HCA), and cyanoacrylate adhesive. The adhesive strength of poly(DHHCA-co-3HPPA) was greater than 25.6 MPa for glass, 29.6 MPa for carbon, 15.7 MPa for steel, and 16.3 MPA for bovine dentin. The adhesion of poly(DHHCA-co-3HPPA) might be the strongest reported for a mussel-mimic adhesive system, and could be a feasible alternative to petroleum adhesives. © 2013 Wiley Publishing Asia Pty Ltd.

  12. GROMOS polarizable charge-on-spring models for liquid urea: COS/U and COS/U2

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lin, Zhixiong; Bachmann, Stephan J.; Gunsteren, Wilfred F. van, E-mail: wfvgn@igc.phys.chem.ethz.ch

    2015-03-07

    Two one-site polarizable urea models, COS/U and COS/U2, based on the charge-on-spring model are proposed. The models are parametrized against thermodynamic properties of urea-water mixtures in combination with the polarizable COS/G2 and COS/D2 models for liquid water, respectively, and have the same functional form of the inter-atomic interaction function and are based on the same parameter calibration procedure and type of experimental data as used to develop the GROMOS biomolecular force field. Thermodynamic, dielectric, and dynamic properties of urea-water mixtures simulated using the polarizable models are closer to experimental data than using the non-polarizable models. The COS/U and COS/U2 modelsmore » may be used in biomolecular simulations of protein denaturation.« less

  13. Distinct mechanisms of relaxation to bioactive components from chamomile species in porcine isolated blood vessels.

    PubMed

    Roberts, R E; Allen, S; Chang, A P Y; Henderson, H; Hobson, G C; Karania, B; Morgan, K N; Pek, A S Y; Raghvani, K; Shee, C Y; Shikotra, J; Street, E; Abbas, Z; Ellis, K; Heer, J K; Alexander, S P H

    2013-11-01

    German chamomile (Matricaria recutita L.), a widely-used herbal medicine, has been reported to have a wide range of biological effects, including smooth muscle relaxation. The aim of this study was to compare the effects of representative compounds from chamomile (apigenin, luteolin, (-)-α-bisabolol, farnesene, umbelliferone; 3-30 μM) on vascular tone using porcine coronary and splenic arteries mounted for isometric tension recording in isolated tissue baths and precontracted with the thromboxane-mimetic U46619. Apigenin, luteolin, and (-)-α-bisabolol produced slow, concentration-dependent relaxations in both the coronary and splenic arteries that were not blocked by inhibition of nitric oxide synthase or potassium channels. Removal of extracellular calcium inhibited the relaxations to all three compounds, and these compounds also inhibited calcium re-addition-evoked contractions, indicating that the relaxation response may be mediated through inhibition of calcium influx. Apigenin and luteolin, but not (-)-α-bisabolol, enhanced the relaxation to the nitric oxide donor sodium nitroprusside, indicating that apigenin and luteolin may act to regulate cyclic GMP levels. Umbelliferone produced a rapid, transient relaxation in the splenic artery, but not the coronary artery, that was inhibited by L-NAME and removal of the endothelium, suggesting an influence on nitric oxide production. Farnesene, at concentrations up to 30 μM, was without effect in either blood vessel. In conclusion, hydroxylated compounds (apigenin, luteolin and (-)-α-bisabolol) found in chamomile all caused a slow relaxation of isolated blood vessels through an effect on calcium influx. Umbelliferone, on the other hand, produced a rapid, transient relaxation dependent upon release of nitric oxide from the endothelium. © 2013.

  14. Canonical Bcl-2 motifs of the Na+/K+ pump revealed by the BH3 mimetic chelerythrine: early signal transducers of apoptosis?

    PubMed

    Lauf, Peter K; Heiny, Judith; Meller, Jarek; Lepera, Michael A; Koikov, Leonid; Alter, Gerald M; Brown, Thomas L; Adragna, Norma C

    2013-01-01

    Chelerythrine [CET], a protein kinase C [PKC] inhibitor, is a prop-apoptotic BH3-mimetic binding to BH1-like motifs of Bcl-2 proteins. CET action was examined on PKC phosphorylation-dependent membrane transporters (Na+/K+ pump/ATPase [NKP, NKA], Na+-K+-2Cl+ [NKCC] and K+-Cl- [KCC] cotransporters, and channel-supported K+ loss) in human lens epithelial cells [LECs]. K+ loss and K+ uptake, using Rb+ as congener, were measured by atomic absorption/emission spectrophotometry with NKP and NKCC inhibitors, and Cl- replacement by NO3ˉ to determine KCC. 3H-Ouabain binding was performed on a pig renal NKA in the presence and absence of CET. Bcl-2 protein and NKA sequences were aligned and motifs identified and mapped using PROSITE in conjunction with BLAST alignments and analysis of conservation and structural similarity based on prediction of secondary and crystal structures. CET inhibited NKP and NKCC by >90% (IC50 values ~35 and ~15 μM, respectively) without significant KCC activity change, and stimulated K+ loss by ~35% at 10-30 μM. Neither ATP levels nor phosphorylation of the NKA α1 subunit changed. 3H-ouabain was displaced from pig renal NKA only at 100 fold higher CET concentrations than the ligand. Sequence alignments of NKA with BH1- and BH3-like motifs containing pro-survival Bcl-2 and BclXl proteins showed more than one BH1-like motif within NKA for interaction with CET or with BH3 motifs. One NKA BH1-like motif (ARAAEILARDGPN) was also found in all P-type ATPases. Also, NKA possessed a second motif similar to that near the BH3 region of Bcl-2. Findings support the hypothesis that CET inhibits NKP by binding to BH1-like motifs and disrupting the α1 subunit catalytic activity through conformational changes. By interacting with Bcl-2 proteins through their complementary BH1- or BH3-like-motifs, NKP proteins may be sensors of normal and pathological cell functions, becoming important yet unrecognized signal transducers in the initial phases of apoptosis. CET

  15. In Vitro Mimetic Models for the Bone-Cartilage Interface Regeneration.

    PubMed

    Bicho, Diana; Pina, Sandra; Oliveira, J Miguel; Reis, Rui L

    2018-01-01

    In embryonic development, pure cartilage structures are in the basis of bone-cartilage interfaces. Despite this fact, the mature bone and cartilage structures can vary greatly in composition and function. Nevertheless, they collaborate in the osteochondral region to create a smooth transition zone that supports the movements and forces resulting from the daily activities. In this sense, all the hierarchical organization is involved in the maintenance and reestablishment of the equilibrium in case of damage. Therefore, this interface has attracted a great deal of interest in order to understand the mechanisms of regeneration or disease progression in osteoarthritis. With that purpose, in vitro tissue models (either static or dynamic) have been studied. Static in vitro tissue models include monocultures, co-cultures, 3D cultures, and ex vivo cultures, mostly cultivated in flat surfaces, while dynamic models involve the use of bioreactors and microfluidic systems. The latter have emerged as alternatives to study the cellular interactions in a more authentic manner over some disadvantages of the static models. The current alternatives of in vitro mimetic models for bone-cartilage interface regeneration are overviewed and discussed herein.

  16. Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

    PubMed Central

    Colin, Didier J.; Hain, Karolina O.; Allan, Lindsey A.; Clarke, Paul R.

    2015-01-01

    Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-xL by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies. PMID:25761368

  17. Microfluidic paper-based device for colorimetric determination of glucose based on a metal-organic framework acting as peroxidase mimetic.

    PubMed

    Ortiz-Gómez, Inmaculada; Salinas-Castillo, Alfonso; García, Amalia García; Álvarez-Bermejo, José Antonio; de Orbe-Payá, Ignacio; Rodríguez-Diéguez, Antonio; Capitán-Vallvey, Luis Fermín

    2017-12-13

    This work presents a microfluidic paper-based analytical device (μPAD) for glucose determination using a supported metal-organic framework (MOF) acting as a peroxidase mimic. The catalytic action of glucose oxidase (GOx) on glucose causes the formation of H 2 O 2 , and the MOF causes the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H 2 O 2 to form a blue-green product with an absorption peak at 650 nm in the detection zone. A digital camera and the iOS feature of a smartphone are used for the quantitation of glucose with the S coordinate of the HSV color space as the analytical parameter. Different factors such as the concentration of TMB, GOx and MOF, pH and buffer, sample volume, reaction time and reagent position in the μPAD were optimized. Under optimal conditions, the value for the S coordinate increases linearly up to 150 μmol·L -1 glucose concentrations, with a 2.5 μmol·L -1 detection limit. The μPAD remains stable for 21 days under conventional storage conditions. Such an enzyme mimetic-based assay to glucose determination using Fe-MIL-101 MOF implemented in a microfluidic paper-based device possesses advantages over enzyme-based assays in terms of costs, durability and stability compared to other existing glucose determination methods. The procedure was applied to the determination of glucose in (spiked) serum and urine. Graphical abstract Schematic representation of microfluidic paper-based analytical device using metal-organic framework as a peroxidase mimic for colorimetric glucose detection with digital camera or smartphone and iOS app readout.

  18. A synthetic eicosanoid LX-mimetic unravels host-donor interactions in allogeneic BMT-induced GvHD to reveal an early protective role for host neutrophils.

    PubMed

    Devchand, Pallavi R; Schmidt, Birgitta A; Primo, Valeria C; Zhang, Qing-yin; Arnaout, M Amin; Serhan, Charles N; Nikolic, Boris

    2005-02-01

    Lipoxin A(4) (LXA(4)) and aspirin-triggered 15-epi-LXA(4) are potent endogenous lipid mediators thought to define the inflammatory set-point. We used single prophylactic administrations of a synthetic aspirin-triggered lipoxin A(4) signal mimetic, ATLa, to probe dynamics of early host-donor interactions in a mouse model for the inflammation-associated multifactorial disease of allogeneic bone marrow transplant (BMT) -induced graft-vs.-host disease (GvHD). We first demonstrated that both host and donor are responsive to the ATLa signals. The simple and restricted regimen of a single prophylactic administration of ATLa [100 ng/mL to donor cells or 1 microg (approximately 50 microg/kg) i.v. to host] was sufficient to delay death. Clinical indicators of weight, skin lesions, diarrhea and eye inflammation were monitored. Histological analyses on day 45 post-BMT showed that the degree of cellular trafficking, particularly neutrophil infiltrate, and protection of end-organ target pathology are different, depending on whether the host or donor was treated with ATLa. Taken together, these results chart some ATLa protective effects on GvHD cellular dynamics over time and identify a previously unrecognized effect of host neutrophils in the early phase post-BMT as important determinants in the dynamics of GvHD onset and progression.-Devchand, P. R., Schmidt, B. A., Primo, V. C., Zhang, Q.-y., Arnaout, M. A., Serhan, C. N., Nikolic, B. A synthetic eicosanoid LX-mimetic unravels host-donor interactions in allogeneic BMT-induced GvHD to reveal an early protective role for host neutrophils.

  19. Continuous volatile fatty acid production from lignocellulosic biomass by a novel rumen-mimetic bioprocess.

    PubMed

    Agematu, Hitosi; Takahashi, Takehiko; Hamano, Yoshio

    2017-11-01

    Lignocellulosic biomass is an attractive source of biofuels and biochemicals, being abundant in various plant sources. However, processing this type of biomass requires hydrolysis of cellulose. The proposed rumen-mimetic bioprocess consists of dry-pulverization of lignocellulosic biomass and pH-controlled continuous cultivation of ruminal bacteria using ammonium as a nitrogen source. In this study, ruminal bacteria were continuously cultivated for over 60 days and used to digest microcrystalline cellulose, rice straw, and Japanese cedar to produce volatile fatty acids (VFAs). The ruminal bacteria grew well in the chemically defined medium. The amounts of VFAs produced from 20 g of cellulose, rice straw, and Japanese cedar were 183 ± 29.7, 69.6 ± 12.2, and 21.8 ± 12.9 mmol, respectively. Each digestion completed within 24 h. The carbon yield was 60.6% when 180 mmol of VFAs was produced from 20 g of cellulose. During the cultivation, the bacteria were observed to form flocs that enfolded the feed particles. These flocs likely contain all of the bacterial species necessary to convert lignocellulosic biomass to VFAs and microbial protein symbiotically. Denaturing gradient gel electrophoresis (DGGE) analysis of PCR-amplified 16S rDNA fragments revealed that the bacterial community was relatively stable after 1 week in cultivation, though it was different from the original community structure. Furthermore, sequence analysis of the DGGE bands indicates that the microbial community includes a cellulolytic bacterium, a bacterium acting synergistically with cellulolytic bacteria, and a propionate-producing bacterium, as well as other anaerobic bacteria. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  20. 7 CFR 51.3742 - U.S. No. 2.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Standards for Grades of Honey Dew and Honey Ball Type Melons Grades § 51.3742 U.S. No. 2. “U.S. No. 2” consists of honey dew or honey ball type melons which are mature, firm, fairly well formed, free from decay...

  1. 7 CFR 51.3742 - U.S. No. 2.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Standards for Grades of Honey Dew and Honey Ball Type Melons Grades § 51.3742 U.S. No. 2. “U.S. No. 2” consists of honey dew or honey ball type melons which are mature, firm, fairly well formed, free from decay...

  2. Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function.

    PubMed

    Chauhan, Jay; Chen, Shen-En; Fenstermacher, Katherine J; Naser-Tavakolian, Aurash; Reingewertz, Tali; Salmo, Rosene; Lee, Christian; Williams, Emori; Raje, Mithun; Sundberg, Eric; DeStefano, Jeffrey J; Freire, Ernesto; Fletcher, Steven

    2015-11-01

    Small-molecule mimetics of the β-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing flap closure, as designed. More generally, a new bioactive scaffold for HIV-1PR inhibition has been discovered, with the most potent compound inhibiting the protease with a modest K(i) of 11 μM. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Synthesis of natural urolithin M6, a galloflavin mimetic, as a potential inhibitor of lactate dehydrogenase A.

    PubMed

    Rupiani, Sebastiano; Guidotti, Laura; Manerba, Marcella; Di Ianni, Lorenza; Giacomini, Elisa; Falchi, Federico; Di Stefano, Giuseppina; Roberti, Marinella; Recanatini, Maurizio

    2016-11-22

    Glycolysis is the main route for energy production in tumors. LDH-A is a key enzyme of this process and its inhibition represents an attractive strategy to hamper cancer cell metabolism. Galloflavin is a reliable LDH-A inhibitor as previously identified by us; however, its poor physicochemical properties and chemical tractability render it unsuitable for further development. Therefore, a rational design was undertaken with the aim to reproduce the pharmacophore of galloflavin on simpler, potentially more soluble and synthetic accessible scaffolds. Following a process of structural simplification, natural urolithin M6 (UM6), which is an ellagitannin metabolite produced by gut microbiota, was identified as a putative galloflavin mimetic. In the present study, the synthesis of UM6 is described for the first time. An efficient synthetic pathway has been developed, which involved five steps from readily accessible starting materials. The key reaction steps, a Suzuki coupling and an intramolecular C-H oxygenation, have been optimized to improve the synthetic feasibility and provide the best conditions in terms of reaction time and yield. Moreover, this route would be suitable to obtain other analogs for SAR studies. Preliminary biological tests revealed that UM6 was able to smoothly reproduce the behavior of galloflavin, confirming that our approach was successful in providing a new and accessible structure in the search for new LDH-A inhibitors.

  4. Genomic organization of the rat alpha 2u-globulin gene cluster.

    PubMed

    McFadyen, D A; Addison, W; Locke, J

    1999-05-01

    The alpha 2u-globulin are a group of similar proteins, belonging to the lipocalin superfamily of proteins, that are synthesized in a subset of secretory tissues in rats. The many alpha 2u-globulin isoforms are encoded by a multigene family that exhibits extensive homology. Despite a high degree of sequence identity, individual family members show diverse expression patterns involving complex hormonal, tissue-specific, and developmental regulation. Analysis suggests that there are approximately 20 alpha 2u-globulin genes in the rat genome. We have used fluorescence in situ hybridization (FISH) to show that the alpha 2u-globulin genes are clustered at a single site on rat Chromosome (Chr) 5 (5q22-24). Southern blots of rat genomic DNA separated by pulsed field gel electrophoresis indicated that the alpha 2u-globulin genes are contained on two NruI fragments with a total size of 880 kbp. Analysis of three P1 clones containing alpha 2u-globulin genes indicated that the alpha 2u-globulin genes are tandemly arranged in a head-to-tail fashion. The organization of the alpha 2u-globulin genes in the rat as a tandem array of single genes differs from the homologous major urinary protein genes in the mouse, which are organized as tandem arrays of divergently oriented gene pairs. The structure of these gene clusters may have consequences for the proposed function, as a pheromone transporter, for the protein products encoded by these genes.

