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Sample records for type m2 sybille

  1. Rezension: Ada Lovelace. Die Pionierin der Computertechnik und ihre Nachfolgerinnen von Sybille Krämer (Hg.

    Directory of Open Access Journals (Sweden)

    Bettina Schabschneider

    2015-12-01

    Full Text Available Ein aktueller von Sybille Krämer herausgegebener Sammelband beleuchtet die Bedeutung der Computertechnik-Pionierin Ada Lovelace. Bettina Schabschneider hat den Band einer detaillierten Lektüre unterzogen und für die MEDIENIMPULSE rezensiert …

  2. 10D massive type IIA supergravities as the uplift of parabolic M2-brane torus bundles

    Energy Technology Data Exchange (ETDEWEB)

    Garcia del Moral, Maria Pilar [Universidad de Antofagasta (Chile). Dept. de Fisica; Restuccia, Alvaro [Universidad de Antofagasta (Chile). Dept. de Fisica; Universidad Simon Bolivar, Caracas (Venezuela, Bolivarian Republic of). Dept. de Fisica

    2016-04-15

    We remark that the two 10D massive deformations of the N = 2 maximal type IIA supergravity (Romans and HLW supergravity) are associated to the low energy limit of the uplift to 10D of M2-brane torus bundles with parabolic monodromy linearly and non-linearly realized respectively. Romans supergravity corresponds to M2-brane compactified on a twice-punctured torus bundle. (copyright 2015 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  3. Optimum design of a self-supported power transmission tower type 2M2 for 230 kW; Diseno optimo de una torre de transmision autosoportada tipo 2M2, para 230 kW

    Energy Technology Data Exchange (ETDEWEB)

    Espejel Valdez, Eduardo [Instituto de Investigaciones Electricas, Cuernavaca (Mexico); Millan Monje, Alejandro; Honk Hernandez, Wenceslao [Comision Federal de Electricidad, (CFE), Mexico, D. F. (Mexico)

    1985-12-31

    A group of specialists from the Comision Federal de Electricidad (CFE) and of the Instituto de Investigaciones Electricas (IIE) analyzes the design of various types of power transmission towers in their application stage, in order to enhance them. In this article the structural characteristics of the self-supported tower type 2M2 for 230 kV of two circuits and of suspension, are presented. [Espanol] Un grupo de especialistas de la Comision Federal de Electricidad (CFE) y del Instituto de Investigaciones Electricas (IIE) analiza el diseno de diversos tipos de torres de transmision en su etapa de aplicacion, con el fin de mejorarlos. En este articulo se presentan las caracteristicas estructurales de la torre autosoportada tipo 2M2 para 230 kV, de dos circuitos y de suspension.

  4. CD16+ Monocytes and Skewed Macrophage Polarization toward M2 Type Hallmark Heart Transplant Acute Cellular Rejection.

    Science.gov (United States)

    van den Bosch, Thierry P P; Caliskan, Kadir; Kraaij, Marina D; Constantinescu, Alina A; Manintveld, Olivier C; Leenen, Pieter J M; von der Thüsen, Jan H; Clahsen-van Groningen, Marian C; Baan, Carla C; Rowshani, Ajda T

