Effects of Laparoscopic Roux-en-Y Gastric Bypass for Type 2 Diabetes Mellitus: Comparison of BMI > 30 and < 30 kg/m2.

PubMed

Ke, Zhigang; Li, Fan; Chen, Jing; Gao, Yu; Zhou, Xunmei; Sun, Fang; Li, Chunxue; Liu, Baohua; Li, Qiang; Zhu, Zhiming; Tong, Weidong

2017-11-01

Recently, many studies focused on type 2 diabetes mellitus (T2DM) patients with body mass index (BMI) < 30 kg/m 2 and suggested that those patients might benefit from Roux-en-Y gastric bypass (RYGB). However, evidence on its effectiveness to improve T2DM patients with BMI < 30 kg/m 2 is still lacking. The aim of this study is to explore whether T2DM patients with BMI < 30 kg/m 2 get similar surgical effect from RYGB compared with those patients with BMI > 30 kg/m 2 . Seventy patients with uncontrolled T2DM underwent laparoscopic RYGB from May 2010 to December 2015 in the GI Department of Daping Hospital. Weight, BMI, waist circumference, glucose, and lipid metabolic parameters were collected and evaluated at baseline and 1, 3, 6, 12, and 24 months postsurgery. Patients with BMI < 30 kg/m 2 were compared with those with BMI > 30 kg/m 2 . Among the 70 patients, 47 (67.1%) BMI < 30 kg/m 2 , and 23 (32.9%) BMI > 30 kg/m 2 . Patients with BMI < 30 kg/m 2 are significantly older; they are female predominant and have longer duration of diabetes. The complete remission of T2DM was 28.2% of the BMI < 30 kg/m 2 group and 57.9% of the BMI > 30 kg/m 2 group (p = 0.029). There was no significant difference in the change of glucose and lipid metabolic parameters of both groups. FPG, 2hPG, and HbA1c% levels were significantly improved after 1 month (p < 0.05), and then remained essentially stable from the sixth month in both groups. The 2-year study has shown that RYGB is a safe and effective procedure in treating T2DM with BMI < 30 kg/m 2 , although the complete remission of T2DM in the BMI < 30 kg/m 2 group is lower than the BMI > 30 kg/m 2 group.

Comparison of Efficacy and Safety of Liraglutide 3.0 mg in Individuals with BMI above and below 35 kg/m²: A Post-hoc Analysis

PubMed Central

le Roux, Carel; Aroda, Vanita; Hemmingsson, Joanna; Cancino, Ana Paula; Christensen, Rune; Pi-Sunyer, Xavier

2018-01-01

Objective To investigate whether the efficacy and safety of liraglutide 3.0 mg differed between two subgroups, BMI 27 to <35 and BMI ≥ 35 kg/m², in individuals without and with type 2 diabetes (T2D). Methods A post-hoc analysis of two 56-week, randomized, double-blind, placebo-controlled trials (SCALE Obesity and Prediabetes; SCALE Diabetes). Subgroup differences in treatment effects of liraglutide 3.0 mg were evaluated by testing the interaction between treatment group and baseline BMI subgroup. Results Significantly greater weight loss (0–56 weeks) was observed with liraglutide 3.0 mg versus placebo in all patient groups while on treatment. There was no evidence that the weight-lowering effect of liraglutide 3.0 mg differed between BMI subgroups (interaction p > 0.05). Similarly, for most secondary endpoints significantly greater improvements were observed with liraglutide 3.0 mg versus placebo, with no indication treatment effects differing between subgroups. The safety profile of liraglutide 3.0 mg was broadly similar across BMI subgroups. Conclusion This post-hoc analysis did not indicate any differences in the treatment effects, or safety profile, of liraglutide 3.0 mg for individuals with BMI 27 to <35 or ≥35 kg/m². Liraglutide 3.0 mg can therefore be considered for individuals with a BMI of ≥35 as well as for those with a BMI of 27 to <35 kg/m². PMID:29145215

SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride], a new nonpeptide antagonist of the bradykinin B1 receptor: biochemical and pharmacological characterization.

PubMed

Gougat, Jean; Ferrari, Bernard; Sarran, Lionel; Planchenault, Claudine; Poncelet, Martine; Maruani, Jeanne; Alonso, Richard; Cudennec, Annie; Croci, Tiziano; Guagnini, Fabio; Urban-Szabo, Katalin; Martinolle, Jean-Pierre; Soubrié, Philippe; Finance, Olivier; Le Fur, Gérard

2004-05-01

The biochemical and pharmacological properties of a novel non-peptide antagonist of the bradykinin (BK) B(1) receptor, SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride] were evaluated. SSR240612 inhibited the binding of [(3)H]Lys(0)-des-Arg(9)-BK to the B(1) receptor in human fibroblast MRC5 and to recombinant human B(1) receptor expressed in human embryonic kidney cells with inhibition constants (K(i)) of 0.48 and 0.73 nM, respectively. The compound selectivity for B(1) versus B(2) receptors was in the range of 500- to 1000-fold. SSR240612 inhibited Lys(0)-desAr(9)-BK (10 nM)-induced inositol monophosphate formation in human fibroblast MRC5, with an IC(50) of 1.9 nM. It also antagonized des-Arg(9)-BK-induced contractions of isolated rabbit aorta and mesenteric plexus of rat ileum with a pA(2) of 8.9 and 9.4, respectively. Antagonistic properties of SSR240612 were also demonstrated in vivo. SSR240612 inhibited des-Arg(9)-BK-induced paw edema in mice (3 and 10 mg/kg p.o. and 0.3 and 1 mg/kg i.p.). Moreover, SSR240612 reduced capsaicin-induced ear edema in mice (0.3, 3 and 30 mg/kg p.o.) and tissue destruction and neutrophil accumulation in the rat intestine following splanchnic artery occlusion/reperfusion (0.3 mg/kg i.v.). The compound also inhibited thermal hyperalgesia induced by UV irradiation (1 and 3 mg/kg p.o.) and the late phase of nociceptive response to formalin in rats (10 and 30 mg/kg p.o.). Finally, SSR240612 (20 and 30 mg/kg p.o.) prevented neuropathic thermal pain induced by sciatic nerve constriction in the rat. In conclusion, SSR240612 is a new, potent, and orally active specific non-peptide bradykinin B(1) receptor antagonist.

Measurement of the 1s2s ^1S0 - 1s2p ^3P1 interval in helium-like silicon.

NASA Astrophysics Data System (ADS)

Redshaw, M.; Harry, R.; Myers, E. G.; Weatherford, C. A.

2001-05-01

Accurate calculation of the energy levels of helium-like ions is a basic problem in relativistic atomic theory. For the n=3D2 levels at moderate Z, published calculations give all ``structure'' but not all explicit QED contributions to order (Zα)^4 a.u.(D.R. Plante, W.R. Johnson and J. Sapirstein, Phys. Rev. A 49), 3519 (1994).^, (K.T. Cheng, M.H. Chen, W.R. Johnson and J. Sapirstein, Phys. Rev. A 50), 247 (1994).. Measurements of the 1s2p ^3P - 1s2s ^3S transitions, which lie in the vacuum ultra-violet, are barely precise enough to challenge the theory. However, the intercombination 1s2s ^1S0 - 1s2p ^3P1 interval lies in the infra-red for Z<40 and enables precision measurements using laser spectroscopy(E.G. Myers, J.K. Thompson, E.P. Gavathas, N.R. Claussen, J.D. Silver and D.J.H. Howie, Phys. Rev. Lett. 75), 3637 (1995).. We aim to measure this interval in Si^12+ using a foil-stripped 1 MeV/u ion beam from the Florida State Van de Graaff accelerator and a single-mode c.w. Nd:YAG laser at 1.319 μm. To obtain a sufficient transition probability, the Si^12+ beam is merged co-linearly with the laser light inside an ultra-high finesse build-up cavity. The results should provide a clear test of current and developing calculations of QED contributions in two-electron ions.

Dysprosium-doped PbGa2S4 laser generating at 4.3 μm directly pumped by 1.7 μm laser diode.

PubMed

Jelínková, Helena; Doroshenko, Maxim E; Jelínek, Michal; Sulc, Jan; Osiko, Vyacheslav V; Badikov, Valerii V; Badikov, Dmitrii V

2013-08-15

In this Letter, we demonstrate the pulsed and CW operation of the Dy:PbGa(2)S(4) laser directly pumped by the 1.7 μm laser diode. In the pulsed regime (pulse duration 5 ms; repetition rate 20 Hz), the maximum mean output power of 9.5 mW was obtained with the slope efficiency of 9.3% with respect to the absorbed pump power. The generated wavelength was 4.32 μm, and the laser beam cross section was approximately Gaussian on both axes. Stable CW laser generation was also successfully obtained with the maximum output power of 67 mW and the slope efficiency of 8%. Depopulation of the lower laser level by 1.7 μm pump radiation absorption followed by 1.3 μm upconversion fluorescence was demonstrated. These results show the possibility of construction of the compact diode-pumped solid-state pulsed or CW laser generating at 4.3 μm in the power level of tens mW operating at room temperature.

Pharmacokinetics and bioavailability of spectinomycin after i.v., i.m., s.c. and oral administration in broiler chickens.

PubMed

Abu-Basha, E A; Gehring, R; Albwa'neh, S J

2007-04-01

A pharmacokinetic and bioavailability study of spectinomycin was conducted in healthy broiler chickens following administration of a single (50 mg/kg bw) intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) dose and oral doses of 50 and 100 mg/kg bw. Following i.v. administration, the elimination half-life (t1/2beta), mean residence time (MRT), volume of distribution at steady-state (Vd(ss)), volume of distribution based on the terminal phase (Vd(z)) and total body clearance (ClB) were 1.46+/-1.10 h, 1.61+/-1.05 h, 0.26+/-0.009 L/kg, 0.34 (0.30-0.38) L/kg and 2.68+/-0.017 mL/min/kg respectively. After i.m. and s.c. dosing, the Cmax was 152.76+/-1.08 and 99.77+/-1.04 microg/mL, achieved at 0.25 (0.25-0.50) and 0.25 (0.25-1.00) h, the t1/2beta was 1.65+/-1.07 and 2.03+/-1.06 h and the absolute bioavailability (F) was 136.1% and 128.8% respectively. A significant difference in Cmax (5.13+/-0.10, 14.26+/-1.12 microg/mL), t1/2beta (3.74+/-1.07, 8.93+/-1.13 h) and ClB/F (22.69+/-0.018, 10.14+/-0.018 mL/min/kg) were found between the two oral doses (50 and 100 mg/kg bw respectively), but there were no differences in the tmax [2.00 (2.00-4.00), 2.00 (2.00-2.00) h] and Vd(z)/F [6.95 (6.34-9.06), 7.98 (4.75-10.62) L/kg). The absolute bioavailability (F) of spectinomycin was 11.8% and 26.4% after oral administration of 50 and 100 mg/kg bw respectively.

TOR and S6K1 promote translation reinitiation of uORF-containing mRNAs via phosphorylation of eIF3h

PubMed Central

Schepetilnikov, Mikhail; Dimitrova, Maria; Mancera-Martínez, Eder; Geldreich, Angèle; Keller, Mario; Ryabova, Lyubov A

2013-01-01

Mammalian target-of-rapamycin (mTOR) triggers S6 kinase (S6K) activation to phosphorylate targets linked to translation in response to energy, nutrients, and hormones. Pathways of TOR activation in plants remain unknown. Here, we uncover the role of the phytohormone auxin in TOR signalling activation and reinitiation after upstream open reading frame (uORF) translation, which in plants is dependent on translation initiation factor eIF3h. We show that auxin triggers TOR activation followed by S6K1 phosphorylation at T449 and efficient loading of uORF-mRNAs onto polysomes in a manner sensitive to the TOR inhibitor Torin-1. Torin-1 mediates recruitment of inactive S6K1 to polysomes, while auxin triggers S6K1 dissociation and recruitment of activated TOR instead. A putative target of TOR/S6K1—eIF3h—is phosphorylated and detected in polysomes in response to auxin. In TOR-deficient plants, polysomes were prebound by inactive S6K1, and loading of uORF-mRNAs and eIF3h was impaired. Transient expression of eIF3h-S178D in plant protoplasts specifically upregulates uORF-mRNA translation. We propose that TOR functions in polysomes to maintain the active S6K1 (and thus eIF3h) phosphorylation status that is critical for translation reinitiation. PMID:23524850

Dose of rocuronium for rapid tracheal intubation following remifentanil 2 μg kg-1 and propofol 2 mg kg-1.

PubMed

Oh, Ah-Young; Cho, Suk-Ju; Seo, Kwang-Suk; Ryu, Jung-Hee; Han, Sung-Hee; Hwang, Jung-Won

2013-09-01

Full relaxation is not mandatory for successful tracheal intubation. We tried to find the dose of rocuronium that gave acceptable intubation conditions in a rapid sequence intubation with remifentanil and propofol. A dose-finding study of rocuronium using a modified Dixon's up-and-down method. A single tertiary care teaching hospital. Patients undergoing elective surgery under general anaesthesia. After premedication with midazolam and glycopyrrolate, anaesthesia was induced using remifentanil 2 μg kg and propofol 2 mg kg, and a predetermined dose of rocuronium was administered. The dose of rocuronium was determined by a modified Dixon's up-and-down method starting from 0.8 mg kg with an interval of 0.1 or 0.05 mg kg. Intubation was performed 60 s after the start of the rocuronium injection. Intubation conditions were graded as excellent, good or poor. Excellent or good were regarded as clinically acceptable. A dose of rocuronium needed for acceptable intubation condition in 50% of patients (ED50) during rapid tracheal intubation after induction of anaesthesia with remifentanil and propofol. Twenty-eight patients were enrolled to obtain six crossovers. The ED50 of rocuronium was 0.20 mg kg (95% confidence interval, CI 0.17 to 0.23 mg kg) by a modified Dixon's up-and-down method. After induction of anaesthesia with remifentanil 2 μg kg and propofol 2 mg kg, the ED50 of rocuronium for acceptable intubation condition was 0.20 mg kg (95% CI, 0.17 to 0.23 mg kg) for rapid sequence intubation. Thus, we recommend that the intubation dose should be 0.8 mg kg. Clinical trial registration KCT0000094.

Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice

PubMed Central

Thomsen, Morgane; Wess, Jürgen; Fulton, Brian S.; Fink-Jensen, Anders; Caine, S. Barak

2014-01-01

Rationale Muscarinic cholinergic M1 and M4 receptors may participate in schizophrenia's etiology, and have been proposed as targets for antipsychotic medications. Objective Here we investigated the involvement of these receptors in behavioral measures pertinent to schizophrenia using knockout mice lacking M1 receptors (M1−/−), M4 receptors (M4−/−) or both (M1−/−M4−/−). Methods We measured prepulse inhibition of startle (PPI) without drugs, and after treatment with scopolamine (0.32–1.8 mg/kg), xanomeline (3.2 mg/kg) oxotremorine (0.032–0.1 mg/kg), clozapine (1.0–5.6 mg/kg), or haloperidol (0.32–3.2 mg/kg). Results In female (but not male) mice, combined deletion of both M1 and M4 receptors decreased PPI relative to wild-type mice, while knockout of either receptor alone had no significant effect. Scopolamine disrupted PPI in wild-type and M4−/− mice, but not in female M1−/−M4−/− or female M1−/− mice. When administered before scopolamine, xanomeline restored PPI in wild-type mice and M1−/− mice, but not in M4−/− mice. In contrast, pretreatment with oxotremorine increased PPI regardless of genotype. Effects of clozapine and haloperidol on PPI were not hindered by either mutation. Conclusions Deletion of both M1 and M4 receptors can disrupt PPI, suggesting that (at least partially redundant) M1 and M4 receptor-dependent functions are involved in sensorimotor gating mechanisms. PPI-disrupting effects of muscarinic antagonists appeared dependent upon M1 receptor blockade. Our data also suggest that xanomeline exerts antipsychotic-like effects mainly through M4 receptor stimulation, while stimulation of non-M1/M4 subtypes may also have antipsychotic potential. Finally, our results do not support a role of M1/M4 receptors in mediating antipsychotic-like effects of clozapine. PMID:20013114

Metal ion displacements in noncentrosymmetric chalcogenides La3Ga1.67S7, La3Ag0.6GaCh7 (Ch=S, Se), and La3MGaSe7 (M=Zn, Cd)

NASA Astrophysics Data System (ADS)

Iyer, Abishek K.; Yin, Wenlong; Rudyk, Brent W.; Lin, Xinsong; Nilges, Tom; Mar, Arthur

2016-11-01

The quaternary Ga-containing chalcogenides La3Ag0.6GaS7, La3Ag0.6GaSe7, La3ZnGaSe7, and La3CdGaSe7, as well as the related ternary chalcogenide La3Ga1.67S7, were prepared by reactions of the elements at 950 °C. They adopt noncentrosymmetric hexagonal structures (space group P63, Z=2) with cell parameters (a=10.2 Å, c=6.1 Å for the sulfides; a=10.6 Å, c=6.4 Å for the selenides) that are largely controlled by the geometrical requirements of one-dimensional stacks of Ga-centered tetrahedra separated by the La atoms. Among these compounds, which share the common formulation La3M1-xGaCh7 (M=Ga, Ag, Zn, Cd; Ch=S, Se), the M atoms occupy sites within a stacking of trigonal antiprisms formed by Ch atoms. The location of the M site varies between extremes with trigonal antiprismatic (CN6) and trigonal planar (CN3) geometry. Partial occupation of these sites and intermediate ones accounts for the considerable versatility of these structures and the occurrence of large metal displacement parameters. The site occupations can be understood in a simple way as being driven by the need to satisfy appropriate bond valence sums for both the M and Ch atoms. Band structure calculations rationalize the substoichiometry observed in the Ag-containing compounds (La3Ag0.6GaS7, La3Ag0.6GaSe7) as a response to overbonding. X-ray photoelectron spectroscopy supports the presence of monovalent Ag atoms in these compounds, which are not charge-balanced.

Density Measurement System for Weights of 1 kg to 20 kg Using Hydrostatic Weighing

NASA Astrophysics Data System (ADS)

Lee, Yong Jae; Lee, Woo Gab; Abdurahman, Mohammed; Kim, Kwang Pyo

This paper presents a density measurement system to determine density of weights from 1 kg to 20 kg using hydrostatic weighing. The system works based on Archimedes principle. The density of reference liquid is determined using this setup while determining the density of the test weight. Density sphere is used as standard density ball to determine density of the reference liquid. A new immersion pan is designed for dual purpose to carry the density sphere and the cylindrical test weight for weighing in liquid. Main parts of the setup are an electronic balance, a thermostat controlled liquid bath, reference weights designed for bottom weighing, dual purpose immersion pans and stepping motors to load and unload in weighing process. The results of density measurement will be evaluated as uncertainties for weights of 1 kg to 20 kg.

Nano-indentation investigations of (As2Se3)1-x: Snx and (As4S3Se3)1-x: Snx glasses

NASA Astrophysics Data System (ADS)

Harea, D. V.; Harea, E. E.; Iaseniuc, O. V.; Iovu, M. S.

2015-02-01

Experimental results on some physical and optical properties of (As2Se3)1-x:Snx and (As4S3Se3)1-x:Snx (x = 0-10 at %) glasses and amorphous films (d~2.0 μm) are presented. The bulk chalcogenide glasses are studied by X-ray diffraction spectroscopy and nanoindentation methods. It is established that the addition of these amounts of tin (x = 0-10 at %) does not lead to significant changes in the physical properties of the glass, such as values of stress and Young's modulus related to the modification of the density and compactness. It has been found that the addition of these amounts of tin in (As4S3Se3)1-x:Snx does not lead to significant changes in the glass physical properties, such as values of stress and Young's modulus related to the modification of the density and compactness. The study of the photoplastic effect is performed in situ, with illumination of the bulk and thin film samples during indentation as well as their indentation after illumination with a green laser (λ = 532 nm) at a power of P = 50 mV/cm2. The hardness is calculated from load-displacement curves by the Oliver-Pharr method. A sharp increase in hardness is registered if the tin concentration exceeds a value of 34% Sn. The hardness H of (As2Se3)1-x:Snx films varies between 115 and 130 kg/mm2. It is found that the hardness H of amorphous thin films is generally higher than the hardness of bulk samples with the same chemical composition. In this study, we are focused on the mechanical characteristics of high-purity As2Se3: Snx thin films. Keyword: Chalcogenide glasses, hardness,

77 FR 64848 - Proposed Collection; Comment Request for Form 1120S, Schedule D, Schedule K-1, and Schedule M-3

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-23

... 1120S, Schedule D, Schedule K-1, and Schedule M-3 AGENCY: Internal Revenue Service (IRS), Treasury... (Loss) Reconciliation for S Corporations With Total Assets of $10 Million or More, and Schedule K-1... Corporation, Schedule D (Form 1120S), Capital Gains and Losses and Built-in Gains, Schedule K-1 (Form 1120S...

Magic wavelengths for the 6{s}^{2}{}^{1}{S}_{0}{--}6s6p{}^{3}{P}_{1}^{o} transition in ytterbium atom

NASA Astrophysics Data System (ADS)

Tang, Zhi-Ming; Yu, Yan-Mei; Jiang, Jun; Dong, Chen-Zhong

2018-06-01

The static and dynamic electric dipole polarizabilities of the 6{s}2{}1{S}0 and 6s6p{}3{P}1o states of Yb are calculated by using the relativistic ab initio method. Focusing on the red detuning region to the 6{s}2{}1{S}0{--}6s6p{}3{P}1o transition, we find two magic wavelengths at 1035.7(2) and 612.9(2) nm for the 6{s}2{}1{S}0{--}6s6p{}3{P}1o,{M}J=0 transition and three magic wavelengths at 1517.68(6), 1036.0(3) and 858(12) nm for the 6{s}2{}1{S}0{--}6s6p{}3{P}1o,{M}J=+/- 1 transitions. Such magic wavelengths are of particular interest for attaining the state-insensitive cooling, trapping, and quantum manipulation of neutral Yb atom.

Intravenous rocuronium 0.3 mg/kg improves the conditions for tracheal intubation in cats: a randomized, placebo-controlled trial.

PubMed

Sakai, Daniel M; Zornow, Kailee Anne; Campoy, Luis; Cable, Christina; Appel, Leslie D; Putnam, Holly J; Martin-Flores, Manuel

2018-01-01

Objectives We evaluated the use of rocuronium 0.3 mg/kg intravenously (IV) to facilitate tracheal intubation in cats anesthetized for elective ovariohysterectomy. Methods Thirty female cats were randomly allocated to receive rocuronium 0.3 mg/kg IV or an equal volume of normal saline, following induction of anesthesia with ketamine and midazolam. Thirty seconds after induction, a single investigator, unaware of treatment allocation, attempted tracheal intubation. The number of attempts and the time to complete intubation were measured. Intubating conditions were assessed as acceptable or unacceptable based on a composite score consisting of five different components. Duration of apnea after induction was measured and cases of hemoglobin desaturation (SpO 2 <90%) were identified. Results Intubation was completed faster (rocuronium 12 s [range 8-75 s]; saline 60 s [range 9-120 s]) and with fewer attempts (rocuronium 1 [range 1-2]; saline 2 [range 1-3], both P = 0.006) in cats receiving rocuronium. Unacceptable intubating conditions on the first attempt occurred in 3/15 cats with rocuronium and in 10/15 with saline ( P = 0.01). Apnea lasted 4 ± 1.6 mins with rocuronium and 2.3 ± 0.5 mins with saline ( P = 0.0007). No cases of desaturation were observed. Conclusions and relevance Rocuronium 0.3 mg/kg IV improves intubating conditions compared with saline and reduces the time and number of attempts to intubate with only a short period of apnea in cats.

PMHS impact response in 3 m/s and 8 m/s nearside impacts with abdomen offset.

PubMed

Miller, Carl S; Madura, Nathaniel H; Schneider, Lawrence W; Klinich, Kathleen D; Reed, Matthew P; Rupp, Jonathan D

2013-11-01

Lateral impact tests were performed using seven male post-mortem human subjects (PMHS) to characterize the force-deflection response of contacted body regions, including the lower abdomen. All tests were performed using a dual-sled, side-impact test facility. A segmented impactor was mounted on a sled that was pneumatically accelerated into a second, initially stationary sled on which a subject was seated facing perpendicular to the direction of impact. Positions of impactor segments were adjusted for each subject so that forces applied to different anatomic regions, including thorax, abdomen, greater trochanter, iliac wing, and thigh, could be independently measured on each PMHS. The impactor contact surfaces were located in the same vertical plane, except that the abdomen plate was offset 5.1 cm towards the subject. The masses of the sleds and the force- deflection characteristics of the energy-absorbing interface material between the sleds were set to provide the impactor sled with a velocity profile that matched the average driver door velocity history produced in a series of side NCAP tests. Impactor padding was also selected so that average ATD pelvis and thorax responses from the same series of side NCAP tests were reproduced when the ATD used in these tests was impacted using the average door-velocity history. Each subject was first impacted on one side of the body using an initial impactor speed of 3 m/s. If a post-test CT scan and strain-gage data revealed two or fewer non-displaced rib fractures, then the PMHS was impacted on the contralateral side of the body at a speed of 8 m/s or 10 m/s. The results of tests in the 3 m/s and 8 m/s conditions were used to develop force-deflection response corridors for the abdomen, force history response corridors for the pelvis (iliac wing and greater trochanter), the midthigh, and the thorax. Response corridors for the lateral acceleration of the pelvis were also developed. Future work will compare side impact ATD

General Formation of M(x)Co(3-x)S4 (M=Ni, Mn, Zn) Hollow Tubular Structures for Hybrid Supercapacitors.

PubMed

Chen, Yu Ming; Li, Zhen; Lou, Xiong Wen David

2015-09-01

A simple and versatile method for general synthesis of uniform one-dimensional (1D) M(x)Co(3-x)S4 (M=Ni, Mn, Zn) hollow tubular structures (HTSs), using soft polymeric nanofibers as a template, is described. Fibrous core-shell polymer@M-Co acetate hydroxide precursors with a controllable molar ratio of M/Co are first prepared, followed by a sulfidation process to obtain core-shell polymer@M(x)Co(3-x)S4 composite nanofibers. The as-made M(x)Co(3-x)S4 HTSs have a high surface area and exhibit exceptional electrochemical performance as electrode materials for hybrid supercapacitors. For example, the MnCo2S4 HTS electrode can deliver specific capacitance of 1094 F g(-1) at 10 A g(-1), and the cycling stability is remarkable, with only about 6% loss over 20,000 cycles. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

20(S)-Protopanaxadiol-Induced Apoptosis in MCF-7 Breast Cancer Cell Line through the Inhibition of PI3K/AKT/mTOR Signaling Pathway.

PubMed

Zhang, Hong; Xu, Hua-Li; Wang, Yu-Chen; Lu, Ze-Yuan; Yu, Xiao-Feng; Sui, Da-Yun

2018-04-02

20(S)-Protopanaxadiol (PPD) is one of the major active metabolites of ginseng. It has been reported that 20(S)-PPD shows a broad spectrum of antitumor effects. Our research study aims were to investigate whether apoptosis of human breast cancer MCF-7 cells could be induced by 20(S)-PPD by targeting the Phosphatidylinositol 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway in vitro and in vivo. Cell cycle analysis was performed by Propidium Iodide (PI) staining. To overexpress and knock down the expression of mTOR, pcDNA3.1-mTOR and mTOR small interfering RNA (siRNA) transient transfection assays were used, respectively. Cell viability and apoptosis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-test and Annexin V /PI double-staining after transfection. The antitumor effect in vivo was determined by the nude mice xenograft assay. After 24 h of incubation, treatment with 20(S)-PPD could upregulate phosphorylated-Phosphatase and tensin homologue deleted on chromosome 10 (p-PTEN) expression and downregulate PI3K/AKT/mTOR-pathway protein expression. Moreover, G0/G1 cell cycle arrest in MCF-7 cells could be induced by 20(S)-PPD treatment at high concentrations. Furthermore, overexpression or knockdown of mTOR could inhibit or promote the apoptotic effects of 20(S)-PPD. In addition, tumor volumes were partially reduced by 20(S)-PPD at 100 mg/kg in a MCF-7 xenograft model. Immunohistochemical staining indicated a close relationship between the inhibition of tumor growth and the PI3K/AKT/mTOR signal pathway. PI3K/AKT/mTOR pathway-mediated apoptosis may be one of the potential mechanisms of 20(S)-PPD treatment.

Tune-out wavelength for the 1 s 2 s3 S - 1 s 3 p 3 P transition of helium: relativistic effects

NASA Astrophysics Data System (ADS)

Drake, Gordon W. F.; Manalo, Jacob

2017-04-01

The tune-out wavelength is the wavelength at which the frequency dependent polarizability of an atom vanishes. It can be measured to very high precision by means of an interferometric comparison between two beams. This paper is part of a joint theoretical/ experimental project with K. Baldwin et al. (Australian National University) and L.-Y. Tang et al. (Wuhan Institute of Physics and Mathematics) to perform a high precision comparison between theory and experiment as a probe of atomic structure, including relativistic and quantum electrodynamic effects. We will report the results of calculations for the tune-out wavelength that is closest to the 1 s 2 s3 S - 1 s 3 p3 P transition of 4He. Our result for the M = 0 magnetic substate, obtained with a fully correlated Hylleraas basis set, is 413 . 079 958 51 (12) nm. This includes a leading relativistic contribution of - 0 . 059 218 5 (16) nm from the Breit interaction as a perturbation, and a relativistic recoil contribution of - 0 . 000 044 47 (17) nm. The results will be compared with recent relativistic CI calculations. Research supported by tha Natural Sciences and Engineering Research Council of Canada.

Heterometal cubane-type MFe(3)S(4) clusters (M = Mo, V) trigonally symmetrized with hydrotris(pyrazolyl)borate(1-) and tris(pyrazolyl)methanesulfonate(1-) capping ligands.

PubMed

Fomitchev, Dmitry V; McLauchlan, Craig C; Holm, R H

2002-02-25

A series of heterometal cubane-type clusters containing [VFe(3)S(4)](2+) and [MoFe(3)S(4)](3+,2+) cores has been prepared. Ligand substitution of [(DMF)(3)VFe(3)S(4)Cl(3)](-) affords [(Tpms)VFe(3)S(4)L(3)](2)(-) (L = Cl(-) (8), EtS(-) (9), p-MeC(6)H(4)S(-), p-MeC(6)H(4)O(-)). A new procedure for the preparation of molybdenum single cubanes is introduced by the reaction of recently reported [(Tp)MoS(S(4))](-) with FeCl(2)/NaSEt to afford [(Tp)MoFe(3)S(4)Cl(3)](-) (1, 75% yield). This procedure is more efficient that the existing multistep synthesis of single cubanes, which generally affords clusters of mirror symmetry. Also prepared were [(Tp)MoFe(3)S(4)L(3)](-) (L = EtS(-) (2), p-MeC(6)H(4)S(-)). Reduction of 1 with borohydride gives [(Tp)MoFe(3)S(4)Cl(3)](2-) (5, 67%). Owing to the nature of the heterometal ligand, all clusters have idealized trigonal symmetry, reflected in their (1)H NMR spectra. Trigonal structures are demonstrated by crystallography of (Bu(4)N)[1,2], (Bu(4)N)(2)[5] x MeCN, and (Me(4)N)(2)[8,9]. The availability of 1 and 5 allows the first comparison of structures and (57)Fe isomer shifts of [MoFe(3)S(4)](3+,2+) in a constant ligand environment. Small increases in most bond distances indicate that an antibonding electron is added in the reduction of 1. Collective synthetic and electrochemical results from this and other studies demonstrate the existence of the series of oxidation states [VFe(3)S(4)](3+,2+,1+) and [MoFe(3)S(4)](4+,3+,2+) whose relative stabilities within a given series are strongly ligand dependent. Isomer shifts indicate that the reduction of 1 largely affects the Fe(3) subcluster and are consistent with the formal descriptions [MoFe(3+)(2)Fe(2+)S(4)](3+) (1) and [MoFe(3+)Fe(2+)(2)S(4)](2+) (5). Reaction of 1 with excess Li(2)S in acetonitrile affords the double cubane [[(Tp)MoFe(3)S(4)Cl(2)](2)(mu(2)(-)S)](2)(-), whose sulfide-bridged structure is supported by two sequential reductions separated by 290 mV, in analogy with

Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration.

PubMed

Müller, Jan; von Bernstorff, Wolfram; Heidecke, Claus-Dieter; Schulze, Tobias

2017-01-01

Introduction . Macrophages are key players in complex biological processes. In response to environmental signals, macrophages undergo polarization towards a proinflammatory (M1) or anti-inflammatory (M2) phenotype. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid that acts via 5 G-protein coupled receptors (S1P 1-5 ) in order to influence a broad spectrum of biological processes. This study assesses S1P receptor expression on macrophages before and after M1 and M2 polarization and performs a comparative analysis of S1P signalling in the two activational states of macrophages. Methods . Bone marrow derived macrophages (BMDM) from C57 BL/6 mice were cultured under either M1- or M2-polarizing conditions. S1P-receptor expression was determined by quantitative RT-PCR. Influence of S1P on macrophage activation, migration, phagocytosis, and cytokine secretion was assessed in vitro. Results . All 5 S1P receptor subclasses were expressed in macrophages. Culture under both M1- and M2-polarizing conditions led to significant downregulation of S1P 1 . In contrast, M1-polarized macrophages significantly downregulated S1P 4 . The expression of the remaining three S1P receptors did not change. S1P increased expression of iNOS under M2-polarizing conditions. Furthermore, S1P induced chemotaxis in M1 macrophages and changed cytokine production in M2 macrophages. Phagocytosis was not affected by S1P-signalling. Discussion . The expression of different specific S1P receptor profiles may provide a possibility to selectively influence M1- or M2-polarized macrophages.

The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist.

PubMed

Bartolomeo, A C; Morris, H; Buccafusco, J J; Kille, N; Rosenzweig-Lipson, S; Husbands, M G; Sabb, A L; Abou-Gharbia, M; Moyer, J A; Boast, C A

2000-02-01

Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i. p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors; that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3 microliter/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects; therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.

EXTraS discovery of a 1.2-s X-ray pulsar in M31

NASA Astrophysics Data System (ADS)

Esposito, P.; Israel, G.; Belfiore, A.; Novara, G.; Sidoli, L.; Rodriguez Castillo, G.; De Luca, A.; Tiengo, A.; Haberl, F.; Salvaterra, R.

2017-10-01

A systematic search for periodic signals in the XMM-Newton's EPIC archive carried out within the EXTraS project resulted in the discovery of a 1.2-s flux modulation in 3XMM J004301.4+413017. It is the first accreting neutron star in M31 for which the spin period has been detected. Besides this distinction, 3XMM J0043 proved to be an interesting system. Doppler shifts of the spin modulation revealed an orbital motion with period of 1.27 d and the analysis of optical data shows that, while the source is likely associated to a globular cluster, a counterpart with V ˜ 22 outside the cluster cannot be excluded. The emission of the pulsar appears rather hard (most data are described by a power law with photon index <1) and, assuming the distance to M31, the 0.3-10 keV luminosity was variable, from ˜3×10^{37} to 2×10^{38} erg/s. Based on this, we discuss two main possible scenarios for 3X J0043: a peculiar low-mass X-ray binary, perhaps similar to 4U 1822-37 or 4U 1626-67, or an intermediate-mass X-ray binary akin Her X-1.

Akt substrate TBC1D1 regulates GLUT1 expression through the mTOR pathway in 3T3-L1 adipocytes

PubMed Central

Zhou, Qiong L.; Jiang, Zhen Y.; Holik, John; Chawla, Anil; Hagan, G. Nana; Leszyk, John; Czech, Michael P.