  5. Synergistic Interactions of a Synthetic Lubricin-Mimetic with Fibronectin for Enhanced Wear Protection

    PubMed Central

    Andresen Eguiluz, Roberto C.; Cook, Sierra G.; Tan, Mingchee; Brown, Cory N.; Pacifici, Noah J.; Samak, Mihir S.; Bonassar, Lawrence J.; Putnam, David; Gourdon, Delphine

    2017-01-01

    Lubricin (LUB), a major mucinous glycoprotein of mammalian synovial fluids, is believed to provide excellent lubrication to cartilage surfaces. Consequently, when joint disease or replacement leads to increased friction and surface damage in the joint, robust synthetic LUB alternatives that could be used therapeutically to improve lubrication and surface protection are needed. Here, we report the characterization of a lubricating multiblock bottlebrush polymer whose architecture was inspired by LUB, and we investigate the role of fibronectin (FN), a glycoprotein found in the superficial zone of cartilage, in mediating the tribological properties of the polymer upon shear between mica surfaces. Our surface forces apparatus (SFA) normal force measurements indicate that the lubricin-mimetic (mimLUB) could be kept anchored between mica surfaces, even under high contact pressures, when an intermediate layer of FN was present. Additional SFA friction measurements show that FN would also extend the wearless friction regime of the polymer up to pressures of 3.4 MPa while ensuring stable friction coefficients (μ ≈ 0.28). These results demonstrate synergistic interactions between mimLUB and FN in assisting the lubrication and wear protection of ideal (mica) substrates upon shear. Collectively, these findings suggest that our proposed mimLUB might be a promising alternative to LUB, as similar mechanisms could potentially facilitate the interaction between the polymer and cartilage surfaces in articular joints and prosthetic implants in vivo. PMID:28702455

  6. Coating of Bio-mimetic Minerals-Substituted Hydroxyapatite on Surgical Grade Stainless Steel 316L by Electrophoretic Deposition for Hard tissue Applications

    NASA Astrophysics Data System (ADS)

    Govindaraj, Dharman; Rajan, Mariappan

    2018-02-01

    Third-era bio-implant materials intend to empower particular live cell reactions at the atomic level, these materials represented with a resorbable and biocompatibility that bodies recuperate once they have been embedded. Necessitate to decrease expenses in public health services has required the utilization of surgical grade stainless steel (SS 316L) as the most inexpensive choice for orthodontic and orthopaedic implants. 316L SS is one of the broadly used implant biomaterials in orthodontic and orthopaedic surgeries. Yet, frequently those discharge for toxic metal ions is confirm from the implants and hence a second surgery is required will remove those implant material. One approach to managing the discharge of toxic metal ions is to coat the implant substance with bio-mimetic minerals in hydroxyapatite (HA). Bio-mimetic minerals such as magnesium (Mg), strontium (Sr), also zinc (Zn) were revealed with animate bone growth furthermore restrain bone resorption both in vitro and in vivo. The present work deals with the electrophoretic deposition (EPD) for multi minerals substituted hydroxyapatite (M-HA) on the surface treated 316L SS under distinctive temperatures (27°C, (room temperature), 60 and 80°C). The resultant coatings were characterized by FT-IR, XRD, SEM-EDX, adhesion strength and leach out analysis.

  7. Vaporization chemistry of hypo-stoichiometric (U,Pu)O 2

    NASA Astrophysics Data System (ADS)

    Viswanathan, R.; Krishnaiah, M. V.

    2001-04-01

    Calculations were performed on hypo-stoichiometric uranium plutonium di-oxide to examine its vaporization behavior as a function of O/ M ( M= U+ Pu) ratio and plutonium content. The phase U (1- y) Pu yO z was treated as an ideal solid solution of (1- y)UO 2+ yPuO (2- x) such that x=(2- z)/ y. Oxygen potentials for different desired values of y, z, and temperature were used as the primary input to calculate the corresponding partial pressures of various O-, U-, and Pu-bearing gaseous species. Relevant thermodynamic data for the solid phases UO 2 and PuO (2- x) , and the gaseous species were taken from the literature. Total vapor pressure varies with O/M and goes through a minimum. This minimum does not indicate a congruently vaporizing composition. Vaporization behavior of this system can at best be quasi-congruent. Two quasi-congruently vaporizing compositions (QCVCs) exist, representing the equalities (O/M) vapor=(O/M) mixed-oxide and (U/Pu) vapor=(U/Pu) mixed-oxide, respectively. The (O/M) corresponding to QCVC1 is lower than that corresponding to QCVC2, but very close to the value where vapor pressure minimum occurs. The O/M values of both QCVCs increase with decrease in plutonium content. The vaporization chemistry of this system, on continuous vaporization under dynamic condition, is discussed.

  8. Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer

    PubMed Central

    Dineen, Sean P.; Roland, Christina L.; Greer, Rachel; Carbon, Juliet G.; Toombs, Jason E.; Gupta, Puja; Bardeesy, Nabeel; Sun, Haizhou; Williams, Noelle; Minna, John D.; Brekken, Rolf A.

    2010-01-01

    Failure of chemotherapy in the treatment of pancreatic cancer is often due to resistance to therapy-induced apoptosis. A major mechanism for such resistance is the expression and activity of inhibitors of apoptosis proteins (IAPs). Smac is a mitochondrial protein that inhibits IAPs. We show that JP1201, a Smac mimetic, is a potent enhancer of chemotherapy in robust mouse models of pancreatic cancer. Combination of JP1201 with gemcitabine reduced primary and metastatic tumor burden in orthotopic xenograft and syngenic tumor models, induced regression of established tumors, and prolonged survival in xenograft and transgenic models of pancreatic cancer. The effect of JP1201 was phenocopied by XIAP siRNA in vitro and correlated with elevated levels of TNFα protein in vivo. The continued development of JP1201 and other strategies designed to enhance therapy-induced apoptosis in pancreatic cancer is warranted. PMID:20332237

  9. The role of ultraviolet colour in the assessment of mimetic accuracy between Batesian mimics and their models: a case study using ant-mimicking spiders

    NASA Astrophysics Data System (ADS)

    Corcobado, Guadalupe; Herberstein, Marie E.; Pekár, Stano

    2016-12-01

    The use of ultraviolet (UV) cues for intra- and inter-specific communication is common in many animal species. Still, the role of UV signals under some predator-prey contexts, such as Batesian mimicry, is not clear. Batesian mimicry is a defensive strategy by which a palatable species (the mimic) resembles an unpalatable or noxious species (the model) to avoid predation. This strategy has evolved independently in many different taxa that are predated by species capable of UV perception. Moreover, there is considerable variation in how accurately Batesian mimics resemble their models across species. Our aim was to investigate how UV colour contributed to mimetic accuracy using several ant-mimicking spider species as a case study. We measured the reflectance spectrum (300-700 nm) for several species of mimics and models, and we tested whether they differ in visible and UV colour. We modelled whether two different predators could discriminate between mimics and models using colour information. We found that generally, ant-mimicking spiders differed significantly from their ant models in UV colour and that information from the visible range of light cannot be extrapolated into the UV. Our modelling suggested that wasps should be able to discriminate between mimics and models combining information from visible and the UV light, whereas birds may not discriminate between them. Thus, we show that UV colour can influence mimic accuracy and we discuss its potential role in Batesian mimicry. We conclude that colour, especially in the UV range, should be taken into account when measuring mimetic accuracy.

  10. 7 CFR 51.3052 - U.S. No. 2.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE REGULATIONS AND STANDARDS UNDER THE AGRICULTURAL MARKETING ACT OF 1946... Standards for Florida Avocados Grades § 51.3052 U.S. No. 2. “U.S. No. 2” consists of avocados of similar...

  11. Antiamnesic properties of analogs and mimetics of the tripeptide human urocortin 3.

    PubMed

    Telegdy, Gyula; Kovács, Anita Kármen; Rákosi, Kinga; Zarándi, Márta; Tóth, Gábor K

    2016-09-01

    Amnesia is a deficit in memory caused by brain damage, disease, or trauma. Until now, there are no successful medications on the drug market available to treat amnesia. Short analogs and mimetics of human urocortin 3 (Ucn 3) tripeptide were synthetized and tested for their action against amnesia induced by eletroconvulsion in mice. Among the 16 investigated derivatives of Ucn 3 tripeptide, eight compounds displayed antiamnesic effect. Our results proved that the configuration of chiral center of glutamine does not affect the antiamnesic properties. Alkyl amide or isoleucyl amide at the C-terminus may lead to antiamnesic compounds. As concerned the N-terminus, acetyl, Boc, and alkyl ureido moieties were found among the active analogs, but the free amino function at the N-terminus usually led to an inactive derivatives. These observations may lead to the design and synthesis of small peptidomimetics and amino acid derivatives as antiamnesic drug candidates, although the elucidation of the mechanism of the action requires further investigations.

  12. CUS2, a Yeast Homolog of Human Tat-SF1, Rescues Function of Misfolded U2 through an Unusual RNA Recognition Motif

    PubMed Central

    Yan, Dong; Perriman, Rhonda; Igel, Haller; Howe, Kenneth J.; Neville, Megan; Ares, Manuel

    1998-01-01

    A screen for suppressors of a U2 snRNA mutation identified CUS2, an atypical member of the RNA recognition motif (RRM) family of RNA binding proteins. CUS2 protein is associated with U2 RNA in splicing extracts and interacts with PRP11, a subunit of the conserved splicing factor SF3a. Absence of CUS2 renders certain U2 RNA folding mutants lethal, arguing that a normal activity of CUS2 is to help refold U2 into a structure favorable for its binding to SF3b and SF3a prior to spliceosome assembly. Both CUS2 function in vivo and the in vitro RNA binding activity of CUS2 are disrupted by mutation of the first RRM, suggesting that rescue of misfolded U2 involves the direct binding of CUS2. Human Tat-SF1, reported to stimulate Tat-specific, transactivating region-dependent human immunodeficiency virus transcription in vitro, is structurally similar to CUS2. Anti-Tat-SF1 antibodies coimmunoprecipitate SF3a66 (SAP62), the human homolog of PRP11, suggesting that Tat-SF1 has a parallel function in splicing in human cells. PMID:9710584

  13. Vibrational wave packets in the B 1Πu and D 1Σu+ states of Cs2: Determination of improved Cs2+(X) and Cs2(B) spectroscopic constants

    NASA Astrophysics Data System (ADS)

    Oldenburg, A. L.; John, P. C.; Eden, J. G.

    2000-12-01

    Vibrational wave packets in the B 1Πu and D 1Σu+ excited states of Cs2 have been studied on the ˜100 fs time scale by pump-probe laser spectroscopy. The temporal behavior of the wave packets was monitored by photoionizing the electronically excited molecule with a time-delayed probe pulse and recording the time and energy-integrated photoelectron signal as a function of time delay between the pump and probe pulses. For the B 1Σu+ experiments, wave packets were produced by exciting the B 1Σu+←X 1Σg+ transition in the ˜740-790 nm region and subsequently detected by photoionizing the molecule at wavelengths between 565 nm and 600 nm. By simulating the experimentally observed transients with the density matrix formalism (and explicitly accounting for laser chirp and |Δv|>1 coherences), improved values for the equilibrium internuclear separation for the Cs2(B1Πu) state and Te for the Cs2+(X) state were determined to be Re(B 1Πu)=4.93±0.03 Å and Te[Cs2+(X)]=29 930±100 cm-1, respectively. Similar experiments were conducted for the D 1Σu+ state. Wave packets composed of vibrational levels (v'≈40-50) perturbed by the bound 2 3Πou state were produced on the D 1Σu+ potential surface by driving the D 1Σu+←X 1Σg+ transition in the 575-610 nm spectral interval.

  14. Kondo Effect of U Impurities in Dilute (YU)2Zn17

    NASA Astrophysics Data System (ADS)

    Takagi, Shigeru; Suzuki, Hiroyuki; Anzai, Kousuke

    2001-10-01

    Extending previous work on single-site properties of U ions in (LaU)2Zn17, we have investigated, from ρ(T), χ(T) and Cp(T) on single crystals, (Y1-xUx)2Zn17 with x=0.025 and 0.050, which has almost the same unit-cell volume as an antiferromagnetic heavy-electron compound U2Zn17. Remarkable features in the dilute-impurity limit have been clarified, which include Kondo behavior of ρ(T), large and almost isotropic χimp(T), and strongly enhanced Cimp(T)/T with gigantic γimp=2.02 2.05 J/K2·mole-U as T→0 due to a low characteristic energy-scale of the system. It is shown that gross features of the data are explained in terms of the conventional Kondo effect in the presence of the crystal field with the U3+ \\varGamma6 doublet ground state. It is also shown that the variation of γ with the unit-cell volume in related systems is not explained as a volume effect on TK and that even the behavior of fictitious “paramagnetic” U2Zn17 is not described as a collection of U impurities in dilute (YU)2Zn17.

  15. HDL mimetic peptide CER-522 treatment regresses left ventricular diastolic dysfunction in cholesterol-fed rabbits.

    PubMed

    Merlet, Nolwenn; Busseuil, David; Mihalache-Avram, Teodora; Mecteau, Melanie; Shi, Yanfen; Nachar, Walid; Brand, Genevieve; Brodeur, Mathieu R; Charpentier, Daniel; Rhainds, David; Sy, Gavin; Schwendeman, Anna; Lalwani, Narendra; Dasseux, Jean-Louis; Rhéaume, Eric; Tardif, Jean-Claude

    2016-07-15

    High-density lipoprotein (HDL) infusions induce rapid improvement of experimental atherosclerosis in rabbits but their effect on ventricular function remains unknown. We aimed to evaluate the effects of the HDL mimetic peptide CER-522 on left ventricular diastolic dysfunction (LVDD). Rabbits were fed with a cholesterol- and vitamin D2-enriched diet until mild aortic valve stenosis and hypercholesterolemia-induced LV hypertrophy and LVDD developed. Animals then received saline or 10 or 30mg/kg CER-522 infusions 6 times over 2weeks. We performed serial echocardiograms and LV histology to evaluate the effects of CER-522 therapy on LVDD. LVDD was reduced by CER-522 as shown by multiple parameters including early filling mitral deceleration time, deceleration rate, Em/Am ratio, E/Em ratio, pulmonary venous velocities, and LVDD score. These findings were associated with reduced macrophages (RAM-11 positive cells) in the pericoronary area and LV, and decreased levels of apoptotic cardiomyocytes in CER-522-treated rabbits. CER-522 treatment also resulted in decreased atheromatous plaques and internal elastic lamina area in coronary arteries. CER-522 improves LVDD in rabbits, with reductions of LV macrophage accumulation, cardiomyocyte apoptosis, coronary atherosclerosis and remodelling. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. 7 CFR 51.1148 - U.S. No. 2.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... tolerances see § 51.1151. (e) Internal quality: Lots meeting the internal requirements for “U.S. Grade AA... 7 Agriculture 2 2010-01-01 2010-01-01 false U.S. No. 2. 51.1148 Section 51.1148 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing...

  17. Interdiffusion in U 3Si-Al, U 3Si 2-Al, and USi-Al dispersion fuels during irradiation

    NASA Astrophysics Data System (ADS)

    Kim, Yeon Soo; Hofman, Gerard L.

    2011-03-01

    Uranium-silicide compound fuel dispersion in an Al matrix is used in research and test reactors worldwide. Interaction layer (IL) growth between fuel particles and the matrix is one of performance issues. The interaction layer growth data for U 3Si, U 3Si 2 and USi dispersions in Al were obtained from both out-of-pile and in-pile tests. The IL is dominantly U(AlSi) 3 from out-of-pile tests, but its (Al + Si)/U ratio from in-pile tests is higher than the out-of-pile data, because of amorphous behavior of the ILs. IL growth correlations were developed for U 3Si-Al and U 3Si 2-Al. The IL growth rates were dependent on the U/Si ratio of the fuel compounds. During irradiation, however, the IL growth rates did not decrease with the decreasing U/Si ratio by fission. It is reasoned that transition metal fission products in the IL compensate the loss of U atoms by providing chemical potential for Al diffusion and volume expansion by solid swelling and gas bubble swelling. The addition of Mo in U 3Si 2 reduces the IL growth rate, which is similar to that of UMo alloy dispersion in a silicon-added Al matrix.