    2017-01-01

    During acute heart transplant rejection, infiltration of lymphocytes and monocytes is followed by endothelial injury and eventually myocardial fibrosis. To date, no information is available on monocyte-macrophage-related cellular shifts and their polarization status during rejection. Here, we aimed to define and correlate monocyte-macrophage endomyocardial tissue profiles obtained at rejection and time points prior to rejection, with corresponding serial blood samples in 25 heart transplant recipients experiencing acute cellular rejection. Additionally, 33 healthy individuals served as control. Using histology, immunohistochemistry, confocal laser scan microscopy, and digital imaging expression of CD14, CD16, CD56, CD68, CD80, and CD163 were explored to define monocyte and macrophage tissue profiles during rejection. Fibrosis was investigated using Sirius Red stainings of rejection, non-rejection, and 1-year biopsies. Expression of co-stimulatory and migration-related molecules on circulating monocytes, and production potential for pro- and anti-inflammatory cytokines were studied using flow cytometry. At tissue level, striking CD16+ monocyte infiltration was observed during rejection ( p  rejection compared to barely present CD68+CD80+ M1 macrophages. Rejection was associated with severe fibrosis in 1-year biopsies ( p  rejection status, decreased frequencies of circulating CD16+ monocytes were found in patients compared to healthy individuals. Rejection was reflected by significantly increased CD54 and HLA-DR expression on CD16+ monocytes with retained cytokine production potential. CD16+ monocytes and M2 macrophages hallmark the correlates of heart transplant acute cellular rejection on tissue level and seem to be associated with fibrosis in the long term.

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

    Science.gov (United States)

    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.

  6. Processing of AISI M2 HSS with addition of NbC by mechanical alloying using two different types of attritor mills

    International Nuclear Information System (INIS)

    Araujo Filho, Oscar Olimpio de; Gonzalez, Cezar Henrique; Urtiga Filho, Severino Leopoldino; Ambrozio Filho, Francisco

    2009-01-01

    The processing of a molybdenum AISI M2 high speed steel with the addition of NbC (6% in mass) by a Powder Metallurgy technique of Mechanical Alloying is the aim of this work. Mechanical Alloying (MA) has been used primarily for particle size reduction, to its present status as an important method for the preparation of either materials with enhanced physical and mechanical properties or, indeed, new phases, or new engineering materials. In this work, niobium carbide (NbC) was added to the AISI M2 HSS powders by Mechanical Alloying technique in two different types of attritor mills and the materials which resulted were characterized by means of SEM plus EDS. The powders were processed in a horizontal attritor Zoz mill and in a vertical attritor mill developed in our laboratory. The parameters of milling were distinct and the results of the processing were compared. (author)

  7. Sleeve gastrectomy with jejunal bypass for the treatment of type 2 diabetes mellitus in patients with body mass index <35 kg/m2. A cohort study.

    Science.gov (United States)

    Alamo, Munir; Sepúlveda, Matías; Gellona, José; Herrera, Mauricio; Astorga, Cristián; Manterola, Carlos

    2012-07-01

    The objective of this study was to evaluate sleeve gastrectomy with jejunal bypass (SGJB) as a surgical treatment for type 2 diabetes mellitus (T2DM) in patients with a body mass index (BMI) Chile were included. SGJB consists of creating a gastric tube, which preserves the pylorus, and performing a jejunoileal anastomosis 300 cm distal to the angle of Treitz. Excess weight loss (EWL) and complete or partial remission of T2DM were reported. Forty-nine patients met the inclusion criteria. The mean age was 49 years (36-62), and 53 % of patients were female. Mean preoperative BMI was 31.6 kg/m(2) (25-34.9 kg/m(2)). Operation time was 123 ± 14 min, with 94.7 % of operations performed laparoscopically. Mean postoperative hospital stay was 2 days. Mean postoperative follow-up was 12 months. Median EWL at 1, 3, 6, 12, and 18 months postoperatively was 31.9 %, 56.9 %, 76.1 %, 81.5 %, and 76.1 %, respectively. Complete T2DM remission was achieved in 81.6 % of patients (40/49) and partial remission in 18.4 % (9/49). Forty of 41 patients (97.6 %) on oral hypoglycemic agents achieved complete T2DM remission, and 100 % of insulin-dependent patients stopped using insulin but were still being treated for T2DM. One patient experienced postoperative gastrointestinal bleeding. There were no deaths. SGJB is an effective treatment for T2DM in patients with BMI <35 kg/m(2).

  8. Attitudes about the safety and efficacy of bariatric surgery among patients with type 2 diabetes and a body mass index of 30-40 kg/m2.