2010-01-01

Multiple studies have suggested that the protein kinase Akt/PKB (protein kinase B) is required for insulin-stimulated glucose transport in skeletal muscle and adipose cells. In an attempt to understand links between Akt activation and glucose transport regulation, we applied mass spectrometry-based proteomics and bioinformatics approaches to identify potential Akt substrates containing the phospho-Akt substrate motif RXRXXpS/T. The present study describes the identification of the Rab GAP (GTPase-activating protein)-domain containing protein TBC1D1 [TBC (Tre-2/Bub2/Cdc16) domain family, member 1], which is closely related to TBC1D4 [TBC domain family, member 4, also denoted AS160 (Akt substrate of 160 kDa)], as an Akt substrate that is phosphorylated at Thr590. RNAi (RNA interference)-me-diated silencing of TBC1D1 elevated basal deoxyglucose uptake by approx. 61% in 3T3-L1 mouse embryo adipocytes, while the suppression of TBC1D4 and RapGAP220 under the same conditions had little effect on basal and insulin-stimulated deoxy-glucose uptake. Silencing of TBC1D1 strongly increased expression of the GLUT1 glucose transporter but not GLUT4 in cultured adipocytes, whereas the decrease in TBC1D4 had no effect. Remarkably, loss of TBC1D1 in 3T3-L1 adipocytes activated the mTOR (mammalian target of rapamycin)-p70 S6 protein kinase pathway, and the increase in GLUT1 expression in the cells treated with TBC1D1 siRNA (small interfering RNA) was blocked by the mTOR inhibitor rapamycin. Furthermore, overexpression of the mutant TBC1D1-T590A, lacking the putative Akt/PKB phosphorylation site, inhibited insulin stimulation of p70 S6 kinase phosphorylation at Thr389, a phosphorylation induced by mTOR. Taken together, our data suggest that TBC1D1 may be involved in controlling GLUT1 glucose transporter expression through the mTOR-p70 S6 kinase pathway. PMID:18215134

Study of dipion transitions among Υ(3S), Υ(2S), and Υ(1S) states

NASA Astrophysics Data System (ADS)

Cronin-Hennessy, D.; Gao, K. Y.; Hietala, J.; Kubota, Y.; Klein, T.; Lang, B. W.; Poling, R.; Scott, A. W.; Smith, A.; Zweber, P.; Dobbs, S.; Metreveli, Z.; Seth, K. K.; Tomaradze, A.; Ernst, J.; Ecklund, K. M.; Severini, H.; Love, W.; Savinov, V.; Lopez, A.; Mehrabyan, S.; Mendez, H.; Ramirez, J.; Huang, G. S.; Miller, D. H.; Pavlunin, V.; Sanghi, B.; Shipsey, I. P. J.; Xin, B.; Adams, G. S.; Anderson, M.; Cummings, J. P.; Danko, I.; Hu, D.; Moziak, B.; Napolitano, J.; He, Q.; Insler, J.; Muramatsu, H.; Park, C. S.; Thorndike, E. H.; Yang, F.; Artuso, M.; Blusk, S.; Khalil, S.; Li, J.; Menaa, N.; Mountain, R.; Nisar, S.; Randrianarivony, K.; Sia, R.; Skwarnicki, T.; Stone, S.; Wang, J. C.; Bonvicini, G.; Cinabro, D.; Dubrovin, M.; Lincoln, A.; Pappas, S. P.; Weinstein, A. J.; Asner, D. M.; Edwards, K. W.; Naik, P.; Briere, R. A.; Ferguson, T.; Tatishvili, G.; Vogel, H.; Watkins, M. E.; Rosner, J. L.; Adam, N. E.; Alexander, J. P.; Cassel, D. G.; Duboscq, J. E.; Ehrlich, R.; Fields, L.; Galik, R. S.; Gibbons, L.; Gray, R.; Gray, S. W.; Hartill, D. L.; Heltsley, B. K.; Hertz, D.; Jones, C. D.; Kandaswamy, J.; Kreinick, D. L.; Kuznetsov, V. E.; Mahlke-Krüger, H.; Mohapatra, D.; Onyisi, P. U. E.; Patterson, J. R.; Peterson, D.; Pivarski, J.; Riley, D.; Ryd, A.; Sadoff, A. J.; Schwarthoff, H.; Shi, X.; Stroiney, S.; Sun, W. M.; Wilksen, T.; Athar, S. B.; Patel, R.; Yelton, J.; Rubin, P.; Cawlfield, C.; Eisenstein, B. I.; Karliner, I.; Kim, D.; Lowrey, N.; Selen, M.; White, E. J.; Wiss, J.; Mitchell, R. E.; Shepherd, M. R.; Besson, D.; Pedlar, T. K.

2007-10-01

We present measurements of decay matrix elements for hadronic transitions of the form Υ(nS)→Υ(mS)ππ, where (n,m)=(3,1),(2,1),(3,2). We reconstruct charged and neutral pion modes with the final state Upsilon decaying to either μ+μ- or e+e-. Dalitz plot distributions for the 12 decay modes are fit individually as well as jointly assuming isospin symmetry, thereby measuring the matrix elements of the decay amplitude. We observe and account for the anomaly previously noted in the dipion invariant mass distribution for the Υ(3S)→Υ(1S)ππ transition and obtain good descriptions of the dynamics of the decay using the most general decay amplitude allowed by partial conservation of the axial-vector current considerations. The fits further indicate that the Υ(2S)→Υ(1S)ππ and Υ(3S)→Υ(2S)ππ transitions also show the presence of terms in the decay amplitude that were previously ignored, although at a relatively suppressed level.

Recent progress in 1.3- and 1.5-μm waveband wafer-fused VCSELs

NASA Astrophysics Data System (ADS)

Mereuta, A.; Caliman, A.; Sirbu, A.; Iakovlev, V.; Ellafi, D.; Rudra, A.; Wolf, P.; Bimberg, D.; Kapon, E.

2016-11-01

The progress of 1.3- and 1.5-μm waveband wafer-fused VCSELs is reported. The emission of single mode power of 6 - 8 mW at room temperature and up to 3 mW at 80°C were demonstrated. 10-Gb/s full wavelength-set VCSEL devices for CWDM systems with high yield and Telcordia-reliability were industrially manufactured. By increasing the compressive strain in the QWs and reducing the cavity photon life time the modulation bandwidth was increased to 11.5 GHz, and large-signal data transmission experiments show error-free operation and open eye diagrams from 25 to 35 Gb/s in both B2B and after 10-km, respectively.

GSK3-mediated raptor phosphorylation supports amino-acid-dependent mTORC1-directed signalling

PubMed Central

Stretton, Clare; Hoffmann, Thorsten M.; Munson, Michael J.; Prescott, Alan; Taylor, Peter M.; Ganley, Ian G.; Hundal, Harinder S.

2015-01-01

The mammalian or mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a ubiquitously expressed multimeric protein kinase complex that integrates nutrient and growth factor signals for the co-ordinated regulation of cellular metabolism and cell growth. Herein, we demonstrate that suppressing the cellular activity of glycogen synthase kinase-3 (GSK3), by use of pharmacological inhibitors or shRNA-mediated gene silencing, results in substantial reduction in amino acid (AA)-regulated mTORC1-directed signalling, as assessed by phosphorylation of multiple downstream mTORC1 targets. We show that GSK3 regulates mTORC1 activity through its ability to phosphorylate the mTOR-associated scaffold protein raptor (regulatory-associated protein of mTOR) on Ser859. We further demonstrate that either GSK3 inhibition or expression of a S859A mutated raptor leads to reduced interaction between mTOR and raptor and under these circumstances, irrespective of AA availability, there is a consequential loss in phosphorylation of mTOR substrates, such as p70S6K1 (ribosomal S6 kinase 1) and uncoordinated-51-like kinase (ULK1), which results in increased autophagic flux and reduced cellular proliferation. PMID:26348909

Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on ω-3 supplementation.

PubMed

Famenini, Sam; Rigali, Elizabeth A; Olivera-Perez, Henry M; Dang, Johnny; Chang, Michael To; Halder, Ramesh; Rao, Rammohan V; Pellegrini, Matteo; Porter, Verna; Bredesen, Dale; Fiala, Milan

2017-01-01

Monocyte/macrophages of patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) are defective in phagocytosis and degradation amyloid β 1-42 (Aβ 1-42 ), but are improved by ω-3 fatty acids (ω-3s). The hypothesis of this study was that active Aβ 1-42 phagocytosis by macrophages prevents brain amyloidosis and thus maintains cognition. We studied the effects of self-supplementation with a drink with ω-3s, antioxidants, and resveratrol on Mini-Mental State Examination (MMSE) scores, macrophage M1M2 phenotype [the ratio of inflammatory cluster of differentiation (CD)54+CD80 and proresolution markers CD163+CD206], and Aβ 1-42 phagocytosis in patients initially diagnosed as having MCI or subjective cognitive impairment (SCI). At baseline, the median MMSE score in patients in both the apolipoprotein E (ApoE) ε3/ε3 and ApoE ε3/ε4 groups was 26.0 and macrophage Aβ 1-42 phagocytosis was defective. The MMSE rate of change increased in the ApoE ε3/ε3 group a median 2.2 points per year (P = 0.015 compared to 0) but did not change in the ApoE ε3/ε4 group (P = 0.014 between groups). In the ApoE ε3/ε3 group, all patients remained cognitively stable or improved; in the ApoE ε3/ε4 group, 1 recovered from dementia, but 3 lapsed into dementia. The macrophage phenotype polarized in patients bearing ApoE ε3/ε3 to an intermediate (green zone) M1-M2 type at the rate of 0.226 U/yr, whereas in patients bearing ApoE ε3/ε4, polarization was negative (P = 0.08 between groups). The baseline M1M2 type in the extreme M1 (red zone) or M2 (white zone) was unfavorable for cognitive outcome. Aβ 1-42 phagocytosis increased in both ApoE groups (P = 0.03 in each groups). In vitro, the lipidic mediator resolvin D1 (RvD1) down regulated the M1 type in patients with ApoE ε3/ε3 but in some patients with ε3/ε4, paradoxically up-regulated the M1 type. Antioxidant/ω-3/resveratrol supplementation was associated with favorable immune and cognitive responses in Apo

Structural and Magnetic Properties of M(mnt)(2) Salts (M = Ni, Pt, Cu) with a Ferrocene-Based Cation, [FcCH(2)N(CH(3))(3)](+). Interplay between M.M and M.S Intermolecular Interactions.

PubMed

Pullen, Anthony E.; Faulmann, Christophe; Pokhodnya, Konstantin I.; Cassoux, Patrick; Tokumoto, Madoka

1998-12-28

A series of metal bis-mnt complexes (mnt = 1,2-dithiolatomaleonitrile) with the trimethylammonium methylferrocene cation have been synthesized and characterized using X-ray diffraction, magnetic susceptibility, and differential scanning calorimetry measurements. The complexes have the formulas (FcCH(2)NMe(3))[Ni(mnt)(2)] (2), (FcCH(2)NMe(3))[Pt(mnt)(2)] (3), and (FcCH(2)NMe(3))(2)[Cu(mnt)(2)] (4) (where Fc = ferrocene). At 300 K, the crystal structures of 1:1 complexes 2 and 3 are very similar. They consist of pairs of [M(mnt)(2)](-) in a slipped configuration packed in stacks. Each [M(mnt)(2)](-) stack is separated from adjacent stacks by two columns of cations. Within the pairs, the [M(mnt)(2)](-) anions interact via short M.S contacts, while there are no short contacts between the pairs. Complex 4, which has a 2:1 stoichiometry, exhibits a markedly different packing arrangement of the anionic units. Due to the special position of the Cu atom in the asymmetric unit cell, [Cu(mnt)(2)](2)(-) dianions are completely isolated from each other. The magnetic susceptibility behavior of the nickel complex is consistent with the presence of magnetically isolated, antiferromagnetically (AF) coupled [Ni(mnt)(2)](-) pairs with the AF exchange parameter, J = -840 cm(-)(1). The platinum complex undergoes an endothermic structural phase transition (T(p)) at 247 K. Below T(p) its structure is characterized by the formation of magnetically isolated [Pt(mnt)(2)](2)(2)(-) dimers in an eclipsed configuration with short Pt.Pt and S.S contacts between monomers. In the magnetic properties, the structural changes reveal themselves as an abrupt susceptibility drop implying a substantial increase of the AF exchange parameter. A mechanism of the phase transition in the platinum compound is proposed. For compound 4, paramagnetic behavior is observed.

Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol.

PubMed

Helms, Christa M; Rogers, Laura S M; Waters, Courtney A; Grant, Kathleen A

2008-07-01

The subtypes of gamma-aminobutyric acid (GABA)(A) receptors mediating the discriminative stimulus effects of ethanol in nonhuman primates are not completely identified. The GABA(A) receptor positive modulator zolpidem has high, intermediate, and low activity at receptors containing alpha(1), alpha(2/3), and alpha(5) subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for alpha(4/6)-containing receptors, higher affinity for alpha(5)- and lower, but equal, affinity for alpha(1)- and alpha(2/3)-, containing GABA(A) receptors, and antagonizes the discriminative stimulus effects of ethanol. This study assessed Ro15-4513 antagonism of the generalization of zolpidem from ethanol in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 g/kg (n = 10) or 2.0 g/kg (n = 7) ethanol (i.g.) from water with a 30-minute pretreatment interval. Zolpidem (0.017 to 5.6 mg/kg, i.m.) completely generalized from ethanol (>or=80% of total session responses on the ethanol-appropriate lever) for 6/7 monkeys trained to discriminate 2.0 g/kg and 4/10 monkeys trained to discriminate 1.0 g/kg ethanol. Zolpidem partially generalized from 1.0 or 2.0 g/kg ethanol in 6/7 remaining monkeys. Ro15-4513 (0.003 to 0.30 mg/kg, i.m., 5-minute pretreatment) shifted the zolpidem dose-response curve to the right in all monkeys showing generalization. Analysis of apparent pK(B) from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro15-4513 binding sites. Main effects of sex and training dose indicated greater potency of Ro15-4513 in males and in monkeys trained to discriminate 1.0 g/kg ethanol. Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABA(A) receptors that contain alpha(1) subunits, however, antagonism by Ro15-4513 of zolpidem generalization

Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats.

PubMed

Galloway, Claire R; Lebois, Evan P; Shagarabi, Shezza L; Hernandez, Norma A; Manns, Joseph R

2014-01-01

Acetylcholine signaling through muscarinic receptors has been shown to benefit memory performance in some conditions, but pan-muscarinic activation also frequently leads to peripheral side effects. Drug therapies that selectively target M1 or M4 muscarinic receptors could potentially improve memory while minimizing side effects mediated by the other muscarinic receptor subtypes. The ability of three recently developed drugs that selectively activate M1 or M4 receptors to improve recognition memory was tested by giving Long-Evans rats subcutaneous injections of three different doses of the M1 agonist VU0364572, the M1 positive allosteric modulator BQCA or the M4 positive allosteric modulator VU0152100 before performing an object recognition memory task. VU0364572 at 0.1 mg/kg, BQCA at 1.0 mg/kg and VU0152100 at 3.0 and 30.0 mg/kg improved the memory performance of rats that performed poorly at baseline, yet the improvements in memory performance were the most statistically robust for VU0152100 at 3.0 mg/kg. The results suggested that selective M1 and M4 receptor activation each improved memory but that the likelihood of obtaining behavioral efficacy at a given dose might vary between subjects even in healthy groups depending on baseline performance. These results also highlighted the potential of drug therapies that selectively target M1 or M4 receptors to improve memory performance in individuals with impaired memory.

Low-dose mannitol (0.3 g kg(-1)) improves the pulsatility index and minimum diastolic blood flow velocity in traumatic brain injury.

PubMed

Nincevic, Zeljko; Mestrovic, Julije; Nincevic, Jasna; Sundov, Zeljko; Kuscevic, Dorjan

2015-01-01

The aim of the study was to investigate the effects of using low-dose mannitol (0.3 g kg(-1)) on the pulsatility index (PI) and minimum diastolic blood flow velocity (FV-min) of the middle cerebral artery in a traumatic brain injury (TBI). Low-dose mannitol (0.3 g kg(-1)) was administered to a group of 20 patients with a TBI. Transcranial Doppler (TCD) ultrasonography was used to monitor the PI and FV-min. The study included patients with a diffuse traumatic brain injury and Glasgow coma score < 8. The initial TCD ultrasonography values were pathological (PI > 1.4 and FV-min < 20 cm s(-1)). TCD ultrasonography examinations were carried out before mannitol administration, immediately after administration and 1, 2 and 3 hours after the administration of mannitol. A one-way analysis of variance revealed significant changes in the PI (F = 8.392; p < 0.001) and FV-min (F = 8.291; p = 0.001) after the use of mannitol. Low-dose mannitol administration appears to be efficacious for improving the indicators of disturbed circulation in a TBI (FV-min increase, PI decrease). The maximum decrease in the PI was recorded 1 hour after the administration of mannitol and was 10.9% of the initial value. The maximum increase in the FV-min was recorded 1 hour after administration and was 29.7% of the initial value. These changes were significant ∼ 2 hours later.

Hypertension and diabetes prevalence among adults with moderately increased BMI (23·0-24·9 kg/m2): findings from a nationwide survey in Bangladesh.

PubMed

Rahman, Muntasirur; Williams, Gail; Mamun, Abdullah Al

2017-06-01

BMI is a proxy for fat accumulation in the body. Increased diabetes and CVD risks have been observed for Asian populations at lower BMI than the WHO-recommended BMI cut-off points for overweight (≥25·0 kg/m2) and obesity (≥30·0 kg/m2). The current study aimed to quantify the increased hypertension (HTN) and type 2 diabetes mellitus (T2DM) prevalence in Bangladeshi adults with moderately increased BMI (23·0-24·9 kg/m2). Data from the most recent Bangladesh Demographic and Health Survey (2011) were analysed. Modified Poisson regression models with robust error variance were used to calculate prevalence ratios (PR) for HTN or T2DM by BMI category, considering BMI=18·5-22·9 kg/m2 as the reference. All analyses incorporated the complex sampling design of the survey. BMI, blood pressure, blood sugar and related information were collected from a nationally representative sample. Adults (n 7433) aged≥35 years. About 12 % of Bangladeshi adults, both male and female, were within the BMI range 23·0-24·9 kg/m2 or moderately overweight. Compared with the reference BMI group (18·5-22·9 kg/m2), they had an increased PR for HTN (1·55-1·77) and T2DM (1·54-1·93). These increased PR are similar to those for the WHO-defined overweight group (BMI=25·0-29·9 kg/m2). Our findings support the recommendation that calls for setting the optimum BMI for Asian populations to 18·5-23·0 kg/m2 for health promotion and for public health interventions like leisure-time physical activity. WHO cut-off points for overweight (≥25 kg/m2) should be used to facilitate international comparisons.

Metal ion displacements in noncentrosymmetric chalcogenides La{sub 3}Ga{sub 1.67}S{sub 7}, La{sub 3}Ag{sub 0.6}GaCh{sub 7} (Ch=S, Se), and La{sub 3}MGaSe{sub 7} (M=Zn, Cd)

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

Iyer, Abishek K.; Yin, Wenlong; Institute of Chemical Materials, China Academy of Engineering Physics, Mianyang 621900

The quaternary Ga-containing chalcogenides La{sub 3}Ag{sub 0.6}GaS{sub 7}, La{sub 3}Ag{sub 0.6}GaSe{sub 7}, La{sub 3}ZnGaSe{sub 7}, and La{sub 3}CdGaSe{sub 7}, as well as the related ternary chalcogenide La{sub 3}Ga{sub 1.67}S{sub 7}, were prepared by reactions of the elements at 950 °C. They adopt noncentrosymmetric hexagonal structures (space group P6{sub 3}, Z=2) with cell parameters (a=10.2 Å, c=6.1 Å for the sulfides; a=10.6 Å, c=6.4 Å for the selenides) that are largely controlled by the geometrical requirements of one-dimensional stacks of Ga-centered tetrahedra separated by the La atoms. Among these compounds, which share the common formulation La{sub 3}M{sub 1–x}GaCh{sub 7} (M=Ga, Ag,more » Zn, Cd; Ch=S, Se), the M atoms occupy sites within a stacking of trigonal antiprisms formed by Ch atoms. The location of the M site varies between extremes with trigonal antiprismatic (CN6) and trigonal planar (CN3) geometry. Partial occupation of these sites and intermediate ones accounts for the considerable versatility of these structures and the occurrence of large metal displacement parameters. The site occupations can be understood in a simple way as being driven by the need to satisfy appropriate bond valence sums for both the M and Ch atoms. Band structure calculations rationalize the substoichiometry observed in the Ag-containing compounds (La{sub 3}Ag{sub 0.6}GaS{sub 7}, La{sub 3}Ag{sub 0.6}GaSe{sub 7}) as a response to overbonding. X-ray photoelectron spectroscopy supports the presence of monovalent Ag atoms in these compounds, which are not charge-balanced. - Graphical abstract: Partial occupation of metal atoms in multiple sites accounts for versatility in Ga-containing chalcogenides La{sub 3}M{sub 1–x}GaCh{sub 7} with noncentrosymmetric hexagonal structures. - Highlights: • La{sub 3}M{sub 1–x}GaCh{sub 7} (M =Ga, Ag, Zn, Cd; Ch =S, Se) adopt related hexagonal structures. • Large displacements of M atoms originate from partial occupation of

Effects of ginseol k-g3, an Rg3-enriched fraction, on scopolamine-induced memory impairment and learning deficit in mice

PubMed Central

Peña, Ike dela; Yoon, Seo Young; Kim, Hee Jin; Park, Sejin; Hong, Eun Young; Ryu, Jong Hoon; Park, Il Ho; Cheong, Jae Hoon

2013-01-01

Background Although ginsenosides such as Rg1, Rb1 and Rg3 have shown promise as potential nutraceuticals for cognitive impairment, their use has been limited due to high production cost and low potency. In particular, the process of extracting pure Rg3 from ginseng is laborious and expensive. Methods We described the methods in preparing ginseol k-g3, an Rg3-enriched fraction, and evaluated its effects on scopolamine-induced memory impairment in mice. Results Ginseol k-g3 (25–200 mg/kg) significantly reversed scopolamine-induced cognitive impairment in the passive avoidance, but not in Y-maze testing. Ginseol k-g3 (50 and 200 mg/kg) improved escape latency in training trials and increased swimming times within the target zone of the Morris water maze. The effect of ginseol k-g3 on the water maze task was more potent than that of Rg3 or Red ginseng. Acute or subchronic (6 d) treatment of ginseol k-g3 did not alter normal locomotor activity of mice in an open field. Ginseol k-g3 did not inhibit acetylcholinesterase activity, unlike donezepil, an acetylcholinesterase inhibitor. Rg3 enrichment through the ginseol k-g3 fraction enhanced the efficacy of Rg3 in scopolamine-induced memory impairment in mice as demonstrated in the Morris water maze task. Conclusion The effects of ginseol k-g3 in ameliorating scopolamine-induced memory impairment in the passive avoidance and Morris water maze tests indicate its specific influence on reference or long-term memory. The mechanism underlying the reversal of scopolamine-induced amnesia by ginseol k-g3 is not yet known, but is not related to anticholinesterase-like activity. PMID:24558303

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)- and (S)-methadone and structurally related opioids

PubMed Central

Morrish, Glynn A; Foster, David J R; Somogyi, Andrew A

2006-01-01

Aims To determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. Methods M3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µm) and the mechanism of inhibition determined for (R)- and (S)-methadone (70–500 µm) using three microsomal samples. Results Glucuronide formation displayed single enzyme kinetics. The M3G Vmax (mean ± SD) was 4.8-fold greater than M6G Vmax (555 ± 110 vs. 115 ± 19 nmol mg−1 protein h−1; P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg−1 protein h−1). Km values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 mm; P = 0.89, 0.02; −0.29, 0.32 mm). M3G and M6G formation was inhibited (P < 0.01) with a significant increase in the M3G/M6G ratio (P < 0.01) for all compounds tested. Detailed analysis with (R)- and (S)-methadone revealed noncompetitive inhibition with (R)-methadone Ki of 320 ± 42 µm and 192 ± 12 µm for M3G and M6G, respectively, and (S)-methadone Ki of 226 ± 30 µm and 152 ± 20 µm for M3G and M6G, respectively. Ki values for M3G inhibition were significantly greater than for M6G for (R)-methadone (P = 0.017, 128; 55, 202 µm) and (S)-methadone (P = 0.026, 75; 22, 128 µm). Conclusions Both methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadone-maintained patients and reduced relative formation of the opioid active M6G compared with M3G. PMID:16487227

Impact of Sleeve Gastrectomy on Type 2 Diabetes Mellitus, Gastric Emptying Time, Glucagon-Like Peptide 1 (GLP-1), Ghrelin and Leptin in Non-morbidly Obese Subjects with BMI 30-35.0 kg/m2: a Prospective Study.

PubMed

Vigneshwaran, B; Wahal, Akshat; Aggarwal, Sandeep; Priyadarshini, Pratyusha; Bhattacharjee, Hemanga; Khadgawat, Rajesh; Yadav, Rajkumar

2016-12-01

The study was conducted to evaluate the impact of laparoscopic sleeve gastrectomy (LSG) on type 2 diabetes mellitus (T2DM) in patients with a body mass index (BMI) of 30.0-35.0 kg/m 2 . Possible mechanisms, including alterations in gastric emptying time (GET), glucagon-like peptide 1 (GLP-1), ghrelin and leptin, were evaluated. Twenty obese patients with T2DM and with a BMI of 30.0-35.0 kg/m 2 underwent LSG during March 2012 to February 2015. Glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and GET were measured at baseline, 3 months, 6 months, 12 months and 24 months after surgery. Fasting and post-prandial levels of serum GLP-1, ghrelin and leptin were measured pre-operatively and after 3 and 6 months. The average duration of follow-up was 17.6 months, and 10 patients had completed 2 years of follow-up. After 2 years, the average BMI decreased from 33.4 ± 1.2 to 26.7 ± 1.8 kg/m 2 . The mean HbA1c decreased from 8.7 ± 1.6 to 6.7 ± 1.5 %, respectively. Ten patients achieved complete remission. Insulin could be stopped in all six patients who were on it pre-operatively. Meal-stimulated GLP-1 response and serum insulin at 30 min showed a significant increase following surgery. There was a significant decrease in GET. This prospective study confirms the positive impact of LSG on diabetic status of non-morbidly obese patients. The possible mechanisms include the rise in post-prandial GLP-1 level induced by accelerated gastric emptying, leading to an increase in insulin secretion. LSG also leads to decreased ghrelin and leptin levels which may have a role in improving glucose homeostasis after surgery.

Comparative analysis of efficacy of lignocaine 1.5 mg/kg and two different doses of dexmedetomidine (0.5 μg/kg and 1 μg/kg) in attenuating the hemodynamic pressure response to laryngoscopy and intubation

PubMed Central

Gulabani, Michell; Gurha, Pavan; Dass, Prashant; Kulshreshtha, Nishi

2015-01-01

Context: Laryngoscopy and intubation cause an intense reflex increase in heart rate, blood pressure, due to an increased sympathoadrenal pressor response. Lignoocaine has shown blunting of pressor response to intubation. Dexmedetomidine has sympatholytic effects. Aims: To the best of our knowledge there is no study comparing the efficacy of lignocaine with two different doses of dexmedetomidine for attenuating the pressor response. With this idea, we planned to conduct the present study. Materials and Methods: After approval by the Hospital Ethics committee, 90 consenting adults aged 18-65 years of age of either sex of non-hypertensive ASA Grade I or II were randomly allocated into three groups. Group D1- IV Dexmedetomidine 0.5μg/kg over 10 minutes Group D2- IV Dexmedetomidine 1μg/kg over 10 minutes Group X- IV Lignocaine 1.5mg/kg in 10 ml normal saline Statistical Analysis Used: ANOVA and Student's t test used for analysis. Results: Dexmedetomidine 1µg/kg was more effective than 0.5µg/kg and lignocaine 1.5mg/kg in attenuating the pressor response. Conclusions: We conclude that dexmedetomidine 1μg/kg adequately attenuates the hemodynamic response to laryngoscopy and endotracheal intubation when compared with dexmedetomidine 0.5μg/kg and lignocaine 1.5mg/kg. PMID:25886414

mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system.

PubMed

Miao, Linqing; Yang, Liu; Huang, Haoliang; Liang, Feisi; Ling, Chen; Hu, Yang

2016-03-30

Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.

Fabrication of a 3D Hierarchical Sandwich Co9 S8 /α-MnS@N-C@MoS2 Nanowire Architectures as Advanced Electrode Material for High Performance Hybrid Supercapacitors.

PubMed

Kandula, Syam; Shrestha, Khem Raj; Kim, Nam Hoon; Lee, Joong Hee

2018-06-01

Supercapacitors suffer from lack of energy density and impulse the energy density limit, so a new class of hybrid electrode materials with promising architectures is strongly desirable. Here, the rational design of a 3D hierarchical sandwich Co 9 S 8 /α-MnS@N-C@MoS 2 nanowire architecture is achieved during the hydrothermal sulphurization reaction by the conversion of binary mesoporous metal oxide core to corresponding individual metal sulphides core along with the formation of outer metal sulphide shell at the same time. Benefiting from the 3D hierarchical sandwich architecture, Co 9 S 8 /α-MnS@N-C@MoS 2 electrode exhibits enhanced electrochemical performance with high specific capacity/capacitance of 306 mA h g -1 /1938 F g -1 at 1 A g -1 , and excellent cycling stability with a specific capacity retention of 86.9% after 10 000 cycles at 10 A g -1 . Moreover, the fabricated asymmetric supercapacitor device using Co 9 S 8 /α-MnS@N-C@MoS 2 as the positive electrode and nitrogen doped graphene as the negative electrode demonstrates high energy density of 64.2 Wh kg -1 at 729.2 W kg -1 , and a promising energy density of 23.5 Wh kg -1 is still attained at a high power density of 11 300 W kg -1 . The hybrid electrode with 3D hierarchical sandwich architecture promotes enhanced energy density with excellent cyclic stability for energy storage. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis.

PubMed

Yu, Jing; Wu, Yimei; Wang, Lu; Zhang, Wen; Xu, Man; Song, Jiayu; Fu, Yu; Cui, Yiyun; Gong, Wei; Li, Shuzhen; Xia, Weiwei; Huang, Songming; Zhang, Aihua; Jia, Zhanjun

2017-11-01

We previously reported that microsomal prostaglandin E synthase-1 (mPGES-1) contributed to adriamycin (Adr)-induced podocyte apoptosis. However, the molecular mechanism remains unclear. Here we studied the role of mPGES-1/PGE2 cascade in activating Stat3 signaling and the contribution of Stat3 in PGE2- and Adr-induced podocyte apoptosis. In murine podocytes, PGE2 dose- and time-dependently increased the phosphorylation of Stat3 in line with the enhanced cell apoptosis and reduced podocyte protein podocin. In agreement with the increased Stat3 phosphorylation, Stat3-derived cytokines including IL-6, IL-17, MCP-1, and ICAM-1 were significantly upregulated following PGE2 treatment. By application of a specific Stat3 inhibitor S3I-201, PGE2-induced podocyte apoptosis was largely abolished in parallel with a blockade of podocin reduction. Next, we observed that Adr treatment also enhanced p-Stat3 and activated mPGES-1/PGE2 cascade. Blockade of Stat3 by S3I-201 significantly ameliorated Adr-induced cell apoptosis and podocin reduction. More interestingly, silencing mPGES-1 in podocytes by mPGES-1 siRNA blocked Adr-induced increments of Stat-3 phosphorylation, PGE2 production, and Stat3-derived inflammatory cytokines. Taken together, this study suggested that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis. Targeting mPGES-1/PGE2/Stat3 signaling might be a potential strategy for the treatment of podocytopathy.

Experimental investigation of 150-KG-scale corium melt jet quenching in water

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

Magallon, D.; Hohmann, H.

This paper compares and discusses the results of two large scale FARO quenching tests known as L-11 and L-14, which involved, respectively, 151 kg of W% 76.7 UO{sub 2} + 19.2 ZrO{sub 2} + 4.1 Zr and 125 kg of W% 80 UO{sub 2} + 20 ZrO{sub 2} melts poured into 600-kg, 2-m-depth water at saturation at 5.0 MPa. The results are further compared with those of two previous tests performed using a pure oxidic melt, respectively 18 and 44 kg of W% 80 UO{sub 2} + 20 ZrO{sub 2} melt quenched in 1-m-depth water at saturation at 5.0 MPa.more » In all the tests, significant breakup and quenching took place during the melt fall through the water. No steam explosion occurred. In the tests performed with a pure oxide UO{sub 2}-ZrO{sub 2} melt, part of the corium (from 1/6 to 1/3) did not breakup and reached the bottom plate still molten whatever the water depth was. Test L-11 data suggest that full oxidation and complete breakup of the melt occurred during the melt fall through the water. A proportion of 64% of the total energy content of the melt was released to the water during this phase ({approximately}1.5 s), against 44% for L-14. The maximum temperature increase of the bottom plate was 330 K (L-14). The mean particle size of the debris ranged between 2.5 and 4.8mm.« less

Core-Shell Fe1- xS@Na2.9PS3.95Se0.05 Nanorods for Room Temperature All-Solid-State Sodium Batteries with High Energy Density.

PubMed

Wan, Hongli; Mwizerwa, Jean Pierre; Qi, Xingguo; Liu, Xin; Xu, Xiaoxiong; Li, Hong; Hu, Yong-Sheng; Yao, Xiayin

2018-03-27

High ionic conductivity electrolyte and intimate interfacial contact are crucial factors to realize high-performance all-solid-state sodium batteries. Na 2.9 PS 3.95 Se 0.05 electrolyte with reduced particle size of 500 nm is first synthesized by a simple liquid-phase method and exhibits a high ionic conductivity of 1.21 × 10 -4 S cm -1 , which is comparable with that synthesized with a solid-state reaction. Meanwhile, a general interfacial architecture, that is, Na 2.9 PS 3.95 Se 0.05 electrolyte uniformly anchored on Fe 1- x S nanorods, is designed and successfully prepared by an in situ liquid-phase coating approach, forming core-shell structured Fe 1- x S@Na 2.9 PS 3.95 Se 0.05 nanorods and thus realizing an intimate contact interface. The Fe 1- x S@Na 2.9 PS 3.95 Se 0.05 /Na 2.9 PS 3.95 Se 0.05 /Na all-solid-state sodium battery demonstrates high specific capacity and excellent rate capability at room temperature, showing reversible discharge capacities of 899.2, 795.5, 655.1, 437.9, and 300.4 mAh g -1 at current densities of 20, 50, 100, 150, and 200 mA g -1 , respectively. The obtained all-solid-state sodium batteries show very high energy and power densities up to 910.6 Wh kg -1 and 201.6 W kg -1 based on the mass of Fe 1- x S at current densities of 20 and 200 mA g -1 , respectively. Moreover, the reaction mechanism of Fe 1- x S is confirmed by means of ex situ X-ray diffraction techniques, showing that partially reversible reaction occurs in the Fe 1- x S electrode after the second cycle, which gives the obtained all-solid-state sodium battery an exceptional cycling stability, exhibiting a high capacity of 494.3 mAh g -1 after cycling at 100 mA g -1 for 100 cycles. This contribution provides a strategy for designing high-performance room temperature all-solid-state sodium battery.

Final report on APMP.M.P-S3: Results of the supplementary comparison in gas media in the range 1.77 MPa to 6.8 MPa

NASA Astrophysics Data System (ADS)

Owen, N.; Bergoglio, M.

2013-01-01

This report provides the results of the supplementary bilateral comparison APMP.M.P-S3 between NMI Australia (NMIA) and INRIM, Italy executed from November 2010 to November 2011. NMIA acted as the pilot laboratory and provided a Ruska G series piston gauge as the transfer standard, with a nominal area 16.8 mm2 requiring a nominal load of 12 kg to balance a pressure of 7.0 MPa. The purpose of this supplementary bilateral comparison was to provide data for linking NMIA to CCM.P-K1.c in the pressure range greater than 4 MPa to extend the range covered by key comparison APMP.M.P-K1c. The original protocol called for the pressure range from 80 kPa to 6.80 MPa. Both participants agreed to limit this comparison range to 1.77 MPa to 6.50 MPa. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the APMP, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.

PubMed

Monn, James A; Prieto, Lourdes; Taboada, Lorena; Hao, Junliang; Reinhard, Matthew R; Henry, Steven S; Beadle, Christopher D; Walton, Lesley; Man, Teresa; Rudyk, Helene; Clark, Barry; Tupper, David; Baker, S Richard; Lamas, Carlos; Montero, Carlos; Marcos, Alicia; Blanco, Jaime; Bures, Mark; Clawson, David K; Atwell, Shane; Lu, Frances; Wang, Jing; Russell, Marijane; Heinz, Beverly A; Wang, Xushan; Carter, Joan H; Getman, Brian G; Catlow, John T; Swanson, Steven; Johnson, Bryan G; Shaw, David B; McKinzie, David L

2015-09-24

Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.

Bacterial treatment of alkaline cement kiln dust using Bacillus halodurans strain KG1.