  18. Isolated Human Pulmonary Artery Structure and Function Pre- and Post-Cardiopulmonary Bypass Surgery.

    PubMed

    Dora, Kim A; Stanley, Christopher P; Al Jaaly, Emad; Fiorentino, Francesca; Ascione, Raimondo; Reeves, Barnaby C; Angelini, Gianni D

    2016-02-23

    Pulmonary dysfunction is a known complication after cardiac surgery using cardiopulmonary bypass, ranging from subclinical functional changes to prolonged postoperative ventilation, acute lung injury, and acute respiratory distress syndrome. Whether human pulmonary arterial function is compromised is unknown. The aim of the present study was to compare the structure and function of isolated and cannulated human pulmonary arteries obtained from lung biopsies after the chest was opened (pre-cardiopulmonary bypass) to those obtained at the end of cardiopulmonary bypass (post-cardiopulmonary bypass) from patients undergoing coronary artery bypass graft surgery. Pre- and post-cardiopulmonary bypass lung biopsies were received from 12 patients undergoing elective surgery. Intralobular small arteries were dissected, cannulated, pressurized, and imaged using confocal microscopy. Functionally, the thromboxane mimetic U46619 produced concentration-dependent vasoconstriction in 100% and 75% of pre- and post-cardiopulmonary bypass arteries, respectively. The endothelium-dependent agonist bradykinin stimulated vasodilation in 45% and 33% of arteries pre- and post-cardiopulmonary bypass, respectively. Structurally, in most arteries smooth muscle cells aligned circumferentially; live cell viability revealed that although 100% of smooth muscle and 90% of endothelial cells from pre-cardiopulmonary bypass biopsies had intact membranes and were considered viable, only 60% and 58%, respectively, were viable from post-cardiopulmonary bypass biopsies. We successfully investigated isolated pulmonary artery structure and function in fresh lung biopsies from patients undergoing heart surgery. Pulmonary artery contractile tone and endothelium-dependent dilation were significantly reduced in post-cardiopulmonary bypass biopsies. The decreased functional responses were associated with reduced cell viability. URL: http://www.isrctn.com/ISRCTN34428459. Unique identifier: ISRCTN 34428459.

  19. Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

    PubMed Central

    Lee, Erinna F.; Clarke, Oliver B.; Evangelista, Marco; Feng, Zhiping; Speed, Terence P.; Tchoubrieva, Elissaveta B.; Strasser, Andreas; Kalinna, Bernd H.; Colman, Peter M.; Fairlie, W. Douglas

    2011-01-01

    Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with “BH3 mimetic” drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment. PMID:21444803

  20. Exact Correlation Functions in S U (2 ) N =2 Superconformal QCD

    NASA Astrophysics Data System (ADS)

    Baggio, Marco; Niarchos, Vasilis; Papadodimas, Kyriakos

    2014-12-01

    We report an exact solution of 2- and 3-point functions of chiral primary fields in S U (2 ) N =2 super-Yang-Mills theory coupled to four hypermultiplets. It is shown that these correlation functions are nontrivial functions of the gauge coupling, obeying differential equations which take the form of the semi-infinite Toda chain. We solve these equations recursively in terms of the Zamolodchikov metric that can be determined exactly from supersymmetric localization on the four-sphere. Our results are verified independently in perturbation theory with a Feynman diagram computation up to 2 loops. This is a short version of a companion paper that contains detailed technical remarks, additional material, and aspects of an extension to the S U (N ) gauge group.

  1. Analysis of oxygen potential of (U 0.7Pu 0.3)O 2±x and (U 0.8Pu 0.2)O 2±x based on point defect chemistry

    NASA Astrophysics Data System (ADS)

    Kato, Masato; Konashi, Kenji; Nakae, Nobuo

    2009-06-01

    Stoichiometries in (U 0.7Pu 0.3)O 2±x and (U 0.8Pu 0.2)O 2±x were analyzed with the experimental data of oxygen potential based on point defect chemistry. The relationship between the deviation x of stoichiometric composition and the oxygen partial pressure P was evaluated using a Kröger-Vink diagram. The concentrations of the point defects in uranium and plutonium mixed oxide (MOX) were estimated from the measurement data of oxygen potentials as functions of temperature and P. The analysis results showed that x was proportional to PO2±1/2 near the stoichiometric region of both (U 0.7Pu 0.3)O 2±x and (U 0.8Pu 0.2)O 2±x, which suggested that intrinsic ionization was the dominant defect. A model to calculate oxygen potential was derived and it represented the experimental data accurately. Further, the model estimated the thermodynamic data, ΔH and ΔS, of stoichiometric (U 0.7Pu 0.3)O 2.00 and (U 0.8Pu 0.2)O 2.00 as -552.5 kJ·mol -1 and -149.7 J·mol -1, and -674.0 kJ · mol -1 and -219.4 J · mol -1, respectively.

  2. Exercise-mimetic AICAR transiently benefits brain function

    PubMed Central

    Guerrieri, Davide; van Praag, Henriette

    2015-01-01

    Exercise enhances learning and memory in animals and humans. The role of peripheral factors that may trigger the beneficial effects of running on brain function has been sparsely examined. In particular, it is unknown whether AMP-kinase (AMPK) activation in muscle can predict enhancement of brain plasticity. Here we compare the effects of running and administration of AMPK agonist 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 500 mg/kg), for 3, 7 or 14 days in one-month-old male C57BL/6J mice, on muscle AMPK signaling. At the time-points where we observed equivalent running- and AICAR-induced muscle pAMPK levels (7 and 14 days), cell proliferation, synaptic plasticity and gene expression, as well as markers of oxidative stress and inflammation in the dentate gyrus (DG) of the hippocampus and lateral entorhinal cortex (LEC) were evaluated. At the 7-day time-point, both regimens increased new DG cell number and brain-derived neurotrophic factor (BDNF) protein levels. Furthermore, microarray analysis of DG and LEC tissue showed a remarkable overlap between running and AICAR in the regulation of neuronal, mitochondrial and metabolism related gene classes. Interestingly, while similar outcomes for both treatments were stable over time in muscle, in the brain an inversion occurred at fourteen days. The compound no longer increased DG cell proliferation or neurotrophin levels, and upregulated expression of apoptotic genes and inflammatory cytokine interleukin-1β. Thus, an exercise mimetic that produces changes in muscle consistent with those of exercise does not have the same sustainable positive effects on the brain, indicating that only running consistently benefits brain function. PMID:26286955

  3. Exercise-mimetic AICAR transiently benefits brain function.

    PubMed

    Guerrieri, Davide; van Praag, Henriette

    2015-07-30

    Exercise enhances learning and memory in animals and humans. The role of peripheral factors that may trigger the beneficial effects of running on brain function has been sparsely examined. In particular, it is unknown whether AMP-kinase (AMPK) activation in muscle can predict enhancement of brain plasticity. Here we compare the effects of running and administration of AMPK agonist 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 500 mg/kg), for 3, 7 or 14 days in one-month-old male C57BL/6J mice, on muscle AMPK signaling. At the time-points where we observed equivalent running- and AICAR-induced muscle pAMPK levels (7 and 14 days), cell proliferation, synaptic plasticity and gene expression, as well as markers of oxidative stress and inflammation in the dentate gyrus (DG) of the hippocampus and lateral entorhinal cortex (LEC) were evaluated. At the 7-day time-point, both regimens increased new DG cell number and brain-derived neurotrophic factor (BDNF) protein levels. Furthermore, microarray analysis of DG and LEC tissue showed a remarkable overlap between running and AICAR in the regulation of neuronal, mitochondrial and metabolism related gene classes. Interestingly, while similar outcomes for both treatments were stable over time in muscle, in the brain an inversion occurred at fourteen days. The compound no longer increased DG cell proliferation or neurotrophin levels, and upregulated expression of apoptotic genes and inflammatory cytokine interleukin-1β. Thus, an exercise mimetic that produces changes in muscle consistent with those of exercise does not have the same sustainable positive effects on the brain, indicating that only running consistently benefits brain function.

  4. Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: implications for therapy.

    PubMed

    Alvarez, Rafael; Casas, Jesús; López, David J; Ibarguren, Maitane; Suari-Rivera, Ariadna; Terés, Silvia; Guardiola-Serrano, Francisca; Lossos, Alexander; Busquets, Xavier; Kakhlon, Or; Escribá, Pablo V

    2017-08-01

    Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble glycogen, which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions. Because soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified WT and GBE1Y329S proteins with different types of model membranes (liposomes). Interestingly, both triheptanoin and some triacylglycerol mimetics (TGMs) we have designed (TGM0 and TGM5) markedly enhance GBE1Y329S activity, possibly enough for reversing APBD symptoms. We show that the GBE1Y329S mutation exposes a hydrophobic amino acid stretch, which can either stabilize and enhance or alternatively, reduce the enzyme activity via alteration of protein-membrane interactions. Additionally, we found that WT, but not Y329S, GBE1 activity is modulated by Ca 2+ and phosphatidylserine, probably associated with GBE1-mediated regulation of energy consumption and storage. The thermal stabilization and increase in GBE1Y329S activity induced by TGM5 and its omega-3 oil structure suggest that this molecule has a considerable therapeutic potential for treating APBD. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  5. TREATMENT OF DIABETES MELLITUS IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA) WITH THE GLUCAGON-LIKE PEPTIDE-1 MIMETIC EXENATIDE.

    PubMed

    Johnson, James G; Langan, Jennifer N; Gilor, Chen

    2016-09-01

    An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.

  6. Inhibition by prostaglandin E(2) of anaphylatoxin C5a- but not zymosan-induced prostanoid release from rat Kupffer cells.

    PubMed

    Pestel, Sabine; Jungermann, Kurt; Götze, Otto; Schieferdecker, Henrike L

    2002-04-01

    The proinflammatory anaphylatoxin C5a induces the release of prostanoids, ie, prostaglandins (PG) and thromboxane (TX), from the resident liver macrophages (Kupffer cells [KC]). Because KC themselves express prostanoid receptors, prostanoids--besides having paracrine functions--might regulate their own release in an autocrine loop. So far, such a possible feedback regulation has not been investigated systematically, probably because of methodological difficulties to measure newly synthesized prostanoids in the presence of added prostanoids. Here, after prelabeling of phospholipids with [(14)C]arachidonate, cellularly formed [(14)C]prostanoids were determined in the presence of added unlabelled prostanoids by thin layer chromatography. In cultured KC, recombinant rat C5a (rrC5a) rapidly increased PGD(2), PGE(2), and TXA(2) release, which was strongly reduced by PGE(2), but neither by PGD(2) nor by the TXA(2) analog U46619. The inhibitory effect of PGE(2) was mimicked by cAMP, indicating that the G(s)-coupled PGE(2) receptors type 2 or 4 were involved. Zymosan also enhanced prostanoid release from KC, but with slightly slower kinetics; this action was neither inhibited by PGE(2) nor by cAMP. Also in perfused rat livers, rrC5a enhanced prostanoid release from KC as shown by prostanoid overflow and thereby indirectly increased glucose output from hepatocytes. Again, PGE(2), but not PGD(2), inhibited rrC5a-elicited prostanoid overflow. This resulted in a complete inhibition of rrC5a-induced, prostanoid-mediated glucose output. Thus, PGE(2) can inhibit specifically the C5a-induced prostanoid release from KC via a feedback mechanism and thereby limit prostanoid-mediated hepatocellular defense reactions, eg, glucose release.

  7. SU(3)_C× SU(2)_L× U(1)_Y( × U(1)_X ) as a symmetry of division algebraic ladder operators

    NASA Astrophysics Data System (ADS)

    Furey, C.

    2018-05-01

    We demonstrate a model which captures certain attractive features of SU(5) theory, while providing a possible escape from proton decay. In this paper we show how ladder operators arise from the division algebras R, C, H, and O. From the SU( n) symmetry of these ladder operators, we then demonstrate a model which has much structural similarity to Georgi and Glashow's SU(5) grand unified theory. However, in this case, the transitions leading to proton decay are expected to be blocked, given that they coincide with presumably forbidden transformations which would incorrectly mix distinct algebraic actions. As a result, we find that we are left with G_{sm} = SU(3)_C× SU(2)_L× U(1)_Y / Z_6. Finally, we point out that if U( n) ladder symmetries are used in place of SU( n), it may then be possible to find this same G_{sm}=SU(3)_C× SU(2)_L× U(1)_Y / Z_6, together with an extra U(1)_X symmetry, related to B-L.

  8. Translational control of human acetyl-CoA carboxylase 1 mRNA is mediated by an internal ribosome entry site in response to ER stress, serum deprivation or hypoxia mimetic CoCl2.

    PubMed

    Damiano, Fabrizio; Testini, Mariangela; Tocci, Romina; Gnoni, Gabriele V; Siculella, Luisa

    2018-04-01

    Acetyl-CoA carboxylase 1 (ACC1) is a cytosolic enzyme catalyzing the rate limiting step in de novo fatty acid biosynthesis. There is mounting evidence showing that ACC1 is susceptible to dysregulation and that it is over-expressed in liver diseases associated with lipid accumulation and in several cancers. In the present study, ACC1 regulation at the translational level is reported. Using several experimental approaches, the presence of an internal ribosome entry site (IRES) has been established in the 5' untranslated region (5' UTR) of the ACC1 mRNA. Transfection experiments with the ACC1 5' UTR inserted in a dicistronic reporter vector show a remarkable increase in the downstream cistron translation, through a cap-independent mechanism. The endoplasmic reticulum (ER) stress condition and the related unfolded protein response (UPR), triggered by treatment with thapsigargin and tunicamycin, cause an increase of the cap-independent translation of ACC1 mRNA in HepG2 cells, despite the overall reduction in global protein synthesis. Other stress conditions, such as serum starvation and incubation with hypoxia mimetic agent CoCl 2 , up-regulate ACC1 expression in HepG2 cells at the translational level. Overall, these findings indicate that the presence of an IRES in the ACC1 5' UTR allows ACC1 mRNA translation in conditions that are inhibitory to cap-dependent translation. A potential involvement of the cap-independent translation of ACC1 in several pathologies, such as obesity and cancer, has been discussed. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. 7 CFR 51.2835 - U.S. No. 2.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false U.S. No. 2. 51.2835 Section 51.2835 Agriculture... Standards for Grades of Onions (Other Than Bermuda-Granex-Grano and Creole Types) Grades § 51.2835 U.S. No... Matter; (4) Seedstems; (5) Sprouts; (6) Mechanical; (7) Dry sunken areas; (8) Disease; (9) Freezing; (10...

  10. 7 CFR 51.2835 - U.S. No. 2.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 2 2011-01-01 2011-01-01 false U.S. No. 2. 51.2835 Section 51.2835 Agriculture... Standards for Grades of Onions (Other Than Bermuda-Granex-Grano and Creole Types) Grades § 51.2835 U.S. No... Matter; (4) Seedstems; (5) Sprouts; (6) Mechanical; (7) Dry sunken areas; (8) Disease; (9) Freezing; (10...