    Science.gov (United States)

    Sarwer, David B; Ritter, Scott; Wadden, Thomas A; Spitzer, Jacqueline C; Vetter, Marion L; Moore, Reneé H

    2013-01-01

    Despite increasing awareness within the medical community about the benefits of bariatric surgery for type 2 diabetes mellitus (T2DM), little is known about patients' attitudes toward bariatric surgery as a treatment for T2DM. The objective of this study was to investigate the attitudes of individuals with T2DM and a body mass index of 30 to 40 kg/m(2) concerning bariatric surgery for the treatment of T2DM. Patients identified from the Pennsylvania Integrated Clinical and Administrative Research Database (PICARD) were surveyed about perceptions of the safety profile and efficacy of bariatric surgery as a treatment for obesity and T2DM and their willingness to be randomly assigned to receive a surgical procedure. A total of 130 individuals of 513 (25.3%) responded. Respondents had a median (interquartile range) age of 58.0 (range 51.0-63.0) years and self-reported body mass index of 32.9 (range 30.9-35.2) kg/m(2). Roughly half (66 of 130) were female. Overall, only 20.3% of respondents had positive views of bariatric surgery, with few reporting that it is a safe (14.3%) and effective (28.5%) treatment for T2DM. Less than 20% of respondents were willing to be randomly assigned to undergo a surgical procedure for the treatment of diabetes (16.1%) or obesity (17.5%). Few obese individuals with T2DM who responded to the survey had positive views about bariatric surgery. Patients' concerns about the procedure's safety profile and efficacy must be addressed to improve the acceptability of bariatric surgery as well as the feasibility of randomized, controlled trials of bariatric surgery for these individuals. Copyright © 2013 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  9. A Trp474Cys mutation in the alpha-subunit of beta-hexosaminidase causes a subacute encephalopathic form of G{sub M2} gangliosidosis, type 1

    Energy Technology Data Exchange (ETDEWEB)

    Petroulakis, E.; Cao, Z.; Salo, T. [Univ. of Manitoba, Winnipeg (Canada)] [and others

    1994-09-01

    Mutations in the HEXA gene that encodes the {alpha}-subunit of the heterodimeric lysosomal enzyme {beta}-hexosaminidase A, or Hex A ({alpha}{beta}), cause G{sub M2} gangliosidosis, type 1. The infantile form (Tay-Sachs disease) results when there is no residual Hex A activity, while less severe and more variable clinical phenotypes result when residual Hex A activity is present. A non-Jewish male who presented with an acute psychotic episode at age 16 was diagnosed with a subacute encephalopathic form of G{sub M2} gangliosidosis. At age 19, chronic psychosis with intermittent acute exacerbations remains the most disabling symptom in this patient and his affected brother although both exhibit some ataxia and moderately severe dysarthria. We have found a 4 bp insertion (+TATC 1278) associated with infantile Tay-Sachs disease on one allele; no previously identified mutation was found on the second allele. SSCP analysis detected a shift in exon 13 and sequencing revealed a G1422C mutation in the second allele that results in a Trp474Cys substitution. The presence of the mutation was confirmed by the loss of HaeIII and ScrFI sites in exon 13 PCR products from the subjects and their father. The mutation was introduced into the {alpha}-subunit cDNA and Hex S ({alpha}{alpha}) and Hex A ({alpha}{beta}) were transiently expressed in monkey COS-7 cells. The Trp474Cys mutant protein had approximately 5% and 12% of wild-type Hex S and Hex A activity, respectively. Western blot analysis revealed a small amount of residual mature {alpha}-subunit and a normal level of precursor protein. We conclude that the Trp474Cys mutation is the cause of the Hex A deficiency associated with a subacute (juvenile-onset) phenotype in this patient. Like other mutations in exon 13 of HEXA, it appears to affect intracellular processing. Studies of the defect in intracellular processing are in progress.

  10. M2e-displaying virus-like particles with associated RNA promote T helper 1 type adaptive immunity against influenza A.