PubMed

Kunal; Rajor, Anita; Siddique, Rafat

2016-01-01

This study was conducted to isolate an acid-producing, alkaliphilic bacterium to reduce the alkalinity of cement industry waste (cement kiln dust). Gram-positive isolate KG1 grew well at pH values of 6-12, temperatures of 28-50°C, and NaCl concentrations of 0-16% and thus was further screened for its potential to reduce the pH of an alkaline medium. Phenotypic characteristics of the KG1 isolate were consistent with those of the genus Bacillus, and the highest level of 16S rRNA gene sequence similarity was found with Bacillus halodurans strain DSM 497 (94.7%). On the basis of its phenotypic characteristics and genotypic distinctiveness from other phylogenetic neighbors belonging to alkaliphilic Bacillus species, the isolated strain was designated B. halodurans strain KG1, with GenBank accession number JQ307184 (= NCIM 5439). Isolate KG1 reduced the alkalinity (by 83.64%) and the chloride content (by 86.96%) of cement kiln dust and showed a potential to be used in the cement industry for a variety of applications. Copyright © 2015 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Bloodless Pediatric Cardiopulmonary Bypass for a 3.2-kg Patient Whose Parents are of Jehovah’s Witness Faith

PubMed Central

Ratliff, Todd M.; Hodge, Ashley B.; Preston, Thomas J.; Galantowicz, Mark; Naguib, Aymen; Gomez, Daniel

2014-01-01

Abstract: Patients and parents of Jehovah’s Witness (JW) faith present multiple challenges to a medical team, especially in the neonatal and pediatric population. The medical team must balance honoring the parents’ request of not receiving blood products and fulfilling our commitment as advocates for the child’s wellbeing. A multidisciplinary approach to cardiac surgery must be embraced for bloodless cardiopulmonary bypass (CPB) to be successful. At our institution, we have developed strategies and techniques for blood conservation that are used preoperatively, intraoperatively, and postoperatively for every CPB case with the goal of a bloodless procedure. These protocols include: preoperative erythropoietin, preoperative iron administration, selection of a CPB circuit specific to the patient’s height and weight, acute normovolemic hemodilution, retrograde autologous prime and venous autologous prime, tranexamic acid administration, zerobalance ultrafiltration, flushing of the pump suckers post-CPB, modified ultrafiltration, and cell salvage. We present an 8-day-old, 3.2-kg patient of JW faith with aortic valve stenosis and regurgitation and a patent foramen ovale who underwent a bloodless left ventricle-to-aorta tunnel repair and aortic valve repair on CPB. PMID:25208437

Investigation of the spin-lattice coupling in M n3G a1 -xS nxN antiperovskites

NASA Astrophysics Data System (ADS)

Shi, Kewen; Sun, Ying; Colin, Claire V.; Wang, Lei; Yan, Jun; Deng, Sihao; Lu, Huiqing; Zhao, Wenjun; Kazunari, Yamaura; Bordet, Pierre; Wang, Cong

2018-02-01

The magnetovolume effects (MVEs) of M n3G a1 -xS nxN antiperovskite compounds have been investigated by means of neutron powder diffraction. Increasing the Sn-doping content at the Ga site leads to the broadening of the magnetic phase transition temperature range and the thermal expansion behavior changes from negative to positive. We establish the relationship between the square of the ordered magnetic moment m2 and the volume variation Δ ωm for the antiferromagnetic phase (Γ5 g magnetic structure with rhombohedral symmetry R 3 ¯m ). The temperature variations of Δ ωm(T ) , m2(T ) and the magnetoelastic coupling constant C (T ) are also quantitatively analyzed according to the itinerant-electron theory. Moreover, the increase of the phonon contribution to the thermal expansion induced by Sn doping and the corresponding decrease of dm/dT are revealed to be the key parameters for tuning the MVEs. Our results allow elucidating and quantifying the mechanism of the spin-lattice coupling and can be used to design magnetic functional materials with controlled thermal expansion behaviors for specific applications.

Permissive role for mGlu1 metabotropic glutamate receptors in excitotoxic retinal degeneration.

PubMed

Liberatore, Francesca; Bucci, Domenico; Mascio, Giada; Madonna, Michele; Di Pietro, Paola; Beneventano, Martina; Puliti, Alda Maria; Battaglia, Giuseppe; Bruno, Valeria; Nicoletti, Ferdinando; Romano, Maria Rosaria

2017-11-05

Neuroprotection is an unmet need in eye disorders characterized by retinal ganglion cell (RGC) death, such as prematurity-induced retinal degeneration, glaucoma, and age-related macular degeneration. In all these disorders excitotoxicity is a prominent component of neuronal damage, but clinical data discourage the development of NMDA receptor antagonists as neuroprotectants. Here, we show that activation of mGlu1 metabotropic glutamate receptors largely contributes to excitotoxic degeneration of RGCs. Mice at postnatal day 9 were challenged with a toxic dose of monosodium glutamate (MSG, 3g/kg), which caused the death of >70% of Brn-3a + RGCs. Systemic administration of the mGlu1 receptor negative allosteric modulator (NAM), JNJ16259685 (2.5mg/kg, s.c.), was largely protective against MSG-induced RGC death. This treatment did not cause changes in motor behavior in the pups. We also injected MSG to crv4 mice, which lack mGlu1 receptors because of a recessive mutation of the gene encoding the mGlu1 receptor. MSG did not cause retinal degeneration in crv4 mice, whereas it retained its toxic activity in their wild-type littermates. These findings demonstrate that mGlu1 receptors play a key role in excitotoxic degeneration of RGCs, and encourage the study of mGlu1 receptor NAMs in models of retinal neurodegeneration. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

1,2,3-triazolate-bridged tetradecametallic transition metal clusters [M14(L)6O6(OMe)18X6] (M=FeIII, CrIII and VIII/IV) and related compounds: ground-state spins ranging from S=0 to S=25 and spin-enhanced magnetocaloric effect.

PubMed

Shaw, Rachel; Laye, Rebecca H; Jones, Leigh F; Low, David M; Talbot-Eeckelaers, Caytie; Wei, Qiang; Milios, Constantinos J; Teat, Simon; Helliwell, Madeleine; Raftery, James; Evangelisti, Marco; Affronte, Marco; Collison, David; Brechin, Euan K; McInnes, Eric J L

2007-06-11

We report the synthesis, by solvothermal methods, of the tetradecametallic cluster complexes [M14(L)6O6(OMe)18Cl6] (M=FeIII, CrIII) and [V14(L)6O6(OMe)18Cl6-xOx] (L=anion of 1,2,3-triazole or derivative). Crystal structure data are reported for the {M14} complexes [Fe14(C2H2N3)6O6(OMe)18Cl6], [Cr14(bta)6O6(OMe)18Cl6] (btaH=benzotriazole), [V14O6(Me2bta)6(OMe)18Cl6-xOx] [Me2btaH=5,6-Me2-benzotriazole; eight metal sites are VIII, the remainder are disordered between {VIII-Cl}2+ and {VIV=O}2+] and for the distorted [FeIII14O9(OH)(OMe)8(bta)7(MeOH)5(H2O)Cl8] structure that results from non-solvothermal synthetic methods, highlighting the importance of temperature regime in cluster synthesis. Magnetic studies reveal the {Fe14} complexes to have ground state electronic spins of SS=0 ground state despite having a very similar structure and all complexes being dominated by intramolecular antiferromagnetic exchange interactions. The {Fe14} complexes undergo a magnetic phase transition to long-range ordering at relatively high temperatures for molecular species, which are governed by the steric bulk of the triazole (TN=1.8 and 3.4 K for L=bta- and H2C2N3-, respectively). The huge spins of the {Fe14} complexes lead to very large magnetocaloric effects (MCE)-the largest known for any material below 10 K-which is further enhanced by spin frustration within the molecules due to the competing antiferromagnetic interactions. The largest MCE is found for [Fe14(C2H2N3)6O6(OMe)18Cl6] with an isothermal magnetic entropy change -DeltaSm of 20.3 J kg-1 K-1 at 6 K for an applied magnetic field change of 0-7 T.

Heat flux measurements of Tb3M series (M=Co, Rh and Ru): Specific heat and magnetocaloric properties

NASA Astrophysics Data System (ADS)

Monteiro, J. C. B.; Lombardi, G. A.; dos Reis, R. D.; Freitas, H. E.; Cardoso, L. P.; Mansanares, A. M.; Gandra, F. G.

2016-12-01

We report on the magnetic properties and magnetocaloric effect (MCE) for the Tb3M series, with M=Co, Rh and Ru, obtained using a heat flux technique. The specific heat of Tb3Co and Tb3Rh are very similar, with a first order type transition occurring around 6 K below the magnetic ordering temperature without any corresponding feature on the magnetization. The slightly enhanced electronic specific heat, the Debye temperature around 150 K and the presence of the magnetic specific heat well above the ordering temperature are also characteristic of many other compounds of the R3M family (R=Rare Earth). The specific heat for Tb3Ru, however, presents two peaks at 37 K and 74 K. The magnetization shows that below the first peak the system presents an antiferromagnetic behavior and is paramagnetic above 74 K. We obtained a magnetocaloric effect for M=Co and Rh, -∆S=12 J/kg K, but for Tb3Ru it is less than 3 J/kg K (μ0∆H=5 T). We believe that the experimental results show that the MCE is directly related with the process of hybridization of the (R)5d-(M)d electrons that occurs in the R3M materials.

[Protein S3 in the human 80S ribosome adjoins mRNA from 3'-side of the A-site codon].

PubMed

Molotkov, M V; Graĭfer, D M; Popugaeva, E A; Bulygin, K N; Meshchaninova, M I; Ven'iaminova, A G; Karpova, G G

2007-01-01

The protein environment of mRNA 3' of the A-site codon (the decoding site) in the human 80S ribosome was studied using a set of oligoribonucleotide derivatives bearing a UUU triplet at the 5'-end and a perfluoroarylazide group at one of the nucleotide residues at the 3'-end of this triplet. Analogues of mRNA were phased into the ribosome using binding at the tRNAPhe P-site, which recognizes the UUU codon. Mild UV irradiation of ribosome complexes with tRNAPhe and mRNA analogues resulted in the predominant crosslinking of the analogues with the 40S subunit components, mainly with proteins and, to a lesser extent, with rRNA. Among the 40S subunit ribosomal proteins, the S3 protein was the main target for modification in all cases. In addition, minor crosslinking with the S2 protein was observed. The crosslinking with the S3 and S2 proteins occurred both in triple complexes and in the absence of tRNA. Within triple complexes, crosslinking with S15 protein was also found, its efficiency considerably falling when the modified nucleotide was moved from positions +5 to +12 relative to the first codon nucleotide in the P-site. In some cases, crosslinking with the S30 protein was observed, it was most efficient for the derivative containing a photoreactive group at the +7 adenosine residue. The results indicate that the S3 protein in the human ribosome plays a key role in the formation of the mRNA binding site 3' of the codon in the decoding site.

Electron impact excitation of the low-lying 3s[3/2]{sub 1} and 3s{sup ′}[1/2]{sub 1} levels in neon for incident energies between 20 and 300 eV

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

Hoshino, M., E-mail: masami-h@sophia.ac.jp; Murai, H.; Kato, H.

2013-11-14

Absolute differential cross sections (DCSs) for electron impact of the two lower-lying 3s[3/2]{sub 1} ({sup 3}P{sub 0}) and 3s{sup ′}[1/2]{sub 1} ({sup 1}P{sub 1}) electronic states in neon (Ne) have been determined for eight incident electron energies in the range 20–300 eV. Comparisons between our results and previous measurements and calculations, where possible, are provided with best agreement being found with the recent large-scale B-spline R-matrix computations [O. Zatsarinny and K. Bartschat, Phys. Rev. A 86, 022717 (2012)]. Based on these DCSs at 100, 200, and 300 eV, a generalised oscillator strength analysis enabled us to determine estimates for themore » optical oscillator strengths of the 3s[3/2]{sub 1} and 3s{sup ′}[1/2]{sub 1} levels. In this case, excellent agreement was found with a range of independent experiments and calculations, giving us some confidence in the validity of our measurement and analysis procedures. Integral cross sections, derived from the present DCSs, were presented graphically and discussed elsewhere [M. Hoshino, H. Murai, H. Kato, Y. Itikawa, M. J. Brunger, and H. Tanaka, Chem. Phys. Lett. 585, 33 (2013)], but are tabulated here for completeness.« less

Metal-metal bonding and aromaticity in [M2(NHCHNH)3]2 (μ-E)2 (E = O, S; M = Nb, Mo, Tc, Ru, Rh).

PubMed

Yan, Xiuli; Meng, Lingpeng; Sun, Zheng; Li, Xiaoyan

2016-02-01

The nature of M-M bonding and aromaticity of [M2(NHCHNH)3]2(μ-E)2 (E = O, S; M = Nb, Mo, Tc, Ru, Rh) was investigated using atoms in molecules (AIM) theory, electron localization function (ELF), natural bond orbital (NBO) and molecular orbital analysis. These analyses led to the following main conclusions: in [M2(NHCHNH)3]2(μ-E)2 (E = O, S; M = Nb, Mo, Tc, Ru, Rh), the Nb-Nb, Ru-Ru, and Rh-Rh bonds belong to "metallic" bonds, whereas Mo-Mo and Tc-Tc drifted toward the "dative" side; all these bonds are partially covalent in character. The Nb-Nb, Mo-Mo, and Tc-Tc bonds are stronger than Ru-Ru and Rh-Rh bonds. The M-M bonds in [M2(NHCHNH)3]2(μ-S)2 are stronger than those in [M2(NHCHNH)3]2(μ-O)2 for M = Nb, Mo, Tc, and Ru. The NICS(1)ZZ values show that all of the studied molecules, except [Ru2(NHCHNH)3]2(μ-O)2, are aromaticity molecules. O-bridged compounds have more aromaticity than S-bridged compounds. Graphical Abstract Left Molecular graph, and right electron localization function (ELF) isosurface of [M2(NHCHNH)3]2(μ-E)2(E = O, S; M = Nb, Mo, Tc, Ru, Rh).

NONOates regulate KCl cotransporter-1 and -3 mRNA expression in vascular smooth muscle cells.

PubMed

Di Fulvio, Mauricio; Lauf, Peter K; Shah, Shalin; Adragna, Norma C

2003-05-01

Nitric oxide (NO) donors regulate KCl cotransport (KCC) activity and cotransporter-1 and -3 (KCC1 and KCC3) mRNA expression in sheep erythrocytes and in primary cultures of rat vascular smooth muscle cells (VSMCs), respectively. In this study, we used NONOates as rapid and slow NO releasers to provide direct evidence implicating NO as a regulator of KCC3 gene expression at the mRNA level. In addition, we used the expression of KCC3 mRNA to further investigate the mechanism of action of these NO donors at the cellular level. Treatment of VSMCs with rapid NO releasers, like NOC-5 and NOC-9, as well as with the direct NO-independent soluble guanylyl cyclase (sGC) stimulator YC-1, acutely increased KCC3 mRNA expression in a concentration- and time-dependent manner. The slow NO releaser NOC-18 had no effect on KCC3 gene expression. A specific NO scavenger completely prevented the NONOate-induced KCC3 mRNA expression. Inhibition of sGC with LY-83583 blocked the NONOate- and YC-1-induced KCC3 mRNA expression. This study shows that in primary cultures of rat VSMCs, the fast NO releasers NOC-9 and NOC-5, but not the slow NO releaser NOC-18, acutely upregulate KCC3 mRNA expression in a NO/sGC-dependent manner.

Glutathione-S-transferase A3 knockout mice are sensitive to acute cytotoxic and genotoxic effects of aflatoxin B1

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

Ilic, Zoran, E-mail: zxi01@health.state.ny.u; Crawford, Dana, E-mail: crawfod@mail.amc.ed; Egner, Patricia A., E-mail: pegner@jhsph.ed

Aflatoxin B1 (AFB1) is a major risk factor for hepatocellular carcinoma (HCC) in humans. However, mice, a major animal model for the study of AFB1 carcinogenesis, are resistant, due to high constitutive expression, in the mouse liver, of glutathione S-transferase A3 subunit (mGSTA3) that is lacking in humans. Our objective was to establish that a mouse model for AFB1 toxicity could be used to study mechanisms of toxicity that are relevant for human disease, i.e., an mGSTA3 knockout (KO) mouse that responds to toxicants such as AFB1 in a manner similar to humans. Exons 3-6 of the mGSTA3 were replacedmore » with a neomycin cassette by homologous recombination. Southern blotting, RT-PCR, Western blotting, and measurement of AFB1-N{sup 7}-DNA adduct formation were used to evaluate the mGSTA3 KO mice. The KO mice have deletion of exons 3-6 of the mGSTA3 gene, as expected, as well as a lack of mGSTA3 expression at the mRNA and protein levels. Three hours after injection of 5 mg/kg AFB1, mGSTA3 KO mice have more than 100-fold more AFB1-N{sup 7}-DNA adducts in their livers than do similarly treated wild-type (WT) mice. In addition, the mGSTA3 KO mice die of massive hepatic necrosis, at AFB1 doses that have minimal toxic effects in WT mice. We conclude that mGSTA3 KO mice are sensitive to the acute cytotoxic and genotoxic effects of AFB1, confirming the crucial role of GSTA3 subunit in protection of normal mice against AFB1 toxicity. We propose the mGSTA3 KO mouse as a useful model with which to study the interplay of risk factors leading to HCC development in humans, as well as for testing of additional possible functions of mGSTA3.« less

mRNA 3' of the A site bound codon is located close to protein S3 on the human 80S ribosome.

PubMed

Molotkov, Maxim V; Graifer, Dmitri M; Popugaeva, Elena A; Bulygin, Konstantin N; Meschaninova, Maria I; Ven'yaminova, Aliya G; Karpova, Galina G

2006-07-01

Ribosomal proteins neighboring the mRNA downstream of the codon bound at the decoding site of human 80S ribosomes were identified using three sets of mRNA analogues that contained a UUU triplet at the 5' terminus and a perfluorophenylazide cross-linker at guanosine, adenosine or uridine residues placed at various locations 3' of this triplet. The positions of modified mRNA nucleotides on the ribosome were governed by tRNA(Phe) cognate to the UUU triplet targeted to the P site. Upon mild UV-irradiation, the mRNA analogues cross-linked preferentially to the 40S subunit, to the proteins and to a lesser extent to the 18S rRNA. Cross-linked nucleotides of 18S rRNA were identified previously. In the present study, it is shown that among the proteins the main target for cross-linking with all the mRNA analogues tested was protein S3 (homologous to prokaryotic S3, S3p); minor cross-linking to protein S2 (S5p) was also detected. Both proteins cross-linked to mRNA analogues in the ternary complexes as well as in the binary complexes (without tRNA). In the ternary complexes protein S15 (S19p) also cross-linked, the yield of the cross-link decreased significantly when the modified nucleotide moved from position +5 to position +12 with respect to the first nucleotide of the P site bound codon. In several ternary complexes minor cross-linking to protein S30 was likewise detected. The results of this study indicate that S3 is a key protein at the mRNA binding site neighboring mRNA downstream of the codon at the decoding site in the human ribosome.

Piezo-, elasto- and acousto-optic properties of Tl3AsS4 crystals.

PubMed

Mytsyk, Bohdan; Kryvyy, Taras; Demyanyshyn, Natalya; Mys, Oksana; Martynyuk-Lototska, Iryna; Kokhan, Oleksandr; Vlokh, Rostyslav

2018-05-10

Complete matrices of piezo-optic and elasto-optic tensors are experimentally determined for Tl 3 AsS 4 crystals. It is revealed that the piezo-optic coefficients are very high, ∼10 -11   N/m 2 in the order of magnitude. This implies that Tl 3 AsS 4 can be referred to the best piezo-optic materials. The same concerns the elasto-optic coefficients, of which absolute values are in the interval 0.28-0.54. It is also found that, at the anisotropic and isotropic interactions with the slowest transverse and longitudinal acoustic waves, the acousto-optic figure of merit reaches extremely high values (1.99×10 -12   s 3 /kg and 9.45×10 -13   s 3 /kg, respectively). In other words, the Tl 3 AsS 4 crystals can be referred to as one of the best acousto-optic materials for the visible and infrared spectral ranges.

M&S Decision/Role-Behavior Decompositions

DTIC Science & Technology

2007-10-17

M &S Decision/Role-Behavior Decompositions Wargaming and Analysis Workshop Military Operations Research Society 17 October 2007 Paul Works, Methods...number. 1. REPORT DATE 17 OCT 2007 2. REPORT TYPE 3. DATES COVERED 00-00-2007 to 00-00-2007 4. TITLE AND SUBTITLE M &S Decision/Role-Behavior...transmission. • Combat models and simulations ( M &S) continue, in most cases, to model “effects-level” representations of SA, decisions, and behaviors. – M &S

GaIn(N)As/GaAs VCSELs emitting in the 1.1-1.3 μm range

NASA Astrophysics Data System (ADS)

Grenouillet, L.; Duvaut, P.; Olivier, N.; Gilet, P.; Grosse, P.; Poncet, S.; Philippe, P.; Pougeoise, E.; Fulbert, L.; Chelnokov, A.

2006-07-01

In the field of datacom, 10 Gbit/s sources with a good coupling in monomode silica fibers, whose dispersion minimum occurs at 1.3 μm, are required. Vertical Cavity Surface Emitting Lasers (VCSELs) emitting at 1.3 μm are key components in this field thanks to their compactness, their ability of being operated at high frequencies, their low threshold current and their low beam divergence. Such devices emitting in this wavelength range have been demonstrated using different materials such as strained GaInAs/GaAs quantum wells [1-3], GaInNAs/GaAs quantum wells [4-7], InAs/GaAs quantum dots [8, 9], and antimonides [10], using either molecular beam epitaxy (MBE) or metalorganic vapor phase epitaxy (MOVPE). In the emerging field of photonics on CMOS, there is a need to bond efficient III-V laser sources on SOI wafers. These components should operate at small voltage and current, have a small footprint, and be efficiently couple to Si waveguides, these latter being transparent above 1.1 μm. Since these requirements resemble VCSEL properties, the development of VCSEL emitting above 1.1 μm could therefore benefit to future new sources for photonics on silicon applications. In this context we developed GaAs-based VCSELs emitting in the 1.1 μm - 1.3 μm range with GaInAs/GaAs or GaInNAs/GaAs quantum wells (QWs) as the active materials.

Delineation of xenobiotic substrate sites in rat glutathione S-transferase M1-1

PubMed Central

Hearne, Jennifer L.; Colman, Roberta F.

2005-01-01

Glutathione S-transferases catalyze the conjugation of glutathione with endogenous and exogenous xenobiotics. Hu and Colman (1995) proposed that there are two distinct substrate sites in rat GST M1-1, a 1-chloro-2,4-dintrobenzene (CDNB) substrate site located in the vicinity of tyrosine-115, and a monobromobimane (mBBr) substrate site. To determine whether the mBBr substrate site is distinguishable from the CDNB substrate site, we tested S-(hydroxyethyl)bimane, a nonreactive derivative of mBBr, for its ability to compete kinetically with the substrates. We find that S-(hydroxyethyl)bimane is a competitive inhibitor (KI = 0.36 μM) when mBBr is used as substrate, but not when CDNB is used as substrate, demonstrating that these two sites are distinct. Using site-directed mutagenesis, we have localized the mBBr substrate site to an area midway through α-helix 4 (residues 90–114) and have identified residues that are important in the enzymatic reaction. Substitution of alanine at positions along α-helix 4 reveals that mutations at positions 103, 104, and 109 exhibit a greater perturbation of the enzymatic reaction with mBBr than with CDNB as substrate. Various other substitutions at positions 103 and 104 reveal that a hydrophobic residue is necessary at each of these positions to maintain optimal affinity of the enzyme for mBBr and preserve the secondary structure of the enzyme. Substitutions at position 109 indicate that this residue is important in the enzyme’s affinity for mBBr but has a minimal effect on Vmax. These results demonstrate that the promiscuity of rat GST M1-1 is in part due to at least two distinct substrate sites. PMID:16195544

Hyperglycemia-induced Bcl-2/Bax-mediated apoptosis of Schwann cells via mTORC1/S6K1 inhibition in diabetic peripheral neuropathy.

PubMed

Zhu, Lin; Hao, Jun; Cheng, Meijuan; Zhang, Cuihong; Huo, Chunxiu; Liu, Yaping; Du, Wei; Zhang, Xianghong

2018-06-15

Schwann cell apoptosis is one of the characteristics of diabetic peripheral neuropathy (DPN). The mammalian target of rapamycin (mTOR) is a multifunctional signaling pathway that regulates cell apoptosis in various types of tissues and cells. To investigate whether the mTOR pathway is involved in cell apoptosis in the Schwann cells of DPN, diabetic mice and rat Schwann cells (RSC96) were chosen to detect phospho-mTOR (Ser 2448), phospho-S6K1 (Thr 389), phospho-4EBP1 (Thr 37/46), Bcl-2, Bax and cleaved caspase-3 by diverse pathological and biological techniques. The results showed that phospho-mTOR (Ser 2448) was decreased in the sciatic nerves of diabetic mice, concomitant with decreased Bcl-2, increased Bax, cleaved caspase-3 and cell apoptosis. In addition, high glucose treatment for 72 h caused a 35.95% decrease in the phospho-mTOR (Ser 2448)/mTOR ratio, a 65.50% decrease in the phospho-S6K1 (Thr 389)/S6K1 ratio, a 3.67-fold increase in the Bax/Bcl-2 ratio and a 1.47-fold increase in the cleaved caspase-3/caspase-3 ratio. Furthermore, mTORC1 inhibition, rather than mTORC2 inhibition, resulted in mitochondrial controlled apoptosis in RSC96 cells by silencing RAPTOR or RICTOR. Again, suppression of the mTORC1 pathway by a chemical inhibitor led to mitochondrial controlled apoptosis in cultured RSC96 cells in vitro. By contrast, activation of the mTORC1 pathway with MHY1485 prevented decreased phospho-S6K1 (Thr 389) levels caused by high glucose and cell apoptosis. Additionally, constitutive activation of S6K1 avoided high glucose-induced cell apoptosis in RSC96 cells. In summary, our findings suggest that activating mTORC1/S6K1 signaling in Schwann cells may be a promising strategy for the prevention and treatment of DPN. Copyright © 2018 Elsevier Inc. All rights reserved.

Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction.

PubMed

Sanna, M Germana; Vincent, Kevin P; Repetto, Emanuela; Nguyen, Nhan; Brown, Steven J; Abgaryan, Lusine; Riley, Sean W; Leaf, Nora B; Cahalan, Stuart M; Kiosses, William B; Kohno, Yasushi; Brown, Joan Heller; McCulloch, Andrew D; Rosen, Hugh; Gonzalez-Cabrera, Pedro J

2016-01-01

The molecular pharmacology of the G protein-coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P3-knockin and S1P3-knockout mice to define the spatial and functional properties of S1P3 in regulating cardiac conduction. We show that S1P3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P3-knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P3-mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Quaternary rare-earth sulfides RE{sub 3}M{sub 0.5}GeS{sub 7} (RE=La–Nd, Sm; M=Co, Ni) and Y{sub 3}Pd{sub 0.5}SiS{sub 7}

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

Iyer, Abishek K.; Yin, Wenlong; Institute of Chemical Materials, China Academy of Engineering Physics, Mianyang 621900

The two metal-deficient series of quaternary Ge-containing sulfides RE{sub 3}M{sub 0.5}GeS{sub 7} (RE = La–Nd, Sm; M = Co, Ni), as well as the related Si-containing sulfide Y{sub 3}Pd{sub 0.5}SiS{sub 7}, were prepared by reactions of the elements at 1050 °C. Single-crystal X-ray diffraction analysis performed on all compounds confirmed noncentrosymmetric hexagonal structures (space group P6{sub 3}, Z =2) with cell parameters in the ranges of a =10.0–10.3 Å and c =5.7–5.8 Å for RE{sub 3}Co{sub 0.5}GeS{sub 7} and RE{sub 3}Ni{sub 0.5}GeS{sub 7}, or a =9.7891(3) Å and c =5.6840(4) Å for Y{sub 3}Pd{sub 0.5}SiS{sub 7}. They are classified asmore » La{sub 3}Mn{sub 0.5}SiS{sub 7}-type structures, with M atoms centred within octahedra (in contrast to La{sub 3}CuSiS{sub 7}-type structures in which M atoms occupy trigonal planar sites) and Ge atoms centred within tetrahedra, both types of polyhedra being arranged in one-dimensional stacks aligned along the c-direction. Charge balance requirements dictate half-occupancy of the M sites. However, bond valence sum arguments indicated that the M atoms are somewhat underbonded within these octahedral sites, so that there is evidence that in some compounds, they can also enter the trigonal planar site at low occupancy (~5%). Magnetic measurements on RE{sub 3}Co{sub 0.5}GeS{sub 7} (RE = Ce, Pr, Sm) revealed paramagnetic behaviour for the Ce and Pr members and apparent antiferromagnetic ordering (T{sub N} =14 K) for the Sm member; fitting to the Curie-Weiss law gave effective magnetic moments consistent with the presence of RE{sup 3+} and Co{sup 2+} species. Band structure calculations on ordered models of La{sub 3}M{sub 0.5}GeS{sub 7} (M = Co, Ni) showed that the Fermi level cuts through M 3d states in the DOS curve and supported the presence of strong M–S and Ge–S bonding interactions. - Graphical abstract: RE{sub 3}M{sub 0.5}GeS{sub 7} (M = Co, Ni) and Y{sub 3}Pd{sub 0.5}SiS{sub 7} contain M atoms partially

High Energy Density Asymmetric Supercapacitor Based on NiOOH/Ni3S2/3D Graphene and Fe3O4/Graphene Composite Electrodes

PubMed Central

Lin, Tsung-Wu; Dai, Chao-Shuan; Hung, Kuan-Chung

2014-01-01

The application of the composite of Ni3S2 nanoparticles and 3D graphene as a novel cathode material for supercapacitors is systematically investigated in this study. It is found that the electrode capacitance increases by up to 111% after the composite electrode is activated by the consecutive cyclic voltammetry scanning in 1 M KOH. Due to the synergistic effect, the capacitance and the diffusion coefficient of electrolyte ions of the activated composite electrode are ca. 3.7 and 6.5 times higher than those of the Ni3S2 electrode, respectively. Furthermore, the activated composite electrode exhibits an ultrahigh specific capacitance of 3296 F/g and great cycling stability at a current density of 16 A/g. To obtain the reasonable matching of cathode/anode electrodes, the composite of Fe3O4 nanoparticles and chemically reduced graphene oxide (Fe3O4/rGO) is synthesized as the anode material. The Fe3O4/rGO electrode exhibits the specific capacitance of 661 F/g at 1 A/g and excellent rate capability. More importantly, an asymmetric supercapacitor fabricated by two different composite electrodes can be operated reversibly between 0 and 1.6 V and obtain a high specific capacitance of 233 F/g at 5 mV/s, which delivers a maximum energy density of 82.5 Wh/kg at a power density of 930 W/kg. PMID:25449978

The Armys M-1 Abrams, M-2/M-3 Bradley, and M-1126 Stryker: Background and Issues for Congress

DTIC Science & Technology

2016-04-05

smoothbore gun 1 x coaxial mounted 7.62 mm M-240 machine gun 1 x roof mounted 12.7 mm M-2 HB machine gun 1 x roof mounted 7.62 mm M-240 machine gun 12...Bradley Fighting Vehicle Table 2. Selected Basic Characteristics— M2 /3-A2 Armament 1 x turret mounted M-242 25mm “Bushmaster” chain gun 2 x turret...mounted TOW anti-tank missiles 1 x coaxial mounted 7.62 mm M-240C machine gun 8 x turret mounted smoke grenade launchers Crew M-2: 3 crew, 6

Effects of S(+)-efonidipine on the rabbit sinus node action potential and calcium channel subunits Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1.

PubMed

Tanaka, Hikaru; Namekata, Iyuki; Ogawa, Toru; Tsuneoka, Yayoi; Komikado, Chisa; Takahara, Akira; Iida-Tanaka, Naoko; Izumi-Nakaseko, Hiroko; Tsuru, Hiromichi; Adachi-Akahane, Satomi

2010-12-15

The effect of S(+)-efonidipine on sinus node action potential and calcium channel α-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue was significantly reduced by S(+)-efonidipine (1 μM), slightly reduced by nifedipine (1 μM), but was not affected by R(-)-efonidipine. S(+)-efonidipine (1 μM), inhibited the expressed Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1 channel currents by 75.7%, 75.3% and 94.0%, nifedipine 84.0%, 43.2% and 14.9%, and R(-)-efonidipine 30.0%, 19.6% and 92.8%, respectively. Thus, the prolongation of the phase 4 depolarization of the rabbit sinus node by S(+)-efonidipine may be explained by blockade of the Ca(V)1.3 channel current. Copyright © 2010 Elsevier B.V. All rights reserved.

26 CFR 1.401(m)-3 - Safe harbor requirements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Safe harbor requirements. 1.401(m)-3 Section 1.401(m)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(m)-3 Safe harbor...

26 CFR 1.401(m)-3 - Safe harbor requirements.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Safe harbor requirements. 1.401(m)-3 Section 1.401(m)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(m)-3 Safe...

The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury

PubMed Central

Ding, Ying; Slepak, Tatiana; Sun, Yan; Martinez, Yania; Xu, Xiao-Ming

2017-01-01

The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Although axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3 mm beyond the injury site at 8 weeks after injury. Concomitantly, treatment with PF-4708671 produced significant locomotor recovery. Pharmacological targeting of S6K1 may therefore constitute an attractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications. SIGNIFICANCE STATEMENT Despite mTOR's well-established function in promoting axon regeneration, the role of its downstream target, S6 kinase 1 (S6K1), has been unclear. We used cellular assays with primary neurons to demonstrate that S6K1 is a negative regulator of neurite outgrowth, and a spinal cord injury model to show that it is a viable pharmacological target for inducing axon regeneration. We provide mechanistic evidence that S6K1's negative feedback to PI3K signaling is involved in axon growth inhibition, and show that phosphorylation of S6K1 is a more

Activation of mGluR2/3 following stress hormone exposure restores sensitivity to alcohol in rats.

PubMed

Jaramillo, Anel A; Randall, Patrick A; Frisbee, Suzanne; Fisher, Kristen R; Besheer, Joyce

2015-09-01

Sensitivity to the interoceptive effects of alcohol is blunted following a period of exposure to the stress hormone corticosterone (CORT), an effect that is suggested to be related, in part, to glutamatergic neuroadaptations. Group II metabotropic glutamate receptors (subtypes 2 and 3; mGluR2/3) modulate several drug- and alcohol-related behaviors, including the interoceptive (discriminative stimulus) effects of alcohol. Therefore, we sought to determine if manipulation of mGluR2/3 would restore sensitivity to the interoceptive effects of alcohol following CORT exposure. Using a two-lever drug discrimination task, male Long-Evans rats were trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water. First, the effect of mGluR2/3 antagonism on the discriminative stimulus effects of alcohol was determined using LY341495 (0.3-3.0 mg/kg; intraperitoneal [IP]). Next, the effects of mGluR2/3 antagonism and activation were assessed in discrimination-trained animals exposed to CORT (300 μg/mL) in the home cage drinking water or water only, for 7 days. Following CORT exposure, decreased sensitivity to alcohol (1 g/kg) was observed. Pretreatment with the mGluR2/3 agonist LY379268 (1.0-3.0 mg/kg; IP), but not the mGluR2/3 antagonist (0.3-1.0 mg/kg; IP), restored sensitivity to alcohol. Additionally, in water controls, mGluR2/3 antagonism and mGluR2/3 activation disrupted expression of the discriminative stimulus effects of alcohol. Together, these findings suggest that blunted sensitivity to the interoceptive effects of alcohol following an episode of heightened stress hormone levels may be due to adaptations in mGluR2/3-related systems. The ability of mGluR2/3 activation to restore sensitivity to alcohol under these conditions lends further support for the importance of these receptors under stress-related conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Methods of using (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid

DOEpatents

Silverman, Richard B; Dewey, Stephen L; Miller, Steven

2015-03-03

(1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid also known as CPP-115 or its pharmaceutically acceptable salts can be used to treat addiction and neurological disorders such as epilepsy without side effects such as visual field defects caused by vigabatrin (Sabril).

M1.3 - a small scaffold for DNA origami

NASA Astrophysics Data System (ADS)

Said, Hassan; Schüller, Verena J.; Eber, Fabian J.; Wege, Christina; Liedl, Tim; Richert, Clemens

2012-12-01

The DNA origami method produces programmable nanoscale objects that form when one long scaffold strand hybridizes to numerous oligonucleotide staple strands. One scaffold strand is dominating the field: M13mp18, a bacteriophage-derived vector 7249 nucleotides in length. The full-length M13 is typically folded by using over 200 staple oligonucleotides. Here we report the convenient preparation of a 704 nt fragment dubbed ``M1.3'' as a linear or cyclic scaffold and the assembly of small origami structures with just 15-24 staple strands. A typical M1.3 origami is large enough to be visualized by TEM, but small enough to show a cooperativity in its assembly and thermal denaturation that is reminiscent of oligonucleotide duplexes. Due to its medium size, M1.3 origami with globally modified staples is affordable. As a proof of principle, two origami structures with globally 5'-capped staples were prepared and were shown to give higher UV-melting points than the corresponding assembly with unmodified DNA. M1.3 has the size of a gene, not a genome, and may function as a model for gene-based nanostructures. Small origami with M1.3 as a scaffold may serve as a workbench for chemical, physical, and biological experiments.The DNA origami method produces programmable nanoscale objects that form when one long scaffold strand hybridizes to numerous oligonucleotide staple strands. One scaffold strand is dominating the field: M13mp18, a bacteriophage-derived vector 7249 nucleotides in length. The full-length M13 is typically folded by using over 200 staple oligonucleotides. Here we report the convenient preparation of a 704 nt fragment dubbed ``M1.3'' as a linear or cyclic scaffold and the assembly of small origami structures with just 15-24 staple strands. A typical M1.3 origami is large enough to be visualized by TEM, but small enough to show a cooperativity in its assembly and thermal denaturation that is reminiscent of oligonucleotide duplexes. Due to its medium size, M1.3

Hydrostatic pressure study on high temperature superconductors: HgBa(2)Casb(m-1)Cu(m)O(2m+2+delta) (m = 1 to 6) and (Cu,C)Ba(2)Ca(m-1)Cu(m)O(2m+3) (m = 3 and 4)

NASA Astrophysics Data System (ADS)

Cao, Yong

1998-12-01

Over the last decade, numerous extensive as well as intensive experimental and theoretical investigations have been carried out since the great discovery of high temperature superconductivity (HTSy) in cuprate superconductors Lasb{2-x}Basb{x}CuOsb4,\\ YBasb2Cusb2Osb{7-delta} and other compounds. Although there is still no widely accepted microscopic theory on the mechanism responsible for such high superconducting transition temperatures (Tsb{c}), systematic trends of the evolution of HTSy with various parameters have been studied and analyzed. One of them is the universal inverse parabolic correlation between the Tsb{c} and the number of carriers per CuOsb2 plane (n) in various cuprate superconductors. The high pressure technique provides a clean way to change the distance between atoms without causing the side effects typical of chemical doping, and thus has long been used to test and provide guidance for theoretical models, as well as give hints about the synthesis of compounds with higher Tsb{c}. Therefore, we have done a systematic study on the pressure effect on Tsb{c} of two homologous superconducting compound series: HgBasb2Casb{m-1}Cusb{m}Osb{2m+2+delta} (Hg-12(m-1)m) (m = 1 to 6) and (Cu,C)Basb2Casb{m-1}Cusb{m}Osb{2m+3+delta} ((Cu,C)-12(m-1)m) (m = 3 and 4). Several factors which influence the hydrostatic pressure effect on Tsb{c} have been systematically analyzed. They include the n, the type of charge reservoir layer, and the number of CuOsb2 layers per unit cell (m). We came to several conclusion: (1) The inverse parabolic Tsb{c}(n) correlation and its universal parameters are valid only under conditions more restrictive than originally expected, and the rigid band model may not hold for some cuprate superconductors under pressure. (2) The pressure coefficient (dTsb{c}/dP) may have a different dependence on n. The compounds with Cu-O chains in their charge reservoir usually show a large linear variation of dTsb{c}/dP with n, while no significant

Straightforward entry to pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones and their ADME properties.