  11. Rational design of dicarboxylato platinum(II) complexes with purine-mimetic ligands as novel anticancer agents.

    PubMed

    Hoffmann, Kamil; Wiśniewska, Joanna; Wojtczak, Andrzej; Sitkowski, Jerzy; Denslow, Agnieszka; Wietrzyk, Joanna; Jakubowski, Mateusz; Łakomska, Iwona

    2017-07-01

    Six novel platinum(II) complexes containing purine-mimetic ligands (5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp), 7-isobutyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp)) and dicarboxylato ligands (glutarato (glut) or cyclobutane-1,1-dicarboxylato (CBDC)) have been prepared and characterized with multinuclear magnetic resonance ( 1 H, 13 C, 15 N, 195 Pt) NMR, infrared (IR) and X-ray crystallography. Spectroscopic data in solid state and in solution unambiguously confirm the square-planar geometry of Pt(II) with two monodentate N3-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine ligands and one O-chelating dicarboxylato ligand. Next, the effect of all the platinum(II) compounds on the viability of normal or cancer cells and their putative mechanisms of action have been investigated. Of the studied platinum(II) complexes, two ([Pt(glut)(dbtp) 2 ] and [Pt(CBDC)(dbtp) 2 ]) overcame the cisplatin resistance in human ovarian tumor cells (A2780cis or OVCAR-3) and arrested the cell cycle at S phase in mice mammary gland cancer cells (4T1), which indicates a mechanism of action different from that of cisplatin. Interestingly, preliminary in vivo toxicity assays revealed that both compounds tested in mice ([Pt(glut)(dbtp) 2 ] 3 and [Pt(CBDC)(dbtp) 2 ] 6) were less toxic in vivo than cisplatin or oxaliplatin. Additionally, compound 6 did not cause myelosuppression and showed over fivefold less accumulation in the liver than its glutarato analog 3. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Empirical Estimation of Local Dielectric Constants: Toward Atomistic Design of Collagen Mimetic Peptides

    PubMed Central

    Pike, Douglas H.; Nanda, Vikas

    2017-01-01

    One of the key challenges in modeling protein energetics is the treatment of solvent interactions. This is particularly important in the case of peptides, where much of the molecule is highly exposed to solvent due to its small size. In this study, we develop an empirical method for estimating the local dielectric constant based on an additive model of atomic polarizabilities. Calculated values match reported apparent dielectric constants for a series of Staphylococcus aureus nuclease mutants. Calculated constants are used to determine screening effects on Coulombic interactions and to determine solvation contributions based on a modified Generalized Born model. These terms are incorporated into the protein modeling platform protCAD, and benchmarked on a data set of collagen mimetic peptides for which experimentally determined stabilities are available. Computing local dielectric constants using atomistic protein models and the assumption of additive atomic polarizabilities is a rapid and potentially useful method for improving electrostatics and solvation calculations that can be applied in the computational design of peptides. PMID:25784456

  13. Uniform ripening (U) encodes a Golden 2-like transcription factor regulating tomato fruit chloroplast development

    USDA-ARS?s Scientific Manuscript database

    Modern tomato (Solanum lycopersicum) varieties are bred for recessive uniform ripening (u) light green fruit phenotypes to facilitate maturity determinations without information about the underlying gene. We show that U encodes a Golden 2-like (GLK) transcription factor, SlGLK2, which determines the...

  14. Simulations of Xe and U diffusion in UO2

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Andersson, Anders D.; Vyas, Shyam; Tonks, Michael R.

    2012-09-10

    Diffusion of xenon (Xe) and uranium (U) in UO{sub 2} is controlled by vacancy mechanisms and under irradiation the formation of mobile vacancy clusters is important. Based on the vacancy and cluster diffusion mechanisms established from density functional theory (DFT) calculations, we derive continuum thermodynamic and diffusion models for Xe and U in UO{sub 2}. In order to capture the effects of irradiation, vacancies (Va) are explicitly coupled to the Xe and U dynamics. Segregation of defects to grain boundaries in UO{sub 2} is described by combining the bulk diffusion model with models of the interaction between Xe atoms andmore » vacancies with grain boundaries, which were derived from atomistic calculations. The diffusion and segregation models were implemented in the MOOSE-Bison-Marmot (MBM) finite element (FEM) framework and the Xe/U redistribution was simulated for a few simple microstructures.« less

  15. Recognition of the 3′ splice site RNA by the U2AF heterodimer involves a dynamic population shift

    PubMed Central

    Voith von Voithenberg, Lena; Sánchez-Rico, Carolina; Kang, Hyun-Seo; Madl, Tobias; Zanier, Katia; Barth, Anders; Warner, Lisa R.; Sattler, Michael; Lamb, Don C.

    2016-01-01

    An essential early step in the assembly of human spliceosomes onto pre-mRNA involves the recognition of regulatory RNA cis elements in the 3′ splice site by the U2 auxiliary factor (U2AF). The large (U2AF65) and small (U2AF35) subunits of the U2AF heterodimer contact the polypyrimidine tract (Py-tract) and the AG-dinucleotide, respectively. The tandem RNA recognition motif domains (RRM1,2) of U2AF65 adopt closed/inactive and open/active conformations in the free form and when bound to bona fide Py-tract RNA ligands. To investigate the molecular mechanism and dynamics of 3′ splice site recognition by U2AF65 and the role of U2AF35 in the U2AF heterodimer, we have combined single-pair FRET and NMR experiments. In the absence of RNA, the RRM1,2 domain arrangement is highly dynamic on a submillisecond time scale, switching between closed and open conformations. The addition of Py-tract RNA ligands with increasing binding affinity (strength) gradually shifts the equilibrium toward an open conformation. Notably, the protein–RNA complex is rigid in the presence of a strong Py-tract but exhibits internal motion with weak Py-tracts. Surprisingly, the presence of U2AF35, whose UHM domain interacts with U2AF65 RRM1, increases the population of the open arrangement of U2AF65 RRM1,2 in the absence and presence of a weak Py-tract. These data indicate that the U2AF heterodimer promotes spliceosome assembly by a dynamic population shift toward the open conformation of U2AF65 to facilitate the recognition of weak Py-tracts at the 3′ splice site. The structure and RNA binding of the heterodimer was unaffected by cancer-linked myelodysplastic syndrome mutants. PMID:27799531

  16. Anti-Tumor Activity of a Novel HS-Mimetic-Vascular Endothelial Growth Factor Binding Small Molecule

    PubMed Central

    Sugahara, Kazuyuki; Thimmaiah, Kuntebommanahalli N.; Bid, Hemant K.; Houghton, Peter J.; Rangappa, Kanchugarakoppal S.

    2012-01-01

    The angiogenic process is controlled by variety of factors of which the vascular endothelial growth factor (VEGF) pathway plays a major role. A series of heparan sulfate mimetic small molecules targeting VEGF/VEGFR pathway has been synthesized. Among them, compound 8 (2-butyl-5-chloro-3-(4-nitro-benzyl)-3H-imidazole-4-carbaldehyde) was identified as a significant binding molecule for the heparin-binding domain of VEGF, determined by high-throughput-surface plasmon resonance assay. The data predicted strong binding of compound 8 with VEGF which may prevent the binding of VEGF to its receptor. We compared the structure of compound 8 with heparan sulfate (HS), which have in common the functional ionic groups such as sulfate, nitro and carbaldehyde that can be located in similar positions of the disaccharide structure of HS. Molecular docking studies predicted that compound 8 binds at the heparin binding domain of VEGF through strong hydrogen bonding with Lys-30 and Gln-20 amino acid residues, and consistent with the prediction, compound 8 inhibited binding of VEGF to immobilized heparin. In vitro studies showed that compound 8 inhibits the VEGF-induced proliferation migration and tube formation of mouse vascular endothelial cells, and finally the invasion of a murine osteosarcoma cell line (LM8G7) which secrets high levels of VEGF. In vivo, these effects produce significant decrease of tumor burden in an experimental model of liver metastasis. Collectively, these data indicate that compound 8 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of endothelial cell migration and angiogenesis mediated by VEGF. In conclusion, compound 8 may normalize the tumor vasculature and microenvironment in tumors probably by inhibiting the binding of VEGF to its receptor. PMID:22916091

  17. Influence of physical preconditioning on the responsiveness of rat pulmonary artery after pulmonary ischemia/reperfusion.

    PubMed

    Delbin, Maria Andréia; Moraes, Camila; Camargo, Enilton; Mussi, Ricardo K; Antunes, Edson; de Nucci, Gilberto; Zanesco, Angelina

    2007-07-01

    The aim of this work was to evaluate the effect of physical preconditioning in the responsiveness of rat pulmonary rings submitted to lung ischemia/reperfusion (IR). Wistar rats were divided into three groups: Sedentary sham-operated (SD/SHAM); sedentary submitted to ischemia/reperfusion (SD/IR) and trained submitted to ischemia/reperfusion (TR/IR) animals. Exercise training consisted in sessions of 60 min/day running sessions, 5 days/week for 8 weeks. Left pulmonary IR was performed by occluding for 90 min and reperfusing for 120 min. After that, pulmonary arteries were isolated and concentration-response curves to acetylcholine (ACh), histamine (HIST), sodium nitroprusside (SNP), phenylephrine and U46619 were obtained. Neither potency (-log EC(50)) nor maximal responses (E(max)) were modified for ACh and HIST in all groups. On the other hand, the potency for SNP was significantly increased in TR/IR group (8.23+/-0.06) compared to SD/IR group (7.85+/-0.04). Contractile responses mediated by a-adrenergic receptor were markedly decreased in IR groups (SD/IR: 6.75+/-0.06 and TR/IR: 6.62+/-0.04) compared to SD/SHAM (7.33+/-0.05). No changes were seen for the U46619 in all groups. In conclusion, the present study shows that exercise training has no protective actions in the local blood vessel where the IR process takes place.

  18. Scope and limitations of carbohydrate hydrolysis for de novo glycan sequencing using a hydrogen peroxide/metallopeptide-based glycosidase mimetic.

    PubMed

    Peng, Tianyuan; Wooke, Zachary; Pohl, Nicola L B

    2018-03-22

    Acidic hydrolysis is commonly used as a first step to break down oligo- and polysaccharides into monosaccharide units for structural analysis. While easy to set up and amenable to mass spectrometry detection, acid hydrolysis is not without its drawbacks. For example, ring-destruction side reactions and degradation products, along with difficulties in optimizing conditions from analyte to analyte, greatly limits its broad utility. Herein we report studies on a hydrogen peroxide/CuGGH metallopeptide-based glycosidase mimetic design for a more efficient and controllable carbohydrate hydrolysis. A library of methyl glycosides consisting of ten common monosaccharide substrates, along with oligosaccharide substrates, was screened with the artificial glycosidase for hydrolytic activity in a high-throughput format with a robotic liquid handling system. The artificial glycosidase was found to be active towards most screened linkages, including alpha- and beta-anomers, thus serving as a potential alternative method for traditional acidic hydrolysis approaches of oligosaccharides. Copyright © 2018 Elsevier Ltd. All rights reserved.

  19. Small nuclear RNA U2 is base-paired to heterogeneous nuclear RNA.

    PubMed

    Calvet, J P; Meyer, L M; Pederson, T

    1982-07-30

    Eukaryotic cells contain a set of low molecular weight nuclear RNA's. One of the more abundant of these is termed U2 RNA. The possibility that U2 RNA is hydrogen-bonded to complementary sequences in other nuclear RNA's was investigated. Cultured human (HeLa) cells were treated with a psoralen derivative that cross-links RNA chains that are base-paired with one another. High molecular weight heterogeneous nuclear RNA was isolated under denaturing conditions, and the psoralen cross-links were reversed. Electrophoresis of the released RNA and hybridization with a human cloned U2 DNA probe revealed that U2 is hydrogen-bonded to complementary sequences in heterogeneous nuclear RNA in vivo. In contrast, U2 RNA is not base-paired with nucleolar RNA, which contains the precursors of ribosomal RNA. The results suggest that U2 RNA participates in messenger RNA processing in the nucleus.

  20. 7 CFR 51.1347 - U.S. No. 2.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., free from scald, hard end, black end, internal breakdown, decay, worms and worm holes, and free from..., CERTIFICATION, AND STANDARDS) United States Standards for Pears for Canning Grades § 51.1347 U.S. No. 2. “U.S...

  1. 7 CFR 51.1347 - U.S. No. 2.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., free from scald, hard end, black end, internal breakdown, decay, worms and worm holes, and free from..., CERTIFICATION, AND STANDARDS) United States Standards for Pears for Canning Grades § 51.1347 U.S. No. 2. “U.S...

  2. Complementary DNA cloning, sequence analysis, and tissue transcription profile of a novel U2AF2 gene from the Chinese Banna mini-pig inbred line.

    PubMed

    Wang, S Y; Huo, J L; Miao, Y W; Cheng, W M; Zeng, Y Z

    2013-04-02

    U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an important gene for pre-messenger RNA splicing in higher eukaryotes. In this study, the Banna mini-pig inbred line (BMI) U2AF2 coding sequence (CDS) was cloned, sequenced, and characterized. The U2AF2 complete CDS was amplified using the reverse transcription-polymerase chain reaction (RT-PCR) technique based on the conserved sequence information of cattle and known highly homologous swine expressed sequence tags. This novel gene was deposited into the National Center for Biotechnology Information database (Accession No. JQ839267). Sequence analysis revealed that the BMI U2AF2 coding sequence consisted of 1416 bp and encoded 471 amino acids with a molecular weight of 53.12 kDa. The protein sequence has high sequence homology with U2AF65 of 6 species - Homo sapiens (100%), Equus caballus (100%), Canis lupus (100%), Macaca mulatta (99.8%), Bos taurus (74.4%), and Mus musculus (74.4%). The phylogenetic tree analysis revealed that BMI U2AF65 has a closer genetic relationship with B. taurus U2AF65 than with U2AF65 of E. caballus, C. lupus, M. mulatta, H. sapiens, and M. musculus. RT-PCR analysis showed that BMI U2AF2 was most highly expressed in the brain; moderately expressed in the spleen, lung, muscle, and skin; and weakly expressed in the liver, kidney, and ovary. Its expression was nearly silent in the spinal cord, nerve fiber, heart, stomach, pancreas, and intestine. Three microRNA target sites were predicted in the CDS of BMI U2AF2 messenger RNA. Our results establish a foundation for further insight into this swine gene.

  3. The GLP-1 mimetic exenatide potentiates insulin secretion in healthy cats.

    PubMed

    Gilor, C; Graves, T K; Gilor, S; Ridge, T K; Rick, M

    2011-07-01

    The glucagon-like peptide-1 mimetic exenatide has a glucose-dependent insulinotropic effect, and it is effective in controlling blood glucose (BG) with minimal side effects in people with type 2 diabetes. Exenatide also delays gastric emptying, increases satiety, and improves β-cell function. We studied the effect of exenatide on insulin secretion during euglycemia and hyperglycemia in cats. Nine young, healthy, neutered, purpose-bred cats were used in a randomized, cross-over design. BG concentrations during an oral glucose tolerance test were determined in these cats previously. Two isoglycemic glucose clamps (mimicking the BG concentration during the oral glucose tolerance test) were performed in each cat on separate days, one without prior treatment (IGC) and the second with exenatide (1 μg/kg) injected subcutaneously 2 h before (ExIGC). BG, insulin, and exenatide concentrations were measured, and glucose infusion rates were recorded and compared in paired tests between the two experiments. After exenatide injection, insulin serum concentrations increased significantly (2.4-fold; range 1.0- to 9.2-fold; P = 0.004) within 15 min. This was followed by a mild decrease in BG concentration and a return of insulin concentration to baseline despite a continuous increase in serum exenatide concentrations. Insulin area under the curve (AUC) during ExIGC was significantly higher than insulin AUC during IGC (AUC ratio, 2.0 ± 0.4; P = 0.03). Total glucose infused was not significantly different between IGC and ExIGC. Exenatide was detectable in plasma at 15 min after injection. The mean exenatide concentration peaked at 45 min and then returned to baseline by 75 min. Exenatide was still detectable in the serum of three of five cats 8 h after injection. No adverse reactions to exenatide were observed. In conclusion, exenatide affects insulin secretion in cats in a glucose-dependent manner, similar to its effect in other species. Although this effect was not accompanied

  4. Normothermic and hypothermic models for studying the deleterious effects of hypoxia-reoxygenation on EDHF-mediated relaxation in isolated porcine coronary arteries.