    Directory of Open Access Journals (Sweden)

    Lorena Itatí Ibañez

    Full Text Available The ectodomain of influenza A matrix protein 2 (M2e is a candidate for a universal influenza A vaccine. We used recombinant Hepatitis B core antigen to produce virus-like particles presenting M2e (M2e-VLPs. We produced the VLPs with and without entrapped nucleic acids and compared their immunogenicity and protective efficacy. Immunization of BALB/c mice with M2e-VLPs containing nucleic acids induced a stronger, Th1-biased antibody response compared to particles lacking nucleic acids. The former also induced a stronger M2e-specific CD4(+ T cell response, as determined by ELISPOT. Mice vaccinated with alum-adjuvanted M2e-VLPs containing the nucleic acid-binding domain were better protected against influenza A virus challenge than mice vaccinated with similar particles lacking this domain, as deduced from the loss in body weight following challenge with X47 (H3N2 or PR/8 virus. Challenge of mice that had been immunized with M2e-VLPs with or without nucleic acids displayed significantly lower mortality, morbidity and lung virus titers than control-immunized groups. We conclude that nucleic acids present in M2e-VLPs correlate with improved immune protection.

  11. Heterotic M2-branes

    Directory of Open Access Journals (Sweden)

    Neil Lambert

    2015-10-01

    Full Text Available We construct the action for N M2-branes on S1/Z2. The resulting theory has a gauge anomaly but this can be cancelled if the two fixed point planes each support 8 chiral Fermions in the fundamental of U(N. Taking the low energy limit leads to the worldsheet theory of N free heterotic strings whose quantization induces an E8 spacetime gauge symmetry on each fixed point plane. Thus this paper presents a non-abelian worldvolume analogue of the classic Hořava–Witten analysis.

  12. The Polyvalent Heat Supply System for Experimental Building of the Passive Type (area of 300 m2 Based on Renewable and Alternative Energy Sources

    Directory of Open Access Journals (Sweden)

    Basok, B.I.

    2014-11-01

    Full Text Available Results of the development and implementation of heat supply system for experimental building of the passive type are presented, optimal operating conditions are investigated, guidelines for the creation of heat supply systems for passive type buildings are provided.

  13. Acute Hypoxia Induced an Imbalanced M1/M2 Activation of Microglia through NF-κB Signaling in Alzheimer’s Disease Mice and Wild-Type Littermates

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    Feng Zhang

    2017-08-01

    Full Text Available Alzheimer’s disease (AD is the most common neurodegenerative disease mainly caused by abnormal tau phosphorylation, amyloid β (Aβ deposition and neuroinflammation. As an important environmental factor, hypoxia has been reported to aggravate AD via exacerbating Aβ and tau pathologies. However, the link between hypoxia and neuroinflammation, especially the changes of pro-inflammatory M1 or anti-inflammation M2 microglia phenotypes in AD, is still far from being clearly investigated. Here, we evaluated the activation of microglia in the brains of APPswe/PS1dE9 transgenic (Tg mice and their wild type (Wt littermates, after a single episode of acute hypoxia (24 h exposure. We found that acute hypoxia activated M1 microglia in both Tg and Wt mice as evidenced by the elevated M1 markers including cluster of differentiation 86 (CD86, tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, C-C motif chemokine ligand 2 (CCL2 and CCL3. In addition, the markers of M2 microglia phenotype (arginase-1 (Arg-1, CD206, IL-4 and IL-10 were decreased after acute hypoxia exposure, suggesting an attenuated M2 phenotype of microglia. Moreover, the activation of microglia and the release of cytokines and chemokines were associated with Nuclear factor-κB (NF-κB induction through toll-like receptor 4 (TLR4. In summary, our findings revealed that acute hypoxia modulated microglia M1/M2 subgroup profile, indicating the pathological role of hypoxia in the neuroinflammation of AD.