PubMed

Jatczak, Martyna; Muylaert, Koen; De Coen, Laurens M; Keemink, Janneke; Wuyts, Benjamin; Augustijns, Patrick; Stevens, Christian V

2014-08-01

A straightforward synthesis of pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones was developed starting from 2-chloropyridine-3-carboxylic acid by esterification, nucleophilic aromatic substitution and amide formation in one step, and ring closure allowing their synthesis with two identical or two different group attached to nitrogen. The structural diversity of these [2,3-d]pyrimidine-2,4(1H,3H)-diones resulted in significant variation in the biopharmaceutical properties. This was reflected by the broad range in fasted state simulated intestinal fluid solubility values (12.6 μM to 13.8 mM), Caco-2 permeability coefficients (1.2 × 10(-6)cm/s to 90.7 × 10(-6)cm/s) and in vitro-predicted human in vivo intrinsic clearance values (0 to 159 ml/min/kg). Copyright © 2014 Elsevier Ltd. All rights reserved.

Synthesis of MFe3S4 clusters containing a planar M(II) site (M = Ni, Pd, Pt), a structural element in the C-cluster of carbon monoxide dehydrogenase.

PubMed

Panda, Rashmishree; Berlinguette, Curtis P; Zhang, Yugen; Holm, Richard H

2005-08-10

Synthesis of an analogue of the C-cluster of C. hydrogenoformans carbon monoxide dehydrogenase requires formation of a planar Ni(II) site and attachment of an exo iron atom in the core unit NiFe(4)S(5). The first objective has been achieved by two reactions: (i) displacement of Ph(3)P or Bu(t)()NC at tetrahedral Ni(II) sites of cubane-type [NiFe(3)S(4)](+) clusters with chelating diphosphines, and (ii) metal atom incorporation into a cuboidal [Fe(3)S(4)](0) cluster with a M(0) reactant in the presence of bis(1,2-dimethylphosphino)ethane (dmpe). The isolated product clusters [(dmpe)MFe(3)S(4)(LS(3))](2-) (M = Ni(II) (9), Pd(II) (12), Pt(II) (13); LS(3) = 1,3,5-tris((4,6-dimethyl-3-mercaptophenyl)thio)-2,4,6-tris(p-tolylthio)benzene(3-)) contain the cores [MFe(3)(mu(2)-S)(mu(3)-S)(3)](+) having planar M(II)P(2)S(2) sites and variable nonbonding M...S distances of 2.6-3.4 A. Reaction (i) involves a tetrahedral --> planar Ni(II) structural change between isomeric cubane and cubanoid [NiFe(3)S(4)](+) cores. Based on the magnetic properties of 12 and earlier considerations, the S = (5)/(2) ground state of the cubanoid cluster arises from the [Fe(3)S(4)](-) fragment, whereas the S = (3)/(2) ground state of the cubane cluster is a consequence of antiferromagnetic coupling between the spins of Ni(2+) (S = 1) and [Fe(3)S(4)](-). Other substitution reactions of [NiFe(3)S(4)](+) clusters and 1:3 site-differentiated [Fe(4)S(4)](2+) clusters are described, as are the structures of 12, 13, [(Me(3)P)NiFe(3)S(4)(LS(3))](2-), and [Fe(4)S(4)(LS(3))L'](2-) (L' = Me(2)NC(2)H(4)S(-), Ph(2)P(O)C(2)H(4)S(-)). This work significantly expands our initial report of cluster 9 (Panda et al. J. Am. Chem. Soc. 2004, 126, 6448-6459) and further demonstrates that a planar M(II) site can be stabilized within a cubanoid [NiFe(3)S(4)](+) core.

The Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain.

PubMed

Wang, Yong-Jie; Zuo, Zhen-Xing; Zhang, Mei; Feng, Zhi-Hui; Yan, Min; Li, Xiang-Yao

2017-04-01

Both pharmacologic and genetic approaches have been used to study the involvement of the muscarinic acetylcholine system in the regulation of chronic pain. Previous studies suggest that the M2 and M4 subtypes of muscarinic acetylcholine receptors (mAChRs) are important targets for the development of chronic pain. (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] octane (PTAC) has agonist effects on muscarinic M2 and M4 receptors and antagonist effects on muscarinic M1, M3, and M5 receptors. However, its analgesic effects have been less studied. Male C57B L/6 mice were anesthetized, and left common peroneal nerve (CPN) ligation was performed to induce neuropathic pain. Before and after the application of PTAC systemically or specifically to the anterior cingulate cortex (ACC), the withdrawal thresholds to mechanical stimulation and static weight balance were measured, and the effects of PTAC on the conditioned place preference (CPP) were further evaluated. Western blotting was used to examine the expression of M1 and M2 in the striatum, ACC, and ventral tegmental area. The application of PTAC ([i.p.] intraperitoneal injection) increased the paw withdraw threshold in both the early (0.05 mg/kg, mean difference [95% confidence interval, CI]: 0.19 [0.05-0.32]; 0.10 mg/kg: mean difference [95% CI]: 0.34 [0.22-0.46]) and the late phases (0.05 mg/kg: mean difference [95% CI]: 0.45 [0.39-0.50]; 0.1 mg/kg: mean difference [95% CI]: 0.44 [0.37-0.51]) after nerve injury and rebalanced the weight distribution on the hind paws of mice (L/R ratio: before, 0.56 ± 0.03. 0.05 mg/kg, 1.00 ± 0.04, 0.10 mg/kg, 0.99 ± 0.03); however, it failed to induce place preference in the CPP (0.05 mg/kg, 2-way analysis of variance, P > .05; 0.2 mg/kg, 2-way analysis of variance, P > .05,). At the same doses, the analgesic effects at D3-5 lasted longer than the effects at D14-16. This may be due to the down-regulation of the M2 and M1 in tested brain regions. These observations

Delineation of xenobiotic substrate sites in rat glutathione S-transferase M1-1.

PubMed

Hearne, Jennifer L; Colman, Roberta F

2005-10-01

Glutathione S-transferases catalyze the conjugation of glutathione with endogenous and exogenous xenobiotics. Hu and Colman (1995) proposed that there are two distinct substrate sites in rat GST M1-1, a 1-chloro-2,4-dintrobenzene (CDNB) substrate site located in the vicinity of tyrosine-115, and a monobromobimane (mBBr) substrate site. To determine whether the mBBr substrate site is distinguishable from the CDNB substrate site, we tested S-(hydroxyethyl)bimane, a nonreactive derivative of mBBr, for its ability to compete kinetically with the substrates. We find that S-(hydroxyethyl)bimane is a competitive inhibitor (K(I) = 0.36 microM) when mBBr is used as substrate, but not when CDNB is used as substrate, demonstrating that these two sites are distinct. Using site-directed mutagenesis, we have localized the mBBr substrate site to an area midway through alpha-helix 4 (residues 90-114) and have identified residues that are important in the enzymatic reaction. Substitution of alanine at positions along alpha-helix 4 reveals that mutations at positions 103, 104, and 109 exhibit a greater perturbation of the enzymatic reaction with mBBr than with CDNB as substrate. Various other substitutions at positions 103 and 104 reveal that a hydrophobic residue is necessary at each of these positions to maintain optimal affinity of the enzyme for mBBr and preserve the secondary structure of the enzyme. Substitutions at position 109 indicate that this residue is important in the enzyme's affinity for mBBr but has a minimal effect on Vmax. These results demonstrate that the promiscuity of rat GST M1-1 is in part due to at least two distinct substrate sites.

Calibration of mass and conventional mass of weights 2 kg, 1 kg, 200 g, 50 g, 1 g and 200 mg

NASA Astrophysics Data System (ADS)

Becerra, Luis Omar; Peña, Luis Manuel; Escalante Vargas, Boris; Cori Almonte, Luz; Martín Quiroga Rojas, Aldo; Bermúdez Coronel, Álvaro; Escobar Soto, Jhon J.; Naula, Wilson; Florencio, Arnaldo; Lourdes Valenzuela, María; Ramos Alfaro, Olman; Prenda Peña, Marcela

2018-01-01

This report describes the results of a supplementary comparison between SIM NMIs, which was carried out to evaluate the consistency of the measurements of calibration in high accuracy mass standards using the normalized error criteria (2 kg, 1 kg, 200 g, 50 g, 1 g and 200 mg). The supplementary comparison was carried out from April 2012 to July 2013. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Synthesis of new visible light active photocatalysts of Ba(In(1/3)Pb(1/3)M'(1/3))O3 (M' = Nb, Ta): a band gap engineering strategy based on electronegativity of a metal component.

PubMed

Hur, Su Gil; Kim, Tae Woo; Hwang, Seong-Ju; Park, Hyunwoong; Choi, Wonyong; Kim, Sung Jin; Kim, Sun Jin; Choy, Jin-Ho

2005-08-11

We have synthesized new, efficient, visible light active photocatalysts through the incorporation of highly electronegative non-transition metal Pb or Sn ions into the perovskite lattice of Ba(In(1/3)Pb(1/3)M'(1/3))O3 (M = Sn, Pb; M' = Nb, Ta). X-ray diffraction, X-ray absorption spectroscopic, and energy dispersive spectroscopic microprobe analyses reveal that tetravalent Pb or Sn ions exist in the B-site of the perovskite lattice, along with In and Nb/Ta ions. According to diffuse UV-vis spectroscopic analysis, the Pb-containing quaternary metal oxides Ba(In(1/3)Pb(1/3)M'(1/3))O3 possess a much narrower band gap (E(g) approximately 1.48-1.50 eV) when compared to the ternary oxides Ba(In(1/2)M'(1/2))O3 (E(g) approximately 2.97-3.30 eV) and the Sn-containing Ba(In(1/3)Sn(1/3)M'(1/3))O3 derivatives (E(g) approximately 2.85-3.00 eV). Such a variation of band gap energy upon the substitution is attributable to the broadening of the conduction band caused by the dissimilar electronegativities of the B-site cations. In contrast to the ternary or the Sn-substituted quaternary compounds showing photocatalytic activity under UV-vis irradiation, the Ba(In(1/3)Pb(1/3)M'(1/3))O3 compounds induce an efficient photodegradation of 4-chlorophenol under visible light irradiation (lambda > 420 nm). The present results highlight that the substitution of electronegative non-transition metal cations can provide a very powerful way of developing efficient visible light harvesting photocatalysts through tuning of the band structure of a semiconductive metal oxide.

Ferroelectric and magnetic properties of Aurivillius Bi{sub m+1}Ti{sub 3}Fe{sub m−3}O{sub 3m+3} thin films

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

Jia, Tingting, E-mail: jia.tingting@nims.go.jp; Kimura, Hideo, E-mail: KIMURA.Hideo@nims.go.jp; Cheng, Zhenxiang

2015-11-15

Aurivillius Bi{sub m+1}Ti{sub 3}Fe{sub m−3}O{sub 3m+3} (m = 4, 5, 6) thin films have been deposited by a pulsed laser deposition system. The x-ray diffraction patterns indicate the formation of orthorhombic phase. The remanent polarization (2P{sub r}) of Bi{sub m+1}Ti{sub 3}Fe{sub m−3}O{sub 3m+3} thin films is decreased with the m-number. Positive-up-negative-down measurements indicate the presence of ferroelectric (FE) polarization in as-obtained thin films. Piezoresponse force microscopy investigations confirm the existence of FE domains and the switchable polarization. Weak magnetic moment is detected in the Aurivillius films at room temperature. The present work suggests the possibility of Aurivillius Bi{sub m+1}Ti{sub 3}Fe{sub m−3}O{sub 3m+3}more » (m = 4, 5, 6) materials as potential room-temperature multiferroics.« less

The Impact of PNPLA3 rs738409 Genetic Polymorphism and Weight Gain ≥10 kg after Age 20 on Non-Alcoholic Fatty Liver Disease in Non-Obese Japanese Individuals

PubMed Central

Nishioji, Kenichi; Mochizuki, Naomi; Kobayashi, Masao; Kamaguchi, Mai; Sumida, Yoshio; Nishimura, Takeshi; Yamaguchi, Kanji; Kadotani, Hiroshi; Itoh, Yoshito

2015-01-01

Non-alcoholic fatty liver disease (NAFLD) in non-obese individuals is inadequately elucidated. We aim to investigate the impact of known genetic polymorphisms on NAFLD and the interaction between genetic risks and weight gain on NAFLD in obese and non-obese Japanese individuals. A total of 1164 participants who received health checkups were included. Participants with excessive alcohol consumption, with viral hepatitis or other inappropriate cases were excluded. Fatty liver was diagnosed by ultrasonography. Participants with a body mass index (BMI) of <18.5 kg/m2, 18.5–22.9 kg/m2, 23.0–24.9 kg/m2 and ≥25 kg/m2 were classified underweight, normal weight, overweight and obese, respectively. Self-administered questionnaire for lifestyle was assessed and a total of 8 previously reported genetic polymorphisms were chosen and examined. In all, 824 subjects were enrolled. The overall prevalence of NAFLD was 33.0%: 0% in underweight, 15.3% in normal weight, 41.1% in overweight and 71.7% in obese individuals. The prevalence of NAFLD is more affected by the G allele of patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 in normal weight (odds ratio (OR) 3.52; 95%-CI: 1.42–8.71; P = 0.0063) and in overweight individuals (OR 2.60; 95%-CI: 1.14–5.91; P = 0.0225) than in obese individuals (not significant). Moreover, the G allele of PNPLA3 rs738409 and weight gain ≥10 kg after age 20 had a joint effect on the risk of NAFLD in the normal weight (OR 12.00; 95% CI: 3.71–38.79; P = 3.3×10−5) and the overweight individuals (OR 13.40; 95% CI: 2.92–61.36; P = 0.0008). The G allele of PNPLA3 rs738409 is a prominent risk factor for NAFLD and the interaction between the PNPLA3 rs738409 and weight gain ≥10 kg after age 20 plays a crucial role in the pathogenesis of NAFLD, especially in non-obese Japanese individuals. PMID:26485523

76 FR 76293 - Airworthiness Directives; BRP-Powertrain GmbH & Co. KG Reciprocating Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-07

... Airworthiness Directives; BRP-Powertrain GmbH & Co. KG Reciprocating Engines AGENCY: Federal Aviation... directive (AD) for BRP- Powertrain GmbH & Co. KG Rotax 912 F2, 912 F3, 912 F4, 912 S2, 912 S3, 912 S4, 914...-Powertrain GmbH & Co. KG, Rotax Aircraft Engines, Mandatory Alert Service Bulletins (ASB) Nos. ASB-912-059...

Design and Synthesis of 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (Citalopram) Analogues as Novel Probes for the Serotonin Transporter S1 and S2 Binding Sites

PubMed Central

Banala, Ashwini K.; Zhang, Peng; Plenge, Per; Cyriac, George; Kopajtic, Theresa; Katz, Jonathan L.; Loland, Claus Juul; Newman, Amy Hauck

2013-01-01

The serotonin transporter (SERT) is the primary target for antidepressant drugs. The existence of a high affinity primary orthosteric binding site (S1) and a low affinity secondary site (S2) has been described and their relation to antidepressant pharmacology has been debated. Herein, structural modifications to the N-, 4, 5, and 4’-positions of (±)citalopram (1) are reported. All of the analogues were SERT-selective and demonstrated that steric bulk was tolerated at the SERT S1 site, including two dimeric ligands (15 and 51.) In addition, 8 analogues were identified with similar potencies to S-1 for decreasing the dissociation of [3H]S-1 from the S1 site, via allosteric modulation at S2. Both dimeric compounds had similar affinities for the SERT S1 site (Ki=19.7 and 30.2 nM, respectively), whereas only the N-substituted analogue, 51, was as effective as S-1 in allosterically modulating the binding of [3H]S-1 via S2. PMID:24237160

Anti-epileptic activity of group II metabotropic glutamate receptor agonists (--)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268) and (--)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795).

PubMed

Moldrich, R X; Jeffrey, M; Talebi, A; Beart, P M; Chapman, A G; Meldrum, B S

2001-07-01

The selective group II metabotropic glutamate receptor (mGlu(2/3)) agonists (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795) have been evaluated as anti-epileptic drugs in dilute brown agouti (DBA/2) mice, lethargic (lh/lh) mice, genetically epilepsy-prone-9 (GEP) rats and amygdala-kindled rats. Sound-induced clonic seizures in DBA/2 mice were transiently inhibited by both agonists intracerebroventricularly (i.c.v.), LY379268 ED(50)=0.08 [0.02-0.33]nmol and LY389795 ED(50)=0.82 [0.27-3.24]nmol or intraperitoneally (i.p.), LY379268 ED(50)=2.9 [0.9-9.6]mg/kg and LY389795 ED(50)=3.4 [1.0-11.7]mg/kg. Both mGlu(2/3) agonists inhibited seizures induced by the group I mGlu receptor agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG), where LY379268, i.c.v. ED(50)=0.3 [0.02-5.0]pmol and LY389795, i.c.v. ED(50)=0.03 [0.05-0.19]nmol. The spike and wave discharge (SWD) duration of absence seizures in lh/lh mice was significantly reduced by both agonists at 1 and 10nmol (i.c.v.) up to 90min following infusion. The electrically induced seizure score and afterdischarge duration of amygdala-kindled rats was partially inhibited by the agonists 30min after i.p. injection of 10mg/kg. The agonists did not inhibit sound-induced seizures in GEP rats (0.1-1mg/kg, 30min 1h, i.p.), but were proconvulsant following sound stimulus (> or =0.1mg/kg). These findings identify a potential role for mGlu(2/3) agonists in the amelioration of generalised and partial epileptic seizures.

Regulation of mTORC1 by PI3K signaling.

PubMed

Dibble, Christian C; Cantley, Lewis C

2015-09-01

The class I phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling network directs cellular metabolism and growth. Activation of mTORC1 [composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8(mLST8), 40-kDa proline-rich Akt substrate (PRAS40), and DEP domain-containing mTOR-interacting protein (DEPTOR)] depends on the Ras-related GTPases (Rags) and Ras homolog enriched in brain (Rheb) GTPase and requires signals from amino acids, glucose, oxygen, energy (ATP), and growth factors (including cytokines and hormones such as insulin). Here we discuss the signal transduction mechanisms through which growth factor-responsive PI3K signaling activates mTORC1. We focus on how PI3K-dependent activation of Akt and spatial regulation of the tuberous sclerosis complex (TSC) complex (TSC complex) [composed of TSC1, TSC2, and Tre2-Bub2-Cdc16-1 domain family member 7 (TBC1D7)] switches on Rheb at the lysosome, where mTORC1 is activated. Integration of PI3K- and amino acid-dependent signals upstream of mTORC1 at the lysosome is detailed in a working model. A coherent understanding of the PI3K-mTORC1 network is imperative as its dysregulation has been implicated in diverse pathologies including cancer, diabetes, autism, and aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

EXACT S-MATRICES FOR AdS3/CFT2

NASA Astrophysics Data System (ADS)

Ahn, Changrim; Bombardelli, Diego

2013-12-01

We propose exact S-matrices for the AdS3/CFT2 duality between type IIB strings on AdS3×S3×M4 with M4 = S3×S1 or T4 and the corresponding two-dimensional conformal field theories. We fix the two-particle S-matrices on the basis of the symmetries su(1|1) and su(1|1)×su(1|1). A crucial justification comes from the derivation of the all-loop Bethe ansatz matching exactly the recent conjecture proposed by Babichenko et al. [J. High Energy Phys.1003, 058 (2010), arXiv:0912.1723 [hep-th

Microsatellite-based fine mapping of the Van der Woude syndrome locus to an interval of 4.1 cM between D1S245 and D1S414

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

Sander, A.; Schmelzle, R.; Murray, J.C.

1995-01-01

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder characterized by lip pits, clefting of the primary or secondary palate, and hypodontia. The gene has been localized, by RFLP-based linkage studies, to region 1q32-41 between D1S65-REN and D1S65-TGFB2. In this study we report the linkage analysis of 15 VWS families, using 18 microsatellite markers. Multipoint linkage analysis places the gene, with significant odds of 2,344:1, in a 4.1-cM interval flanked by D1S245 and D1S414. Two-point linkage analysis demonstrates close linkage of VWS with D1S205 (lod score [Z] = 24.41 at {theta} = .00) and with D1S491 (Z =more » 21.23 at {theta} = .00). The results revise the previous assignment of the VWS locus and show in an integrated map of the region 1q32-42 that the VWS gene resides more distally than previously suggested. When information about heterozygosity of the closely linked marker D1S491 in the affected members of the VWS family with a microdeletion is taken into account, the VWS critical region can be further narrowed, to the 3.6-cM interval between D1S491 and D1S414. 38 refs., 3 figs., 2 tabs.« less

FRET-based sensors for the human M1-, M3-, and M5-acetylcholine receptors.

PubMed

Ziegler, Nicole; Bätz, Julia; Zabel, Ulrike; Lohse, Martin J; Hoffmann, Carsten

2011-02-01

Based on the recently developed approach to generate fluorescence resonance energy transfer (FRET)-based sensors to measure GPCR activation, we generated sensor constructs for the human M(1)-, M(3)-, and M(5)-acetylcholine receptor. The receptors were labeled with cyan fluorescent protein (CFP) at their C-terminus, and with fluorescein arsenical hairpin binder (FlAsH) via tetra-cysteine tags inserted in the third intracellular loop. We then measured FRET between the donor CFP and the acceptor FlAsH in living cells and real time. Agonists like acetylcholine, carbachol, or muscarine activate each receptor construct with half-maximal activation times between 60 and 70ms. Removal of the agonist caused the reversal of the signal. Compared with all other agonists, oxotremorine M differed in two major aspects: it caused significantly slower signals at M(1)- and M(5)-acetylcholine receptors and the amplitude of these signals was larger at the M(1)-acetylcholine receptor. Concentration-response curves for the agonists reveal that all agonists tested, with the mentioned exception of oxotremorine M, caused similar maximal FRET-changes as acetylcholine for the M(1)-, M(3)- and M(5)-acetylcholine receptor constructs. Taken together our data support the notion that orthosteric agonists behave similar at different muscarinic receptor subtypes but that kinetic differences can be observed for receptor activation. Copyright © 2010 Elsevier Ltd. All rights reserved.

Ada (Trademark) Training Curriculum. Software Engineering Methodologies M201 Teacher’s Guide. Volume 3.

DTIC Science & Technology

1986-01-01

TRAINING CURRICULUM SOFTWARE 3/5’ENGNEERNG ETHODOLOGES 281 TEACHER’S GUIDE VOLMEU SOTC N TA A 96DA0 -3CK L(U) S F TECH INC ALTHAM MA 1986 DAAB9?-83-C...La. V)W V 0 W Wx ci >A. I- 8 0 x I- W L) 0 Z I- c 0.-ZW (n .w (x a. CLV 4 WZ0 o 0 W 1r 0 X 0 ZwI La. a) >1 0 ZU z W IA. 0 w W .... WW I 14-4D - Z 0 x...WWO= z (a~ I-- (i " c w m cal x Z w WW0.WW= woC-0ww cc Q z = lW"x w’-4ww 0 X=.-U ==L~lIl Ca- LUw w C. wow m ).i~ -4,C I -s-0. s- zwi LU -4 LU 0 LU W

Women with a BMI ≥ 30kg/m² and their experience of maternity care: A meta ethnographic synthesis.

PubMed

Jones, Catriona; Jomeen, Julie

2017-10-01

this paper is a report of a systematic review and meta-ethnography of the experiences of women with body mass index (BMI) ≥ 30kg/m² and their experience of maternity care. systematic review methods identified 12 qualitative studies about women's experiences of maternity care when their BMI ≥ 30kg/m². Findings from the identified studies were synthesised into themes, using metaethnography. SYNTHESIS AND FINDINGS: the meta-ethnography produced four key concepts; Initial encounters, Negotiating risk, Missing out and The positive intervention, which represent the experiences of maternity care for women with BMI ≥ 30kg/m² KEY CONCLUSION: many women with BMI ≥ 30kg/m² appear to be dissatisfied with the approaches taken to discuss weight status during maternity encounters. When weight is not addressed during these encounters women appear to be equally dissatisfied. The absence of open and honest discussions about weight, the feeling of being denied of a normal experience, and an over emphasis on the risks imposed upon pregnancy and childbirth by obesity, leave women feeling dissatisfied and disenfranchised. Sensitive care and practical advice about diet and exercise can help women move towards feeling more in control of their weight management. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Microwave Assisted Synthesis of 1-[5-(Substituted Aryl)-1H-Pyrazol-3-yl]-3,5-Diphenyl-1H-1,2,4-Triazole as Antinociceptive and Antimicrobial Agents

PubMed Central

Khanage, Shantaram Gajanan; Mohite, Popat Baban; Pandhare, Ramdas Bhanudas; Raju, S. Appala

2014-01-01

Purpose: An efficient technique has been developed for microwave assisted synthesis of 1-[5-(substituted aryl)-1H-pyrazol-3-yl]-3,5-diphenyl-1H-1,2,4-triazole as antinociceptive and antimicrobial agents. Methods: The desired compounds (S1-S10) were synthesized by the microwave irradiation via cyclization of formerly synthesized chalcones of 3,5-diphenyl-1H-1,2,4-triazole and hydrazine hydrate in mild acidic condition. All newly synthesized compounds were subjected to study their antinociceptive and antimicrobial activity. The analgesic potential of compounds was tested by acetic acid induced writhing response and hot plate method. The MIC values for antimicrobial activity were premeditated by liquid broth method. Results: The compounds S1, S2, S4, S6 and S10 were found to be excellent peripherally acting analgesic agents when tested on mice by acetic acid induced writhing method and compounds S3, S6 and S1 at dose level of 100 mg/kg were exhibited superior centrally acting antinociceptive activity when tested by Eddy’s hot plate method. In antimicrobial activity compound S10 found to be broad spectrum antibacterial agent at MIC value of 15.62 µg/ml and compound S6 was exhibited antifungal potential at 15.62 µg/mL on both fungal strains. Conclusion: Some novel pyrazoles clubbed with 1,2,4-triazole derivatives were synthesized and evaluated as possible antimicrobial, centrally and peripherally acting analgesics. PMID:24511473

S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial.

PubMed

Yamada, Y; Denda, T; Gamoh, M; Iwanaga, I; Yuki, S; Shimodaira, H; Nakamura, M; Yamaguchi, T; Ohori, H; Kobayashi, K; Tsuda, M; Kobayashi, Y; Miyamoto, Y; Kotake, M; Shimada, K; Sato, A; Morita, S; Takahashi, S; Komatsu, Y; Ishioka, C

2018-03-01

Combination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS). Patients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150 mg/m2 and bevacizumab 7.5 mg/kg on day 1, oral S-1 80 mg/m2 twice daily for 2 weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100 mg/m2 and bevacizumab 5 mg/kg on days 1 and 15, S-1 80 mg/m2 twice daily for 2 weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin. Between June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI 9.6-11.6) in the control group and 14.0 months (95% CI 12.4-15.5) in the experimental group (HR 0.84, 95% CI 0.70-1.02; P < 0.0001 for noninferiority, P = 0.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher. S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment. UMIN000007834.

The 5HT(1A) receptor ligand, S15535, antagonises G-protein activation: a [35S]GTPgammaS and [3H]S15535 autoradiography study.

PubMed

Newman-Tancredi, A; Rivet, J; Chaput, C; Touzard, M; Verrièle, L; Millan, M J

1999-11-19

4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine (S15535) is a highly selective ligand at 5-HT(1A) receptors. The present study compared its autoradiographic labelling of rat brain sections with its functional actions, visualised by guanylyl-5'-[gamma-thio]-triphosphate ([35S]GTPgammaS) autoradiography, which affords a measure of G-protein activation. [3H]S15535 binding was highest in hippocampus, frontal cortex, entorhinal cortex, lateral septum, interpeduncular nucleus and dorsal raphe, consistent with specific labelling of 5-HT(1A) receptors. In functional studies, S15535 (10 microM) did not markedly stimulate G-protein activation in any brain region, but abolished the activation induced by the selective 5-HT(1A) agonist, (+)-8-hydroxy-dipropyl-aminotetralin ((+)-8-OH-DPAT, 1 microM), in structures enriched in [3H]S15535 labelling. S15535 did not block 5-HT-stimulated activation in caudate nucleus or substantia nigra, regions where (+)-8-OH-DPAT was ineffective and [3H]S15535 binding was absent. Interestingly, S15535 attenuated (+)-8-OH-DPAT and 5-HT-stimulated G-protein activation in dorsal raphe, a region in which S15535 is known to exhibit agonist properties in vivo [Lejeune, F., Millan, M.J., 1998. Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)(1A) receptors: WAY100,635-reversible actions of the highly selective ligands, flesinoxan and S15535. Synapse 30, 172-180.]. The present data show that (i) [3H]S15535 labels pre- and post-synaptic populations of 5-HT(1A) sites in rat brain sections, (ii) S15535 exhibits antagonist properties at post-synaptic 5-HT(1A) receptors in corticolimbic regions, and (iii) S15535 also attenuates agonist-stimulated G-protein activation at raphe-localised 5-HT(1A) receptors.

Mass: 100 mg, 10 g, 100 g, 1 kg, 10 kg and 50 kg

NASA Astrophysics Data System (ADS)

Kaçmaz, Sevda; Davidson, Stuart

2017-01-01

Bilateral mass comparison of mass standards of 100 mg, 2 g, 20 g, 500 g and 10 kg was carried out in 2011 to 2012 between UME and NPL. UME was the pilot laboratory. For all mass standards, the results show adequate agreement between the laboratories. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Toxicological evaluation of two novel bitter modifying flavour compounds: 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)imidazolidine-2,4-dione and 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione.

PubMed

Karanewsky, Donald S; Arthur, Amy J; Liu, Hanghui; Chi, Bert; Ida, Lily; Markison, Stacy

2016-01-01

A toxicological evaluation of two novel bitter modifying flavour compounds, 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1 H -pyrazol-4-yl)-1-(3-hydroxybenzyl)imidazolidine-2,4-dione (S6821, CAS 1119831-25-2) and 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1 H -pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (S7958, CAS 1217341-48-4), were completed for the purpose of assessing their safety for use in food and beverage applications. S6821 undergoes oxidative metabolism in vitro , and in rat pharmacokinetic studies both S6821 and S7958 are rapidly converted to the corresponding O-sulfate and O-glucuronide conjugates. S6821 was not found to be mutagenic or clastogenic in vitro , and did not induce micronuclei in bone marrow polychromatic erythrocytes in vivo . S7958, a close structural analog of S6821, was also found to be non-mutagenic in vitro . In short term and subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for both S7958 and S6821 was 100 mg/kg bw/day (highest dose tested) when administered as a food ad-mix for either 28 or 90 consecutive days, respectively. Furthermore, S6821 demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOAEL of 1000 mg/kg bw/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.

Characterization of three types of human alpha s1-casein mRNA transcripts.

PubMed Central

Johnsen, L B; Rasmussen, L K; Petersen, T E; Berglund, L

1995-01-01

Here we report the molecular cloning and sequencing of three types of human alpha s1-casein transcripts and present evidence indicating that exon skipping is responsible for deleted mRNA transcripts. The largest transcript comprised 981 bp encoding a signal peptide of 15 amino acids followed by the mature alpha s1-casein sequence of 170 amino acids. Human alpha s1-casein has been reported to exist naturally as a multimer in complex with kappa-casein in mature human milk, thereby being unique among alpha s1-caseins [Rasmussen, Due and Petersen (1995) Comp. Biochem. Physiol., in the press]. The present demonstration of three cysteines in the mature protein provides a molecular explanation of the interactions in this complex. Tissue-specific expression of human alpha s1-casein was indicated by Northern-blot analysis. In addition, two cryptic exons were localized in the bovine alpha s1-casein gene. Images Figure 3 PMID:7619062

Rearrangements of mycoreovirus 1 S1, S2 and S3 induced by the multifunctional protein p29 encoded by the prototypic hypovirus Cryphonectria hypovirus 1 strain EP713.

PubMed

Tanaka, Toru; Sun, Liying; Tsutani, Kouhei; Suzuki, Nobuhiro

2011-08-01

Mycoreovirus 1 (MyRV1), a member of the family Reoviridae possessing a genome consisting of 11 dsRNA segments (S1-S11), infects the chestnut blight fungus and reduces its virulence (hypovirulence). Studies have previously demonstrated reproducible induction of intragenic rearrangements of MyRV1 S6 (S6L: almost full-length duplication) and S10 (S10ss: internal deletion of three-quarters of the ORF), mediated by the multifunctional protein p29 encoded by the prototype hypovirus, Cryphonectria hypovirus 1 (CHV1) strain EP713, of the family Hypoviridae with ssRNA genomes. The current study showed that CHV1 p29 also induced rearrangements of the three largest MyRV1 segments, S1, S2 and S3, which encode structural proteins. These rearranged segments involved in-frame extensions of almost two-thirds of the ORFs (S1L, S2L and S3L, respectively), which is rare for a reovirus rearrangement. MyRV1 variants carrying S1L, S2L or S3L always contained S10ss (MyRV1/S1L+S10ss2, MyRV1/S2L+S10ss2 or MyRV1/S3L+S10ss2). Levels of mRNAs for the rearranged and co-existing unaltered genome segments in fungal colonies infected with each of the MyRV1 variants appeared to be comparable to those for the corresponding normal segments in wild-type MyRV1-infected colonies, suggesting that the rearranged segments were fully competent for packaging and transcription. Protein products of the rearranged segments were detectable in fungal colonies infected with S2L MyRV1/S2L+S10ss2 and S3L MyRV1/S3L+S10ss2, whilst S1L-encoded protein remained undetectable. S1L, S2L and S3L were associated with enhancement of the aerial hyphae growth rate. This study has provided additional examples of MyRV1 intragenic rearrangements induced by p29, and suggests that normal S1, S2 and S3 are required for the symptoms caused by MyRV1.

Ultrahigh-performance pseudocapacitor based on phase-controlled synthesis of MoS2 nanosheets decorated Ni3S2 hybrid structure through annealing treatment

NASA Astrophysics Data System (ADS)

Huang, Long; Hou, Huijie; Liu, Bingchuan; Zeinu, Kemal; Zhu, Xiaolei; Yuan, Xiqing; He, Xiulin; Wu, Longsheng; Hu, Jingping; Yang, Jiakuan

2017-12-01

In this work, a hierarchical Ni3S2@MoS2 hybrid structure was synthesized by an effective strategy with a combined hydrothermal route and subsequent annealing treatment. When tested as supercapacitor electrodes, the Ni3S2@MoS2 composites exhibited high specific capacitance of 1418.5 F g-1 at 0.5 A g-1, which also showed a good capacitance retention of 75.8% at 5 A g-1 after 1250 cycles. The Ni3S2@MoS2 composites demonstrated 1.9 fold higher specific capacitance compared to the amorphous shell counterpart (NixSy@MoS2). Furthermore, the assembled asymmetric supercapacitor (Ni3S2@MoS2//rGO) also demonstrated a capacitance of 61 F g-1 at 0.5 A g-1, with energy and power densities of 21.7 Wh kg-1 at 400 W kg-1 and 12 Wh kg-1 at 2400 W kg-1 under an operating window of 1.6 V. The asymmetric supercapacitor also showed a favorable cycle stability with 72% capacity retention over 4000 cycles at 10 A g-1. The improved electrochemical performance is attributed to the synergetic effect of the large accessible surface area and optimal contacts between the MoS2 and the electrolyte, as well as high capacitance of the metallic Ni3S2 core.

NbS2 Nanosheets with M/Se (M = Fe, Co, Ni) Codopants for Li+ and Na+ Storage.