    PubMed

    Ziberna, Lovro; Lunder, Mojca; Kuzner, Jernej; Drevensek, Gorazd

    2009-01-01

    The vasomotor response of the coronary artery is altered by hypoxia-reoxygenation (H-R) induced damage. The aim of our study was to compare and evaluate normothermic and hypothermic models which are suitable for future drug studies of vasoprotective action against H-R injury. Porcine coronary arterial rings were isolated and placed in Krebs-Henseleit (K-H) solution. Rings were exposed to normoxic conditions (control group) and two different H-R conditions: the first induced by a 95% N(2)-5% CO(2) gas mixture (40- and 60-min hypoxia) in a normothermic protocol, and the second induced by hypothermic (4 degrees C) hypoxia-reoxygenation in an air-tight beaker filled with K-H solution (24- and 48-hours hypoxia). Reoxygenation was applied by introducing K-H solution aerated with a 95% O(2)-5% CO(2) mixture under normothermic (37 degrees C) conditions. To test the EDHF-mediated relaxation by substance P, rings were first incubated in L-NNA, nitric oxide synthase inhibitor, and indomethacin, cyclooxygenase inhibitor, and then pre-contracted with thromboxane analogue U-46619. Analysis of the maximum relaxation of the arterial rings was performed by one-way ANOVA, followed by Bonferroni's post-test. Distal segments of the coronary artery responded faster to contraction induced by U-46619 and were relaxed by substance P to a greater extent than proximal segments. Maximal relaxations of arterial rings induced by a 10 nM solution of substance P were significantly reduced (p<0.001) from the values for normoxic rings (81.0+/-1.0%, n=30) after 40-min H-R (50.5+/-5.3%, n=30), 60-min H-R (32.1+/-3.5%, n=30), 24-hours hypothermic H-R (56.0+/-2.3%, n=30) and after 48-hours hypothermic H-R (38.5+/-5.1%, n=30). The model employing 40-min normothermic H-R is as effective as 24-hours hypothermic H-R, and 60-min normothermic H-R as 48-hours hypothermic H-R for studying the deleterious effects of H-R on EDHF-mediated relaxation.

  5. Rapid synthesis of carbohydrate derivatives, including mimetics of C-linked disaccharides and C-linked aza disaccharides, using the hetero-Diels-Alder reaction.

    PubMed

    Burland, Peter A; Coisson, David; Osborn, Helen M I

    2010-11-05

    In this work we demonstrate the value of performing a hetero-Diels-Alder reaction (HDAR) between Danishefsky's diene and a range of aldehydes or imines, under microwave irradiation. By using a range of aldehydes and imines, including those derived from carbohydrates, access to functionalized 2,3-dihydro-4H-pyran-4-ones or 2,3-dihydro-4-pyridinones in good to excellent synthetic yields is possible. A particular strength of the methodology is its ability to access mimetics of C-linked disaccharides and C-linked aza disaccharides, targets of current therapeutic interest, in a rapid, convenient, and diastereoselective manner. The effect of high pressure on the HDARs involving carbohydrate-derived aldehydes and imines is also explored, with enhancement in yields occurring for the aldehyde substrates. Finally, HDARs using carbohydrate derived ketones, enones, and enals are described under a range of conditions. Optimum results were obtained under high-pressure conditions, with highly functionalized carbohydrate derivatives being afforded, in good yields, in this way.

  6. Additional records and descriptions of the ant-mimetic plant bug genus Pilophorus from Thailand (Hemiptera: Heteroptera: Miridae: Phylinae: Pilophorini).

    PubMed

    Yasunaga, Tomohide; Yamada, Kazutaka; Artchawakom, Taksin

    2014-05-09

    Eleven species of the ant-mimetic plant bug genus Pilophorus Hahn from Thailand are documented, with photographic images of live individuals. Four new species with conventional, moderate antlike shape, Pilophorus meteorus, P. saovapruki, P. subparallelus and P. suwimonae, are described. Two known Thai species, P. alstoni Schuh and P. typicus (Distant), are further reported and diagnosed. Biological information including host association is provided for P. alstoni, P. meteorus, P. saovapruki and P. typicus. A checklist of all currently known species of Pilophorus in Thailand and a key to known Thai species are included. Pilophorus typicus is reported from Singapore for the first time.

  7. HscA and HscB stimulate [2Fe-2S] cluster transfer from IscU to apoferredoxin in an ATP-dependent reaction.

    PubMed

    Chandramouli, Kala; Johnson, Michael K

    2006-09-19

    The role of the Azotobacter vinelandii HscA/HscB cochaperone system in ISC-mediated iron-sulfur cluster biogenesis has been investigated in vitro by using CD and EPR spectrometry to monitor the effect of HscA, HscB, MgATP, and MgADP on the time course of cluster transfer from [2Fe-2S]IscU to apo-Isc ferredoxin. CD spectra indicate that both HscB and HscA interact with [2Fe-2S]IscU and the rate of cluster transfer was stimulated more than 20-fold in the presence stoichiometric HscA and HscB and excess MgATP. No stimulation was observed in the absence of either HscB or MgATP, and cluster transfer was found to be an ATP-dependent reaction based on concomitant phosphate production and the enhanced rates of cluster transfer in the presence of KCl which is known to stimulate HscA ATPase activity. The results demonstrate a role of the ISC HscA/HscB cochaperone system in facilitating efficient [2Fe-2S] cluster transfer from the IscU scaffold protein to acceptor proteins and that [2Fe-2S] cluster transfer from IscU is an ATP-dependent process. The data are consistent with the proposed regulation of the HscA ATPase cycle by HscB and IscU [Silberg, J. J., Tapley, T. L., Hoff, K. G., and Vickery, L. E. (2004) J. Biol. Chem. 279, 53924-53931], and mechanistic proposals for coupling of the HscA ATPase cycle with cluster transfer from [2Fe-2S]IscU to apo-IscFdx are discussed.

  8. Superoxide Dismutase (SOD)-mimetic M40403 Is Protective in Cell and Fly Models of Paraquat Toxicity

    PubMed Central

    Filograna, Roberta; Godena, Vinay K.; Sanchez-Martinez, Alvaro; Ferrari, Emanuele; Casella, Luigi; Beltramini, Mariano; Bubacco, Luigi; Whitworth, Alexander J.; Bisaglia, Marco

    2016-01-01

    Parkinson disease is a debilitating and incurable neurodegenerative disorder affecting ∼1–2% of people over 65 years of age. Oxidative damage is considered to play a central role in the progression of Parkinson disease and strong evidence links chronic exposure to the pesticide paraquat with the incidence of the disease, most probably through the generation of oxidative damage. In this work, we demonstrated in human SH-SY5Y neuroblastoma cells the beneficial role of superoxide dismutase (SOD) enzymes against paraquat-induced toxicity, as well as the therapeutic potential of the SOD-mimetic compound M40403. Having verified the beneficial effects of superoxide dismutation in cells, we then evaluated the effects using Drosophila melanogaster as an in vivo model. Besides protecting against the oxidative damage induced by paraquat treatment, our data demonstrated that in Drosophila M40403 was able to compensate for the loss of endogenous SOD enzymes, acting both at a cytosolic and mitochondrial level. Because previous clinical trials have indicated that the M40403 molecule is well tolerated in humans, this study may have important implication for the treatment of Parkinson disease. PMID:26953346

  9. The Role of U2AF1 Mutations in the Pathogenesis of Myelodysplastic Syndromes

    DTIC Science & Technology

    2015-10-01

    mutation, U2AF1(S34F), on hematopoiesis and pre-mRNA splicing in vivo, we created doxycycline-inducible U2AF1(WT) and U2AF1(S34F) transgenic mice...U2AF1(S34F) versus U2AF1(WT). Together, these results suggest that mutant U2AF1 expression contributes to the altered hematopoiesis and pre-mRNA...Spliceosome, Mouse Model, Hematopoiesis , RNA-seq, U2AF1 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME

  10. Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors.

    PubMed

    Sharp, Phillip P; Garnier, Jean-Marc; Hatfaludi, Tamas; Xu, Zhen; Segal, David; Jarman, Kate E; Jousset, Hélène; Garnham, Alexandra; Feutrill, John T; Cuzzupe, Anthony; Hall, Peter; Taylor, Scott; Walkley, Carl R; Tyler, Dean; Dawson, Mark A; Czabotar, Peter; Wilks, Andrew F; Glaser, Stefan; Huang, David C S; Burns, Christopher J

    2017-12-14

    A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c- MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.

  11. An in vitro study of interactions between insulin-mimetic zinc(II) complexes and selected plasma components.

    PubMed

    Enyedy, Eva Anna; Horváth, László; Gajda-Schrantz, Krisztina; Galbács, Gábor; Kiss, Tamás

    2006-12-01

    The speciations of some potent insulin-mimetic zinc(II) complexes of bidentate ligands: maltol and 1,2-dimethyl-3-hydroxypyridinone with (O,O) and picolinic acid with (N,O) coordination modes, were studied via solution equilibrium investigations of the ternary complex formation in the presence of small relevant bioligands of the blood serum such as cysteine, histidine and citric acid. Results show that formation of the ternary complexes, especially with cysteine, is favoured at physiological pH range in almost all systems studied. Besides these low molecular mass binders, serum proteins among others albumin and transferrin can bind zinc(II) or its complexes. Accordingly, the distribution of zinc(II) between the small and high molecular mass fractions of the serum was also studied by ultrafiltration. Modelling calculations relating to the distribution of zinc(II), using the stability constants of the ternary complexes studied and those of the serum proteins reported in the literature, confirmed the ultrafiltration results, namely, the primary role of albumin in zinc(II) binding among the low and high molecular mass components of the serum.

  12. Ising versus S U (2) 2 string-net ladder

    NASA Astrophysics Data System (ADS)

    Vidal, Julien

    2018-03-01

    We consider the string-net model obtained from S U (2) 2 fusion rules. These fusion rules are shared by two different sets of anyon theories. In this paper, we study the competition between the two corresponding non-Abelian quantum phases in the ladder geometry. A detailed symmetry analysis shows that the nontrivial low-energy sector corresponds to the transverse-field cluster model that displays a critical point described by the s o (2) 1 conformal field theory. Other sectors are obtained by freezing spins in this model.

  13. Building Customized University-to-Business (U2B) Partnerships

    ERIC Educational Resources Information Center

    Irvine, George; Verma, Lisa

    2013-01-01

    Continuing education (CE) units throughout the United States have successfully built University-to-Business (U2B) partnerships to provide greater value to their community partners and to increase revenue for the university. Our experience in building U2B partnerships and feedback from our partners--businesses, corporations, state agencies, and…

  14. U3Si2 behavior in H2O: Part I, flowing steam and the effect of hydrogen

    NASA Astrophysics Data System (ADS)

    Wood, E. Sooby; White, J. T.; Grote, C. J.; Nelson, A. T.

    2018-04-01

    Recent interest in U3Si2 as an advanced light water reactor fuel has driven assessment of numerous properties, but characterization of its response to H2O environments is absent from the literature. The behavior of U3Si2 in H2O containing atmospheres is investigated and presented in a two-part series of articles aimed to understand the degradation mechanism of U3Si2 in H2O. Reported here are thermogravimetric data for U3Si2 exposed to flowing steam at 250-470 °C. Additionally the response of U3Si2 to flowing Ar-6% H2 from 350 to 400 °C is presented. Microstructural degradation is observed following hours of exposure at 350 °C in steam. U3Si2 undergoes pulverization on the timescale of minutes when temperatures are increased above 400 °C. This mechanism is accelerated in flowing Ar-H2 at the same temperatures.

  15. Accurate ab initio calculations which demonstrate a 3 Pi u ground state for Al2

    NASA Technical Reports Server (NTRS)

    Bauschlicher, Charles W., Jr.; Partridge, Harry; Langhoff, Stephen R.; Taylor, Peter R.; Walch, Stephen P.

    1986-01-01

    The spectroscopic parameters and separations between the three low-lying X 3 Pi u, A 3 Sigma g -, and a 1 Sigma g + states of Al2 are studied as a function of both the one-particle and n-particle basis set. Approximate correlation treatments are calibrated against full Cl calculations correlating the six valence electrons in a double-zeta plus two d-function basis set. Since the CASSCF/MRCI 3 Pi u to 3 Sigma g - separation is in excellent agreement wtih the FCI value, the MRCI calculations were carried out in an extended (20s13p6d4f)/(6s5p3d2f) gaussian basis. Including a small correction for relativistic effects, the best estimate is that 3 Sigma g - state lies 174/cm above the 3 Pi u ground state. The 1 Sigma g + state lies at least 2000/cm higher in energy. At the CPF level, inclusion of 2s and 2p correlation has little effect on D sub e, reduces T sub e by only 26/cm, and shortens the bond lengths by about 0.02 a sub o. Further strong support for a 3 Pi u ground state comes from the experimental absorption spectra, since both observed transitions can be convincingly assigned as 3 Pi u yields 3 Pi g. The (2) 3 Pi g state is observed to be sensitive to the level of correlation treatment, and to have its minimum shifted to shorter rho values, such that the strongest experimental absorption peak probably corresponds to the 0 yields 2 transition.

  16. Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome.

    PubMed

    Parrini, Martina; Ghezzi, Diego; Deidda, Gabriele; Medrihan, Lucian; Castroflorio, Enrico; Alberti, Micol; Baldelli, Pietro; Cancedda, Laura; Contestabile, Andrea

    2017-12-04

    Down syndrome (DS) is caused by the triplication of human chromosome 21 and represents the most frequent genetic cause of intellectual disability. The trisomic Ts65Dn mouse model of DS shows synaptic deficits and reproduces the essential cognitive disabilities of the human syndrome. Aerobic exercise improved various neurophysiological dysfunctions in Ts65Dn mice, including hippocampal synaptic deficits, by promoting synaptogenesis and neurotransmission at glutamatergic terminals. Most importantly, the same intervention also prompted the recovery of hippocampal adult neurogenesis and synaptic plasticity and restored cognitive performance in trisomic mice. Additionally, the expression of brain-derived neurotrophic factor (BDNF) was markedly decreased in the hippocampus of patients with DS. Since the positive effect of exercise was paralleled by increased BDNF expression in trisomic mice, we investigated the effectiveness of a BDNF-mimetic treatment with 7,8-dihydroxyflavone at alleviating intellectual disabilities in the DS model. Pharmacological stimulation of BDNF signaling rescued synaptic plasticity and memory deficits in Ts65Dn mice. Based on our findings, Ts65Dn mice benefit from interventions aimed at promoting brain plasticity, and we provide evidence that BDNF signaling represents a potentially new pharmacological target for treatments aimed at rescuing cognitive disabilities in patients with DS.

  17. Lymphatic Transport and Lymphocyte Targeting of a Triglyceride Mimetic Prodrug Is Enhanced in a Large Animal Model: Studies in Greyhound Dogs.

    PubMed

    Han, Sifei; Hu, Luojuan; Gracia; Quach, Tim; Simpson, Jamie S; Edwards, Glenn A; Trevaskis, Natalie L; Porter, Christopher J H

    2016-10-03

    In previous studies, a triglyceride (TG) mimetic prodrug of the model immunomodulator mycophenolic acid (MPA) was shown to significantly enhance lymphatic transport of MPA-related species in the rat. The rat gastrointestinal tract, however, is somewhat different from that in higher order species such as dogs and humans and may underestimate lymphatic transport. Here the effectiveness of the prodrug strategy has been examined in conscious greyhound dogs, the GI physiology of which is more representative of that in humans. The bioavailability and lymphatic transport of free MPA and total MPA related materials were examined following oral administration of the parent drug (MPA) and the prodrug (2-MPA-TG) to both thoracic lymph duct cannulated and intact (noncannulated) greyhound dogs. The enrichment of free MPA in lymph nodes and lymph-derived lymphocytes was also determined to examine the efficiency of drug targeting to potential sites of action within the lymph. Via biochemical integration into a series of site-specific metabolic processes, the prodrug markedly increased (288-fold) lymphatic transport of total MPA related material (present as re-esterified 2-MPA-TG) when compared to the parent MPA and the extent of lymphatic transport was significantly greater in the dog (36.4% of the dose recovered in lymph) when compared to the previous data in the rat (13.4% of the dose). Conversion from 2-MPA-TG derivatives to parent MPA occurred in vivo, resulting in a marked increase in MPA concentrations in lymph nodes (5-6-fold) and lymph lymphocytes (21-fold), when compared to animals administered the parent drug. In conclusion, the data demonstrate that the TG prodrug of MPA facilitates efficient delivery of MPA to the lymphatic system in dogs and suggest that the TG prodrug strategy may more effectively facilitate targeted delivery in large animals than in rats.

  18. Collagen mimetic peptide engineered M13 bacteriophage for collagen targeting and imaging in cancer.

    PubMed

    Jin, Hyo-Eon; Farr, Rebecca; Lee, Seung-Wuk

    2014-11-01

    Collagens are over-expressed in various human cancers and subsequently degraded and denatured by proteolytic enzymes, thus making them a target for diagnostics and therapeutics. Genetically engineered bacteriophage (phage) is a promising candidate for the development of imaging or therapeutic materials for cancer collagen targeting due to its promising structural features. We genetically engineered M13 phages with two functional peptides, collagen mimetic peptide and streptavidin binding peptide, on their minor and major coat proteins, respectively. The resulting engineered phage functions as a therapeutic or imaging material to target degraded and denatured collagens in cancerous tissues. We demonstrated that the engineered phages are able to target and label abnormal collagens expressed on A549 human lung adenocarcinoma cells after the conjugation with streptavidin-linked fluorescent agents. Our engineered collagen binding phage could be a useful platform for abnormal collagen imaging and drug delivery in various collagen-related diseases. Published by Elsevier Ltd.