  14. M2-F1 cockpit

    Science.gov (United States)

    1963-01-01

    This photo shows the cockpit configuration of the M2-F1 wingless lifting body. With a top speed of about 120 knots, the M2-F1 had a simple instrument panel. Besides the panel itself, the ribs of the wooden shell (left) and the control stick (center) are also visible. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got the M2-F1 airborne to prove it could fly safely and to train pilots before they were towed behind a C-47

  15. Surface immobilisation of transition metal substituted Krebs type polyoxometalates, [X2W20M2O70(H2O)6]n− (X = Bi or Sb, M = Co2+ or Cu2+), by the layer by layer technique

    International Nuclear Information System (INIS)

    Murphy, Aidan Fagan; McCormac, Timothy

    2011-01-01

    A series of transition metal (i.e. Cu 2+ and Co 2+ ) substituted Krebs type polyoxometalates (POMs), of the general formula [X 2 W 20 M 2 O 70 (H 2 O) 6 ] n− , X = Sb or Bi, M = Co(II) or Cu(II), have been successfully immobilised onto carbon electrode surfaces through the employment of the layer-by-layer (LBL) technique. This involved the construction of alternating anionic POM, [X 2 W 20 M 2 O 70 (H 2 O) 6 ] n− , layers and the cationic metallodendrimer, Ru(II)-metallodendrimer as the cationic layers, in addition to a [poly(diallyldimethylammonium chloride)] PDDA base layer. Stable multielectron redox couples associated with the W–O framework, for the Krebs type POMs, and the Ru(III/II) for the metallodendrimer, were clearly observed upon layer construction and redox switching within the pH domain of 2–6.5. The constructed multilayer assemblies exhibited pH dependent redox activity and thin layer behaviour up to 100 mV s −1 . The porosity and permeability of the individual multilayer assemblies towards an anionic probe were determined by AC impedance and cyclic voltammetry. The surface morphology of each multilayer was also determined by Atomic Force Microscopy (AFM).

  16. Unpredictability of internal M2

    Directory of Open Access Journals (Sweden)

    H. van Haren

    2007-06-01

    Full Text Available Current observations from a shelf sea, continental slopes and the abyssal North-East Atlantic Ocean are all dominated by the semidiurnal lunar (M2 tide. It is shown that motions at M2 vary at usually large barotropic and coherent baroclinic scales, >50 km horizontally and >0.5 H vertically. H represents the waterdepth. Such M2-scales are observed even close to topography, the potential source of baroclinic, "internal" tidal waves. In contrast, incoherent small-scale, ~10 km horizontally and ~0.1 H vertically, baroclinic motions are dominated around f, the local inertial frequency, and/or near 2Ω≈S2, the semidiurnal solar tidal frequency. Ω represents the Earth's rotational vector. This confirms earlier suggestions that small-scale baroclinic M2-motions generally do not exist in the ocean in any predictable manner, except in beams very near, <10 km horizontally, to their source. As a result, M2-motions are not directly important for generating shear and internal wave induced mixing. Indirectly however, they may contribute to ocean mixing if transfer to small-scale motions at f and/or S2 and at high internal wave frequencies can be proven. Also far from topography, small-scale motions are found at either one or both of the latter frequencies. Different suggestions for the scales at these particular frequencies are discussed, ranging from the variability of "background" density gradients and associated divergence and focusing of internal wave rays to the removal of the internal tidal energy by non-linear interactions. Near f and S2 particular short-wave inertio-gravity wave bounds are found in the limits of strong and very weak stratification, which are often observed in small-scale layers.