PubMed

Zhang, Jianli; Du, Chengfeng; Dai, Zhengfei; Chen, Wei; Zheng, Yun; Li, Bing; Zong, Yun; Wang, Xin; Zhu, Junwu; Yan, Qingyu

2017-10-24

Transition metal (M = Fe, Co, Ni) and Se codoped two-dimensional uniform NbS 2 (M x Nb 1-x S 2-y Se y ) nanosheets were synthesized via a facile oil-phase synthetic process. The morphology of M x Nb 1-x S 2-y Se y can be adjusted by tuning the amount of metal and Se introduced into NbS 2 . Among them, the optimized Fe 0.3 Nb 0.7 S 1.6 Se 0.4 nanosheets, with lateral sizes of 1-2 μm and approximately 5 nm thick, achieve the best Li-ion and Na-ion storage properties. For example, the Fe 0.3 Nb 0.7 S 1.6 Se 0.4 nanosheets depict excellent rate capabilities with fifth-cycle specific capacities of 461.3 mAh g -1 at 10 A g -1 for Li storage and 136 mAh g -1 at 5 A g -1 for Na storage. More significantly, ultralong cyclic stabilities were achieved with reversible specific capacities of 444 mAh g -1 at 5 A g -1 during the 3000th cycle for Li storage and 250 mAh g -1 at 1 A g -1 during the 750th cycle for Na storage. Post-treatment high-resolution transmission electron microscopy was studied to prove that the reversible Li-ion storage in NbS 2 was based on a conversion reaction mechanism.

Electron Excitation Rate Coefficients for Transitions from the IS21S Ground State to the 1S2S1,3S and 1S2P1,3P0 Excited States of Helium

NASA Astrophysics Data System (ADS)

Aggarwal, K. M.; Kingston, A. E.; McDowell, M. R. C.

1984-03-01

The available experimental and theoretical electron impact excitation cross section data for the transitions from the 1s2 1S ground state to the 1s2s 1,3S and 1s2p 1,3P0 excited states of helium are assessed. Based on this assessed data, excitation rate coefficients are calculated over a wide electron temperature range below 3.0×106K. A comparison with other published results suggests that the rates used should be lower by a factor of 2 or more.

Atomic alignment effect on reactivity and on product alignment in the energy-transfer reaction of oriented Ar (3P2, 4s [3/2]2, M(J) = 2) + Kr (4p6, 1S0) → Ar (3p6, 1S0) + Kr (5p [3/2]2).

PubMed

Ohoyama, H

2015-03-12

Steric effect for the formation of Kr (5p [3/2]₂) in the energy transfer reaction of Ar (³P₂, 4s [3/2]₂) + Kr has been studied by using an oriented Ar (³P₂, 4s [3/2]₂, M(J) = 2) beam at a collision energy of ∼0.09 eV. The emission intensity of Kr (5p [3/2]₂) is ca. 2 times enhanced when the angular momentum (J(Ar)) of Ar (³P₂) is aligned perpendicular to the relative velocity vector (v(R)). In addition, the Kr (5p [3/2]₂) emission is highly polarized parallel to v(R) (I(∥)/I(⊥) ∼ 1.2) when JAr is aligned perpendicular to v(R). The observed polarization moments indicate that the alignment of the unpaired Ar (3p) orbital of Ar (³P₂) to v(R), (Σ (|L′| = 0), Π (|L′| = 1)), dominates the energy transfer probability (σ(Π)(∥): σ(Σ)(∥): σ(Π)(⊥): σ(Σ)(⊥) = 0.49:1.33:0.55:1.23) and also the alignment of the Kr (5p) orbital of Kr (5p [3/2]₂) to v(R): the Σ-configuration of the Ar (3p) orbital leads to the parallel alignment (Σ-configuration) of the Kr(5p) orbital to v(R), conversely, the Π-configuration of Ar (3p) orbital leads to the perpendicular alignment (Π-configuration) of the Kr(5p) orbital. In addition, the selectivity of the alignment of the Kr (5p) orbital turns out to vary from perpendicular to parallel as the collision energy increases after a threshold down to 0.03 eV.

Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway.

PubMed

Pazini, Francis L; Cunha, Mauricio P; Rosa, Julia M; Colla, André R S; Lieberknecht, Vicente; Oliveira, Ágatha; Rodrigues, Ana Lúcia S

2016-12-01

Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 μg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.

Positive and negative modulation of circadian activity rhythms by mGluR5 and mGluR2/3 metabotropic glutamate receptors.

PubMed

Gannon, Robert L; Millan, Mark J

2011-01-01

Glutamate released from retinal ganglion cells conveys information about the daily light:dark cycle to master circadian pacemaker neurons within the suprachiasmatic nucleus that then synchronize internal circadian rhythms with the external day-length. Glutamate activation of ionotropic glutamate receptors in the suprachiasmatic nucleus is well established, but the function of the metabotropic glutamate receptors that are also located in this nucleus is not known. Therefore, in this study we evaluated agonists and antagonists acting at orthosteric or allosteric sites for mGluR5 and mGluR2/3 metabotropic glutamate receptors for their ability to modulate light-induced phase advances and delays of hamster circadian activity rhythms. mGluR5 allosteric antagonists fenobam, MPEP and MTEP, each 10 mg/kg, potentiated light-induced phase advances of hamster circadian activity rhythms, while the mGluR5 agonists CHPG, (S)-3,5-DHPG or positive allosteric modulator CDPPB had no effect. Neither mGluR5 agonists nor antagonists had any effect on light-induced phase delays of activity rhythms. The competitive mGluR2/3 antagonist LY341495, 10 mg/kg, also potentiated light-induced phase advances, but inhibited light-induced phase delays. The mGluR2/3 agonists LY354740 and LY404039 were without effect on phase advances while a third agonist LY379268, 10 mg/kg, inhibited both light-induced advances and delays. Finally, mGluR2/3 agonists LY379268 and LY404039 also inhibited light-induced phase delays of activity rhythms. These results suggest that during light-induced phase advances, mGluR2/3 and mGluR5 receptors act to negatively modulate the effects of light on the circadian pacemaker or its output(s). mGluR5 receptors do not appear to be involved during light-induced phase delays. In contrast, the role for mGluR2/3 receptors during phase delays is more complicated as both agonists and antagonists inhibit light-induced phase delays. Dysfunctions in human circadian rhythms have been

High-pressure/high-temperature synthesis and characterization of the first palladium or platinum containing lithium transition-metal sulfides Li2M3S4 (M=Pd, Pt)

NASA Astrophysics Data System (ADS)

Heymann, Gunter; Niehaus, Oliver; Krüger, Hannes; Selter, Philipp; Brunklaus, Gunther; Pöttgen, Rainer

2016-10-01

The new lithium transition-metal sulfides Li2M3S4 (M=Pd, Pt) were obtained via multianvil high-pressure/high-temperature syntheses at 8 GPa and 1150 °C starting from a stoichiometric mixture of lithium nitride, sulfur, and palladium or platinum. Single crystal structure analyses indicated the space group P21/c (no. 14) with the following lattice parameters and refinement results: a=492.9(1), b=1005.9(2), c=614.9(2) pm, β=110.9 (1)°, R1=0.0165, wR2=0.0308 (all data) for Li2Pd3S4 and a=498.2(1), b=1005.5(2), c=613.0(2) pm, β=110.8(1)°, R1=0.0215, wR2=0.0450 (all data) for Li2Pt3S4. The crystal structures are built up from two distinct Pd/Pt sites, one of which is a special position (0,0,0), two sulfur sites, and one lithium site. The atoms Pd2/Pt2 form isolated square planar PdS4/PtS4 units, whereas the Pd1/Pt1 atoms form pairs of square planar PdS4/PtS4 units, which are connected via a common edge. These two structural motives built up a three-dimensional network structure by linking through common corners. The lithium atoms are positioned inside of the so formed channels. Li2M3S4 (M=Pd, Pt) are isostructural to the minerals jaguéite, Cu2Pd3Se4 and chrisstanleyite, Ag2Pd3Se4, which are up to now the only representatives of this structure type. Both compounds were studied with respect to their magnetic properties and can be classified as Pauli paramagnetic or diamagnetic. Regarding the possibility of lithium mobility inside the channels, of the structure, solid state 7Li NMR and high-temperature single crystal investigations revealed localization of the lithium atoms on their crystallographic sites.

Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice.

PubMed

Joseph, Lauren; Thomsen, Morgane

2017-06-30

Muscarinic M 1 /M 4 receptor stimulation can reduce abuse-related effects of cocaine and may represent avenues for treating cocaine addiction. Muscarinic antagonists can mimic and enhance effects of cocaine, including discriminative stimulus (S D ) effects, but the receptor subtypes mediating those effects are not known. A better understanding of the complex cocaine/muscarinic interactions is needed to evaluate and develop potential muscarinic-based medications. Here, knockout mice lacking M 1 , M 2 , or M 4 receptors (M 1 -/- , M 2 -/- , M 4 -/- ), as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline. Muscarinic receptor antagonists with no subtype selectivity (scopolamine), or preferential affinity at the M 1 , M 2 , or M 4 subtype (telenzepine, trihexyphenidyl; methoctramine, AQ-RA 741; tropicamide) were tested alone and in combination with cocaine. In intact animals, antagonists with high affinity at M 1 /M 4 receptors partially substituted for cocaine and increased the S D effect of cocaine, while M 2 -preferring antagonists did not substitute, and reduced the S D effect of cocaine. The cocaine-like effects of scopolamine were absent in M 1 -/- mice. The cocaine S D attenuating effects of methoctramine were absent in M 2 -/- mice and almost absent in M 1 -/- mice. The findings indicate that the cocaine-like S D effects of muscarinic antagonists are primarily mediated through M 1 receptors, with a minor contribution of M 4 receptors. The data also support our previous findings that stimulation of M 1 receptors and M 4 receptors can each attenuate the S D effect of cocaine, and show that this can also be achieved by blocking M 2 autoreceptors, likely via increased acetylcholine release. Copyright © 2017 Elsevier B.V. All rights reserved.

A Retrospective Study of thrombolysis with 0.6 mg/kg Recombinant Tissue Plasminogen Activator (rt-PA) in Mild Stroke.

PubMed

Yang, Jie; Yu, Fei; Liu, Hong; An, Hedi; Xiong, Ran; Huang, Dongya

2016-08-11

We sought to assess the safety, effectiveness and cost of 0.6 mg/kg rt-PA treatment for patients with acute mild stroke and to compare that with 0.9 mg/kg. We retrospectively analyzed consecutive acute ischemic stroke patients who had a NIHSS score ≤5 at admission and who were treated with rt-PA within 4.5 hours of symptom onset. The demographic data, clinical outcomes and hospitalization cost were analyzed. A total of 108 patients were included. Forty six patients (42.6%) received a 0.6 mg/kg dosage of rt-PA. The baseline characteristics of the two groups were well matched (p > 0.05). Regarding the safety and effectiveness, the 0.6 mg/kg dosage group had a comparable proportion of symptomatic intracranial hemorrhage (sICH) (0.6 mg/kg, 4.3% vs 0.9 mg/kg, 4.8%; p > 0.05), early neurological deterioration (END) (19.6% vs 17.7%; p > 0.05), in-hospital mortality (4.3% vs 1.6%; p > 0.05), and a similar rate of favorable functional outcome (mRS score 0-1) at 3 months (73.9% vs 71.0%; p > 0.05) to those who received the standard dosage. However, the hospital cost was markedly lower in the 0.6 mg/kg group (0.6  mg/kg, 3,401.7 USD vs 0.9  mg/kg, 4,157.4 USD; p < 0.01). Our study suggest that 0.6 mg/kg rt-PA shared similar effectiveness and safety profile compared with that of 0.9 mg/kg in treating mild stroke, but cost less.

GSK-3 directly regulates phospho-4EBP1 in renal cell carcinoma cell-line: an intrinsic subcellular mechanism for resistance to mTORC1 inhibition.

PubMed

Ito, Hiromi; Ichiyanagi, Osamu; Naito, Sei; Bilim, Vladimir N; Tomita, Yoshihiko; Kato, Tomoyuki; Nagaoka, Akira; Tsuchiya, Norihiko

2016-07-07

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin 1 (mTORC1) signaling pathway is aberrantly activated in renal cell carcinoma (RCC). We previously demonstrated glycogen synthase kinase-3β (GSK-3β) positively regulated RCC proliferation. The aim of this study was to evaluate the role of GSK-3 in the PI3K/Akt/mTORC1 pathway and regulation of the downstream substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), ribosomal protein S6 kinase (S6K), and ribosomal protein S6 (S6RP). We used human RCC cell lines (ACHN, Caki1, and A498) and, as normal controls, human renal proximal tubular epithelial cell (HRPTEpC) and non-tumorous kidney tissues that were obtained surgically for treatment of RCC patients. Rapamycin-resistant ACHN (ACHN/RR) cells were generated with chronic exposure of ACHN to rapamycin ranging from 1nM finally to 1 μM. Cell viability, cell cycling and direct interaction between GSK-3β and 4EBP1 were evaluated with MTS assay, flowcytometry and in vitro kinase assay with recombinant GSK-3β and 4EBP1products, respectively. Protein expression and phosphorylation of molecules associated with the PI3K/Akt/mTORC1 pathway were examined by immunoblotting. Effects of drug combination were determined as the combination index with CompuSyn software. Overexpression and phosphorylation of 4EBP1 and S6RP together with GSK-3 activation were observed in RCC cell lines, but not in human normal kidney cells and tissues. Cell proliferation, p4EBP1 and pS6RP were strongly suppressed by GSK-3 inhibition. Rapamycin and LY294002 sufficiently decreased pS6RP, but only moderately p4EBP1. In vitro kinase assays showed that recombinant GSK-3β phosphorylated recombinant 4EBP1, and the effect was blocked by GSK-3 inhibitors. Different from rapamycin, AR- A014418 remarkably inhibited cell proliferation, and rapidly suppressed p4EBP1 and pS6RP in ACHN and ACHN/RR (in 30 min to 1 h). AR- A014418 and rapamycin combination showed

Testosterone regulation of Akt/mTORC1/FoxO3a Signaling in Skeletal Muscle

PubMed Central

White, James P.; Gao, Song; Puppa, Melissa J.; Sato, Shuichi; Welle, Stephen L.; Carson, James A.

2012-01-01

Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C2C12 myotubes. C57BL/6 mice were either castrated for 42 days or castrated and treated with the nandrolone decanoate (ND) (6 mg/kg bw/wk). Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets. Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C2C12 myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt/m

Biosynthesis of reovirus-specified polypeptides: the reovirus s1 mRNA encodes two primary translation products

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

Jacobs, B.L.; Samuel, C.E.

1985-05-01

Reovirus serotypes 1 (Lang strain) and 3 (Dearing strain) code for a hitherto unrecognized low-molecular-weight polypeptide of Mr approximately 12,000. This polypeptide (p12) was synthesized in vitro in L-cell-free protein synthesizing systems programmed with either reovirus serotype 1 mRNA, reovirus serotype 3 mRNA, or with denatured reovirus genome double-stranded RNA, and in vivo in L-cell cultures infected with either reovirus serotype. Pulse-chase experiments in vivo, and the relative kinetics of synthesis of p12 in vitro, indicate that it is a primary translation product. Fractionation of reovirus mRNAs by velocity sedimentation and translation of separated mRNAs in vitro suggests that p12more » is coded for by the s1 mRNA, which also codes for the previously recognized sigma 1 polypeptide. Synthesis of both p12 and sigma 1 in vitro in L-cell-free protein synthesizing systems programmed with denatured reovirus genome double-stranded RNA also suggests that these two polypeptides can be coded by the same mRNA species. It is proposed that the Mr approximately 12,000 polypeptide encoded by the S1 genome segment be designated sigma 1bNS, and that the polypeptide previously designated sigma 1 be renamed sigma 1a.« less

Determination of the 1s2{\\ell }2{{\\ell }}^{\\prime } state production ratios {{}^{4}P}^{o}/{}^{2}P, {}^{2}D/{}^{2}P and {{}^{2}P}_{+}/{{}^{2}P}_{-} from fast (1{s}^{2},1s2s\\,{}^{3}S) mixed-state He-like ion beams in collisions with H2 targets

NASA Astrophysics Data System (ADS)

Benis, E. P.; Zouros, T. J. M.

2016-12-01

New results are presented on the ratio {R}m={σ }{T2p}( {}4P)/{σ }{T2p}({}2P) concerning the production cross sections of Li-like 1s2s2p quartet and doublet P states formed in energetic ion-atom collisions by single 2p electron transfer to the metastable 1s2s {}3S component of the He-like ion beam. Spin statistics predict a value of R m = 2 independent of the collision system in disagreement with most reported measurements of {R}m≃ 1{--}9. A new experimental approach is presented for the evaluation of R m having some practical advantages over earlier approaches. It also allows for the determination of the separate contributions of ground- and metastable-state beam components to the measured spectra. Applying our technique to zero-degree Auger projectile spectra from 4.5 MeV {{{B}}}3+ (Benis et al 2002 Phys. Rev. A 65 064701) and 25.3 MeV {{{F}}}7+ (Zamkov et al 2002 Phys. Rev. A 65 062706) mixed state (1{s}2 {}1S,1s2s {}3S) He-like ion collisions with H2 targets, we report new values of {R}m=3.5+/- 0.4 for boron and {R}m=1.8+/- 0.3 for fluorine. In addition, the ratios of {}2D/{}2P and {{}2P}+/{{}2P}- populations from either the metastable and/or ground state beam component, also relevant to this analysis, are evaluated and compared to previously reported results for carbon collisions on helium (Strohschein et al 2008 Phys. Rev. A 77 022706) including a critical comparison to theory.

Tuberous sclerosis complex tumor suppressor–mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent

PubMed Central

Jaeschke, Anja; Hartkamp, Joerg; Saitoh, Masao; Roworth, Wendy; Nobukuni, Takahiro; Hodges, Angela; Sampson, Julian; Thomas, George; Lamb, Richard

2002-01-01

The evolution of mitogenic pathways has led to the parallel requirement for negative control mechanisms, which prevent aberrant growth and the development of cancer. Principally, such negative control mechanisms are represented by tumor suppressor genes, which normally act to constrain cell proliferation (Macleod, K. 2000. Curr. Opin. Genet. Dev. 10:81–93). Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder, characterized by mutations in either TSC1 or TSC2, whose gene products hamartin (TSC1) and tuberin (TSC2) constitute a putative tumor suppressor complex (TSC1-2; van Slegtenhorst, M., M. Nellist, B. Nagelkerken, J. Cheadle, R. Snell, A. van den Ouweland, A. Reuser, J. Sampson, D. Halley, and P. van der Sluijs. 1998. Hum. Mol. Genet. 7:1053–1057). Little is known with regard to the oncogenic target of TSC1-2, however recent genetic studies in Drosophila have shown that S6 kinase (S6K) is epistatically dominant to TSC1-2 (Tapon, N., N. Ito, B.J. Dickson, J.E. Treisman, and I.K. Hariharan. 2001. Cell. 105:345–355; Potter, C.J., H. Huang, and T. Xu. 2001. Cell. 105:357–368). Here we show that loss of TSC2 function in mammalian cells leads to constitutive S6K1 activation, whereas ectopic expression of TSC1-2 blocks this response. Although activation of wild-type S6K1 and cell proliferation in TSC2-deficient cells is dependent on the mammalian target of rapamycin (mTOR), by using an S6K1 variant (GST-ΔC-S6K1), which is uncoupled from mTOR signaling, we demonstrate that TSC1-2 does not inhibit S6K1 via mTOR. Instead, we show by using wortmannin and dominant interfering alleles of phosphatidylinositide-3-OH kinase (PI3K) that increased S6K1 activation is contingent upon the suppression of TSC2 function by PI3K in normal cells and is PI3K independent in TSC2-deficient cells. PMID:12403809

Measurement of the radiative decay and energy of the metastable $${(2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{(J=0)}$$ level in Fe XVII

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

Beiersdorfer, P.; Lopez-Urrutia, J. R. Crespo; Trabert, E.

Measurements at the Livermore electron beam ion trap have been performed in order to infer the energy and the radiative lifetime of themore » $${(1{s}^{2}2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=0}$$ level in the Fe xvii spectrum. This is the longest-lived level in the neonlike iron ion, and its radiative decay produces the Fe xvii line at 1153 Å, feeding the population of the $${(1{s}^{2}2{s}^{2}2{p}_{3/2}^{5}3{s}_{1/2})}_{J=1}$$ upper level of one of the most prominent lines in the Fe xvii L-shell X-ray spectrum, commonly dubbed $3G$. In the presence of a strong ($$\\geqslant $$ few kG) magnetic field, the $${(1{s}^{2}2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=0}$$ level has a finite probability to decay directly to the $${(1{s}^{2}2{s}^{2}2{p}^{6})}_{J=0}$$ neonlike ground level via the emission of an L-shell X-ray. Our measurements allow us to observe this X-ray line in the Fe xvii L-shell spectrum and from it to infer the radiative rate for the magnetic dipole decay of the $${(1{s}^{2}2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=0}$$ level to the $${(1{s}^{2}2{s}^{2}2{p}_{3/2}^{5}3{s}_{1/2})}_{J=1}$$. Our result of $$(1.45\\pm 0.15)\\times {10}^{4}$$ s-1 is in agreement with predictions. We have also measured the wavelength of the associated X-ray line to be 16.804 ± 0.002 Å, which means that the line is displaced 1.20 ± 0.05 eV from the neighboring $${(2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=1}\\to {(2{s}^{2}2{p}^{6})}_{J=0}$$ transition, commonly labeled $3F$. Furthermore, from our measurement, we infer 5950570 ± 710 cm-1 for the energy of the $${(1{s}^{2}2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=0}$$ level.« less

Measurement of the radiative decay and energy of the metastable $${(2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{(J=0)}$$ level in Fe XVII

DOE PAGES

Beiersdorfer, P.; Lopez-Urrutia, J. R. Crespo; Trabert, E.

2016-01-20

Measurements at the Livermore electron beam ion trap have been performed in order to infer the energy and the radiative lifetime of themore » $${(1{s}^{2}2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=0}$$ level in the Fe xvii spectrum. This is the longest-lived level in the neonlike iron ion, and its radiative decay produces the Fe xvii line at 1153 Å, feeding the population of the $${(1{s}^{2}2{s}^{2}2{p}_{3/2}^{5}3{s}_{1/2})}_{J=1}$$ upper level of one of the most prominent lines in the Fe xvii L-shell X-ray spectrum, commonly dubbed $3G$. In the presence of a strong ($$\\geqslant $$ few kG) magnetic field, the $${(1{s}^{2}2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=0}$$ level has a finite probability to decay directly to the $${(1{s}^{2}2{s}^{2}2{p}^{6})}_{J=0}$$ neonlike ground level via the emission of an L-shell X-ray. Our measurements allow us to observe this X-ray line in the Fe xvii L-shell spectrum and from it to infer the radiative rate for the magnetic dipole decay of the $${(1{s}^{2}2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=0}$$ level to the $${(1{s}^{2}2{s}^{2}2{p}_{3/2}^{5}3{s}_{1/2})}_{J=1}$$. Our result of $$(1.45\\pm 0.15)\\times {10}^{4}$$ s-1 is in agreement with predictions. We have also measured the wavelength of the associated X-ray line to be 16.804 ± 0.002 Å, which means that the line is displaced 1.20 ± 0.05 eV from the neighboring $${(2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=1}\\to {(2{s}^{2}2{p}^{6})}_{J=0}$$ transition, commonly labeled $3F$. Furthermore, from our measurement, we infer 5950570 ± 710 cm-1 for the energy of the $${(1{s}^{2}2{s}^{2}2{p}_{1/2}^{5}3{s}_{1/2})}_{J=0}$$ level.« less

Etude des mécanismes d'ionisation de H{2}O par interaction He^{*}(2 ^1S, 2 ^3S)/Ne^{*}(^3P{0}, ^3P{2})+H{2}O

NASA Astrophysics Data System (ADS)

Le Nadan, André; Sinou, Guillaume; Tuffin, Firmin

1993-06-01

Experimental observations of Penning ionisation of H{2}O by the helium metastables 21S and 23S and by the neon metastables ^3P{0} and ^3P{2} are reported. The kinetic energies of the ions created during the collision process (both parent and fragment) are analysed. Certain particularities of the experimental results are explained by involving the hypothesis of transfers of vibrational energy to kinetic energy. Furthermore, the forms of the energy distributions of the fragment ions are explained by th predissociation of the ^2B{2} state of H{2}O+. Nous avons étudié l'ionisation Penning de H{2}O par des métastables 21S et 23S de l'hélium, ainsi que ^3P{0} et ^3P{2} du néon. Nous avons analysé l'énergie cinétique des ions créés au cours de la collision (parents et fragments). Afin d'interpréter certaines particularités expérimentales, l'hypothèse de transferts d'énergie de vibration en énergie cinétique est proposées. Par ailleurs, les caractéristiques des distributions en énergie des ions fragments sont expliquées par la prédissociation de l'état ^2B{2} de H{2}O+.

The Moon mineralogy mapper (M3) on Chandrayaan-1

USGS Publications Warehouse

Pieters, C.M.; Boardman, J.; Buratti, B.; Chatterjee, A.; Clark, R.; Glavich, T.; Green, R.; Head, J.; Isaacson, P.; Malaret, E.; McCord, T.; Mustard, J.; Petro, N.; Runyon, C.; Staid, M.; Sunshine, J.; Taylor, L.; Tompkins, S.; Varanasi, P.; White, M.

2009-01-01

The Moon Mineralogy Mapper (M3) is a NASA-supported guest instrument on ISRO's remote sensing mission to Moon, Chandrayaan-1. The M3 is an imaging spectrometer that operates from the visible into the near-infrared (0.42-3.0 ??m) where highly diagnostic mineral absorption bands occur. Over the course of the mission M3 will provide low resolution spectroscopic data for the entire lunar surface at 140 m/pixel (86 spectral channels) to be used as a base-map and high spectral resolution science data (80 m/pixel; 260 spectral channels) for 25-50% of the surface. The detailed mineral assessment of different lunar terrains provided by M3 is principal information needed for understanding the geologic evolution of the lunar crust and lays the foundation for focused future in-depth exploration of the Moon.

ABCG2-overexpressing S1-M1-80 cell xenografts in nude mice keep original biochemistry and cell biological properties.

PubMed

Wang, Fang; Liang, Yong-Ju; Wu, Xing-Ping; Su, Xiao-Dong; Fu, Li-Wu

2012-03-01

S1-M1-80 cells, derived from human colon carcinoma S1 cells, are mitoxantrone-selected ABCG2-overexpressing cells and are widely used in in vitro studies of multidrug resistance(MDR). In this study, S1-M1-80 cell xenografts were established to investigate whether the MDR phenotype and cell biological properties were maintained in vivo. Our results showed that the proliferation, cell cycle, and ABCG2 expression level in S1-M1-80 cells were similar to those in cells isolated from S1-M1-80 cell xenografts (named xS1-M1-80 cells). Consistently, xS1-M1-80 cells exhibited high levels of resistance to ABCG2 substrates such as mitoxantrone and topotecan, but remained sensitive to the non-ABCG2 substrate cisplatin. Furthermore, the specific ABCG2 inhibitor Ko143 potently sensitized xS1-M1-80 cells to mitoxantrone and topotecan. These results suggest that S1-M1-80 cell xenografts in nude mice retain their original cytological characteristics at 9 weeks. Thus, this model could serve as a good system for further investigation of ABCG2-mediated MDR.

Anaphase-Promoting Complex/Cyclosome-Cdh1-Mediated Proteolysis of the Forkhead Box M1 Transcription Factor Is Critical for Regulated Entry into S Phase▿

PubMed Central

Park, Hyun Jung; Costa, Robert H.; Lau, Lester F.; Tyner, Angela L.; Raychaudhuri, Pradip

2008-01-01

The forkhead box M1 (FoxM1) transcription factor is overexpressed in many cancers, and in mouse models it is required for tumor progression. FoxM1 activates expression of the cell cycle genes required for both S and M phase progression. Here we demonstrate that FoxM1 is degraded in late mitosis and early G1 phase by the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. FoxM1 interacts with the APC/C complex and its adaptor, Cdh1. Expression of Cdh1 stimulated degradation of the FoxM1 protein, and depletion of Cdh1 resulted in stabilization of the FoxM1 protein in late mitosis and in early G1 phase of the cell cycle. Cdh1 has been implicated in regulating S phase entry. We show that codepletion of FoxM1 inhibits early S phase entry observed in Cdh1-depleted cells. The N-terminal region of FoxM1 contains both destruction box (D box) and KEN box sequences that are required for targeting by Cdh1. Mutation of either the D box sequence or the KEN box sequence stabilized FoxM1 and blocked Cdh1-induced proteolysis. Cells expressing a nondegradable form of FoxM1 entered S phase rapidly following release from M phase arrest. Together, our observations show that FoxM1 is one of the targets of Cdh1 in late M or early G1 phase and that its proteolysis is important for regulated entry into S phase. PMID:18573889

Anaphase-promoting complex/cyclosome-CDH1-mediated proteolysis of the forkhead box M1 transcription factor is critical for regulated entry into S phase.

PubMed

Park, Hyun Jung; Costa, Robert H; Lau, Lester F; Tyner, Angela L; Raychaudhuri, Pradip

2008-09-01

The forkhead box M1 (FoxM1) transcription factor is overexpressed in many cancers, and in mouse models it is required for tumor progression. FoxM1 activates expression of the cell cycle genes required for both S and M phase progression. Here we demonstrate that FoxM1 is degraded in late mitosis and early G(1) phase by the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. FoxM1 interacts with the APC/C complex and its adaptor, Cdh1. Expression of Cdh1 stimulated degradation of the FoxM1 protein, and depletion of Cdh1 resulted in stabilization of the FoxM1 protein in late mitosis and in early G(1) phase of the cell cycle. Cdh1 has been implicated in regulating S phase entry. We show that codepletion of FoxM1 inhibits early S phase entry observed in Cdh1-depleted cells. The N-terminal region of FoxM1 contains both destruction box (D box) and KEN box sequences that are required for targeting by Cdh1. Mutation of either the D box sequence or the KEN box sequence stabilized FoxM1 and blocked Cdh1-induced proteolysis. Cells expressing a nondegradable form of FoxM1 entered S phase rapidly following release from M phase arrest. Together, our observations show that FoxM1 is one of the targets of Cdh1 in late M or early G(1) phase and that its proteolysis is important for regulated entry into S phase.

Unique Roll-Off Roof for Housing 1.3 m Telescope at Devasthal, Nainital

NASA Astrophysics Data System (ADS)

Bangia, Tarun

2017-06-01

Aryabhatta Research Institute of Observational Sciences (ARIES) had set up a 1.3 m telescope at Devasthal, Nainital, India in the year 2010. Country's largest roll-off roof was indigenously designed, fabricated and installed on top of a building (17 × 8 m) for housing 1.3 m telescope. Telescope was supplied by M/s DFM Engineering Inc., USA to ARIES and was installed in the building with unique roll-off roof to protect it from external environment. Roll-off roof was designed and fabricated considering various parameters and available manpower and resources at ARIES. This paper presents mechanical development work, simple but distinct design approach and innovative selection of materials to economically manufacture roll-off roof of large size (8 × 8 × 4 m) at hilly remote site of Devasthal situated in Central Himalayan region. All operations in the roof viz. opening of shutters and rolling of roof were motorized to facilitate observers during night observations.

Effect of Zb states on ϒ (3 S )→ϒ (1 S )π π decays

NASA Astrophysics Data System (ADS)

Chen, Yun-Hua; Daub, Johanna T.; Guo, Feng-Kun; Kubis, Bastian; Meißner, Ulf-G.; Zou, Bing-Song

2016-02-01

Within the framework of dispersion theory, we analyze the dipion transitions between the lightest ϒ states, ϒ (n S )→ϒ (m S )π π with m 3 . In particular, we consider the possible effects of two intermediate bottomoniumlike exotic states Zb(10610 ) and Zb(10650 ). The π π rescattering effects are taken into account in a model-independent way using dispersion theory. We confirm that matching the dispersive representation to the leading chiral amplitude alone cannot reproduce the peculiar two-peak π π mass spectrum of the decay ϒ (3 S )→ϒ (1 S )π π . The existence of the bottomoniumlike Zb states can naturally explain this anomaly. We also point out the necessity of a proper extraction of the coupling strengths for the Zb states to ϒ (n S )π , which is only possible if a Flatté-like parametrization is used in the data analysis for the Zb states.

In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist.

PubMed

Panayi, Fany; Sors, Aurore; Bert, Lionel; Martin, Brigitte; Rollin-Jego, Gaelle; Billiras, Rodolphe; Carrié, Isabelle; Albinet, Karine; Danober, Laurence; Rogez, Nathalie; Thomas, Jean-Yves; Pira, Luigi; Bertaina-Anglade, Valérie; Lestage, Pierre

2017-05-15

S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties. In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10mg/kg i.p.). Acute oral administration of S 38093 at 0.1mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1mg/kg i.p. Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10mg/kg p.o. also decreased the barbital-induced sleeping time in rats. Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents. Copyright © 2017 Elsevier B.V. All rights reserved.

mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate.

PubMed

Marat, Andrea L; Wallroth, Alexander; Lo, Wen-Ting; Müller, Rainer; Norata, Giuseppe Danilo; Falasca, Marco; Schultz, Carsten; Haucke, Volker

2017-06-02

Nutrient sensing by mechanistic target of rapamycin complex 1 (mTORC1) on lysosomes and late endosomes (LyLEs) regulates cell growth. Many factors stimulate mTORC1 activity, including the production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] by class I phosphatidylinositol 3-kinases (PI3Ks) at the plasma membrane. We investigated mechanisms that repress mTORC1 under conditions of growth factor deprivation. We identified phosphatidylinositol 3,4-bisphosphate [PI(3,4)P 2 ], synthesized by class II PI3K β (PI3KC2β) at LyLEs, as a negative regulator of mTORC1, whereas loss of PI3KC2β hyperactivated mTORC1. Growth factor deprivation induced the association of PI3KC2β with the Raptor subunit of mTORC1. Local PI(3,4)P 2 synthesis triggered repression of mTORC1 activity through association of Raptor with inhibitory 14-3-3 proteins. These results unravel an unexpected function for local PI(3,4)P 2 production in shutting off mTORC1. Copyright © 2017, American Association for the Advancement of Science.

Oral toxicity evaluation of kefir-isolated Lactobacillus kefiranofaciens M1 in Sprague-Dawley rats.

PubMed

Owaga, E E; Chen, M J; Chen, W Y; Chen, C W; Hsieh, R H

2014-08-01

Lactobacilli kefiranofaciens M1 has shown novel immunomodulation and anti-allergy probiotic attributes in cell and animal models. An acute oral toxicity assessment of L. kefiranofaciens M1 was evaluated in Sprague-Dawley rats. The rats were randomly assigned to four groups (12 rats/sex/group): the low dose group was orally gavaged with L. kefiranofaciens M1 at 3.0×10(8)cfu/kg bw while the medium dose and high dose groups received 9.0×10(9)cfu/kg bw and 1.8×10(10)cfu/kg bw, respectively, for 28days. The control group received phosphate buffer saline. The body weights were measured weekly while blood samples were collected for haematology and serum biochemistry tests. Histopathology of the organs (heart, liver, kidney, adrenal glands, spleen, ovary, testis), and urinalysis were conducted on study termination. The body weight gain of the L. kefiranofaciens M1 and control groups were comparable during the administration period. Overall, L. kefiranofaciens M1 did not induce adverse effects on haematology, serum biochemistry, and urinalysis parameters. Gross and microscopic histopathology of the organs revealed no toxicity effect of L. kefiranofaciens M1. In conclusion, 1.8×10(10)cfu/kg bw of L. kefiranofaciens M1 was considered as the no-observed-adverse-effect-level (NOAEL), which was the highest dose tested in the present study. Copyright © 2014 Elsevier Ltd. All rights reserved.

Electronic, Magnetic, and Redox Properties of [MFe(3)S(4)] Clusters (M = Cd, Cu, Cr) in Pyrococcus furiosus Ferredoxin.

PubMed

Staples, Christopher R.; Dhawan, Ish K.; Finnegan, Michael G.; Dwinell, Derek A.; Zhou, Zhi Hao; Huang, Heshu; Verhagen, Marc F. J. M.; Adams, Michael W. W.; Johnson, Michael K.

1997-12-03

The ground- and excited-state properties of heterometallic [CuFe(3)S(4)](2+,+), [CdFe(3)S(4)](2+,+), and [CrFe(3)S(4)](2+,+) cubane clusters assembled in Pyrococcus furiosus ferredoxin have been investigated by the combination of EPR and variable-temperature/variable-field magnetic circular dichroism (MCD) studies. The results indicate Cd(2+) incorporation into [Fe(3)S(4)](0,-) cluster fragments to yield S = 2 [CdFe(3)S(4)](2+) and S = (5)/(2) [CdFe(3)S(4)](+) clusters and Cu(+) incorporation into [Fe(3)S(4)](+,0) cluster fragments to yield S = (1)/(2) [CuFe(3)S(4)](2+) and S = 2 [CuFe(3)S(4)](+) clusters. This is the first report of the preparation of cubane type [CrFe(3)S(4)](2+,+) clusters, and the combination of EPR and MCD results indicates S = 0 and S = (3)/(2) ground states for the oxidized and reduced forms, respectively. Midpoint potentials for the [CdFe(3)S(4)](2+,+), [CrFe(3)S(4)](2+,+), and [CuFe(3)S(4)](2+,+) couples, E(m) = -470 +/- 15, -440 +/- 10, and +190 +/- 10 mV (vs NHE), respectively, were determined by EPR-monitored redox titrations or direct electrochemistry at a glassy carbon electrode. The trends in redox potential, ground-state spin, and electron delocalization of [MFe(3)S(4)](2+,+) clusters in P. furiosus ferredoxin are discussed as a function of heterometal (M = Cr, Mn, Fe, Co, Ni, Cu, Zn, Cd, and Tl).