  19. Preparation of UO2, ThO2 and (Th,U)O2 pellets from photochemically-prepared nano-powders

    NASA Astrophysics Data System (ADS)

    Pavelková, Tereza; Čuba, Václav; de Visser-Týnová, Eva; Ekberg, Christian; Persson, Ingmar

    2016-02-01

    Photochemically-induced preparation of nano-powders of crystalline uranium and/or thorium oxides and their subsequent pelletizing has been investigated. The preparative method was based on the photochemically induced formation of amorphous solid precursors in aqueous solution containing uranyl and/or thorium nitrate and ammonium formate. The EXAFS analyses of the precursors shown that photon irradiation of thorium containing solutions yields a compound with little long-range order but likely "ThO2 like" and the irradiation of uranium containing solutions yields the mixture of U(IV) and U(VI) compounds. The U-containing precursors were carbon free, thus allowing direct heat treatment in reducing atmosphere without pre-treatment in the air. Subsequent heat treatment of amorphous solid precursors at 300-550 °C yielded nano-crystalline UO2, ThO2 or solid (Th,U)O2 solutions with high purity, well-developed crystals with linear crystallite size <15 nm. The prepared nano-powders of crystalline oxides were pelletized without any binder (pressure 500 MPa), the green pellets were subsequently sintered at 1300 °C under an Ar:H2 (20:1) mixture (UO2 and (Th,U)O2 pellets) or at 1600 °C in ambient air (ThO2 pellets). The theoretical density of the sintered pellets varied from 91 to 97%.

  20. 7 CFR 51.1149 - U.S. No. 2 Russet.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... tolerances see § 51.1151. (b) Internal quality: Lots meeting the internal requirements for “U.S. Grade AA... 7 Agriculture 2 2010-01-01 2010-01-01 false U.S. No. 2 Russet. 51.1149 Section 51.1149 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing...

  1. Zn2+ selectively stabilizes FdU-substituted DNA through a unique major groove binding motif

    PubMed Central

    Ghosh, Supratim; Salsbury, Freddie R.; Horita, David A.; Gmeiner, William H.

    2011-01-01

    We report, based on semi-empirical calculations, that Zn2+ binds duplex DNA containing consecutive FdU–dA base pairs in the major groove with distorted trigonal bipyramidal geometry. In this previously uncharacterized binding motif, O4 and F5 on consecutive FdU are axial ligands while three water molecules complete the coordination sphere. NMR spectroscopy confirmed Zn2+ complexation occurred with maintenance of base pairing while a slight hypsochromic shift in circular dichroism (CD) spectra indicated moderate structural distortion relative to B-form DNA. Zn2+ complexation inhibited ethidium bromide (EtBr) intercalation and stabilized FdU-substituted duplex DNA (ΔTm > 15°C). Mg2+ neither inhibited EtBr complexation nor had as strong of a stabilizing effect. DNA sequences that did not contain consecutive FdU were not stabilized by Zn2+. A lipofectamine preparation of the Zn2+–DNA complex displayed enhanced cytotoxicity toward prostate cancer cells relative to the individual components prepared as lipofectamine complexes indicating the potential utility of Zn2+–DNA complexes for cancer treatment. PMID:21296761

  2. Extreme Mechanical Behavior of Nacre-Mimetic Graphene-Oxide and Silk Nanocomposites.

    PubMed

    Xie, Wanting; Tadepalli, Sirimuvva; Park, Sang Hyun; Kazemi-Moridani, Amir; Jiang, Qisheng; Singamaneni, Srikanth; Lee, Jae-Hwang

    2018-02-14

    Biological materials have the ability to withstand extreme mechanical forces due to their unique multilevel hierarchical structure. Here, we fabricated a nacre-mimetic nanocomposite comprised of silk fibroin and graphene oxide that exhibits hybridized dynamic responses arising from alternating high-contrast mechanical properties of the components at the nanoscale. Dynamic mechanical behavior of these nanocomposites is assessed through a microscale ballistic characterization using a 7.6 μm diameter silica sphere moving at a speed of approximately 400 m/s. The volume fraction of graphene oxide in these composites is systematically varied from 0 to 32 vol % to quantify the dynamic effects correlating with the structural morphologies of the graphene oxide flakes. Specific penetration energy of the films rapidly increases as the distribution of graphene oxide flakes evolves from noninteracting, isolated sheets to a partially overlapping continuous sheet. The specific penetration energy of the nanocomposite at the highest graphene oxide content tested here is found to be significantly higher than that of Kevlar fabrics and close to that of pure multilayer graphene. This study evidently demonstrates that the morphologies of nanoscale constituents and their interactions are critical to realize scalable high-performance nanocomposites using typical nanomaterial constituents having finite dimensions.

  3. The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons

    PubMed Central

    2014-01-01

    6-hydroxydopamine (6-OHDA) is one of the most commonly used toxins for modeling degeneration of dopaminergic (DA) neurons in Parkinson's disease. 6-OHDA also causes axonal degeneration, a process that appears to precede the death of DA neurons. To understand the processes involved in 6-OHDA-mediated axonal degeneration, a microdevice designed to isolate axons fluidically from cell bodies was used in conjunction with green fluorescent protein (GFP)-labeled DA neurons. Results showed that 6-OHDA quickly induced mitochondrial transport dysfunction in both DA and non-DA axons. This appeared to be a general effect on transport function since 6-OHDA also disrupted transport of synaptophysin-tagged vesicles. The effects of 6-OHDA on mitochondrial transport were blocked by the addition of the SOD1-mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), as well as the anti-oxidant N-acetyl-cysteine (NAC) suggesting that free radical species played a role in this process. Temporally, microtubule disruption and autophagy occurred after transport dysfunction yet before DA cell death following 6-OHDA treatment. The results from the study suggest that ROS-mediated transport dysfunction occurs early and plays a significant role in inducing axonal degeneration in response to 6-OHDA treatment. PMID:24885281

  4. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration.

    PubMed

    Singh, Sandeep; Singh, Abhishek Kumar; Garg, Geetika; Rizvi, Syed Ibrahim

    2018-01-15

    In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D-galactose (D-gal) induced accelerated and natural aging models of rat. Fisetin was supplemented (15mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500mg/kg b.w subcutaneously) and naturally aged rats for 6weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane-bound ion transporter activities in brain tissues. Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1β and TNF-α) and Sirt-2 genes respectively in aging brain. The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Radioligand binding and functional characterization of recombinant human NmU1 and NmU2 receptors stably expressed in clonal human embryonic kidney-293 cells.

    PubMed

    Aiyar, Nambi; Disa, Jyoti; Foley, James J; Buckley, Peter T; Wixted, William E; Pullen, Mark; Shabon, Usman; Dul, Edward; Szekeres, Philip G; Elshourbagy, Nabil A; Sarau, Henry M; Appelbaum, Edward; Bolaky, Jane

    2004-09-01

    Neuromedin U (NmU) is a smooth muscle contracting peptide. Recently, two G-protein-coupled receptors for NmU (NmU1R and NmU2R) have been cloned having approximately 50% homology. They have distinct patterns of expression suggesting they may have different biological functions. This study provides a comprehensive characterization of both NmU receptors expressed in human embryonic kidney 293 cells. [125I]hNmU binding to the recombinant NmU receptors was rapid, saturable, of high affinity and to a single population of binding sites. Exposure of these cells to NmU isopeptides resulted in an increase in intracellular [Ca2+]i release (EC50 value of 0.50 +/- 0.10 nmol/l) and inositol phosphate formation (EC50 1.6 +/- 0.2 and 1.50 +/- 0.4 nmol/l for NmU1R and NmU2R respectively). Furthermore, hNmU inhibited forskolin (3 micromol/l)-stimulated accumulation of cAMP in intact HEK-293 cells expressing either NmU1R or NmU2R. The inhibitory effect was significant for the cells expressing NmU2R with IC50 value of 0.80 +/- 0.21 nmol/l. In summary, both NmU1R and NmU2R in HEK-293 cells have similar signaling capability. Copyright 2004 S. Karger AG, Basel

  6. The high-temperature heat capacity of the (Th,U)O 2 and (U,Pu)O 2 solid solutions

    DOE PAGES

    Valu, S. O.; Benes, O.; Manara, D.; ...

    2016-11-09

    The enthalpy increment data for the (Th,U)O 2 and (U,Pu)O 2 solid solutions are reviewed and complemented with new experimental data (400–1773 K) and many-body potential model simulations. The results of the review show that from room temperature up to about 2000 K the enthalpy data are in agreement with the additivity rule (Neumann-Kopp) in the whole composition range. Above 2000 K the effect of Oxygen Frenkel Pair (OFP) formation leads to an excess enthalpy (heat capacity) that is modeled using the enthalpy and entropy of OFP formation from the end-members. Here, a good agreement with existing experimental work ismore » observed, and a reasonable agreement with the results of the many-body potential model, which indicate the presence of the diffuse Bredig (superionic) transition that is not found in the experimental enthalpy increment data.« less

  7. Metal stabilization of collagen and de novo designed mimetic peptides

    PubMed Central

    Parmar, Avanish S.; Xu, Fei; Pike, Douglas H.; Belure, Sandeep V.; Hasan, Nida F.; Drzewiecki, Kathryn E.; Shreiber, David I.; Nanda, Vikas

    2017-01-01

    We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix. PMID:26225466

  8. Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides.

    PubMed

    Parmar, Avanish S; Xu, Fei; Pike, Douglas H; Belure, Sandeep V; Hasan, Nida F; Drzewiecki, Kathryn E; Shreiber, David I; Nanda, Vikas

    2015-08-18

    We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo- and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal-specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix.

  9. Local structure and charge distribution in the UO(2)-U(4)O(9) system.

    PubMed

    Conradson, Steven D; Manara, Dario; Wastin, Franck; Clark, David L; Lander, Gerard H; Morales, Luis A; Rebizant, Jean; Rondinella, Vincenzo V

    2004-11-01

    Analysis of X-ray absorption fine structure spectra of UO(2+x) for x = 0-0.20 (UO(2)--U(4)O(9)) reveals that the adventitious O atoms are incorporated as oxo groups with U--O distances of 1.74 A, most likely associated with U(VI), that occur in clusters so that the UO(2) fraction of the material largely remains intact. In addition to the formation of some additional longer U--O bonds, the U sublattice consists of an ordered portion that displays the original U--U distance and a spectroscopically silent, glassy part. This is very different from previous models derived from neutron diffraction that maintained long U--O distances and high U--O coordination numbers. UO(2+x) also differs from PuO(2+x) in its substantially shorter An-oxo distances and no sign of stable coordination with H(2)O and its hydrolysis products.

  10. Peroxide generation by p47phox-Src activation of Nox2 has a key role in protein kinase C-induced arterial smooth muscle contraction.

    PubMed

    Gupte, Sachin A; Kaminski, Pawel M; George, Shimran; Kouznestova, Lioubov; Olson, Susan C; Mathew, Rajamma; Hintze, Thomas H; Wolin, Michael S

    2009-04-01

    Protein kinase C (PKC) stimulation of NAD(P)H oxidases (Nox) is an important component of multiple vascular disease processes; however, the relationship between oxidase activation and the regulation of vascular smooth muscle contraction by PKC remains poorly understood. Therefore, we examined the signaling cascade of PKC-elicited Nox activation and the role of superoxide and hydrogen peroxide in mediating PKC-induced vascular contraction. Endothelium-denuded bovine coronary arteries showed a PKC-dependent basal production of lucigenin (5 muM)-detected Nox oxidase-derived superoxide, which was stimulated fourfold by PKC activation with 10 muM phorbol 12,13-dibutyrate (PDBu). PDBu appeared to increase superoxide generation by Nox2 through both p47(phox) and peroxide-dependent Src activation mechanisms based on the actions of inhibitors, properties of Src phosphorylation, and the loss of responses in aorta from mice deficient in Nox2 and p47(phox). The actions of inhibitors of contractile regulating mechanisms, scavengers of superoxide and peroxide, and responses in knockout mouse aortas suggest that a major component of the contraction elicited by PDBu appeared to be mediated through peroxide derived from Nox2 activation stimulating force generation through Rho kinase and calmodulin kinase-II mechanisms. Superoxide generated by PDBu also attenuated relaxation to nitroglycerin. Peroxide-derived from Nox2 activation by PKC appeared to be a major contributor to the thromboxane A(2) receptor agonist U46619 (100 nM)-elicited contraction of coronary arteries. Thus a p47(phox) and Src kinase activation of peroxide production by Nox2 appears to be an important contributor to vascular contractile mechanisms mediated through activation of PKC.

  11. Human U2 snRNA Genes Exhibit a Persistently Open Transcriptional State and Promoter Disassembly at Metaphase▿

    PubMed Central

    Pavelitz, Thomas; Bailey, Arnold D.; Elco, Christopher P.; Weiner, Alan M.

    2008-01-01

    In mammals, small multigene families generate spliceosomal U snRNAs that are nearly as abundant as rRNA. Using the tandemly repeated human U2 genes as a model, we show by footprinting with DNase I and permanganate that nearly all sequences between the enhancer-like distal sequence element and the initiation site are protected during interphase whereas the upstream half of the U2 snRNA coding region is exposed. We also show by chromatin immunoprecipitation that the SNAPc complex, which binds the TATA-like proximal sequence element, is removed at metaphase but remains bound under conditions that induce locus-specific metaphase fragility of the U2 genes, such as loss of CSB, BRCA1, or BRCA2 function, treatment with actinomycin D, or overexpression of the tetrameric p53 C terminus. We propose that the U2 snRNA promoter establishes a persistently open state to facilitate rapid reinitiation and perhaps also to bypass TFIIH-dependent promoter melting; this open state would then be disassembled to allow metaphase chromatin condensation. PMID:18378697

  12. U 3Si 2 behavior in H 2O: Part I, flowing steam and the effect of hydrogen

    DOE PAGES

    Wood, Elizabeth Sooby; White, Joshua Taylor; Grote, Christopher John; ...

    2018-01-17

    Recent interest in U 3Si 2 as an advanced light water reactor fuel has driven assessment of numerous properties, but characterization of its response to H 2O environments is absent from the literature. The behavior of U 3Si 2 in H 2O containing atmospheres is investigated and presented in a two-part series of articles aimed to understand the degradation mechanism of U 3Si 2 in H 2O. Reported here are thermogravimetric data for U 3Si 2 exposed to flowing steam at 250–470 °C. Additionally the response of U 3Si 2 to flowing Ar-6% H 2 from 350 to 400 °Cmore » is presented. Microstructural degradation is observed following hours of exposure at 350 °C in steam. U 3Si 2 undergoes pulverization on the timescale of minutes when temperatures are increased above 400 °C. In conclusion, this mechanism is accelerated in flowing Ar-H 2 at the same temperatures.« less

  13. U 3Si 2 behavior in H 2O: Part I, flowing steam and the effect of hydrogen

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wood, Elizabeth Sooby; White, Joshua Taylor; Grote, Christopher John

    Recent interest in U 3Si 2 as an advanced light water reactor fuel has driven assessment of numerous properties, but characterization of its response to H 2O environments is absent from the literature. The behavior of U 3Si 2 in H 2O containing atmospheres is investigated and presented in a two-part series of articles aimed to understand the degradation mechanism of U 3Si 2 in H 2O. Reported here are thermogravimetric data for U 3Si 2 exposed to flowing steam at 250–470 °C. Additionally the response of U 3Si 2 to flowing Ar-6% H 2 from 350 to 400 °Cmore » is presented. Microstructural degradation is observed following hours of exposure at 350 °C in steam. U 3Si 2 undergoes pulverization on the timescale of minutes when temperatures are increased above 400 °C. In conclusion, this mechanism is accelerated in flowing Ar-H 2 at the same temperatures.« less

  14. BH3-mimetic small molecule inhibits the growth and recurrence of adenoid cystic carcinoma

    PubMed Central

    Acasigua, Gerson A.; Warner, Kristy A.; Nör, Felipe; Helman, Joseph; Pearson, Alexander T.; Fossati, Anna C.; Wang, Shaomeng; Nör, Jacques E.