  17. Semisynthetic analogues of toxiferine I and their pharmacological properties at α7 nAChRs, muscle-type nAChRs, and the allosteric binding site of muscarinic M2 receptors

    DEFF Research Database (Denmark)

    Zlotos, D.P.; Tränkle, C; Holzgrabe, U

    2014-01-01

    A new series of analogues of the calabash curare alkaloid toxiferine I was prepared and pharmacologically evaluated at α7 and muscle-type nAChRs and the allosteric site of muscarinic M2 receptors. The new ligands differ from toxiferine I by the absence of one (2a–c) or two (3a–c) hydroxy groups......, saturation of the exocyclic double bonds, and various N-substituents (methyl, allyl, 4-nitrobenzyl). At the muscle-type nAChRs, most ligands showed similar binding to the muscle relaxant alcuronium, indicating neuromuscular blocking activity, with the nonhydroxylated analogues 3b (Ki = 75 nM) and 3c (Ki = 82...... nM) displaying the highest affinity. At α7 nAChRs, all ligands showed a moderate to low antagonistic effect, suggesting that the alcoholic functions are not necessary for antagonistic action. Compound 3c exerted the highest preference for the muscle-type nAChRs (Ki = 82 nM) over α7 (IC50 = 21 μ...

  18. Store-Carry and Forward-Type M2M Communication Protocol Enabling Guide Robots to Work together and the Method of Identifying Malfunctioning Robots Using the Byzantine Algorithm

    Directory of Open Access Journals (Sweden)

    Yoshio Suga

    2016-11-01

    Full Text Available This paper concerns a service in which multiple guide robots in an area display arrows to guide individual users to their destinations. It proposes a method of identifying malfunctioning robots and robots that give wrong directions to users. In this method, users’ mobile terminals and robots form a store-carry and forward-type M2M communication network, and a distributed cooperative protocol is used to enable robots to share information and identify malfunctioning robots using the Byzantine algorithm. The robots do not directly communicate with each other, but through users’ mobile terminals. We have introduced the concept of the quasi-synchronous number, so whether a certain robot is malfunctioning can be determined even when items of information held by all of the robots are not synchronized. Using simulation, we have evaluated the proposed method in terms of the rate of identifying malfunctioning robots, the rate of reaching the destination and the average length of time to reach the destination.

  19. The cost-effectiveness of dulaglutide versus liraglutide for the treatment of type 2 diabetes mellitus in Spain in patients with BMI ≥30 kg/m2.

    Science.gov (United States)

    Dilla, Tatiana; Alexiou, Dimitra; Chatzitheofilou, Ismini; Ayyub, Ruba; Lowin, Julia; Norrbacka, Kirsi

    2017-05-01

    Dulaglutide 1.5 mg once weekly is a novel glucagon-like peptide 1 (GLP-1) receptor agonist, for the treatment of type two diabetes mellitus (T2DM). The objective was to estimate the cost-effectiveness of dulaglutide once weekly vs liraglutide 1.8 mg once daily for the treatment of T2DM in Spain in patients with a BMI ≥30 kg/m 2 . The IMS CORE Diabetes Model (CDM) was used to estimate costs and outcomes from the perspective of Spanish National Health System, capturing relevant direct medical costs over a lifetime time horizon. Comparative safety and efficacy data were derived from direct comparison of dulaglutide 1.5 mg vs liraglutide 1.8 mg from the AWARD-6 trial in patients with a body mass index (BMI) ≥30 kg/m 2 . All patients were assumed to remain on treatment for 2 years before switching treatment to basal insulin at a daily dose of 40 IU. One-way sensitivity analyses (OWSA) and probabilistic sensitivity analyses (PSA) were conducted to explore the sensitivity of the model to plausible variations in key parameters and uncertainty of model inputs. Under base case assumptions, dulaglutide 1.5 mg was less costly and more effective vs liraglutide 1.8 mg (total lifetime costs €108,489 vs €109,653; total QALYS 10.281 vs 10.259). OWSA demonstrated that dulaglutide 1.5 mg remained dominant given plausible variations in key input parameters. Results of the PSA were consistent with base case results. Primary limitations of the analysis are common to other cost-effectiveness analyses of chronic diseases like T2DM and include the extrapolation of short-term clinical data to the lifetime time horizon and uncertainty around optimum treatment durations. The model found that dulaglutide 1.5 mg was more effective and less costly than liraglutide 1.8 mg for the treatment of T2DM in Spain. Findings were robust to plausible variations in inputs. Based on these results, dulaglutide may result in cost savings to the Spanish National Health System.