Weight outcomes audit in 1.3 million adults during their first 3 months' attendance in a commercial weight management programme.

PubMed

Stubbs, R James; Morris, Liam; Pallister, Carolyn; Horgan, Graham; Lavin, Jacquie H

2015-09-10

Over sixty percent of adults in the UK are now overweight/obese. Weight management on a national scale requires behavioural and lifestyle solutions that are accessible to large numbers of people. Evidence suggests commercial weight management programmes help people manage their weight but there is little research examining those that pay to attend such programmes rather than being referred by primary care. The objective of this analysis was to evaluate the effectiveness of a UK commercial weight management programme in self-referred, fee-paying participants. Electronic weekly weight records were collated for self-referred, fee-paying participants of Slimming World groups joining between January 2010 and April 2012. This analysis reports weight outcomes in 1,356,105 adult, non-pregnant participants during their first 3 months' attendance. Data were analysed by regression, ANOVA and for binomial outcomes, chi-squared tests using the R statistical program. Mean (SD) age was 42.3 (13.6) years, height 1.65 m (0.08) and start weight was 88.4 kg (18.8). Mean start BMI was 32.6 kg/m(2) (6.3 kg/m(2)) and 5 % of participants were men. Mean weight change of all participants was -3.9 kg (3.6), percent weight change -4.4 (3.8), and BMI change was -1.4 kg/m(2) (1.3). Mean attendance was 7.8 (4.3) sessions in their first 3 months. For participants attending at least 75 % of possible weekly sessions (n = 478,772), mean BMI change was -2.5 kg/m(2) (1.3), weight change -6.8 kg (3.7) and percent weight change -7.5 % (3.5). Weight loss was greater in men than women absolutely (-6.5 (5.3) kg vs -3.8 (3.4) kg) and as a percentage (5.7 % (4.4) vs 4.3 % (3.7)), respectively. All comparisons were significant (p < 0.001). Level of attendance and percent weight loss in the first week of attendance together accounted for 55 % of the variability in weight lost during the study period. A large-scale commercial lifestyle-based weight management programme had a significant impact on weight loss

High-pressure/high-temperature synthesis and characterization of the first palladium or platinum containing lithium transition-metal sulfides Li{sub 2}M{sub 3}S{sub 4} (M=Pd, Pt)

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

Heymann, Gunter, E-mail: Gunter.Heymann@uibk.ac.at; Niehaus, Oliver; Krüger, Hannes

The new lithium transition-metal sulfides Li{sub 2}M{sub 3}S{sub 4} (M=Pd, Pt) were obtained via multianvil high-pressure/high-temperature syntheses at 8 GPa and 1150 °C starting from a stoichiometric mixture of lithium nitride, sulfur, and palladium or platinum. Single crystal structure analyses indicated the space group P2{sub 1}/c (no. 14) with the following lattice parameters and refinement results: a=492.9(1), b=1005.9(2), c=614.9(2) pm, β=110.9 (1)°, R1=0.0165, wR2=0.0308 (all data) for Li{sub 2}Pd{sub 3}S{sub 4} and a=498.2(1), b=1005.5(2), c=613.0(2) pm, β=110.8(1)°, R1=0.0215, wR2=0.0450 (all data) for Li{sub 2}Pt{sub 3}S{sub 4}. The crystal structures are built up from two distinct Pd/Pt sites, one of whichmore » is a special position (0,0,0), two sulfur sites, and one lithium site. The atoms Pd2/Pt2 form isolated square planar PdS{sub 4}/PtS{sub 4} units, whereas the Pd1/Pt1 atoms form pairs of square planar PdS{sub 4}/PtS{sub 4} units, which are connected via a common edge. These two structural motives built up a three-dimensional network structure by linking through common corners. The lithium atoms are positioned inside of the so formed channels. Li{sub 2}M{sub 3}S{sub 4} (M=Pd, Pt) are isostructural to the minerals jaguéite, Cu{sub 2}Pd{sub 3}Se{sub 4} and chrisstanleyite, Ag{sub 2}Pd{sub 3}Se{sub 4}, which are up to now the only representatives of this structure type. Both compounds were studied with respect to their magnetic properties and can be classified as Pauli paramagnetic or diamagnetic. Regarding the possibility of lithium mobility inside the channels, of the structure, solid state {sup 7}Li NMR and high-temperature single crystal investigations revealed localization of the lithium atoms on their crystallographic sites. - Graphical abstract: The ternary lithium transition-metal sulfides Li{sub 2}M{sub 3}S{sub 4} (M=Pd, Pt) were prepared via multianvil high-pressure/high-temperature syntheses. They are built up from square planar PtS

Supersymmetric M3-branes and G2 manifolds

NASA Astrophysics Data System (ADS)

Cvetič, M.; Gibbons, G. W.; Lü, H.; Pope, C. N.

2002-01-01

We obtain a generalisation of the original complete Ricci-flat metric of G2 holonomy on R4×S 3 to a family with a nontrivial parameter λ. For generic λ the solution is singular, but it is regular when λ={-1,0,+1}. The case λ=0 corresponds to the original G2 metric, and λ={-1,1} are related to this by an S3 automorphism of the SU(2) 3 isometry group that acts on the S3× S3 principal orbits. We then construct explicit supersymmetric M3-brane solutions in D=11 supergravity, where the transverse space is a deformation of this class of G2 metrics. These are solutions of a system of first-order differential equations coming from a superpotential. We also find M3-branes in the deformed backgrounds of new G2 holonomy metrics that include one found by A. Brandhuber, J. Gomis, S. Gubser and S. Gukov, and show that they also are supersymmetric.

Fast-timing study of the l -forbidden 1 /2+→3 /2+ M 1 transition in 129Sn

NASA Astrophysics Data System (ADS)

Licǎ, R.; Mach, H.; Fraile, L. M.; Gargano, A.; Borge, M. J. G.; Mǎrginean, N.; Sotty, C. O.; Vedia, V.; Andreyev, A. N.; Benzoni, G.; Bomans, P.; Borcea, R.; Coraggio, L.; Costache, C.; De Witte, H.; Flavigny, F.; Fynbo, H.; Gaffney, L. P.; Greenlees, P. T.; Harkness-Brennan, L. J.; Huyse, M.; Ibáñez, P.; Judson, D. S.; Konki, J.; Korgul, A.; Kröll, T.; Kurcewicz, J.; Lalkovski, S.; Lazarus, I.; Lund, M. V.; Madurga, M.; Mǎrginean, R.; Marroquín, I.; Mihai, C.; Mihai, R. E.; Morales, A. I.; Nácher, E.; Negret, A.; Page, R. D.; Pakarinen, J.; Pascu, S.; Paziy, V.; Perea, A.; Pérez-Liva, M.; Picado, E.; Pucknell, V.; Rapisarda, E.; Rahkila, P.; Rotaru, F.; Swartz, J. A.; Tengblad, O.; Van Duppen, P.; Vidal, M.; Wadsworth, R.; Walters, W. B.; Warr, N.; IDS Collaboration

2016-04-01

The levels in 129Sn populated from the β- decay of 129In isomers were investigated at the ISOLDE facility of CERN using the newly commissioned ISOLDE Decay Station (IDS). The lowest 1 /2+ state and the 3 /2+ ground state in 129Sn are expected to have configurations dominated by the neutron s1 /2 (l =0 ) and d3 /2 (l =2 ) single-particle states, respectively. Consequently, these states should be connected by a somewhat slow l -forbidden M 1 transition. Using fast-timing spectroscopy we have measured the half-life of the 1 /2+ 315.3-keV state, T1 /2= 19(10) ps, which corresponds to a moderately fast M 1 transition. Shell-model calculations using the CD-Bonn effective interaction, with standard effective charges and g factors, predict a 4-ns half-life for this level. We can reconcile the shell-model calculations to the measured T1 /2 value by the renormalization of the M 1 effective operator for neutron holes.

Broken S 3L×S 3R flavor symmetry and leptonic CP violation

NASA Astrophysics Data System (ADS)

Si, Zong-guo; Yang, Xing-hua; Zhou, Shun

2017-11-01

In the framework of the canonical seesaw model, we present a simple but viable scenario to explicitly break an S 3L×S 3R flavor symmetry in the leptonic sector. It turns out that the leptonic flavor mixing matrix is completely determined by the mass ratios of the charged leptons (i.e., m e/m μ and m μ/m τ) and those of light neutrinos (i.e., m 1/m 2 and m 2/m 3). The latest global-fit results of the three neutrino mixing angles {θ 12, θ 13, θ 23} and two neutrino mass-squared differences at the 3σ level are used to constrain the parameter space of {m 1/m 2,m 2/m 3}. The predictions for the mass spectrum and flavor mixing are highlighted: (1) the neutrino mass spectrum shows a hierarchical pattern and a normal ordering, e.g., m 1≈2.2 meV, m 2≈8.8 meV and m 3≈52.7 meV (2) only the first octant of θ 23 is allowed, namely, 41.8°≲θ 23≲43.3° (3) the Dirac CP-violating phase δ≈-22° deviates significantly from the maximal value -90°. All these predictions are ready to be tested in ongoing and forthcoming neutrino oscillation experiments. Moreover, we demonstrate that the cosmological matter-antimatter asymmetry can be explained via resonant leptogenesis, including the individual lepton-flavor effects. In our scenario, leptonic CP violation at low- and high-energy scales is closely connected. Supported by NNSFC (11325525), National Recruitment Program for Young Professionals and CAS Center for Excellence in Particle Physics (CCEPP)

Tri-Ponderal Mass Index vs. Fat Mass/Height3 as a Screening Tool for Metabolic Syndrome Prediction in Colombian Children and Young People

PubMed Central

Correa-Bautista, Jorge Enrique; Carrillo, Hugo Alejandro; Schmidt-RioValle, Jacqueline; González-Ruíz, Katherine

2018-01-01

Tri-ponderal mass index (TMI) and fat mass index (FMI) have been proposed as alternative approaches for assessing body fat since BMI does not ensure an accurate screening for obesity and overweight status in children and adolescents. This study proposes thresholds of the TMI and FMI for the prediction of metabolic syndrome (MetS) in children and young people. For this purpose, a cross-sectional study was conducted on 4673 participants (57.1% females), who were 9–25 years of age. As part of the study, measurements of the subjects’ weight, waist circumference, serum lipid indices, blood pressure and fasting plasma glucose were taken. Body composition was measured by bioelectrical impedance analysis (BIA). The TMI and FMI were calculated as weight (kg)/height (m3) and fat mass (kg)/height (m3), respectively. Following the International Diabetes Federation (IDF) definition, MetS is defined as including three or more metabolic abnormalities. Cohort-specific thresholds were established to identify Colombian children and young people at high risk of MetS. The thresholds were applied to the following groups: (i) a cohort of children where the girls’ TMI ≥ 12.13 kg/m3 and the boys’ TMI ≥ 12.10 kg/m3; (ii) a cohort of adolescents where the girls’ TMI ≥ 12.48 kg/m3 and the boys’ TMI ≥ 11.19 kg/m3; (iii) a cohort of young adults where the women’s TMI ≥ 13.21 kg/m3 and the men’s TMI ≥ 12.19 kg/m3. The FMI reference cut-off values used for the different groups were as follows: (i) a cohort of children where the girls’ FMI ≥ 2.59 fat mass/m3 and the boys’ FMI ≥ 1.98 fat mass/m3; (ii) a cohort of adolescents where the girls’ FMI ≥ 3.12 fat mass/m3 and the boys’ FMI ≥ 1.46 fat mass/m3; (iii) a cohort of adults where the women’s FMI ≥ 3.27 kg/m3 and the men’s FMI ≥ 1.65 kg/m3. Our results showed that the FMI and TMI had a moderate discriminatory power to detect MetS in Colombian children, adolescents, and young adults. PMID

mTORC1 Inhibition via Rapamycin Promotes Triacylglycerol Lipolysis and Release of Free Fatty Acids in 3T3-L1 Adipocytes

PubMed Central

Soliman, Ghada A.; Acosta-Jaquez, Hugo A.; Fingar, Diane C.

2017-01-01

Signaling by mTOR complex 1 (mTORC1) promotes anabolic cellular processes in response to growth factors, nutrients, and hormonal cues. Numerous clinical trials employing the mTORC1 inhibitor rapamycin (aka sirolimus) to immuno-suppress patients following organ transplantation have documented the development of hypertriglyceridemia and elevated serum free fatty acids (FFA). We therefore investigated the cellular role of mTORC1 in control of triacylglycerol (TAG) metabolism using cultured murine 3T3-L1 adipocytes. We found that treatment of adipocytes with rapamycin reduced insulin-stimulated TAG storage ~50%. To determine whether rapamycin reduces TAG storage by upregulating lipolytic rate, we treated adipocytes in the absence and presence of rapamycin and isoproterenol, a β2-adrenergic agonist that activates the cAMP/protein kinase A (PKA) pathway to promote lipolysis. We found that rapamycin augmented isoproterenol-induced lipolysis without altering cAMP levels. Rapamycin enhanced the isoproterenol-stimulated phosphorylation of hormone sensitive lipase (HSL) on Ser-563 (a PKA site), but had no effect on the phosphorylation of HSL S565 (an AMPK site). Additionally, rapamycin did not affect the isoproterenol-mediated phosphorylation of perilipin, a protein that coats the lipid droplet to initiate lipolysis upon phosphorylation by PKA. These data demonstrate that inhibition of mTORC1 signaling synergizes with the β-adrenergic-cAMP/PKA pathway to augment phosphorylation of HSL to promote hormone-induced lipolysis. Moreover, they reveal a novel metabolic function for mTORC1; mTORC1 signaling suppresses lipolysis, thus augmenting TAG storage. PMID:21042876

Discrimination of putative M1 and M2 muscarinic receptor subtypes in rat brain by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)

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

Norman, A.B.; Creese, I.

1986-03-01

The EC/sub 50/ of EEDQ for the inhibition of (/sup 3/H)(-)QNB binding in vitro was approximately 3 fold lower for homogenates of hippocampus than brainstem (containing predominantly putative M/sub 1/ and M/sub 2/ muscarinic receptor subtypes respectively). Furthermore, the time-dependent loss of (/sup 3/H)(-)QNB binding produced by 100 ..mu..M EEDQ was faster in homogenates of hippocampus than brainstem. Administration of EEDQ (20 mg/kg i.p.) irreversibly reduced the Bmax of (/sup 3/H)(-)QNB binding by 56% and 34% in hippocampus and brainstem respectively. Pirenzepine competition for the remaining (/sup 3/H)(-)QNB binding sites following in vitro and in vivo treatment with EEDQ revealedmore » a significant increase in the proportion of (/sup 3/H)(-)QNB binding sites having low affinity for pirenzepine (M/sub 2/ receptors), indicating that the high affinity pirenzepine binding sites (M/sub 1/ receptors) were selectively and irreversibly lost. Thus, EEDQ discriminates the same putative M/sub 1/ and M/sub 2/ muscarinic receptor subtypes that are discriminated by pirenzepine. The reduction of (/sup 3/H)(-)QNB binding could be prevented both in vitro and in vivo by atropine or scopolamine. These data may indicate differences in the accessibility of these putative receptor subtypes to EEDQ or, alternatively, differences in the availability of carboxyl groups able to interact with EEDQ at the ligand recognition site of M/sub 1/ and M/sub 2/ muscarinic receptors.« less

La 1–xBi 1+xS 3 ( x ≈ 0.08): An n-Type Semiconductor

DOE PAGES

Han, Fei; Liu, Huimei; Malliakas, Christos D.; ...

2016-03-21

We study the new bismuth chalcogenide La 0.92Bi 1.08S 3 which crystallizes in the monoclinic space group C2/m with a = 28.0447(19) Å, b = 4.0722(2) Å, c = 14.7350(9) Å, and β = 118.493(5)°. The structure of La 0.92Bi 1.08S 3 is built of NaCl-type Bi 2S 5 blocks and BiS 4 and LaS 5 infinitely long chains, forming a compact three-dimensional framework with parallel tunnels. Optical spectroscopy and resistivity measurements reveal a semiconducting behavior with a band gap of ~1 eV and activation energy for transport of 0.36(1) eV. Thermopower measurements suggest the majority carriers of La 0.92Bimore » 1.08S 3 are electrons. Heat capacity measurements indicate no phase transitions from 2 to 300 K. Lastly, band structure calculations at the density functional theory level confirm the semiconducting nature and the indirect gap of La 0.92Bi 1.08S 3.« less

Solid state saturable absorbers for Q-switching at 1 and 1.3μm: investigation and modeling

NASA Astrophysics Data System (ADS)

Šulc, Jan; Arátor, Pavel; Jelínková, Helena; Nejezchleb, Karel; Škoda, Václav; Kokta, Milan R.

2008-02-01

Yttrium and Lutecium garnets (YAG and LuAG) doped by Chromium or Vanadium ions (Cr 4+ or V 3+) were investigated as saturable absorbers potentially useful for passive Q-switching at wavelengths 1 μm and/or 1.3 μm. For comparison also color center saturable absorber LiF:F - II and Cobalt doped spinel (Co:MALO) were studied. Firstly, low power absorption spectra were recorded for all samples. Next, absorbers transmission in dependence on incident energy/power density was measured using the z-scan method. Crystals Cr:YAG, Cr:LuAG, V:YAG, and LiF:F - II were tested at wavelength 1064 nm. Therefore Alexandrite laser pumped Q-switched Nd:YAG laser was used as a radiation source (pulse length 6.9 ns, energy up to 1.5 mJ). Crystals V:YAG, V:LuAG, and Co:MALO were tested at wavelength 1338 nm. So diode pumped Nd:YAG/V:YAG microchip laser was used as a radiation source (pulse length 6.2 ns, energy up to 0.1 mJ). Using measured data fitting, and by their comparison with numerical model of a "thick" saturable absorber transmission for Q-switched Gaussian laser beam, following parameters were estimated: saturable absorber initial transmission T 0, saturation energy density w s, ground state absorption cross-section σ GSA, saturated absorber transmission T s, excited state absorption cross-section σ ESA, ratio γ = σ GSA/σ ESA, and absorbing ions density. For V:YAG crystal, a polarization dependence of T s was also investigated. With the help of rate equation numerical solution, an impact of saturable absorber parameters on generated Q-switched pulse properties was studied in plane wave approximation. Selected saturable absorbers were also investigated as a Q-switch and results were compared with the model.

Concentrations of tylvalosin and 3-O-acetyltylosin attained in the synovial fluid of swine after administration by oral gavage at 50 and 5 mg/kg.

PubMed

Canning, P; Bates, J; Hammen, K; Coetzee, J; Wulf, L; Rajewski, S; Wang, C; Karriker, L

2016-12-01

The objectives of this study were to determine the concentration of tylvalosin (TVN) and its metabolite, 3-O-acetyltylosin (3AT) in the synovial fluid of growing pigs when administered as a single bolus by oral gavage at target doses of 50 mg/kg (Trial 1) and 5 mg/kg (Trial 2). TVN is a water soluble macrolide antimicrobial used in swine production. The stability of the drug in synovial fluid samples stored at -70 °C up to 28 days was also evaluated in Trial 2. In Trial 1, eight pigs were randomly assigned to one of eight time points for euthanasia and synovial fluid collection: 0, 1, 2, 3, 4, 6, 9, 12 h postgavage. For Trial 2, 24 pigs were randomly allocated to one terminal collection time point at 0, 2, 4, 6, 8 or 10 h postgavage. Synovial fluid was analyzed to determine TVN and 3AT concentrations. TVN and 3AT were detected in Trial 1 at all time points, except 0 h. At 2 h postgavage for trial 2, the mean concentrations peaked at 31.17 ng/mL (95% CI: 18.62-52.16) for TVN and at 58.82 ng/mL (95% CI: 35.14-98.46) for 3AT. Storage duration did not impact TVN or 3AT concentrations (P-value 0.9732). © 2016 John Wiley & Sons Ltd.

Dielectron widths of the Gamma(1S,2S,3S) resonances.

PubMed

Rosner, J L; Adam, N E; Alexander, J P; Berkelman, K; Cassel, D G; Duboscq, J E; Ecklund, K M; Ehrlich, R; Fields, L; Galik, R S; Gibbons, L; Gray, R; Gray, S W; Hartill, D L; Heltsley, B K; Hertz, D; Jones, C D; Kandaswamy, J; Kreinick, D L; Kuznetsov, V E; Mahlke-Krüger, H; Meyer, T O; Onyisi, P U E; Patterson, J R; Peterson, D; Phillips, E A; Pivarski, J; Riley, D; Ryd, A; Sadoff, A J; Schwarthoff, H; Shi, X; Stroiney, S; Sun, W M; Wilksen, T; Weinberger, M; Athar, S B; Avery, P; Breva-Newell, L; Patel, R; Potlia, V; Stoeck, H; Yelton, J; Rubin, P; Cawlfield, C; Eisenstein, B I; Karliner, I; Kim, D; Lowrey, N; Naik, P; Sedlack, C; Selen, M; White, E J; Wiss, J; Shepherd, M R; Besson, D; Pedlar, T K; Cronin-Hennessy, D; Gao, K Y; Gong, D T; Hietala, J; Kubota, Y; Klein, T; Lang, B W; Poling, R; Scott, A W; Smith, A; Dobbs, S; Metreveli, Z; Seth, K K; Tomaradze, A; Zweber, P; Ernst, J; Arms, K; Severini, H; Dytman, S A; Love, W; Mehrabyan, S; Savinov, V; Aquines, O; Li, Z; Lopez, A; Mendez, H; Ramirez, J; Huang, G S; Miller, D H; Pavlunin, V; Sanghi, B; Shipsey, I P J; Xin, B; Adams, G S; Anderson, M; Cummings, J P; Danko, I; Napolitano, J; He, Q; Insler, J; Muramatsu, H; Park, C S; Thorndike, E H; Coan, T E; Gao, Y S; Liu, F; Stroynowski, R; Artuso, M; Blusk, S; Butt, J; Li, J; Menaa, N; Mountain, R; Nisar, S; Randrianarivony, K; Redjimi, R; Sia, R; Skwarnicki, T; Stone, S; Wang, J C; Zhang, K; Csorna, S E; Bonvicini, G; Cinabro, D; Dubrovin, M; Lincoln, A; Asner, D M; Edwards, K W; Briere, R A; Chen, J; Ferguson, T; Tatishvili, G; Vogel, H; Watkins, M E

2006-03-10

We determine the dielectron widths of the Gamma(1S), Gamma(2S), and Gamma(3S) resonances with better than 2% precision by integrating the cross section of e+e- -->Gamma over the e+e- center-of-mass energy. Using e+e- energy scans of the Gamma resonances at the Cornell Electron Storage Ring and measuring Gamma production with the CLEO detector, we find dielectron widths of 1.252+/-0.004(sigma(stat))+/-0.019(sigma(syst)) keV, 0.581+/-0.004+/-0.009 keV, and 0.413+/-0.004+/-0.006 keV for the Gamma(1S), Gamma(2S), and Gamma(3S), respectively.

Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor.

PubMed

Mallon, Robert; Feldberg, Larry R; Lucas, Judy; Chaudhary, Inder; Dehnhardt, Christoph; Santos, Efren Delos; Chen, Zecheng; dos Santos, Osvaldo; Ayral-Kaloustian, Semiramis; Venkatesan, Aranapakam; Hollander, Irwin

2011-05-15

The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy. In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (∼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor). Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587. ©2011 AACR.

Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis

PubMed Central

Natsuizaka, Mitsuteru; Naganuma, Seiji; Kagawa, Shingo; Ohashi, Shinya; Ahmadi, Azal; Subramanian, Harry; Chang, Sanders; Nakagawa, Kei J.; Ji, Xinjun; Liebhaber, Stephen A.; Klein-Szanto, Andres J.; Nakagawa, Hiroshi

2012-01-01

Insulin-like growth factor binding protein (IGFBP)-3 regulates cell proliferation and apoptosis in esophageal squamous cell carcinoma (ESCC) cells. We have investigated how the hypoxic tumor microenvironment in ESCC fosters the induction of IGFBP3. RNA interference experiments revealed that hypoxia-inducible factor (HIF)-1α, but not HIF-2α, regulates IGFBP3 mRNA induction. By chromatin immunoprecipitation and transfection assays, HIF-1α was found to transactivate IGFBP3 through a novel hypoxia responsive element (HRE) located at 57 kb upstream from the transcription start site. Metabolic labeling experiments demonstrated hypoxia-mediated inhibition of global protein synthesis. 7-Methyl GTP-cap binding assays suggested that hypoxia suppresses cap-dependent translation. Experiments using pharmacological inhibitors for mammalian target of rapamycin (mTOR) suggested that a relatively weak mTOR activity may be sufficient for cap-dependent translation of IGFBP3 under hypoxic conditions. Bicistronic RNA reporter transfection assays did not validate the possibility of an internal ribosome entry site as a potential mechanism for cap-independent translation for IGFBP3 mRNA. Finally, IGFBP3 mRNA was found enriched to the polysomes. In aggregate, our study establishes IGFBP3 as a direct HIF-1α target gene and that polysome enrichment of IGFBP3 mRNA may permit continuous translation under hypoxic conditions.—Natsuizaka, M., Naganuma, S., Kagawa, S., Ohashi, S., Ahmadi, A., Subramanian, H., Chang, S., Nakagawa, K. J., Ji, X., Liebhaber, S. A., Klein-Szanto, A. J., Nakagawa, H. Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis. PMID:22415309

LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs.

PubMed

Hong, Sungki; Freeberg, Mallory A; Han, Ting; Kamath, Avani; Yao, Yao; Fukuda, Tomoko; Suzuki, Tsukasa; Kim, John K; Inoki, Ken

2017-06-26

The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5'TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5'TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5' and 3'UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5'UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3'UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis.

Precision Laser Spectroscopic Measurement of Helium -4(1S2S S(3) to 1S2P P(3)) Lamb Shift and Fine Structure

NASA Astrophysics Data System (ADS)

Dixson, Ronald Gene

This thesis is a presentation of the results of a precise measurement of the absolute wavelength and fine structure splitting of the 1s2s ^3S to 1s2p ^3P transition of the ^4He atom. The experiment described in this thesis is the first one in which laser spectroscopy has been done on the 2 ^3S to 2^3 P transition in a metastable atomic beam. The energy interval between the 2^3S and the 2^3P state is precisely determined by comparison of the absolute wavelength of the transition with our standard laser (an iodine stabilized He-Ne laser with an accuracy of 1.6 parts in 10^{10 }) in a Fabry-Perot interferometer. The experimental Lamb shift of the transition is determined by subtracting from the measured frequency the precisely known non-quantum electrodynamic contributions to the theoretical value of the interval. From our measurements of the absolute wavelength, the following weighted (2J + 1) average for the 2^3S to 2^3P transition frequency and experimental Lamb Shift are obtained:eqalign{& rm f_{2S{-}2P} = 276 736 495.59 (5) rm MHz.cr& {bf L}[ 2^3Sto2 ^3P] = 5311.26 (5) rm MHz.cr} Our value for the Lamb Shift is in agreement with the best previous measurement but a factor of 60 more precise. It is also two orders of magnitude more precise than the present theoretical calculation, presenting quite a challenge to theorists. Nevertheless, this work is very timely since it is anticipated (DRA94) (MOR94) that the theory will reach this level in the near future. The measured fine structure splittings of the 2^3P level are: eqalign{rm 2^3P_0to rm2^3P_2 &: 31908.135 (3) rm MHzcrrm 2^3P_1to rm2^3P_2 &: sk{5}2291.173 (3) rm MHz}These results are more precise than previous microwave measurements and in significant disagreement with them, a situation which is especially timely and interesting since new theoretical calculations of these fine structure intervals (DRA94) at this level of precision are nearing completion.

M60A3 Tank Procedure Guides

DTIC Science & Technology

1985-02-01

no longer needed. Pleai do not return it to the U.S. Army Research Institute for the Behavioral and Social Sciencis . NOTE, This Research Product Is not...B. L., Vaughan, J. J., Jr., and Schaefer, R. H. Development of M1 Abrams Tank Sustainment Training Material . ARI Research Report 1334, June 1982. .5...place of the M60A3 Operator’s Manual or M60A3 training materials . The guides will aid you in remembering long or difficult sets of procedures. In

Interference-free determination of sub ng kg-1 levels of long-lived 93Zr in the presence of high concentrations (μg kg-1) of 93Mo and 93Nb using ICP-MS/MS.

PubMed

Petrov, Panayot; Russell, Ben; Douglas, David N; Goenaga-Infante, Heidi

2018-01-01

Long-lived high abundance radionuclides are of increasing interest with regard to decommissioning of nuclear sites and longer term nuclear waste storage and disposal. In many cases, no routine technique is available for their measurement in nuclear waste and low-level (ng kg -1 ) environmental samples. Recent advances in ICP-MS technology offer attractive features for the selective and sensitive determination of a wide range of long-lived radionuclides. In this work, inductively coupled plasma-tandem mass spectrometry (ICP-MS/MS)-based methodology, suitable for accurate routine determinations of 93 Zr at very low (ng kg -1 ) levels in the presence of high levels (μg kg -1 ) of the isobaric interferents 93 Nb and 93 Mo (often present in nuclear waste samples), is reported for the first time. Additionally, a novel and systematic strategy for method development based on the use of non-radioactive isotopes is proposed. It relies on gas-phase chemical reactions for different molecular ion formation to achieve isobaric interference removal. Using cell gas mixtures of NH 3 /He/H 2 or H 2 /O 2 , and suitable mass shifts, the signal from the 93 Nb and 93 Mo isobaric interferences on 93 Zr were suppressed by up to 5 orders of magnitude. The achieved limit of detection for 93 Zr was 1.3 × 10 -5  Bq g -1 (equivalent to 0.14 ng kg -1 ). The sample analysis time is 2 min, which represents a significant improvement in terms of sample throughput, compared to liquid scintillation counting methods. The method described here can be used for routine measurements of 93 Zr at environmentally relevant levels. It can also be combined with radiometric techniques for use towards the standardisation of 93 Zr measurements. Graphical abstract Interference-free determination of 93 Zr in the presence of high concentrations of isobaric 93 Mo and 93 Nb by ICP-MS/MS.

3μm - 1.6μm Double Resonance Spectroscopy of CH_4

NASA Astrophysics Data System (ADS)

Schwartz, George; Belaas, Erik; Yang, Shaoyue; Lehmann, Kevin

2016-06-01

The Near-IR Spectrum of CH_4 is dense with many overlapping bands that perturb each other by vibrational and ro-vibrational interactions. Assignments of the individual lines are needed in order to simulate the spectrum as a function of pressure and temperature, as needed in the search for CH_4 in extrasolar planets. Both the group at the University College, London^1 and that at the University of Reins^2 have produced theoretical spectra that allows simulation up to the high temperatures expected on ``Hot Jupiters''. The accuracy of these theoretical spectra need to be further tested. Because CH_4 is a light spherical top, assignment of its perturbed spectra is a formable challenge as none of the lines allowed in the rigid rotor approximation have ground vibrational state combination differences. We are using IR-IR double resonance to observe modulation in the strength of near-IR absorption caused by a modulation of a 3 μm OPO beam that is tuned to a particular transition in the C-H stretching fundamental of CH_4. This produces V-type double resonance transitions (which share the lower state with the pump transition), which provides firm assignments for lines normally observed in absorption in the near-IR. We also observe sequential double resonance which reveals transitions that have a known rotational level of the ν_3 fundamental as the lower state and reaches final states in the 9000 cm-1 spectral region. These are states of A, E, F_1 vibrational symmetries which are forbidden in transitions from the ground vibrational state. These 3 level double resonance transitions are Doppler Free and have a linewidth of ˜10 MHz due to a combination of near-IR laser jitter and power broadening of the mid-IR transition. We also observed many 4-level double resonance transitions that we have tentatively assigned as arising from the ν_4 fundamental level. These are distinguished from the 3-level double resonance transitions by they being Doppler broadened and having a large

Self-template synthesis of double shelled ZnS-NiS1.97 hollow spheres for electrochemical energy storage

NASA Astrophysics Data System (ADS)

Wei, Chengzhen; Ru, Qinglong; Kang, Xiaoting; Hou, Haiyan; Cheng, Cheng; Zhang, Daojun

2018-03-01

In this work, double shelled ZnS-NiS1.97 hollow spheres have been achieved via a simple self-template route, which involves the synthesis of Zn-Ni solid spheres precursors as the self-template and then transformation into double shelled ZnS-NiS1.97 hollow spheres by sulfidation treatment. The as-prepared double shelled ZnS-NiS1.97 hollow spheres possess a high surface area (105.26 m2 g-1) and porous structures. Benefiting from the combined characteristics of novel structures, multi-component, high surface area and porous. When applied as electrode materials for supercapacitors, the double shelled ZnS-NiS1.97hollow spheres deliver a large specific capacitance of 696.8C g-1 at 5.0 A g-1 and a remarkable long lifespan cycling stability (less 5.5% loss after 6000 cycles). Moreover, an asymmetric supercapacitor (ASC) was assembled by utilizing ZnS-NiS1.97 (positive electrode) and activated carbon (negative electrode) as electrode materials. The as-assembled device possesses an energy density of 36 W h kg-1, which can be yet retained 25.6 W h kg-1 even at a power density of 2173.8 W Kg-1, indicating its promising applications in electrochemical energy storage. More importantly, the self-template route is a simple and versatile strategy for the preparation of metal sulfides electrode materials with desired structures, chemical compositions and electrochemical performances.

EPR study of chromium-doped forsterite crystals: Cr3+( M1) with associated trivalent ions Al3+ and Sc3+

NASA Astrophysics Data System (ADS)

Ryabov, I. D.

2012-10-01

Electron paramagnetic resonance (EPR) study of single crystals of forsterite co-doped with chromium and scandium has revealed, apart from the known paramagnetic centers Cr3+( M1) and Cr3+( M1)- V_{{{{Mg}}^{2 + } }} ( M2) (Ryabov in Phys Chem Miner 38:177-184, 2011), a new center Cr3+( M1)- V_{{{{Mg}}^{2 + } }} ( M2)-Sc3+ formed by a Cr3+ ion substituting for Mg2+ at the M1 structural position with a nearest-neighbor Mg2+ vacancy at the M2 position and a Sc3+ ion presumably at the nearest-neighbor M1 position. For this center, the conventional zero-field splitting parameters D and E and the principal g values have been determined as follows: D = 33,172(29) MHz, E = 8,482(13) MHz, g = [1.9808(2), 1.9778(2), 1.9739(2)]. The center has been compared with the known ion pair Cr3+( M1)-Al3+ (Bershov et al. in Phys Chem Miner 9:95-101, 1983), for which the refined EPR data have been obtained. Based on these data, the known sharp M1″ line at 13,967 cm-1 (with the splitting of 1.8 cm-1), observed in low-temperature luminescence spectra of chromium-doped forsterite crystals (Glynn et al. in J Lumin 48, 49:541-544, 1991), has been ascribed to the Cr3+( M1)-Al3+ center. It has been found that the concentration of the new center increases from 0 up to 4.4 × 1015 mg-1, whereas that of the Cr3+( M1) and Cr3+( M1)- V_{{{{Mg}}^{2 + } }} ( M2) centers quickly decreases from 7.4 × 1015 mg-1 down to 3 × 1015 mg-1 and from 2.7 × 1015 mg-1 down to 0.5 × 1015 mg-1, i.e., by a factor of 2.5 and 5.4, respectively, with an increase of the Sc content from 0 up to 0.22 wt % (at the same Cr content 0.25 wt %) in the melt. When the Sc content exceeds that of Cr, the concentration of the new center decreases most likely due to the formation of the Sc3+( M1)- V_{{{{Mg}}^{2 + } }} ( M2)-Sc3+ complex instead of the Cr3+( M1)- V_{{{{Mg}}^{2 + } }} ( M2)-Sc3+ center. The formation of such ordered neutral complex is in agreement with the experimental results, concerning the incorporation of Sc

Synthesis, structure and reactivity of tetranuclear square-type complexes of rhenium and manganese bearing pyrimidine-2-thiolate (pymS) ligands: versatile and efficient precursors for mono- and polynuclear compounds containing M(CO)(3) (M = Re, Mn) fragments.

PubMed

Kabir, S E; Alam, J; Ghosh, S; Kundu, K; Hogarth, G; Tocher, D A; Hossain, G M G; Roesky, H W

2009-06-21

Reactions of M(2)(CO)(10) (M = Re, Mn) with pyrimidine-2-thiol (pymSH) in the presence of Me(3)NO afford the tetranuclear square-type complexes [M(4)(CO)(12)(micro-kappa(3)-pymS)(4)] (, M = Re; , M = Mn). Both consist of four M(CO)(3) (M = Re, Mn) units, pairs of which are joined by tridentate pyrimidine-2-thiolate ligands. Treatment of with a variety of donor ligands results in cleavage of the square to afford mononuclear species with either a mono- or bidentate pyrimidine-2-thiolate ligand. Triphenylphosphine reacts with to give [Mn(CO)(3)(PPh(3))(kappa(2)-pymS)] () in which the pyrimidine-2-thiolate coordinates in a bidentate fashion. With diamines [M(CO)(3)(kappa(2)-L)(kappa(1)-pymS)] () (M = Re, Mn; L = 2,2'- bipy, 1,10-phen, en) result in which the pyrimidine-2-thiolate binds in a monodentate fashion through sulfur. With diphosphines, complexes with different stoichiometries and pyrimidine-2-thiolate binding modes are obtained depending on the nature of the metal and diphosphine. With dppm and dppe, gives [Re(CO)(2)(kappa(1)-pymS)(kappa(2)-dppm)] () and [Re(CO)(2)(kappa(2)-pymS)(kappa(1)-dppe)(2)] (), respectively, whereas affords [Mn(CO)(2)(kappa(2)-pymS)(kappa(1)-dppm)(2)] () and [Mn(CO)(2)(kappa(2)-pyS)(kappa(2)-dppe)] () under similar conditions. Reactions of with [Os(3)(CO)(10)(NCMe)(2)] affords mixed-metal butterfly clusters [MOs(3)(CO)(13)(micro(3)-kappa(2)-pymS)] () in which the group 7 metal occupies a wing-tip position and the pyrimidine-2-thiolate ligand caps a triangular Os(2)M face. With Ru(3)(CO)(12), carbon-sulfur bond cleavage occurs to give the tetranuclear clusters [MRu(3)(CO)(14)(micro(4)-S)(micro-kappa(1):eta(1)-pym)] () bearing both the extruded sulfur and the heterocyclic ring. The molecular structures of , and have been established by X-ray diffraction allowing the binding mode of the pyrimidine-2-thiolate ligands to be probed.

Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling

PubMed Central

Lee, Yeunkum; Kim, Sun Gyun; Lee, Bokyoung; Zhang, Yinhua; Kim, Yoonhee; Kim, Shinhyun; Kim, Eunjoon; Kang, Hyojin; Han, Kihoon

2017-01-01

Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1) signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT) mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1), TSC2 and Ras homolog enriched in striatum (Rhes), via 94 common interactors that we denominated “Shank3-mTORC1 interactome”. We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD). Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream regulators of mTORC1

[Protein S3 fragments neighboring mRNA during elongation and translation termination on the human ribosome].

PubMed

Khaĭrulina, Iu S; Molotkov, M V; Bulygin, K N; Graĭfer, D M; Ven'yaminova, A G; Frolova, L Iu; Stahl, J; Karpova, G G

2008-01-01

Protein S3 fragments were determined that crosslink to modified mRNA analogues in positions +5 to +12 relative to the first nucleotide in the P-site binding codon in model complexes mimicking states of ribosomes at the elongation and translation termination steps. The mRNA analogues contained a Phe codon UUU/UUC at the 5'-termini that could predetermine the position of the tRNA(Phe) on the ribosome by the location of P-site binding and perfluorophenylazidobenzoyl group at a nucleotide in various positions 3' of the UUU/UUC codon. The crosslinked S3 protein was isolated from 80S ribosomal complexes irradiated with mild UV light and subjected to cyanogen bromide-induced cleavage at methionine residues with subsequent identification of the crosslinked oligopeptides. An analysis of the positions of modified oligopeptides resulting from the cleavage showed that, in dependence on the positions of modified nucleotides in the mRNA analogue, the crosslinking sites were found in the N-terminal half of the protein (fragment 2-127) and/or in the C-terminal fragment 190-236; the latter reflects a new peculiarity in the structure of the mRNA binding center in the ribosome, unknown to date. The results of crosslinking did not depend on the type of A-site codon or on the presence of translation termination factor eRF1.

Tensionless string spectra on AdS3

NASA Astrophysics Data System (ADS)

Gaberdiel, Matthias R.; Gopakumar, Rajesh

2018-05-01

The spectrum of superstrings on AdS3 × S3 × M 4 with pure NS-NS flux is analysed for the background where the radius of the AdS space takes the minimal value ( k = 1). Both for M 4 = S3 × S1 and M 4 = T 4 we show that there is a special set of physical states, coming from the bottom of the spectrally flowed continuous representations, which agree in precise detail with the single particle spectrum of a free symmetric product orbifold. For the case of AdS3 × S3 × T 4 this relies on making sense of the world-sheet theory at k = 1, for which we make a concrete proposal. We also comment on the implications of this striking result.

Stat3-induced S1PR1 expression is critical for persistent Stat3 activation in tumors

PubMed Central

Lee, Heehyoung; Deng, Jiehui; Kujawski, Maciej; Yang, Chunmei; Liu, Yong; Herrmann, Andreas; Kortylewski, Marcin; Horne, David; Somlo, George; Forman, Stephen; Jove, Richard; Yu, Hua

2011-01-01

IL-6/Jak2 signaling is viewed critical for persistent Stat3 activation in cancer. However, IL-6-induced Stat3 activity is transient in normal physiology. Here we identify a mechanism important for persistent Stat3 activation in tumor cells and the tumor microenvironment. We show that sphingosine-1-phosphate receptor 1 (S1PR1), a G-protein-coupled receptor for lysophospholipid sphingosine-1-phosphate (S1P), is elevated in Stat3-positive tumors. Stat3 is a transcription factor for the S1pr1 gene. Enhanced S1pr1 expression activates Stat3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis. Conversely, silencing S1pr1 in tumor cells or immune cells inhibits tumor Stat3 activity, tumor growth and metastasis. S1P/S1PR1-induced Stat3 activation is persistent, in contrast to transient Stat3 activation by IL-6. S1PR1 activates Stat3 in part by upregulating Jak2 tyrosine kinase activity. We demonstrate that Stat3-induced S1pr1 expression, as well as S1P/S1PR1 pathway, is important for persistent Stat3 activation in cancer cells and the tumor microenvironment and for malignant progression. PMID:21102457

Probing the central engine and environment of AGN using ARIES 1.3-m and 3.6-m telescopes

NASA Astrophysics Data System (ADS)

Chand, Hum; Rakshit, Suvendu; Jalan, Priyanka; Ojha, Vineet; Srianand, Raghunathan; Vivek, Mariappan; Mishra, Sapna; Omar, Amitesh; Kumar, Parveen; Joshi, Ravi; Gopal-Krishna; Kumar, Rathna

2018-04-01

We discuss three long term observational programmes to probe the central engine and environment of active galactic nuclei (AGN) using the recently installed ARIES 1.3-m and 3.6-m telescopes. The first programme is on the photometric reverberation mapping of low luminosity AGN by mainly using the ARIES 1.3-m telescope. The major impact of this programme other than to estimate the black hole mass will be to extend the broad line region (BLR) radius-luminosity (RBLR-LAGN) relation to the unexplored low luminosity regime, and to constrain the AGN broad line region geometry. The second programme is to use long slit spectroscopy on the ARIES 3.6-m telescope to discover new high redshift quasar pairs with angular separation less than 1-arcmin. Here, the background QSOs sight-line will be used to probe the environment of the foreground QSOs at kpc-Mpc scales. The major impact of this programme will be on the discovery of new pairs which have been missed in the SDSS survey due to fiber collision below 1-arcmin separation, and use them to understand about any excess overdensity around the QSO, any anisotropic emission of QSOs, and/or any episodic activity of QSOs. The third programme is related to spectral variability studies of the C IV broad absorption line (BAL) QSOs, based on low resolution spectroscopy using the ARIES 3.6-m telescope. Here, those most interesting cases will be monitored, where the BAL flow emerges afresh or disappears completely in the C IV trough of BAL QSOs sample as seen in SDSS multi-epoch observations. Continuous monitoring of such a sample will be important for our understanding of the nature and origin of the flow, along with their stability and dynamical evolution.

Analgesic, anticonvulsant and antioxidant activities of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride in mice.

PubMed

Salat, Kinga; Moniczewski, Andrzej; Salat, Robert; Janaszek, Monika; Filipek, Barbara; Malawska, Barbara; Wieckowski, Krzysztof

2012-03-01

Recently we have shown that 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride (LPP1) is an antinociceptive and local anesthetic agent in rodents. Below an extended study of the pharmacological activity of LPP1 is described. In vitro LPP1 has no affinity for GABA(A), opioidergic μ and serotonergic 5-HT(1A) receptors. The total antioxidant capacity of LPP1 (1-10mM) measured as ABTS radical cation-scavenging activity showed that LPP1 has dose-dependent antioxidant properties in vitro. Low plasma concentration of this compound detected by means of HPLC method 30min after its intraperitoneal administration suggests a rapid conversion to metabolite(s) which may be responsible for its analgesic and anticonvulsant activities in vivo. In vivo the compound's influence on the electroconvulsive threshold and its activity in the maximal electroshock seizure test (MES) were evaluated. The results demonstrated that LPP1 had an anticonvulsant activity in the MES model (ED(50)=112mg/kg) and at a dose of 50mg/kg was able to elevate the electroconvulsive threshold for 8mA as compared to the vehicle-treated mice. The analgesic activity of LPP1 was investigated in the acetic acid-induced writhing test in two groups of mice: animals with sensory C-fibers ablated, and mice with C-fibers unimpaired. It proved the potent activity of this compound in both groups (approximately 85% as compared to the vehicle-treated mice). The adverse effects of LPP1 were evaluated as acute toxicity (LD(50)=747.8mg/kg) and motor coordination impairments in the rotarod and chimney tests. The results from these tests show that LPP1 at doses higher than 100mg/kg is likely to impair the motor performance of experimental animals. Concluding, LPP1 is an analgesic and anticonvulsant compound which has antioxidant properties in vitro. Further studies are necessary to assess whether the antioxidant activity and the receptor profiling demonstrated in vitro can be confirmed for its

Clickable, hydrophilic ligand for fac-[M(I)(CO)3](+) (M = Re/(99m)Tc) applied in an S-functionalized α-MSH peptide.

PubMed

Kasten, Benjamin B; Ma, Xiaowei; Liu, Hongguang; Hayes, Thomas R; Barnes, Charles L; Qi, Shibo; Cheng, Kai; Bottorff, Shalina C; Slocumb, Winston S; Wang, Jing; Cheng, Zhen; Benny, Paul D

2014-03-19

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction was used to incorporate alkyne-functionalized dipicolylamine (DPA) ligands (1 and 3) for fac-[M(I)(CO)3](+) (M = Re/(99m)Tc) complexation into an α-melanocyte stimulating hormone (α-MSH) peptide analogue. A novel DPA ligand with carboxylate substitutions on the pyridyl rings (3) was designed to increase the hydrophilicity and to decrease in vivo hepatobiliary retention of fac-[(99m)Tc(I)(CO)3](+) complexes used in single photon emission computed tomography (SPECT) imaging studies with targeting biomolecules. The fac-[Re(I)(CO)3(3)] complex (4) was used for chemical characterization and X-ray crystal analysis prior to radiolabeling studies between 3 and fac-[(99m)Tc(I)(OH2)3(CO)3](+). The corresponding (99m)Tc complex (4a) was obtained in high radiochemical yields, was stable in vitro for 24 h during amino acid challenge and serum stability assays, and showed increased hydrophilicity by log P analysis compared to an analogous complex with nonfunctionalized pyridine rings (2a). An α-MSH peptide functionalized with an azide was labeled with fac-[M(I)(CO)3](+) using both click, then chelate (CuAAC reaction with 1 or 3 followed by metal complexation) and chelate, then click (metal complexation of 1 and 3 followed by CuAAC with the peptide) strategies to assess the effects of CuAAC conditions on fac-[M(I)(CO)3](+) complexation within a peptide framework. The peptides from the click, then chelate strategy had different HPLC tR's and in vitro stabilities compared to those from the chelate, then click strategy, suggesting nonspecific coordination of fac-[M(I)(CO)3](+) using this synthetic route. The fac-[M(I)(CO)3](+)-complexed peptides from the chelate, then click strategy showed >90% stability during in vitro challenge conditions for 6 h, demonstrated high affinity and specificity for the melanocortin 1 receptor (MC1R) in IC50 analyses, and led to moderately high uptake in B16F10 melanoma cells

Acoustic anisotropy of acoustooptic TI(3)AsS(4) crystals.

PubMed

Martynyuk-Lototska, Iryna; Kushnirevych, Marian; Zapeka, Bohdan; Krupych, Oleh; Kokhan, Oleksandr; Pogodin, Artem; Peresh, Eugen; Mys, Oksana; Vlokh, Rostyslav

2015-02-20

We present comprehensive experimental measurements and analysis of anisotropy of the acoustic wave velocities for TI(3)AsS(4) crystals, including the obliquity and nonorthogonality of the acoustic waves, and the deviations from purely longitudinal and transverse polarization types. We have found that the crystals under analysis are characterized by rather low transverse wave velocities v(23) and v(32), which are both equal to 630 m/s. It is shown that the efficiency of acoustooptic (AO) interactions in TI(3)AsS(4) can be notably increased when providing anisotropic interaction with the slowest transverse acoustic wave. Under the previously mentioned conditions, the AO figure-of-merit can be estimated to be extremely high, i.e., approximately 3×10(-12) s(3)/kg.

Early activation of mTORC1 signalling in response to mechanical overload is independent of phosphoinositide 3-kinase/Akt signalling

PubMed Central

Miyazaki, Mitsunori; McCarthy, John J; Fedele, Mark J; Esser, Karyn A

2011-01-01

Abstract The mammalian target of rapamycin complex 1 (mTORC1) functions as a central integrator of a wide range of signals that modulate protein metabolism and cell growth. However, the contributions of individual pathways regulating mTORC1 activity in skeletal muscle are poorly defined. The purpose of this study was to determine the regulatory mechanisms that contribute to mTORC1 activation during mechanical overload-induced skeletal muscle hypertrophy. Consistent with previous studies, mechanical overload induced progressive hypertrophy of the plantaris muscle which was associated with significant increases in total RNA content and protein metabolism. mTORC1 was activated after a single day of overload as indicated by a significant increase in S6K1 phosphorylation at T389 and T421/S424. In contrast, Akt activity, as assessed by Akt phosphorylation status (T308 and S473), phosphorylation of direct downstream targets (glycogen synthase kinase 3 β, proline-rich Akt substrate 40 kDa and tuberous sclerosis 2 (TSC2)) and a kinase assay, was not significantly increased until 2–3 days of overload. Inhibition of phosphoinositide 3-kinase (PI3K) activity by wortmannin was sufficient to block insulin-dependent signalling but did not prevent the early activation of mTORC1 in response to overload. We identified that the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent pathway was activated at day 1 after overload. In addition, a target of MEK/ERK signalling, phosphorylation of TSC2 at S664, was also increased at this early time point. These observations demonstrate that in vivo, mTORC1 activation at the early phase of mechanical overload in skeletal muscle occurs independently of PI3K/Akt signalling and provide evidence that the MEK/ERK pathway may contribute to mTORC1 activation through phosphorylation of TSC2. PMID:21300751

Superior exercise performance in lifelong Tibetan residents of 4,400 m compared with Tibetan residents of 3,658 m.

PubMed

Curran, L S; Zhuang, J; Droma, T; Moore, L G

1998-01-01

Few environments challenge human populations more than high altitude, since the accompanying low oxygen pressures (hypoxia) are pervasive and impervious to cultural modification. Work capacity is an important factor in a population's ability to thrive in such an environment. The performance of work or exercise is a measure of the integrated functioning of the O2 transport system, with maximal O2 uptake (.VO2max) a convenient index of that function. Hypoxia limits the ability to transport oxygen: maximal O2 uptake decreases with ascent to high altitude, and years of high altitude residence do not restore sea level .VO2max values. Since Tibetans live and work at some of the highest altitudes in the world, their ability to exercise at very high altitude (>4,000 m) may define the limits of human adaptation to hypoxia. We transported 20 Tibetan lifelong residents of > or =4,400 m down to 3,658 m in order to compare them with 16 previously studied Tibetan residents of Lhasa (3,658 m). The two groups of Tibetans were matched for age, weight, and height. All studies were performed in Lhasa within 3 days of the 4,400 m Tibetans' arrival. Standard test protocol and criteria were used for attaining .VO2max on a Monark bicycle ergometer, while measuring oxygen uptake (.VO2, ml/kg - min STPD), heart rate (bpm), minute ventilation (VE, 1/min BTPS), and arterial oxygen saturation (SaO2, %). The 4,400 m compared with 3,658 m residents had, at maximal effort, similar .VO2 (48.5 +/- 1.2 vs. 51.2 +/- 1.4 ml/kg - min, P = NS), higher workload attained (211 +/- 6 vs. 177 +/- 7 watts, P < 0.01), lower heart rate(176 +/- 2 vs. 191 +/- 2 bpm, P < 0.01), lower ventilation (127 +/- 5 vs. 149 +/- 5 l/min BTPS, P < 0.01), and similar SaO2(81.9 +/- 1.0 vs. 83.7 +/- 1.2%, P = NS). Furthermore, over the range of submaximal workloads, 4,400 m compared with 3,658 m Tibetans had lower .VO2 (P < 0.01), lower heart rates (P < 0.01), and lower ventilation (P < 0.01) and SaO2 (P < 0.05). We conclude

Myocardial uptake and kinetic properties of technetium-99m-Q3 in dogs

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

Gerson, M.C.; Millard, R.W.; McGoron, A.J.

1994-10-01

We postulated that {sup 99m}Tc-Q3, a cationic imaging agent, produces myocardial activity related to myocardial blood flow during myocardial ischemia and pharmacologic coronary artery vasodilation, and shows little or no myocardial redistribution over 4 hr after intravenous injection. In six Group 1 dogs, the chest was opened, the left circumflex coronary artery was acutely ligated, and dipyridamole (0.32, 0.56 or 0.84 mg/kg) was infused into the right atrium, followed by 10 mCi of {sup 99m}Tc-Q3. Myocardial blood flow was measured by radiolabeled microspheres. The animals were euthanized and 357 myocardial samples were assayed in a well counter for {sup 99m}Tcmore » activity. One week later, radiolabeled microsphere activity was counted and myocardial blood flow calculated. In nine Group 2 dogs, a variable occluder was placed around the left circumflex coronary artery and an ischemic level of circumflex blood flow was maintained constant over 4 hr as measured by an ultrasonic flow meter. Dipyridamole (0.56 mg/kg) was then infused into the right atrium followed by 10mCi of {sup 99m}Tc-Q3. Gamma camera images were acquired at 5, 15, 30, 60, 120 and 240 min following k{sup 99m}Tc-Q3 injection. Microsphere blood flow and endocardial biopsies (n - 6 dogs) were performed at 30, 60, 120 and 240 min following {sup 99m}TcQ3 injection. 31 refs., 9 figs., 1 tab.« less

Calculations of resonances parameters for the ((2s2) 1Se, (2s2p) 1,3P0) and ((3s2) 1Se, (3s3p) 1,3P0) doubly excited states of helium-like ions with Z≤10 using a complex rotation method implemented in Scilab

NASA Astrophysics Data System (ADS)

Gning, Youssou; Sow, Malick; Traoré, Alassane; Dieng, Matabara; Diakhate, Babacar; Biaye, Mamadi; Wagué, Ahmadou

2015-01-01

In the present work a special computational program Scilab (Scientific Laboratory) in the complex rotation method has been used to calculate resonance parameters of ((2s2) 1Se, (2s2p) 1,3P0) and ((3s2) 1Se, (3s3p) 1,3P0) states of helium-like ions with Z≤10. The purpose of this study required a mathematical development of the Hamiltonian applied to Hylleraas wave function for intrashell states, leading to analytical expressions which are carried out under Scilab computational program. Results are in compliance with recent theoretical calculations.

Energy system contribution during 200- to 1500-m running in highly trained athletes.

PubMed

Spencer, M R; Gastin, P B

2001-01-01

The purpose of the present study was to profile the aerobic and anaerobic energy system contribution during high-speed treadmill exercise that simulated 200-, 400-, 800-, and 1500-m track running events. Twenty highly trained athletes (Australian National Standard) participated in the study, specializing in either the 200-m (N = 3), 400-m (N = 6), 800-m (N = 5), or 1500-m (N = 6) event (mean VO2 peak [mL x kg(-1)-min(-1)] +/- SD = 56+/-2, 59+/-1, 67+/-1, and 72+/-2, respectively). The relative aerobic and anaerobic energy system contribution was calculated using the accumulated oxygen deficit (AOD) method. The relative contribution of the aerobic energy system to the 200-, 400-, 800-, and 1500-m events was 29+/-4, 43+/-1, 66+/-2, and 84+/-1%+/-SD, respectively. The size of the AOD increased with event duration during the 200-, 400-, and 800-m events (30.4+/-2.3, 41.3+/-1.0, and 48.1+/-4.5 mL x kg(-1), respectively), but no further increase was seen in the 1500-m event (47.1+/-3.8 mL x kg(-1)). The crossover to predominantly aerobic energy system supply occurred between 15 and 30 s for the 400-, 800-, and 1500-m events. These results suggest that the relative contribution of the aerobic energy system during track running events is considerable and greater than traditionally thought.

[Synergistic lethal effect of combined treatment of arsenic trioxide and aclacinomycin on human acute myeloid leukemia cell line KG-1a].

PubMed

Ye, Y B; Xu, X J; Chen, Y H; Zhang, M W; Qiu, D F; Guo, Z W; He, H Q

2017-04-23

Objective: To investigate the synergistic lethal effect and mechanism of arsenic trioxide (ATO) and aclacinomycin (ACM) on human acute myeloid leukemia cell line KG-1a. Methods: Colony-forming assay was used to detect the proliferation of KG-1a cells treated with different concentration of ATO and ACM. Compusyn software was used to analyze the synergistic effect of ATO and ACM. Flow cytometry and Wright's staining were used to analyze the apoptotic rate of KG-1a cells induced by combined treatment of ATO and ACM. Western blot was used to determine the expression of proteins associated with apoptosis. Results: The cytotoxicity of arsenic trioxide or aclacinomycin alone was in a dose-dependent manner. Flow cytometry analysis showed that the apoptotic rate of KG-1a cells treated with both 0.4 μmol/L ATO and 10 nmol/L ACM was (34.5±3.1)%, significantly higher than (7.6±1.1)% of 0.4 μmol/L ATO treatment or (18.7±2.3) % of 10 nmol/L ACM treatment alone ( P <0.05). The apoptotic rate of KG-1a cells treated with both 1.5 μmol/L ATO and 37.5 nmol/L ACM was (52.5±4.7)%, significantly higher than (19.1±3.2)% of 1.5 μmol/L ATO treatment or (27.7±2.2)% of 37.5 nmol/L ACM treatment alone ( P <0.05). The apoptotic rate of KG-1a cells treated with both 3.0 μmol/L ATO and 75 nmol/L ACM was (61.3±4.5)%, significantly higher than (29.5±2.5)% of 3.0 μmol/L ATO treatment or (28.6±3.4) % of 75 nmol/L ACM treatment alone ( P <0.05). In addition, the result of Wright's staining showed that combined treatment of ATO and ACM induced a more apparent phenotype of apoptosis when compared with single agent treatment. Compusyn software analysis showed that the combination index (CI) value of combined treatment group was less than 1, which indicated the synergistic effect of these two agents. Conclusions: Combined treatment of ATO and ACM shows a synergistic lethal effect on human acute myeloid leukemia cell line KG-1a via activating the apoptotic pathway, which inhibits cell

Low irradiances affect abscisic acid, indole-3-acidic acid, and cytokinin levels of wheat (Triticum aestivum L.) tissues

NASA Technical Reports Server (NTRS)

Nan, R.; Carman, J. G.; Salisbury, F. B.

1999-01-01

Wheat (Triticum aestivum L.) plants were grown under four irradiance levels: 1,400, 400, 200, and 100 micromol m-2 s-1. Leaves and roots were sampled before, during, and after the boot stage, and levels of abscisic acid (ABA), indole-3-acetic acid (IAA), zeatin, zeatin riboside, dihydrozeatin, dihydrozeatin riboside, isopentenyl adenine, and isopentenyl adenosine were quantified using noncompetitive indirect ELISA systems. Levels of IAA in leaves and roots of plants exposed to 100 micromol m-2 s-1 of irradiance were 0.7 and 2.9 micromol kg-1 dry mass (DM), respectively. These levels were 0.2 and 1.0 micromol kg-1 DM, respectively, when plants were exposed to 1,400 micromol m-2 s-1. Levels of ABA in leaves and roots of plants exposed to 100 micromol m-2 s-1 were 0.65 and 0.55 micromol kg-1 DM, respectively. They were 0.24 micromol kg-1 DM (both leaves and roots) when plants were exposed to 1,400 micromol m-2 s-1. Levels of isopentenyl adenosine in leaves (24.3 nmol kg-1 DM) and roots (29.9 nmol kg-1 DM) were not affected by differences in the irradiance regime. Similar values were obtained in a second experiment. Other cytokinins could not be detected (<10 nmol kg 1 DM) in either experiment with the sample sizes used (150-600 mg DM for roots and shoots, respectively).

Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats.

PubMed

Harris, Christopher M; Mittelstadt, Scott; Banfor, Patricia; Bousquet, Peter; Duignan, David B; Gintant, Gary; Hart, Michelle; Kim, Youngjae; Segreti, Jason

2016-10-01

Inhibition of the sphingosine-1-phosphate (S1P)-catabolizing enzyme S1P lyase (S1PL) elevates the native ligand of S1P receptors and provides an alternative mechanism for immune suppression to synthetic S1P receptor agonists. S1PL inhibition is reported to preferentially elevate S1P in lymphoid organs. Tissue selectivity could potentially differentiate S1PL inhibitors from S1P receptor agonists, the use of which also results in bradycardia, atrioventricular block, and hypertension. But it is unknown if S1PL inhibition would also modulate cardiac S1P levels or cardiovascular function. The S1PL inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile was used to determine the relationship in rats between drug concentration, S1P levels in select tissues, and circulating lymphocytes. Repeated oral doses of the S1PL inhibitor fully depleted circulating lymphocytes after 3 to 4 days of treatment in rats. Full lymphopenia corresponded to increased levels of S1P of 100- to 1000-fold in lymph nodes, 3-fold in blood (but with no change in plasma), and 9-fold in cardiac tissue. Repeated oral dosing of the S1PL inhibitor in telemeterized, conscious rats resulted in significant bradycardia within 48 hours of drug treatment, comparable in magnitude to the bradycardia induced by 3 mg/kg fingolimod. These results suggest that S1PL inhibition modulates cardiac function and does not provide immune suppression with an improved cardiovascular safety profile over fingolimod in rats. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Proteogenomic analysis of NCC-S1M, a gastric cancer stem cell-like cell line that responds to anti-PD-1.

PubMed

Park, Jun Won; Um, Hyejin; Yang, Hanna; Ko, Woori; Kim, Dae-Yong; Kim, Hark Kyun

2017-03-11

To elucidate signaling pathways that regulate gastric cancer stem cell (CSC) phenotypes and immune checkpoint, we performed a proteogenomic analysis of NCC-S1M, which is a gastric cancer cell line with CSC-like characteristics and is the only syngeneic gastric tumor cell line transplant model created in the scientific community. We found that the NCC-S1M allograft was responsive to anti-PD-1 treatment, and overexpressed Cd274 encoding PD-L1. PD-L1 was transcriptionally activated by loss of the TGF-β signaling. Il1rl1 protein was overexpressed in NCC-S1M cells compared with NCC-S1 cells that are less tumorigenic and less chemoresistant. Il1rl1 knockdown in NCC-S1M cells reduced tumorigenic potential and in vivo chemoresistance. Our proteogenomic analysis demonstrates a role of Smad4 loss in the PD-L1 immune evasion, as well as Il1rl1's role in CSC-like properties of NCC-S1M. Copyright © 2017 Elsevier Inc. All rights reserved.

Naturally tuned quantum critical point in the S =1 kagomé YCa3(VO) 3(BO3)4

NASA Astrophysics Data System (ADS)

Silverstein, Harlyn J.; Sinclair, Ryan; Sharma, Arzoo; Qiu, Yiming; Heinmaa, Ivo; Leitmäe, Alexander; Wiebe, Christopher R.; Stern, Raivo; Zhou, Haidong

2018-04-01

Although S =1 /2 kagomé systems have been intensely studied theoretically, and within the past decade been realized experimentally, much less is known about the S =1 analogs. While the theoretical ground state is still under debate, it has been found experimentally that S =1 kagomé systems either order at low temperatures or enter a spin glass state. In this work, YCa3(VO) 3(BO3)4 (YCVBO) is presented, with trivalent vanadium. Owing to its unusual crystal structure, the metal-metal bonding is highly connected along all three crystallographic directions, atypical of other kagomé materials. Using neutron scattering it is shown that YCVBO fails to order down to at least 50 mK and exhibits broad and dispersionless excitations. 11B NMR provides evidence of fluctuating spins at low temperatures while dc magnetization shows critical scaling that is also observed in systems near a quantum critical point such as Herbertsmithite, despite its insulating nature and S =1 magnetism. The evidence shown indicates that YCVBO is naturally tuned to be a quantum disordered magnet in the limit of T =0 K.

Design and synthesis of highly potent benzodiazepine gamma-secretase inhibitors: preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide by use of an asymmetric Ireland-Claisen rearrangement.

PubMed

Churcher, Ian; Williams, Susie; Kerrad, Sonia; Harrison, Timothy; Castro, José L; Shearman, Mark S; Lewis, Huw D; Clarke, Earl E; Wrigley, Jonathan D J; Beher, Dirk; Tang, Yui S; Liu, Wensheng

2003-06-05

Novel benzodiazepine-containing gamma-secretase inhibitors for potential use in Alzheimer's disease have been designed that incorporate a substituted hydrocinnamide C-3 side chain. A syn combination of alpha-alkyl or aryl and beta-hydroxy or hydroxymethyl substituents was shown to give highly potent compounds. In particular, (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)butyramide (34) demonstrated excellent in vitro potency (IC(50) = 0.06 nM). 34 could also be selectively methylated to give [(3)H]-28, which is of use in radioligand binding assays.

Antidepressant-like effect of m-trifluoromethyl-diphenyl diselenide in the mouse forced swimming test involves opioid and serotonergic systems.

PubMed

Brüning, César Augusto; Souza, Ana Cristina Guerra; Gai, Bibiana Mozzaquatro; Zeni, Gilson; Nogueira, Cristina Wayne

2011-05-11

Serotonergic and opioid systems have been implicated in major depression and in the action mechanism of antidepressants. The organoselenium compound m-trifluoromethyl-diphenyl diselenide (m-CF(3)-PhSe)(2) shows antioxidant and anxiolytic activities and is a selective inhibitor of monoamine oxidase A activity. The present study was designed to investigate the antidepressant-like effect of (m-CF(3)-PhSe)(2) in female mice, employing the forced swimming test. The involvement of the serotonergic and opioid systems in the antidepressant-like effect of (m-CF(3)-PhSe)(2) was appraised. (m-CF(3)-PhSe)(2) at doses of 50 and 100mg/kg (p.o.) exhibited antidepressant-like action in the forced swimming test. The effect of (m-CF(3)-PhSe)(2) (50mg/kg p.o.) was prevented by pretreatment of mice with WAY100635 (0.1mg/kg, s.c. a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a non-selective 5HT(2A/2C) receptor antagonist), ondansetron (1mg/kg, i.p., a selective 5-HT(3) receptor antagonist) and naloxone (1mg/kg, i.p., a non-selective antagonist of opioid receptors). These results suggest that (m-CF(3)-PhSe)(2) produced an antidepressant-like effect in the mouse forced swimming test and this effect seems most likely to be mediated through an interaction with serotonergic and opioid systems. Copyright © 2011 Elsevier B.V. All rights reserved.

Upf1 senses 3′UTR length to potentiate mRNA decay

PubMed Central

Hogg, J. Robert; Goff, Stephen P.

2010-01-01

Summary The selective degradation of mRNAs by the nonsense-mediated decay pathway is a quality control process with important consequences for human disease. From initial studies using RNA hairpin-tagged mRNAs for purification of messenger ribonucleoproteins assembled on transcripts with HIV-1 3′ untranslated region (3′UTR) sequences, we uncover a two-step mechanism for Upf1-dependent degradation of mRNAs with long 3′UTRs. We demonstrate that Upf1 associates with mRNAs in a 3′UTR length-dependent manner and is highly enriched on transcripts containing 3′UTRs known to elicit NMD. Surprisingly, Upf1 recruitment and subsequent RNA decay can be antagonized by retroviral RNA elements that promote translational readthrough. By modulating the efficiency of translation termination, recognition of long 3′UTRs by Upf1 is uncoupled from the initiation of decay. We propose a model for 3′UTR length surveillance in which equilibrium binding of Upf1 to mRNAs precedes a kinetically distinct commitment to RNA decay. PMID:21029861

Temperature-dependent thermal and thermoelectric properties of n -type and p -type S c1 -xM gxN

NASA Astrophysics Data System (ADS)

Saha, Bivas; Perez-Taborda, Jaime Andres; Bahk, Je-Hyeong; Koh, Yee Rui; Shakouri, Ali; Martin-Gonzalez, Marisol; Sands, Timothy D.

2018-02-01

Scandium Nitride (ScN) is an emerging rocksalt semiconductor with octahedral coordination and an indirect bandgap. ScN has attracted significant attention in recent years for its potential thermoelectric applications, as a component material in epitaxial metal/semiconductor superlattices, and as a substrate for defect-free GaN growth. Sputter-deposited ScN thin films are highly degenerate n -type semiconductors and exhibit a large thermoelectric power factor of ˜3.5 ×10-3W /m -K2 at 600-800 K. Since practical thermoelectric devices require both n- and p-type materials with high thermoelectric figures-of-merit, development and demonstration of highly efficient p-type ScN is extremely important. Recently, the authors have demonstrated p-type S c1 -xM gxN thin film alloys with low M gxNy mole-fractions within the ScN matrix. In this article, we demonstrate temperature dependent thermal and thermoelectric transport properties, including large thermoelectric power factors in both n- and p-type S c1 -xM gxN thin film alloys at high temperatures (up to 850 K). Employing a combination of temperature-dependent Seebeck coefficient, electrical conductivity, and thermal conductivity measurements, as well as detailed Boltzmann transport-based modeling analyses of the transport properties, we demonstrate that p-type S c1 -xM gxN thin film alloys exhibit a maximum thermoelectric power factor of ˜0.8 ×10-3W /m -K2 at 850 K. The thermoelectric properties are tunable by adjusting the M gxNy mole-fraction inside the ScN matrix, thereby shifting the Fermi energy in the alloy films from inside the conduction band in case of undoped n -type ScN to inside the valence band in highly hole-doped p -type S c1 -xM gxN thin film alloys. The thermal conductivities of both the n- and p-type films were found to be undesirably large for thermoelectric applications. Thus, future work should address strategies to reduce the thermal conductivity of S c1 -xM gxN thin-film alloys, without affecting

Effect of Sr doping on the magnetic exchange interactions in manganites of type L a 1 - x S r x M n y A 1 - y O 3 ( A = Ga , Ti ; 0.1 ≤ y ≤ 1 )

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

Furrer, Albert; Podlesnyak, Andrey A.; Pomjakushina, Ekaterina

Strontium doping transforms manganites of type La 1 - x Sr x Mn O 3 from an insulating antiferromagnet ( x = 0 ) to a metallic ferromagnet ( x > 0.16 ) due to the induced charge carriers (holes). We employed neutron scattering experiments in order to investigate the effect of Sr doping on a tailor-made compound of composition La 0.7 S r 0.3 M n 0.1 Ti 0.3 G a 0.6 O 3 . By the simultaneous doping with S r 2 + and Ti 4 + ions, the compound remains in the insulating state so thatmore » the magnetic interactions for large Sr doping can be studied in the absence of charge carriers. At T C = 215 K , there is a first-order reconstructive phase transition from the trigonal R - 3 c structure to the orthorhombic Pnma structure via an intermediate virtual configuration described by the common monoclinic subgroup P2 1 / c . The magnetic excitations associated with Mn 3 + dimers give evidence for two different nearest-neighbor ferromagnetic exchange interactions, in contrast to the undoped compound LaM n y A 1 - y O 3 where both ferromagnetic and antiferromagnetic interactions are present. Furthemore, the doping-induced changes of the exchange coupling originates from different Mn-O-Mn bond angles determined by neutron diffraction. The large fourth-nearest-neighbor interaction found for metallic manganites is absent in the insulating state. Here, we argue that the Ruderman-Kittel-Kasuya-Yosida interaction reasonably accounts for all the exchange couplings derived from the spin-wave dispersion in metallic manganites.« less

Effect of Sr doping on the magnetic exchange interactions in manganites of type L a 1 - x S r x M n y A 1 - y O 3 ( A = Ga , Ti ; 0.1 ≤ y ≤ 1 )

DOE PAGES

Furrer, Albert; Podlesnyak, Andrey A.; Pomjakushina, Ekaterina; ...

2017-03-14

Strontium doping transforms manganites of type La 1 - x Sr x Mn O 3 from an insulating antiferromagnet ( x = 0 ) to a metallic ferromagnet ( x > 0.16 ) due to the induced charge carriers (holes). We employed neutron scattering experiments in order to investigate the effect of Sr doping on a tailor-made compound of composition La 0.7 S r 0.3 M n 0.1 Ti 0.3 G a 0.6 O 3 . By the simultaneous doping with S r 2 + and Ti 4 + ions, the compound remains in the insulating state so thatmore » the magnetic interactions for large Sr doping can be studied in the absence of charge carriers. At T C = 215 K , there is a first-order reconstructive phase transition from the trigonal R - 3 c structure to the orthorhombic Pnma structure via an intermediate virtual configuration described by the common monoclinic subgroup P2 1 / c . The magnetic excitations associated with Mn 3 + dimers give evidence for two different nearest-neighbor ferromagnetic exchange interactions, in contrast to the undoped compound LaM n y A 1 - y O 3 where both ferromagnetic and antiferromagnetic interactions are present. Furthemore, the doping-induced changes of the exchange coupling originates from different Mn-O-Mn bond angles determined by neutron diffraction. The large fourth-nearest-neighbor interaction found for metallic manganites is absent in the insulating state. Here, we argue that the Ruderman-Kittel-Kasuya-Yosida interaction reasonably accounts for all the exchange couplings derived from the spin-wave dispersion in metallic manganites.« less

Group III mGlu receptor agonists potentiate the anticonvulsant effect of AMPA and NMDA receptor block.