    2015-01-01

    Objectives To evaluate the anti-tumor effect of BM-1197, a new potent and highly specific small molecule inhibitor of Bcl-2/Bcl-xL, in preclinical models of human adenoid cystic carcinoma (ACC). Methods Low passage primary human adenoid cystic carcinoma cells (UM-HACC-2A,-2B,-5,-6) and patient-derived xenograft (PDX) models (UM-PDX-HACC) were developed from surgical specimens obtained from 4 patients. The effect of BM-1197 on cell viability and cell cycle were evaluated in vitro using this panel of low passage ACC cells. The effect of BM-1197 on tumor growth, recurrence and tumor cell apoptosis in vivo was evaluated with the PDX model of ACC (UM-PDX-HACC-5). Results Exposure of low passage primary human ACC cells to BM-1197 mediated an IC50 of 0.92-2.82 μM. This correlated with an increase in the fraction of apoptotic cells (p<0.0001) and an increase in caspase-3 activity (p<0.0001), but no noticeable differences in cell cycle (p>0.05). In vivo, BM-1197 inhibited tumor growth (p=0.0256) and induced tumor cell apoptosis (p=0.0165) without causing significant systemic toxicities, as determined by mouse weight over time. Surprisingly, weekly BM-1197 decreased the incidence of tumor recurrence (p=0.0297), as determined by Kaplan-Meier analysis. Conclusion These data demonstrated that single agent BM-1197 induces apoptosis and inhibits tumor growth in preclinical models of adenoid cystic carcinoma. Notably, single agent BM-1197 inhibited tumor recurrence, which is considered a major clinical challenge in the clinical management of adenoid cystic carcinoma. Collectively, these results suggest that patients with adenoid cystic carcinoma might benefit from therapy with a BH3-mimetic small molecule. PMID:26121939

  15. Cell-free expressed bacteriorhodopsin in different soluble membrane mimetics: biophysical properties and NMR accessibility.

    PubMed

    Etzkorn, Manuel; Raschle, Thomas; Hagn, Franz; Gelev, Vladimir; Rice, Amanda J; Walz, Thomas; Wagner, Gerhard

    2013-03-05

    Selecting a suitable membrane-mimicking environment is of fundamental importance for the investigation of membrane proteins. Nonconventional surfactants, such as amphipathic polymers (amphipols) and lipid bilayer nanodiscs, have been introduced as promising environments that may overcome intrinsic disadvantages of detergent micelle systems. However, structural insights into the effects of different environments on the embedded protein are limited. Here, we present a comparative study of the heptahelical membrane protein bacteriorhodopsin in detergent micelles, amphipols, and nanodiscs. Our results confirm that nonconventional environments can increase stability of functional bacteriorhodopsin, and demonstrate that well-folded heptahelical membrane proteins are, in principle, accessible by solution-NMR methods in amphipols and phospholipid nanodiscs. Our data distinguish regions of bacteriorhodopsin that mediate membrane/solvent contacts in the tested environments, whereas the protein's functional inner core remains almost unperturbed. The presented data allow comparing the investigated membrane mimetics in terms of NMR spectral quality and thermal stability required for structural studies. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Mimetics of Suppressor of cytokine signalling 3: novel potential therapeutics in triple breast cancer.

    PubMed

    La Manna, Sara; Lee, Eunmi; Ouzounova, Maria; Di Natale, Concetta; Novellino, Ettore; Merlino, Antonello; Korkaya, Hasan; Marasco, Daniela

    2018-05-11

    Suppressor of cytokine signaling (SOCS) family of proteins plays critical role in the regulation of immune responses controlling JAK/STAT mediated inflammatory cytokines. Among the members, SOCS1 and SOCS3 contain a kinase inhibitory region (KIR) and SOCS3 binds to JAK/STAT/gp130 complex by inhibiting the downstream signaling and suppressing inflammatory cytokines. Loss or reduced levels of SOCS3 have been linked to cancer-associated inflammation and suppressive immunity leading to enhanced tumour growth and metastasis. In line with these reports, we previously demonstrated that proteolytic degradation of SOCS3 in triple negative breast cancer (TNBC) subtype drives the expression of inflammatory cytokines. Therefore, we postulated that SOCS3 mimetics might suppress the inflammatory cytokine production in TNBC subtype and inhibit tumor growth and metastasis. Here we designed and characterized five linear peptides derived from the N-terminal region of SOCS3 encompassing regions that interface with the JAK2/gp130 complex by using the Circular Dichroism and Surface Plasmon Resonance spectroscopies. The KIRESS peptide resulted the sequence containing the most part of the hot-spots required for binding to JAK2 and was further investigated in vivo in mouse xenografts of MDA-MB-231-luci tumours as models of human TNBC subtype. Expectedly, this peptide showed a significant inhibition of primary tumour growth and pulmonary metastasis. Our studies suggest that SOCS3 peptidomimetics may possess a therapeutic potential in aggressive cancers, such as TNBC subtype, with activated inflammatory cytokines. This article is protected by copyright. All rights reserved. © 2018 UICC.

  17. Tetrahalide complexes of the [U(NR)2]2+ ion: synthesis, theory, and chlorine K-edge X-ray absorption spectroscopy.

    PubMed

    Spencer, Liam P; Yang, Ping; Minasian, Stefan G; Jilek, Robert E; Batista, Enrique R; Boland, Kevin S; Boncella, James M; Conradson, Steven D; Clark, David L; Hayton, Trevor W; Kozimor, Stosh A; Martin, Richard L; MacInnes, Molly M; Olson, Angela C; Scott, Brian L; Shuh, David K; Wilkerson, Marianne P

    2013-02-13

    Synthetic routes to salts containing uranium bis-imido tetrahalide anions [U(NR)(2)X(4)](2-) (X = Cl(-), Br(-)) and non-coordinating NEt(4)(+) and PPh(4)(+) countercations are reported. In general, these compounds can be prepared from U(NR)(2)I(2)(THF)(x) (x = 2 and R = (t)Bu, Ph; x = 3 and R = Me) upon addition of excess halide. In addition to providing stable coordination complexes with Cl(-), the [U(NMe)(2)](2+) cation also reacts with Br(-) to form stable [NEt(4)](2)[U(NMe)(2)Br(4)] complexes. These materials were used as a platform to compare electronic structure and bonding in [U(NR)(2)](2+) with [UO(2)](2+). Specifically, Cl K-edge X-ray absorption spectroscopy (XAS) and both ground-state and time-dependent hybrid density functional theory (DFT and TDDFT) were used to probe U-Cl bonding interactions in [PPh(4)](2)[U(N(t)Bu)(2)Cl(4)] and [PPh(4)](2)[UO(2)Cl(4)]. The DFT and XAS results show the total amount of Cl 3p character mixed with the U 5f orbitals was roughly 7-10% per U-Cl bond for both compounds, which shows that moving from oxo to imido has little effect on orbital mixing between the U 5f and equatorial Cl 3p orbitals. The results are presented in the context of recent Cl K-edge XAS and DFT studies on other hexavalent uranium chloride systems with fewer oxo or imido ligands.

  18. HscA and HscB stimulate [2Fe-2S] cluster transfer from IscU to apo-ferredoxin in an ATP-dependent reaction†

    PubMed Central

    Chandramouli, Kala; Johnson, Michael K.

    2008-01-01

    The role of the Azotobacter vinelandii HscA/HscB co-chaperone system in ISC-mediated iron-sulfur cluster biogenesis has been investigated in vitro by using CD and EPR spectrometry to monitor the effect of HscA, HscB, MgATP, and MgADP on the time course of cluster transfer from [2Fe-2S]IscU to apo-Isc ferredoxin. CD spectra indicate that both HscB and HscA interact with [2Fe-2S] IscU and the rate of cluster transfer was stimulated more than 20-fold in the presence stoichiometric HscA and HscB and excess MgATP. No stimulation was observed in the absence of either HscB or MgATP and cluster transfer was found to be an ATP-dependent reaction based on concomitant phosphate production and the enhanced rates of cluster transfer in the presence of KCl which is known to stimulated HscA ATPase activity. The results demonstrate a role of the ISC HscA/HscB co-chaperone system in facilitating efficient [2Fe-2S] cluster transfer from the IscU scaffold protein to acceptor proteins and that [2Fe-2S] cluster transfer from IscU is an ATP-dependent process. The data are consistent with the proposed regulation of the HscA ATPase cycle by HscB and IscU (Silberg, J. J., Tapley, T. L., Hoff, K. G., and Vickery, L. E. (2004) J. Biol. Chem. 279, 53924-53931), and mechanistic proposals for coupling of the HscA ATPase cycle with cluster transfer from [2Fe-2S]IscU to apo-IscFdx are discussed. PMID:16964969

  19. 11 CFR 100.11 - State (2 U.S.C. 431(12)).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 11 Federal Elections 1 2010-01-01 2010-01-01 false State (2 U.S.C. 431(12)). 100.11 Section 100.11 Federal Elections FEDERAL ELECTION COMMISSION GENERAL SCOPE AND DEFINITIONS (2 U.S.C. 431) General Definitions § 100.11 State (2 U.S.C. 431(12)). State means each State of the United States, the District of...

  20. Microstructure of the irradiated U 3Si 2/Al silicide dispersion fuel

    NASA Astrophysics Data System (ADS)

    Gan, J.; Keiser, D. D.; Miller, B. D.; Jue, J.-F.; Robinson, A. B.; Madden, J. W.; Medvedev, P. G.; Wachs, D. M.

    2011-12-01

    The silicide dispersion fuel of U 3Si 2/Al is recognized as the best performance fuel for many nuclear research and test reactors with up to 4.8 gU/cm 3 fuel loading. An irradiated U 3Si 2/Al dispersion fuel ( 235U ˜ 75%) from the high-flux side of a fuel plate (U0R040) from the Reduced Enrichment for Research and Test Reactors (RERTR)-8 test was characterized using transmission electron microscopy (TEM). The fuel was irradiated in the Advanced Test Reactor (ATR) for 105 days. The average irradiation temperature and fission density of the U 3Si 2 fuel particles for the TEM sample are estimated to be approximately 110 °C and 5.4 × 10 27 f/m 3. The characterization was performed using a 200-kV TEM. The U/Si ratio for the fuel particle and (Si + Al)/U for the fuel-matrix-interaction layer are approximately 1.1 and 4-10, respectively. The estimated average diameter, number density and volume fraction for small bubbles (<1 μm) in the fuel particle are ˜94 nm, 1.05 × 10 20 m -3 and ˜11%, respectively. The results and their implication on the performance of the U 3Si 2/Al silicide dispersion fuel are discussed.

  1. Virus-mimetic polyplex particles for systemic and inflammation-specific targeted delivery of large genetic contents.

    PubMed

    Kang, S; Lu, K; Leelawattanachai, J; Hu, X; Park, S; Park, T; Min, I M; Jin, M M

    2013-11-01

    Systemic and target-specific delivery of large genetic contents has been difficult to achieve. Although viruses effortlessly deliver kilobase-long genome into cells, its clinical use has been hindered by serious safety concerns and the mismatch between native tropisms and desired targets. Nonviral vectors, in contrast, are limited by low gene transfer efficiency and inherent cytotoxicity. Here we devised virus-mimetic polyplex particles (VMPs) based on electrostatic self-assembly among polyanionic peptide (PAP), cationic polymer polyethyleneimine (PEI) and nucleic acids. We fused PAP to the engineered ligand-binding domain of integrin αLβ2 to target intercellular adhesion molecule-1 (ICAM-1), an inducible marker of inflammation. Fully assembled VMPs packaged large genetic contents, bound specifically to target molecules, elicited receptor-mediated endocytosis and escaped endosomal pathway, resembling intracellular delivery processes of viruses. Unlike conventional PEI-mediated transfection, molecular interaction-dependent gene delivery of VMPs was unaffected by the presence of serum and achieved higher efficiency without toxicity. By targeting overexpressed ICAM-1, VMPs delivered genes specifically to inflamed endothelial cells and macrophages both in vitro and in vivo. Simplicity and versatility of the platform and inflammation-specific delivery may open up opportunities for multifaceted gene therapy that can be translated into the clinic and treat a broad range of debilitating immune and inflammatory diseases.

  2. Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden.

    PubMed

    Kataoka, Yu; Andrews, Jordan; Duong, MyNgan; Nguyen, Tracy; Schwarz, Nisha; Fendler, Jessica; Puri, Rishi; Butters, Julie; Keyserling, Constance; Paolini, John F; Dasseux, Jean-Louis; Nicholls, Stephen J

    2017-06-01

    CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study. Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001. CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis. 369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group. A B-PAV ≥30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV ≥30% but not in those with B-PAV <30% (-0.45%±2.65% vs. +0.34%±1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV ≥30% (-0.96%±0.34% vs. -0.25%±0.31%, P=0.01), whereas there were no differences between placebo (+0.09%±0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%±0.32%, P=0.39; 6 mg/kg; +0.27%±0.36%, P=0.76; 12 mg/kg; +0.32%±0.37%, P=0.97). Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy.

  3. Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden

    PubMed Central

    Kataoka, Yu; Andrews, Jordan; Duong, MyNgan; Nguyen, Tracy; Schwarz, Nisha; Fendler, Jessica; Puri, Rishi; Butters, Julie; Keyserling, Constance; Paolini, John F.; Dasseux, Jean-Louis

    2017-01-01

    Background CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study. Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001. Methods CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis. 369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group. Results A B-PAV ≥30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV ≥30% but not in those with B-PAV <30% (−0.45%±2.65% vs. +0.34%±1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV ≥30% (−0.96%±0.34% vs. −0.25%±0.31%, P=0.01), whereas there were no differences between placebo (+0.09%±0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%±0.32%, P=0.39; 6 mg/kg; +0.27%±0.36%, P=0.76; 12 mg/kg; +0.32%±0.37%, P=0.97). Conclusions Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy. PMID:28567351

  4. Crystallographic and magnetic properties of Cu2U-type hexaferrite

    NASA Astrophysics Data System (ADS)

    Kamishima, K.; Tajima, R.; Watanabe, K.; Kakizaki, K.; Fujimori, A.; Sakai, M.; Watanabe, K.; Abe, H.

    2015-02-01

    We have investigated the synthesis conditions, and the magnetic properties of the Cu2U-type hexagonal ferrite, Ba4Cu2Fe36O60. The Cu2U-type hexaferrite was synthesized at the sintering temperature of 1050 °C with the initial composition of Ba4.4Cu2Fe37.6O62.8 (Cu2U+0.2T-block). The saturation magnetizations at 300 K and 5 K are 46.8 A m2/kg and 65.0 A m2/kg, respectively. The Curie temperature is 420 °C which is lower than that of the M-type ferrite (450 °C) but higher than that of the Cu2Y-type ferrite (320 °C). The amount of the nonmagnetic impurity in this sample is estimated to be about 10 wt% by the electron probe micro analysis. We estimated the expected saturation magnetization to be 65.2 A m2/kg, by assuming the model of a Néel-type ferrimagnetic structure and the reduction of magnetization by the 10 wt% nonmagnetic impurity. This is consistent with the observed magnetization of 65.0 A m2/kg at 5 K.

  5. (234)U/(238)U signatures associated with uranium ore bodies: part 2 Manyingee.

    PubMed

    Lowson, Richard T; McIntyre, Mark G

    2013-04-01

    The Manyingee ore body is a roll-front U ore body located at depth in the Cretaceous sandstone sediments of a Proterozoic palaeo valley. It is located in a confined aquifer. The aquifer is recharged 4 km upstream by the Ashburton River. Groundwater samples were collected at and up to 4.7 km downstream of the ore body. The ground water (234)U/(238)U activity ratios (AR) were elevated to 1.86 in the vicinity of the ore body and then declined to 1.06 over the 4.7 km transect. The elevated (234)U/(238)U ARs are attributed to selective leaching of (234)U sites by oxidising waters, with α recoil as a necessary precursor to produce activated (234)U sites. Direct ejection into another phase following α recoil is considered to be a minor contributor to (234)U -(238)U disequilibrium in this environment. The profile is considered to be typical of the (234)U/(238)U AR profile at and down gradient of the redox front of a U ore body. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  6. High temperature heat capacity of (U, Am)O2±x

    NASA Astrophysics Data System (ADS)

    Epifano, E.; Beneš, O.; Vălu, O. S.; Zappey, J.; Lebreton, F.; Martin, P. M.; Guéneau, C.; Konings, R. J. M.