  20. M2 polarization enhances silica nanoparticle uptake by macrophages

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    Jessica eHoppstädter

    2015-03-01

    Full Text Available While silica nanoparticles have enabled numerous industrial and medical applications, their toxicological safety requires further evaluation. Macrophages are the major cell population responsible for nanoparticle clearance in vivo. The prevailing macrophage phenotype largely depends on the local immune status of the host. Whereas M1-polarized macrophages are considered as pro-inflammatory macrophages involved in host defense, M2 macrophages exhibit anti-inflammatory and wound-healing properties, but also promote tumor growth.We employed different models of M1 and M2 polarization: GM-CSF/LPS/IFN-gamma was used to generate primary human M1 cells and M-CSF/IL-10 to differentiate M2 monocyte-derived macrophages. PMA-differentiated THP-1 cells were polarized towards an M1 type by LPS/IFN-gamma and towards M2 by IL-10. Uptake of fluorescent silica nanoparticles (Ø 26 and 41 nm and microparticles (Ø 1.75 µm was quantified. At the concentration used (50 µg/ml, silica nanoparticles did not influence cell viability as assessed by MTT assay. Nanoparticle uptake was enhanced in M2-polarized primary human monocyte-derived macrophages compared with M1 cells, as shown by flow cytometric and microscopic approaches. In contrast, the uptake of microparticles did not differ between M1 and M2 phenotypes. M2 polarization was also associated with increased nanoparticle uptake in the macrophage-like THP-1 cell line. In accordance, in vivo polarized M2-like primary human tumor-associated macrophages (TAM obtained from lung tumors took up more nanoparticles than M1-like alveolar macrophages isolated from the surrounding lung tissue.In summary, our data indicate that the M2 polarization of macrophages promotes nanoparticle internalization. Therefore, the phenotypical differences between macrophage subsets should be taken into consideration in future investigations on nanosafety, but might also open up therapeutic perspectives allowing to specifically target M2

  1. Anatomy of a Discovery: M1 and M2 Macrophages

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    Charles Dudley Mills

    2015-05-01

    Full Text Available M1 and M2 macrophage-type responses kill or repair in vivo. The unique ability of macrophages to make these polar opposite type of responses provides primary host protection and maintains tissue homeostasis throughout the animal kingdom. In humans and other higher animals M1 and M2-type macrophage responses also initiate and direct T cells/adaptive immunity to provide additional protection such as Th1 (cytotoxic or Th2 (antibody-mediated type responses. Hence, macrophages were renamed M1 and M2 to indicate the central role of macrophages/innate immunity in immune systems. These findings indicate that the long held notion that adaptive immunity controls innate immunity was backward: a sea change in understanding how immune responses occur. The clinical impact of M1/kill and M2/repair responses is immense playing pivotal roles in curing (or causing many diseases including infections, cancer, autoimmunity and atherosclerosis. How M1/M2 came to be is an interesting story that, like life, involved Direction, Determination, Discouragement and Discovery.

  2. TNF Counterbalances the Emergence of M2 Tumor Macrophages

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    Franz Kratochvill

    2015-09-01

    Full Text Available Cancer can involve non-resolving, persistent inflammation where varying numbers of tumor-associated macrophages (TAMs infiltrate and adopt different activation states between anti-tumor M1 and pro-tumor M2 phenotypes. Here, we resolve a cascade causing differential macrophage phenotypes in the tumor microenvironment. Reduction in TNF mRNA production or loss of type I TNF receptor signaling resulted in a striking pattern of enhanced M2 mRNA expression. M2 gene expression was driven in part by IL-13 from eosinophils co-recruited with inflammatory monocytes, a pathway that was suppressed by TNF. Our data define regulatory nodes within the tumor microenvironment that balance M1 and M2 populations. Our results show macrophage polarization in cancer is dynamic and dependent on the balance between TNF and IL-13, thus providing a strategy for manipulating TAMs.