PubMed

De Sarro, Giovambattista; Chimirri, Alba; Meldrum, Brian S

2002-09-06

We report the anticonvulsant action in DBA/2 mice of two mGlu Group III receptor agonists: (R,S)-4-phosphonophenylglycine, (R,S)-PPG, a compound with moderate mGlu8 selectivity, and of (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid, ACPT-1, a selective agonist for mGlu4alpha receptors. Both compounds, given intracerebroventricularly at doses which did not show marked anticonvulsant activity, produced a consistent shift to the left of the dose-response curves (i.e. enhanced the anticonvulsant properties) of 1-(4'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one hydrochloride, CFM-2, a noncompetitive AMPA receptor antagonist, and 3-((+/-)-2-carboxypiperazin-4-yl)-1-phosphonic acid, CPPene, a competitive NMDA receptor antagonist, in DBA/2 mice. In addition, (R,S)-PPG and ACPT-1 administered intracerebroventricularly prolonged the time course of the anticonvulsant properties of CFM-2 (33 micromol/kg, i.p.) and CPPene (3.3 micromol/kg, i.p.) administered intraperitoneally. We conclude that modest reduction of synaptic glutamate release by activation of Group III metabotropic receptors potentiates the anticonvulsant effect of AMPA and NMDA receptor blockade. Copyright 2002 Elsevier Science B.V.

Role of polyamines at the G1/S boundary and G2/M phase of the cell cycle.

PubMed

Yamashita, Tomoko; Nishimura, Kazuhiro; Saiki, Ryotaro; Okudaira, Hiroyuki; Tome, Mayuko; Higashi, Kyohei; Nakamura, Mizuho; Terui, Yusuke; Fujiwara, Kunio; Kashiwagi, Keiko; Igarashi, Kazuei

2013-06-01

The role of polyamines at the G1/S boundary and in the G2/M phase of the cell cycle was studied using synchronized HeLa cells treated with thymidine or with thymidine and aphidicolin. Synchronized cells were cultured in the absence or presence of α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, plus ethylglyoxal bis(guanylhydrazone) (EGBG), an inhibitor of S-adenosylmethionine decarboxylase. When polyamine content was reduced by treatment with DFMO and EGBG, the transition from G1 to S phase was delayed. In parallel, the level of p27(Kip1) was greatly increased, so its mechanism was studied in detail. Synthesis of p27(Kip1) was stimulated at the level of translation by a decrease in polyamine levels, because of the existence of long 5'-untranslated region (5'-UTR) in p27(Kip1) mRNA. Similarly, the transition from the G2/M to the G1 phase was delayed by a reduction in polyamine levels. In parallel, the number of multinucleate cells increased by 3-fold. This was parallel with the inhibition of cytokinesis due to an unusual distribution of actin and α-tubulin at the M phase. Since an association of polyamines with chromosomes was not observed by immunofluorescence microscopy at the M phase, polyamines may have only a minor role in structural changes of chromosomes at the M phase. In general, the involvement of polyamines at the G2/M phase was smaller than that at the G1/S boundary. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Anti-(+)-Methamphetamine Monoclonal Antibody mAb7F9 Attenuates Acute (+)-Methamphetamine Effects on Intracranial Self-Stimulation in Rats

PubMed Central

Harris, Andrew C.; LeSage, Mark G.; Shelley, David; Perry, Jennifer L.; Pentel, Paul R.; Owens, S. Michael

2015-01-01

Passive immunization with monoclonal antibodies (mAbs) against (+)-methamphetamine (METH) is being evaluated for the treatment of METH addiction. A human/mouse chimeric form of the murine anti-METH mAb7F9 has entered clinical trials. This study examined the effects of murine mAb7F9 on certain addiction-related behavioral effects of METH in rats as measured using intracranial self-stimulation (ICSS). Initial studies indicated that acute METH (0.1-0.56 mg/kg, s.c.) lowered the minimal (threshold) stimulation intensity that maintained ICSS. METH (0.3 mg/kg, s.c.) also blocked elevations in ICSS thresholds (anhedonia-like behavior) during spontaneous withdrawal from a chronic METH infusion (10 mg/kg/day x 7 days). In studies examining effects of i.v. pretreatment with mAb7F9 (at 30, 100, or 200 mg/kg), 200 mg/kg blocked the ability of an initial injection of METH (0.3 mg/kg, s.c.) to reduce baseline ICSS thresholds, but was less capable of attenuating the effect of subsequent daily injections of METH. MAb7F9 (200 mg/kg) also produced a small but significant reduction in the ability of METH (0.3 mg/kg, s.c.) to reverse METH withdrawal-induced elevations in ICSS thresholds. These studies demonstrate that mAb7F9 can partially attenuate some addiction-related effects of acute METH in an ICSS model, and provide some support for the therapeutic potential of mAb7F9 for the treatment of METH addiction. PMID:25742165

Clickable, Hydrophilic Ligand for fac-[MI(CO)3]+ (M = Re/99mTc) Applied in an S-Functionalized α-MSH Peptide

PubMed Central

2015-01-01

The copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) click reaction was used to incorporate alkyne-functionalized dipicolylamine (DPA) ligands (1 and 3) for fac-[MI(CO)3]+ (M = Re/99mTc) complexation into an α-melanocyte stimulating hormone (α-MSH) peptide analogue. A novel DPA ligand with carboxylate substitutions on the pyridyl rings (3) was designed to increase the hydrophilicity and to decrease in vivo hepatobiliary retention of fac-[99mTcI(CO)3]+ complexes used in single photon emission computed tomography (SPECT) imaging studies with targeting biomolecules. The fac-[ReI(CO)3(3)] complex (4) was used for chemical characterization and X-ray crystal analysis prior to radiolabeling studies between 3 and fac-[99mTcI(OH2)3(CO)3]+. The corresponding 99mTc complex (4a) was obtained in high radiochemical yields, was stable in vitro for 24 h during amino acid challenge and serum stability assays, and showed increased hydrophilicity by log P analysis compared to an analogous complex with nonfunctionalized pyridine rings (2a). An α-MSH peptide functionalized with an azide was labeled with fac-[MI(CO)3]+ using both click, then chelate (CuAAC reaction with 1 or 3 followed by metal complexation) and chelate, then click (metal complexation of 1 and 3 followed by CuAAC with the peptide) strategies to assess the effects of CuAAC conditions on fac-[MI(CO)3]+ complexation within a peptide framework. The peptides from the click, then chelate strategy had different HPLC tR’s and in vitro stabilities compared to those from the chelate, then click strategy, suggesting nonspecific coordination of fac-[MI(CO)3]+ using this synthetic route. The fac-[MI(CO)3]+-complexed peptides from the chelate, then click strategy showed >90% stability during in vitro challenge conditions for 6 h, demonstrated high affinity and specificity for the melanocortin 1 receptor (MC1R) in IC50 analyses, and led to moderately high uptake in B16F10 melanoma cells. Log P analysis of the 99m

Thermal performance of 625-kg/cu m elastomeric ablative materials on spherically blunted 0.44-radian cones

NASA Technical Reports Server (NTRS)

Champman, A. J.

1972-01-01

Spherically blunted 0.44-radian (25 deg) half-angle conical models coated with elastomeric ablative materials were tested in supersonic arc-heated wind tunnels to evaluate performance of the ablators over a range of conditions typical of lifting entry. Four test conditions were combinations of stagnation point-heat transfer rates of 2.3 and 4.5 MW/m2 and stagnation pressures of 20 and 2kN/m2. Afterbody values of heat transfer rate and pressure were 0.05 to 0.20 of stagnation point values. Stagnation enthalpy varied from 4.4 to 25 MJ/kg (1900 to 11000 Btu/lbm) and free-stream Mach number was in a range from 3.5 to 4. Ablative materials retained the spherical nose shape throughout tests at the lower heat transfer level, but receded, assuming a flattened nose shape, during tests at the high heat transfer level. The residue layer that formed on the conical after-body was weak, friable, and extensively cracked. The reference ablative material, which contained phenolic microspheres, generally retained the conical shape on the model afterbody. However, a modified ablator, in which phenolic microspheres were replaced with silica microspheres, deformed and separated from the undegraded material, and thereby produced a very uneven surface. Substrate temperatures and ablator recession were in good agreement with values computed by a numerical analysis.

The NO signaling pathway differentially regulates KCC3a and KCC3b mRNA expression.

PubMed

Di Fulvio, Mauricio; Lauf, Peter K; Adragna, Norma C

2003-11-01

Nitric oxide (NO) donors and protein kinase G (PKG) acutely up-regulate K-Cl cotransporter-1 and -3 (KCC1 and KCC3) mRNA expression in vascular smooth muscle cells (VSMCs). Here, we report the presence, relative abundance, and regulation by sodium nitroprusside (SNP) of the novel KCC3a and KCC3b mRNAs, in primary cultures of rat VSMCs. KCC3a and KCC3b mRNAs were expressed in an approximate 3:1 ratio, as determined by semiquantitative RT-PCR analysis. SNP as well as YC-1 and 8-Br-cGMP, a NO-independent stimulator of soluble guanylyl cyclase (sGC) and PKG, respectively, increased KCC3a and KCC3b mRNA expression by 2.5-fold and 8.1-fold in a time-dependent manner, following a differential kinetics. Stimulation of the NO/sGC/PKG signaling pathway with either SNP, YC-1, or 8-Br-cGMP decreased the KCC3a/KCC3b ratio from 3.0+/-0.4 to 0.9+/-0.1. This is the first report on a differential regulation by the NO/sGC/PKG signaling pathway of a cotransporter and of KCC3a and KCC3b mRNA expression.

Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses.

PubMed

Demont, Emmanuel H; Bailey, James M; Bit, Rino A; Brown, Jack A; Campbell, Colin A; Deeks, Nigel; Dowell, Simon J; Eldred, Colin; Gaskin, Pam; Gray, James R J; Haynes, Andrea; Hirst, David J; Holmes, Duncan S; Kumar, Umesh; Morse, Mary A; Osborne, Greg J; Renaux, Jessica F; Seal, Gail A L; Smethurst, Chris A; Taylor, Simon; Watson, Robert; Willis, Robert; Witherington, Jason

2016-02-11

FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.

Thermodynamic Studies on NdFeO 3(s)

NASA Astrophysics Data System (ADS)

Parida, S. C.; Dash, Smruti; Singh, Ziley; Prasad, R.; Jacob, K. T.; Venugopal, V.

2002-02-01

The enthalpy increments and the standard molar Gibbs energy of formation of NdFeO3(s) have been measured using a high-temperature Calvet microcalorimeter and a solid oxide galvanic cell, respectively. A λ-type transition, related to magnetic order-disorder transformation (antiferromagnetic to paramagnetic), is apparent from the heat capacity data at ∼687 K. Enthalpy increments, except in the vicinity of transition, can be represented by a polynomial expression: {H°m(T)-H°m(298.15 K)}/J·mol-1 (±0.7%)=-53625.6+146.0(T/K) +1.150×10-4(T/K)2 +3.007×106(T/K)-1; (298.15≤T/K ≤1000). The heat capacity, the first differential of {H°m(T)-H°m(298.15 K)} with respect to temperature, is given by Cop, m/J·K-1·mol-1=146.0+2.30×10-4(T/K)-3.007×106(T/K)-2. The reversible emf's of the cell, (-) Pt/{NdFeO3(s) +Nd2O3(s)+Fe(s)}//YDT/CSZ//{Fe(s)'FeO'(s)}/Pt(+), were measured in the temperature range from 1004 to 1208 K. It can be represented within experimental error by a linear equation: E/V:(0.1418±0.0003)-(3.890±0.023)×10-5(T/K). The Gibbs energy of formation of solid NdFeO3 calculated by the least-squares regression analysis of the data obtained in the present study, and data for Fe0.95O and Nd2O3 from the literature, is given by ΔfG°m(NdFeO3, s)/kJ·mol-1(±2.0)=-1345.9+0.2542(T/K); (1000≤T/K ≤1650). The error in ΔfG°m(NdFeO3, s, T) includes the standard deviation in emf and the uncertainty in the data taken from the literature. Values of ΔfH°m(NdFeO3, s, 298.15 K) and S°m(NdFeO3, s, 298.15 K) calculated by the second law method are -1362.5 (±6) kJ·mol-1 and 123.9 (±2.5) J·K-1·mol-1, respectively. Based on the thermodynamic information, an oxygen potential diagram for the system Nd-Fe-O was developed at 1350 K.

L-689,660, a novel cholinomimetic with functional selectivity for M1 and M3 muscarinic receptors.

PubMed Central

Hargreaves, R. J.; McKnight, A. T.; Scholey, K.; Newberry, N. R.; Street, L. J.; Hutson, P. H.; Semark, J. E.; Harley, E. A.; Patel, S.; Freedman, S. B.

1992-01-01

1. L-689,660, 1-azabicyclo[2.2.2]octane, 3-(6-chloropyrazinyl)maleate, a novel cholinomimetic, demonstrated high affinity binding (pKD (apparent) 7.42) at rat cerebral cortex muscarinic receptors. L-689,660 had a low ratio (34) of pKD (apparent) values for the displacement of binding of the antagonist ([3H]-N-methylscopolamine ([3H]-NMS) compared with the displacement of the agonist [3H]-oxotremorine-M ([3H]-Oxo-M), in rat cerebral cortex. Low NMS/Oxo-M ratios have been shown previously to be a characteristic of compounds that are low efficacy partial agonists with respect to stimulation of phosphatidyl inositol turnover in the cerebral cortex. 2. L-689,660 showed no muscarinic receptor subtype selectivity in radioligand binding assays but showed functional selectivity in pharmacological assays. At M1 muscarinic receptors in the rat superior cervical ganglion, L-689,660 was a potent (pEC50 7.3 +/- 0.2) full agonist in comparison with (+/-)-muscarine. At M3 receptors in the guinea-pig ileum myenteric plexus-longitudinal muscle or in trachea, L-689,660 was again a potent agonist (pEC50 7.5 +/- 0.2 and 7.7 +/- 0.3 respectively) but had a lower maximum response than carbachol. In contrast L-689,660 was an antagonist at M2 receptors in guinea-pig atria (pA2 7.2 (95% confidence limits 7, 7.4)) and at muscarinic autoreceptors in rat hippocampal slices. 3. The putative M1-selective muscarinic agonist, AF102B (cis-2-methylspiro-(1,3-oxathiolane 5,3')-quinuclidine hydrochloride) was found to have a profile similar to L-689,660 but had up to 100 times less affinity in binding and functional assays.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1422595

A new series of oxycarbonate superconductors (Cu(0.5)C(0.5))(m)Ba(m+1)Ca(n-1)Cu(n)O2(m+n)+1

NASA Technical Reports Server (NTRS)

Takayama-Muromachi, E.; Kawashima, T.; Matsui, Y.

1995-01-01

We found a new series of oxycarbonate superconductors in the Ba-CaCu-C-O system under high pressure of 5 GPa. Their ideal formula is (Cu(0.5)C(0.5)(m)Ba(m+1)Ca(n-1)Cu(n)O2)((m+n)+1) ((Cu,C)-m(m+1)(n-1)n). Thus far, n = 3, 4 members of the m = 1 series, (Cu,C)-1223 and (Cu,C)-1234, have been prepared in bulk while n = 4, 5 members, (Cu,C)-2334 and (Cu,C)-2345, have been prepared for the m = 2 series. (Cu,C)-1223 shows superconductivity below 67 K while T(sub c)'s of other compounds are above 110 K. In particular, (Cu,C)-1234 has the highest T(sub c) of 117 K.

Escherichia coli Ribosomal Protein S1 Unfolds Structured mRNAs Onto the Ribosome for Active Translation Initiation

PubMed Central

Duval, Mélodie; Korepanov, Alexey; Fuchsbauer, Olivier; Fechter, Pierre; Haller, Andrea; Fabbretti, Attilio; Choulier, Laurence; Micura, Ronald; Klaholz, Bruno P.; Romby, Pascale; Springer, Mathias; Marzi, Stefano

2013-01-01

Regulation of translation initiation is well appropriate to adapt cell growth in response to stress and environmental changes. Many bacterial mRNAs adopt structures in their 5′ untranslated regions that modulate the accessibility of the 30S ribosomal subunit. Structured mRNAs interact with the 30S in a two-step process where the docking of a folded mRNA precedes an accommodation step. Here, we used a combination of experimental approaches in vitro (kinetic of mRNA unfolding and binding experiments to analyze mRNA–protein or mRNA–ribosome complexes, toeprinting assays to follow the formation of ribosomal initiation complexes) and in vivo (genetic) to monitor the action of ribosomal protein S1 on the initiation of structured and regulated mRNAs. We demonstrate that r-protein S1 endows the 30S with an RNA chaperone activity that is essential for the docking and the unfolding of structured mRNAs, and for the correct positioning of the initiation codon inside the decoding channel. The first three OB-fold domains of S1 retain all its activities (mRNA and 30S binding, RNA melting activity) on the 30S subunit. S1 is not required for all mRNAs and acts differently on mRNAs according to the signals present at their 5′ ends. This work shows that S1 confers to the ribosome dynamic properties to initiate translation of a large set of mRNAs with diverse structural features. PMID:24339747

Roux-en-Y gastric bypass stands the test of time: 5-year results in low body mass index (30-35 kg/m(2)) Indian patients with type 2 diabetes mellitus.

PubMed

Lakdawala, Muffazal; Shaikh, Shehla; Bandukwala, Saifee; Remedios, Carlyne; Shah, Miloni; Bhasker, Aparna Govil

2013-01-01

Our objective was to evaluate the long-term results of laparoscopic Roux-en-Y gastric bypass on excess weight loss, remission of the metabolic syndrome, and complications in Indian patients with uncontrolled type 2 diabetes mellitus (T2DM) with a body mass index of 30-35 kg/m(2). The setting was a corporate hospital in Mumbai, India. The present prospective observational study was begun in January 2006. A total of 52 patients with uncontrolled T2DM and a body mass index of 30-35 kg/m(2) elected to undergo laparoscopic Roux-en-Y gastric bypass. The duration of T2DM was 3.5-14.5 years (median 8.4). Of the 52 patients, 61.5% had hypertension and 59.6% had dyslipidemia. Remission of T2DM and other components of the metabolic syndrome were assessed. All patients were followed up for 5 years. The median percentage of excess weight loss was 72.2% at 1 year and 67.8% at 5 years. Of the 52 patients, 84.6% had achieved euglycemia and 73.1% had achieved complete remission, 23.1% partial remission, and 3.84% no remission at 1 year. Weight regain occurred in 8 patients. They required antihypertensive drugs and statins, decreasing the complete remission rate to 57.7% and partial remission rate to 38.5% at 5 years. However, 96.2% improvement in metabolic status was found at the end of 5 years. Laparoscopic Roux-en-Y gastric bypass is a safe, efficacious, and cost-effective treatment for uncontrolled T2DM in patients with a body mass index of 30-35 kg/m(2). Early-onset T2DM, better weight loss, and greater C-peptide levels were predictors of success after surgery. The improvement after surgery in hyperglycemia, hypertension, and dyslipidemia could help in controlling the occurrence of micro- and macrovascular complications and decrease the morbidity and mortality associated with T2DM. Copyright © 2013 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Liraglutide attenuates the osteoblastic differentiation of MC3T3-E1 cells by modulating AMPK/mTOR signaling

PubMed Central

Hu, Xiong-Ke; Yin, Xin-Hua; Zhang, Hong-Qi; Guo, Chao-Feng; Tang, Ming-Xing

2016-01-01

Liraglutide, a synthetic analogue of glucagon-like peptide-1, is utilized in the treatment of type 2 diabetes and obesity. Liraglutide has been previously demonstrated to prevent osteoblastic differentiation of human vascular smooth muscle cells, resulting in the slowing of arterial calcification, however, its effect on bone formation remains unclear. The present study investigated the effect of liraglutide on osteoblastic differentiation using Alizarin Red S staining, and examined the molecular mechanisms underlying the regulatory effect by western blot analysis. The present study demonstrated that protein expression levels of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) were downregulated in MC3T3-E1 cells during osteoblastic differentiation in commercial osteogenic differentiation medium, whereas protein expression levels of transforming growth factor-β (TGF-β) and phosphorylated mammalian target of rapamycin (p-mTOR) increased. Liraglutide was subsequently demonstrated to dose-dependently attenuate the osteoblastic differentiation of MC3T3-E1 cells, to upregulate p-AMPK, and downregulate p-mTOR and TGF-β protein expression levels. Treatment with an AMPK-specific inhibitor, Compound C, eradicated the effect of liraglutide on osteoblastic differentiation, and p-mTOR and TGF-β downregulation. An mTOR activator, MHY1485, also abolished the inhibitory effect of liraglutide on osteoblastic differentiation, and resulted in p-mTOR and TGF-β downregulation, but did not attenuate the liraglutide-induced increase in p-AMPK protein expression levels. The results of the present study demonstrate that liraglutide attenuates osteoblastic differentiation of MC3T3-E1 cells via modulation of AMPK/mTOR signaling. The present study revealed a novel function of liraglutide, which contributes to the understanding of its pharmacological and physiological effects in clinical settings. PMID:27600753

3H-1,2-dithiole-3-thione protects retinal pigment epithelium cells against Ultra-violet radiation via activation of Akt-mTORC1-dependent Nrf2-HO-1 signaling.

PubMed

Li, Ke-Ran; Yang, Su-Qing; Gong, Yi-Qing; Yang, Hong; Li, Xiu-Miao; Zhao, Yu-Xia; Yao, Jin; Jiang, Qin; Cao, Cong

2016-05-06

Excessive UV radiation and reactive oxygen species (ROS) cause retinal pigment epithelium (RPE) cell injuries. Nrf2 regulates transcriptional activation of many anti-oxidant genes. Here, we tested the potential role of 3H-1,2-dithiole-3-thione (D3T) against UV or ROS damages in cultured RPE cells (both primary cells and ARPE-19 line). We showed that D3T significantly inhibited UV-/H2O2-induced RPE cell death and apoptosis. UV-stimulated ROS production was dramatically inhibited by D3T pretreatment. D3T induced Nrf2 phosphorylation in cultured RPE cells, causing Nrf2 disassociation with KEAP1 and its subsequent nuclear accumulation. This led to expression of antioxidant response elements (ARE)-dependent gene heme oxygenase-1 (HO-1). Nrf2-HO-1 activation was required for D3T-mediated cytoprotective effect. Nrf2 shRNA knockdown or S40T dominant negative mutation as well as the HO-1 inhibitor Zinc protoporphyrin (ZnPP) largely inhibited D3T's RPE cytoprotective effects against UV radiation. Yet, exogenous overexpression Nrf2 enhanced D3T's activity in RPE cells. Further studies showed that D3T activated Akt/mTORC1 in cultured RPE cells. Akt-mTORC1 inhibitors, or Akt1 knockdown by shRNA, not only inhibited D3T-induced Nrf2-HO-1 activation, but also abolished the RPE cytoprotective effects. In vivo, D3T intravitreal injection protected from light-induced retinal dysfunctions in mice. Thus, D3T protects RPE cells from UV-induced damages via activation of Akt-mTORC1-Nrf2-HO-1 signaling axis.

77 FR 66534 - Airworthiness Directives; BRP-Powertrain GmbH & Co KG Rotax Reciprocating Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-06

... Rotax 912 F2; 912 F3; 912 F4; 912 S2; 912 S3; and 912 S4 reciprocating engines. The word ``not'' was...-Powertrain GmbH & Co KG Rotax 912 F2; 912 F3; 912 F4; 912 S2; 912 S3; and 912 S4 reciprocating engines. As...

A 3.125-Gb/s inductorless transimpedance amplifier for optical communication in 0.35 μm CMOS

NASA Astrophysics Data System (ADS)

Hui, Xu; Jun, Feng; Quan, Liu; Wei, Li

2011-10-01

A 3.125-Gb/s transimpedance amplifier (TIA) for an optical communication system is realized in 0.35 μm CMOS technology. The proposed TIA employs a regulated cascode configuration as the input stage, and adopts DC-cancellation techniques to stabilize the DC operating point. In addition, noise optimization is processed. The on-wafer measurement results show the transimpedance gain of 54.2 dBΩ and -3 dB bandwidth of 2.31 GHz. The measured average input referred noise current spectral density is about . The measured eye diagram is clear and symmetrical for 2.5-Gb/s and 3.125-Gb/s PRBS. Under a single 3.3-V supply voltage, the TIA consumes only 58.08 mW, including 20 mW from the output buffer. The whole die area is 465 × 435 μm2.

La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1).

PubMed

Fonseca, Bruno D; Zakaria, Chadi; Jia, Jian-Jun; Graber, Tyson E; Svitkin, Yuri; Tahmasebi, Soroush; Healy, Danielle; Hoang, Huy-Dung; Jensen, Jacob M; Diao, Ilo T; Lussier, Alexandre; Dajadian, Christopher; Padmanabhan, Niranjan; Wang, Walter; Matta-Camacho, Edna; Hearnden, Jaclyn; Smith, Ewan M; Tsukumo, Yoshinori; Yanagiya, Akiko; Morita, Masahiro; Petroulakis, Emmanuel; González, Jose L; Hernández, Greco; Alain, Tommy; Damgaard, Christian K

2015-06-26

The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5'TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)*

PubMed Central

Fonseca, Bruno D.; Zakaria, Chadi; Jia, Jian-Jun; Graber, Tyson E.; Svitkin, Yuri; Tahmasebi, Soroush; Healy, Danielle; Hoang, Huy-Dung; Jensen, Jacob M.; Diao, Ilo T.; Lussier, Alexandre; Dajadian, Christopher; Padmanabhan, Niranjan; Wang, Walter; Matta-Camacho, Edna; Hearnden, Jaclyn; Smith, Ewan M.; Tsukumo, Yoshinori; Yanagiya, Akiko; Morita, Masahiro; Petroulakis, Emmanuel; González, Jose L.; Hernández, Greco; Alain, Tommy; Damgaard, Christian K.

2015-01-01

The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5′TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1. PMID:25940091

Rare-earth transition-metal gallium chalcogenides RE3MGaCh7 (M=Fe, Co, Ni; Ch=S, Se)

NASA Astrophysics Data System (ADS)

Rudyk, Brent W.; Stoyko, Stanislav S.; Oliynyk, Anton O.; Mar, Arthur

2014-02-01

Six series of quaternary rare-earth transition-metal chalcogenides RE3MGaCh7 (M=Fe, Co, Ni; Ch=S, Se), comprising 33 compounds in total, have been prepared by reactions of the elements at 1050 °C (for the sulphides) or 900 °C (for the selenides). They adopt noncentrosymmetric hexagonal structures (ordered Ce3Al1.67S7-type, space group P63, Z=2) with cell parameters in the ranges of a=9.5-10.2 Å and c=6.0-6.1 Å for the sulphides and a=10.0-10.5 Å and c=6.3-6.4 Å for the selenides as refined from powder X-ray diffraction data. Single-crystal structures were determined for five members of the sulphide series RE3FeGaS7 (RE=La, Pr, Tb) and RE3CoGaS7 (RE=La, Tb). The highly anisotropic crystal structures consist of one-dimensional chains of M-centred face-sharing octahedra and stacks of Ga-centred tetrahedra all pointing in the same direction. Magnetic measurements on the sulphides reveal paramagnetic behaviour in some cases and long-range antiferromagnetic behaviour with low Néel temperatures (15 K or lower) in others. Ga L-edge XANES spectra support the presence of highly cationic Ga tetrahedral centres with a tendency towards more covalent Ga-Ch character on proceeding from the sulphides to the selenides. Band structure calculations on La3FeGaS7 indicate that the electronic structure is dominated by Fe 3d-based states near the Fermi level.

A two-step hydrothermal synthesis approach to synthesize NiCo2S4/NiS hollow nanospheres for high-performance asymmetric supercapacitors

NASA Astrophysics Data System (ADS)

Xu, Rui; Lin, Jianming; Wu, Jihuai; Huang, Miaoliang; Fan, Leqing; He, Xin; Wang, Yiting; Xu, Zedong

2017-11-01

In this work, a high-performance asymmetric supercapacitor device based on NiCo2S4/NiS hollow nanospheres as the positive electrode and the porous activated carbon as the negative electrode was successfully fabricated via a facile two-step hydrothermal synthesis approach. This NiCo2S4/NiS//activated carbon asymmetric supercapacitor achieved a high energy density of 43.7 Wh kg-1 at a power density of 160 W kg-1, an encouraging specific capacitance of 123 F g-1 at a current density of 1 mA cm-2, as well as a long-term performance with capacitance degradation of 5.2% after 3000 consecutive cycles at 1 mA cm-2. Moreover, the NiCo2S4/NiS electrode also demonstrated an excellent specific capacitance (1947.5 F g-1 at 3 mA cm-2) and an outstanding cycling stability (retaining 90.3% after 1000 cycles). The remarkable electrochemical performances may be attributed to the effect of NiS doping on NiCo2S4 which could enlarge the surface area and increase the surface roughness.

On the Dust Environment of Comet C/2012 S1 (ISON) from 12 AU Pre-perihelion to the End of its Activity around Perihelion

NASA Astrophysics Data System (ADS)

Moreno, F.; Pozuelos, F.; Aceituno, F.; Casanova, V.; Duffard, R.; López-Moreno, J. J.; Molina, A.; Ortiz, J. L.; Santos-Sanz, P.; Sota, A.; Diepvens, A.; Segundo, A. S.; Bell, C.; Labordena, C.; Bryssinck, E.; Cortés, E.; Reina, E.; García, F.; Gómez, F.; Limón, F.; Soldán, F.; Tifner, F.; Muler, G.; Almendros, I.; Aledo, J.; Bel, J.; Carrillo, J.; Castellano, J.; Curto, J.; Gaitan, J.; Salto, J. L.; Lopesino, J.; Lozano, J.; Hernández, J. F.; González, J. J.; Martín, J. L.; Aymamí, J. M.; Bosch, J. M.; Fernández, J. M.; Vidal, J. R.; Montoro, L.; Tremosa, L.; Campas, M.; Canales, O.; Dekelver, P. J.; Benavides, R.; Naves, R.; Castillo, R.; Climent, T.; Cupillari, T.; Yanamandra-Fisher, P.

2014-08-01

A Monte Carlo dust tail model has been applied to extract the dust environment parameters of the comet C/2012 S1 (ISON) from both Earth-based and SOHO LASCO C3 observations, performed from about six astronomical units (AU) inbound, to just after perihelion passage, when only a small portion of the original comet nucleus has survived in the form of a cloud of tiny particles. The early Afρ and image data are consistent with particle ejection from an extended active area located at latitudes 35°N to 90°N (for a prograde rotating nucleus), with the spin axis having a large obliquity (I ~ 70°). This configuration nicely fits the early images and Afρ data until 3.9 AU inbound, when the emission should become isotropic in order to fit the data. The analysis of LASCO images reveals that, assuming an original nucleus of RN = 500 m with ρ = 1000 kg m-3, at least half of its mass was vaporized when the comet was at about 17 R ⊙ inbound. We conclude that at that time the nucleus suffered a cataclysmic fragmentation releasing a huge amount of material of 2.3 ×1011 kg, equivalent to a sphere of 380 m in radius with density 1000 kg m-3. The surviving material after perihelion passage consists of very small dust particles of 0.1-50 μm in radius with a total mass of just 6.7×108 kg.

Hydrogen sulfide upregulated mRNA expressions of sodium bicarbonate cotransporter1, trefoil factor1 and trefoil factor2 in gastric mucosa in rats.

PubMed

Cheraghi, Parisa; Mard, Seyyed Ali; Nagi, Tahereh

2016-01-01

Hydrogen sulfide (H 2 S) has been shown to protect the gastric mucosa through several protective mechanisms but till now its effect on mRNA expression of sodium bicarbonate cotransporter 1 (NBC1), trefoil factor1 (TFF1) and trefoil factor2 (TFF2) was not investigated. This study was aimed to evaluate the effect of H 2 S on mRNA expression of NBC1, TFF1 and TFF2 in rat gastric mucosa in response to gastric distention. Thirty two rats were randomly assigned into four equal groups. They were control (C), distention (D), propargylglycine (PAG)-, and NaHS-treated groups. To evaluate the effect of exogenous and endogenous H 2 S on gene expression of NBC1, TFF1 and TFF2, two groups of rats were received H 2 S donor, intra-peritoneal NaHS (80 µg Kg -1 ), and PAG (50 mg kg -1 ), accompanied to stimulate the gastric acid secretion, respectively. Under general anesthesia and laparotomy, a catheter was inserted into the stomach through duodenum for instillation of isotonic saline for gastric distention. Ninety min after beginning the experiment, animals were sacrificed and the gastric mucosa was collected to determine total acid content of gastric effluents and to quantify the mRNA expression of studied genes by quantitative real-time polymerase chain reaction (qRT-PCR). Results showed that A) gastric distention increased the level of mRNA expressions of NBC1, TFF1 and TFF2; B) these levels in NaHS-treated rats were significantly higher than those in Distention group; and C) PAG decreased the expression levels of NBC1 and TFF1. The Findings showed H 2 S upregulated gene expression of NBC1, TFF1 and TFF2 in gastric mucosa.

Inhibition of mTOR Pathway by Rapamycin Decreases P-glycoprotein Expression and Spontaneous Seizures in Pharmacoresistant Epilepsy.

PubMed

Chi, Xiaosa; Huang, Cheng; Li, Rui; Wang, Wei; Wu, Mengqian; Li, Jinmei; Zhou, Dong

2017-04-01

The mammalian target of rapamycin (mTOR) has been demonstrated to mediate multidrug resistance in various tumors by inducing P-glycoprotein (P-gp) overexpression. Here, we investigated the correlation between the mTOR pathway and P-gp expression in pharmacoresistant epilepsy. Temporal cortex specimens were obtained from patients with refractory mesial temporal lobe epilepsy (mTLE) and age-matched controls who underwent surgeries at West China Hospital of Sichuan University between June 2014 and May 2015. We established a rat model of epilepsy kindled by coriaria lactone (CL) and screened pharmacoresistant rats (non-responders) using phenytoin. Non-responders were treated for 4 weeks with vehicle only or with the mTOR pathway inhibitor rapamycin at doses of 1, 3, and 6 mg/kg. Western blotting and immunohistochemistry were used to detect the expression of phospho-S6 (P-S6) and P-gp at different time points (1 h, 8 h, 1 day, 3 days, 1 weeks, 2 weeks, and 4 weeks) after the onset of treatment. Overexpression of P-S6 and P-gp was detected in both refractory mTLE patients and non-responder rats. Rapamycin showed an inhibitory effect on P-S6 and P-gp expression 1 week after treatment in rats. In addition, the expression levels of P-S6 and P-gp in the 6 mg/kg group were significantly lower than those in the 1 mg/kg or the 3 mg/kg group at the same time points (all P < 0.05). Moreover, rapamycin decreased the duration and number of CL-induced seizures, as well as the stage of non-responders (all P < 0.05). The current study indicates that the mTOR signaling pathway plays a critical role in P-gp expression in drug-resistant epilepsy. Inhibition of the mTOR pathway by rapamycin may be a potential therapeutic approach for pharmacoresistant epilepsy.

Differential Regulation of ERK1/2 and mTORC1 Through T1R1/T1R3 in MIN6 Cells.

PubMed

Wauson, Eric M; Guerra, Marcy L; Dyachok, Julia; McGlynn, Kathleen; Giles, Jennifer; Ross, Elliott M; Cobb, Melanie H

2015-08-01

The MAPKs ERK1/2 respond to nutrients and other insulin secretagogues in pancreatic β-cells and mediate nutrient-dependent insulin gene transcription. Nutrients also stimulate the mechanistic target of rapamycin complex 1 (mTORC1) to regulate protein synthesis. We showed previously that activation of both ERK1/2 and mTORC1 in the MIN6 pancreatic β-cell-derived line by extracellular amino acids (AAs) is at least in part mediated by the heterodimeric T1R1/T1R3, a G protein-coupled receptor. We show here that AAs differentially activate these two signaling pathways in MIN6 cells. Pretreatment with pertussis toxin did not prevent the activation of either ERK1/2 or mTORC1 by AAs, indicating that G(I) is not central to either pathway. Although glucagon-like peptide 1, an agonist for a G(s-)coupled receptor, activated ERK1/2 well and mTORC1 to a small extent, AAs had no effect on cytosolic cAMP accumulation. Ca(2+) entry is required for ERK1/2 activation by AAs but is dispensable for AA activation of mTORC1. Pretreatment with UBO-QIC, a selective G(q) inhibitor, reduced the activation of ERK1/2 but had little effect on the activation of mTORC1 by AAs, suggesting a differential requirement for G(q). Inhibition of G(12/13) by the overexpression of the regulator of G protein signaling domain of p115 ρ-guanine nucleotide exchange factor had no effect on mTORC1 activation by AAs, suggesting that these G proteins are also not involved. We conclude that AAs regulate ERK1/2 and mTORC1 through distinct signaling pathways.