    2017-10-01

    Mixed uranium and americium dioxides (U, Am)O2±x are candidates as possible transmutation targets for generation IV reactors. In this work, the enthalpy increments of this solid solution were measured in the 470-1750 K temperature range by drop calorimetry for Am/(Am + U) ratios equal to 0.32, 0.39, 0.49, 0.58 and 0.68. Then, the heat capacity functions were obtained by derivation of the enthalpy data. The results of this work were compared to the heat capacity and enthalpy functions reported in the literature for the UO2 [1] and AmO2 [2] binary oxides and for the U0.9Am0.1O2±x, U0.8Am0.2O2±x mixed oxides [3]. From the obtained trend, it was found out that an excess contribution to the enthalpy increment appears for T > 1100 K in the compositions with Am/(Am + U)≥0.4 and a possible explanation attributing this effect to oxygen hypostoichiometry is provided. Finally, to verify the hypothesis, thermodynamic computations based on the CALPHAD method were performed for AmO2-x under air and the results confirmed that the source of the excess contribution is the formation of oxygen vacancies.

  7. 28 CFR 2.38 - Community supervision by U.S. Probation Officers.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 1 2011-07-01 2011-07-01 false Community supervision by U.S. Probation Officers. 2.38 Section 2.38 Judicial Administration DEPARTMENT OF JUSTICE PAROLE, RELEASE, SUPERVISION AND... § 2.38 Community supervision by U.S. Probation Officers. (a) Pursuant to sections 3655 and 4203(b)(4...

  8. 28 CFR 2.38 - Community supervision by U.S. Probation Officers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 1 2013-07-01 2013-07-01 false Community supervision by U.S. Probation Officers. 2.38 Section 2.38 Judicial Administration DEPARTMENT OF JUSTICE PAROLE, RELEASE, SUPERVISION AND... § 2.38 Community supervision by U.S. Probation Officers. (a) Pursuant to sections 3655 and 4203(b)(4...

  9. 28 CFR 2.38 - Community supervision by U.S. Probation Officers.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Community supervision by U.S. Probation Officers. 2.38 Section 2.38 Judicial Administration DEPARTMENT OF JUSTICE PAROLE, RELEASE, SUPERVISION AND... § 2.38 Community supervision by U.S. Probation Officers. (a) Pursuant to sections 3655 and 4203(b)(4...

  10. U2AF1 mutations alter splice site recognition in hematological malignancies.

    PubMed

    Ilagan, Janine O; Ramakrishnan, Aravind; Hayes, Brian; Murphy, Michele E; Zebari, Ahmad S; Bradley, Philip; Bradley, Robert K

    2015-01-01

    Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3' splice site recognition factor U2AF1 alter its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3' splice site motif in patients, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1's zinc finger domains. © 2015 Ilagan et al.; Published by Cold Spring Harbor Laboratory Press.

  11. Gaseous swelling of U 3 Si 2 during steady-state LWR operation: A rate theory investigation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Miao, Yinbin; Gamble, Kyle A.; Andersson, David

    Rate theory simulations of fission gas behavior in U 3Si 2 are reported for light water reactor (LWR) steady-state operation scenarios. We developed a model of U 3Si 2 and implemented into the GRASS-SST code based on available research reactor post-irradiation examination (PIE) data, and density functional theory (DFT) calculations of key material properties. Simplified peripheral models were also introduced to capture the fuel-cladding interaction. The simulations identified three regimes of U 3Si 2 swelling behavior between 390 K and 1190 K. Under typical steady-state LWR operating conditions where U 3Si 2 temperature is expected to be below 1000 K,more » intragranular bubbles are dominant and fission gas is retained in those bubbles. The consequent gaseous swelling is low and associated degradation in the fuel thermal conductivity is also limited. Those predictions of U 3Si 2 performance during steady-state operations in LWRs suggest that this fuel material is an appropriate LWR candidate fuel material. Fission gas behavior models established based on this work are being coupled to the thermo-mechanical simulation of the fuel behavior using the BISON fuel performance multi-dimensional finite element code.« less

  12. Gaseous swelling of U 3 Si 2 during steady-state LWR operation: A rate theory investigation

    DOE PAGES

    Miao, Yinbin; Gamble, Kyle A.; Andersson, David; ...

    2017-07-25

    Rate theory simulations of fission gas behavior in U 3Si 2 are reported for light water reactor (LWR) steady-state operation scenarios. We developed a model of U 3Si 2 and implemented into the GRASS-SST code based on available research reactor post-irradiation examination (PIE) data, and density functional theory (DFT) calculations of key material properties. Simplified peripheral models were also introduced to capture the fuel-cladding interaction. The simulations identified three regimes of U 3Si 2 swelling behavior between 390 K and 1190 K. Under typical steady-state LWR operating conditions where U 3Si 2 temperature is expected to be below 1000 K,more » intragranular bubbles are dominant and fission gas is retained in those bubbles. The consequent gaseous swelling is low and associated degradation in the fuel thermal conductivity is also limited. Those predictions of U 3Si 2 performance during steady-state operations in LWRs suggest that this fuel material is an appropriate LWR candidate fuel material. Fission gas behavior models established based on this work are being coupled to the thermo-mechanical simulation of the fuel behavior using the BISON fuel performance multi-dimensional finite element code.« less

  13. The effect of sodium thiopental as a GABA mimetic drug in neonatal period on expression of GAD65 and GAD67 genes in hippocampus of newborn and adult male rats.

    PubMed

    Naseri, Masoud; Parham, Abbas; Moghimi, Ali

    2017-09-01

    Development of the nervous system in human and most animals is continued after the birth. Critical role of this period in generation and specialization of the neuronal circuits is confirmed in numerous studies. Any pharmacological intervention in this period may result in structural, functional or behavioral abnormalities. In this study, sodium thiopental a GABA mimetic drug was administrated to newborn rats and their GAD65 and GAD67 expression in hippocampus was evaluated before and after puberty. Newborn male Wistar rats were received sodium thiopental (35 mg/kg) daily for 11 days (from 4 to 14 days after birth). Expression of GAD65 and GAD67 in their hippocampus was compared with control groups in 15 and 45 days after birth with RT-qPCR method. Significant down regulation of GAD65 and GAD67 gene expression was observed in treated rats compared with control group in 45 days after birth animals. But no significant difference was shown between experimental and control groups 15 days after birth animals. The effect of sodium thiopental on GAD65 and GAD67 expression only at adult rats showed a latent period of influence which can be attributed to dosage or intension of sodium thiopental neurotoxicity. Significant down regulation of GAD65 and GAD67 showed unwanted effect of sodium thiopental as GABA mimetic drug in critical period of development.

  14. Of Mice and Men: The Benefits of Caloric Restriction, Exercise, and Mimetics

    PubMed Central

    Mercken, Evi M.; Carboneau, Bethany A.; Krzysik-Walker, Susan M.; de Cabo, Rafael

    2012-01-01

    During aging there is an increasing imbalance of energy intake and expenditure resulting in obesity, frailty, and metabolic disorders. For decades, research has shown that caloric restriction (CR) and exercise can postpone detrimental aspects of aging. These two interventions invoke a similar physiological signature involving pathways associated with stress responses and mitochondrial homeostasis. Nonetheless, CR is able to delay aging processes that result in an increase of both mean and maximum lifespan, whereas exercise primarily increases healthspan. Due to the strict dietary regime necessary to achieve the beneficial effects of CR, most studies to date have focused on rodents and non-human primates. As a consequence, there is vast interest in the development of compounds such as resveratrol, metformin and rapamycin that would activate the same metabolic- and stress-response pathways induced by these interventions without actually restricting caloric intake. Therefore the scope of this review is to (i) describe the benefits of CR and exercise in healthy individuals, (ii) discuss the role of these interventions in the diseased state, and (iii) examine some of the promising pharmacological alternatives such as CR- and exercise-mimetics. PMID:22210414

  15. Discrete conservation properties for shallow water flows using mixed mimetic spectral elements

    NASA Astrophysics Data System (ADS)

    Lee, D.; Palha, A.; Gerritsma, M.

    2018-03-01

    A mixed mimetic spectral element method is applied to solve the rotating shallow water equations. The mixed method uses the recently developed spectral element histopolation functions, which exactly satisfy the fundamental theorem of calculus with respect to the standard Lagrange basis functions in one dimension. These are used to construct tensor product solution spaces which satisfy the generalized Stokes theorem, as well as the annihilation of the gradient operator by the curl and the curl by the divergence. This allows for the exact conservation of first order moments (mass, vorticity), as well as higher moments (energy, potential enstrophy), subject to the truncation error of the time stepping scheme. The continuity equation is solved in the strong form, such that mass conservation holds point wise, while the momentum equation is solved in the weak form such that vorticity is globally conserved. While mass, vorticity and energy conservation hold for any quadrature rule, potential enstrophy conservation is dependent on exact spatial integration. The method possesses a weak form statement of geostrophic balance due to the compatible nature of the solution spaces and arbitrarily high order spatial error convergence.

  16. Temperature Dependence of the Collisional Removal of O2(A(sup 3)Sigma(sup +)(sub u), upsilon=9 ) with O2 and N2

    NASA Technical Reports Server (NTRS)

    Hwang, Eunsook S.; Copeland, Richard A.

    1997-01-01

    The temperature dependence of the collisional removal of O2 molecules in the upsilon = 9 level of the A(sup 3)Sigma(sup +)(sub u) electronic state has been studied for the colliders O2 and N2, over the temperature range 150 to 300 K. In a cooled flow cell, the output of a pulsed dye laser excites the O2 to the upsilon = 9 level of the A(sup 3)Sigma(sup +)(sub u) state, and the output of a time-delayed second laser monitors the temporal evolution of this level via a resonance-enhanced ionization. We find the u thermally averaged removal cross section for O2 collisions is constant (approx. 10 A(sup 2)) between room temperature and 200 K, then increases rapidly with decreasing temperature, doubling by 150 K. In contrast, the N2 cross section at 225 K is approx. 8% smaller and gradually increases to a value at 150 K that is approx. 60% larger than the room temperature value. The difference between the temperature dependence of the O2 and N2 collision cross section implies that the removal by oxygen becomes more important at the lower temperatures found in the mesosphere, but removal by N2 still dominates.

  17. VizieR Online Data Catalog: H2 d3{Pi}u excitation by elec

    NASA Astrophysics Data System (ADS)

    Liu, X.; Shemansky, D. E.; Yoshii, J.; Johnson, P. V.; Malone, C. P.; Ajello, J. M.

    2016-05-01

    Electron-impact excitation of H2 triplet states plays an imp role in the heating of outer planet upper thermospheres. The d3{Pi}u state is the third ungerade triplet state, and the d3{Pi}u-a3{Sigma}g+ emission is the largest cascade channel for the a3{Sigma}g+ state. Accurate energies of the d3{Pi}u-(v, J) levels are calculated from an ab initio potential energy curve. Radiative lifetimes of the d3{Pi}u(v,J) levels are obtained by an accurate evaluation of the d3{Pi}u-a3{Sigma}g+ transition probabilities. The emission yields are determined from experimental lifetimes and calculated radiative lifetimes and are further verified by comparing experimental and synthetic d3{Pi}u-a3{Sigma}g+ spectra at 20eV impact energy. Spectral analysis revealed that multipolar components beyond the dipolar term are required to model the X1{Sigma}g+-d3{Pi}u excitation, and significant cascade excitation occurs at the d3{Pi}u (v=0,1) levels. Kinetic energy (Ek) distributions of H atoms produced via predissociation of the 3{Pi}u state and the d3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ cascade dissociative emission are obtained. Predissociation of the d3{Pi}u state produces H atoms with an average Ek of 2.3+/-0.4 eV/atom, while the Ekdistribution of the d3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ channel is similar to that of the X1{Sigma}g+-a3{Sigma}g+-b3{Sigma}u+ channel and produces H(1s) atoms with an average Ek of 1.15+/-0.05eV/atom. On average, each H2 excited to the d3{Pi}u state in an H2-dominated atmosphere deposits 3.3+/-0.4eV into the atmosphere, while each H2directly excited to the a3{Sigma}g+ state gives 2.2-2.3eV to the atmosphere. The spectral distribution of the calculated a3{Sigma}g+-b3{Sigma}u+ continuum emission due to the X1{Sigma}g+-d3{Pi}u excitation is significantly different from that of direct a3{Sigma}g+ excitation. (2 data files).

  18. Synthesis of α,α-Difluorinated Phosphonate pSer/pThr Mimetics via Rhodium-Catalyzed Asymmetric Hydrogenation of β-Difluorophosphonomethyl α-(Acylamino)acrylates.

    PubMed

    Chen, Hong-Xue; Kang, Jie; Chang, Rong; Zhang, Yun-Lai; Duan, Hua-Zhen; Li, Yan-Mei; Chen, Yong-Xiang

    2018-06-01

    A novel and facile synthetic strategy for α,α-difluorinated phosphonate mimetics of phosphoserine/phosphothreonine utilizing rhodium-catalyzed asymmetric hydrogenation was developed. The dehydrogenated substrate β-difluorophosphonomethyl α-(acylamino)acrylates were first prepared from protected serine/threonine followed by asymmetric hydrogenation using the rhodium-DuPhos catalytic system to generate the chiral center(s). These important phosphonate building blocks were successfully incorporated into phosphatase-resistant peptides, which displayed similar inhibition to the 14-3-3 ζ protein as the parent pSer/pThr peptides.

  19. Precise 238U(n,2n)237U reaction cross-section measurements using the activation facility at TUNL

    NASA Astrophysics Data System (ADS)

    Krishichayan, Fnu; Bhike, M.; Tornow, W.

    2014-09-01

    Accurate neutron-induced 238U(n,2n)237U reaction data are required for many practical applications, especially in the field of nuclear energy, including advanced heavy water reactors, where 238U is used as the breeding material to regenerate the fissile material 239Pu. Precise (n,2n) cross-section measurements of 238U are underway at TUNL with mono-energetic neutrons in the 8.0 to 14.0 MeV energy range in steps of 0.25 MeV using the activation technique. After activation of the 0.5 inch diameter and 442 mg 238U foil, the activity of the 208 keV characteristic γ-line is tracked for 6 weeks with a high efficient HPGe clover detector to determine the initial activity needed for the cross-section determination. Results of the cross-section measurements, determined relative to 27Al and 197Au neutron activation monitor foils, and the comparison with theoretical models will be presented during the meeting.

  20. Wing patterning gene redefines the mimetic history of Heliconius butterflies.

    PubMed

    Hines, Heather M; Counterman, Brian A; Papa, Riccardo; Albuquerque de Moura, Priscila; Cardoso, Marcio Z; Linares, Mauricio; Mallet, James; Reed, Robert D; Jiggins, Chris D; Kronforst, Marcus R; McMillan, W Owen

    2011-12-06

    The mimetic butterflies Heliconius erato and Heliconius melpomene have undergone parallel radiations to form a near-identical patchwork of over 20 different wing-pattern races across the Neotropics. Previous molecular phylogenetic work on these radiations has suggested that similar but geographically disjunct color patterns arose multiple times independently in each species. The neutral markers used in these studies, however, can move freely across color pattern boundaries, and therefore might not represent the history of the adaptive traits as accurately as markers linked to color pattern genes. To assess the evolutionary histories across different loci, we compared relationships among races within H. erato and within H. melpomene using a series of unlinked genes, genes linked to color pattern loci, and optix, a gene recently shown to control red color-pattern variation. We found that although unlinked genes partition populations by geographic region, optix had a different history, structuring lineages by red color patterns and supporting a single origin of red-rayed patterns within each species. Genes closely linked (80-250 kb) to optix exhibited only weak associations with color pattern. This study empirically demonstrates the necessity of examining phenotype-determining genomic regions to understand the history of adaptive change in rapidly radiating lineages. With these refined relationships, we resolve a long-standing debate about the origins of the races within each species, supporting the hypothesis that the red-rayed Amazonian pattern evolved recently and expanded, causing disjunctions of more ancestral patterns.