  3. Anti-influenza M2e antibody

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M.

    2013-04-16

    Humanized recombinant and monoclonal antibodies specific for the ectodomain of the influenza virus M2 ion channel protein are disclosed. The antibodies of the invention have anti-viral activity and may be useful as anti-viral therapeutics and/or prophylactic/vaccine agents for inhibiting influenza virus replication and for treating individuals infected with influenza.

  4. Anti-influenza M2e antibody

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M [Santa Fe, NM

    2011-12-20

    Humanized recombinant and monoclonal antibodies specific for the ectodomain of the influenza virus M2 ion channel protein are disclosed. The antibodies of the invention have anti-viral activity and may be useful as anti-viral therapeutics and/or prophylactic/vaccine agents for inhibiting influenza virus replication and for treating individuals infected with influenza.

  5. M2-F1 simulator cockpit

    Science.gov (United States)

    1963-01-01

    This early simulator of the M2-F1 lifting body was used for pilot training, to test landing techniques before the first ground tow attempts, and to test new control configurations after the first tow attempts and wind-tunnel tests. The M2-F1 simulator was limited in some ways by its analog simulator. It had only limited visual display for the pilot, as well. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got the M2-F1 airborne

  6. PsasM2I, a type II restriction-modification system in Pseudomonas savastanoi pv. savastanoi: differential distribution of carrier strains in the environment and the evolutionary history of homologous RM systems in the Pseudomonas syringae complex.

    Science.gov (United States)

    Cinelli, Tamara; Moscetti, Ilaria; Marchi, Guido

    2014-11-01

    A type II restriction-modification system was found in a native plasmid of Pseudomonas savastanoi pv. savastanoi MLLI2. Functional analysis of the methyltransferase showed that the enzyme acts by protecting the DNA sequence CTGCAG from cleavage. Restriction endonuclease expression in recombinant Escherichia coli cells resulted in mutations in the REase sequence or transposition of insertion sequence 1A in the coding sequence, preventing lethal gene expression. Population screening detected homologous RM systems in other P. savastanoi strains and in the Pseudomonas syringae complex. An epidemiological survey carried out by sampling olive and oleander knots in two Italian regions showed an uneven diffusion of carrier strains, whose presence could be related to a selective advantage in maintaining the RM system in particular environments or subpopulations. Moreover, carrier strains can coexist in the same orchards, plants, and knot tissues with non-carriers, revealing unexpected genetic variability on a very small spatial scale. Phylogenetic analysis of the RM system and housekeeping gene sequences in the P. syringae complex demonstrated the ancient acquisition of the RM systems. However, the evolutionary history of the gene complex also showed the involvement of horizontal gene transfer between related strains and recombination events.

  7. Polysaccharide Agaricus blazei Murill stimulates myeloid derived suppressor cell differentiation from M2 to M1 type, which mediates inhibition of tumour immune-evasion via the Toll-like receptor 2 pathway.

    Science.gov (United States)

    Liu, Yi; Zhang, Lingyun; Zhu, Xiangxiang; Wang, Yuehua; Liu, WenWei; Gong, Wei

    2015-11-01

    Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing animals and play a critical negative role during tumor immunotherapy. Strategies for inhibition of MDSCs are expected to improve cancer immunotherapy. Polysaccharide Agaricus blazei Murill (pAbM) has been found to have anti-cancer activity, but the underlying mechanism of this is poorly understood. Here, pAbM directly activated the purified MDSCs through inducing the expression of interleukin-6 (IL-6), IL-12, tumour necrosis factor and inducible nitric oxide synthase (iNOS), CD86, MHC II, and pSTAT1 of it, and only affected natural killer and T cells in the presence of Gr-1(+) CD11b(+) monocytic MDSCs. On further analysis, we demonstrated that pAbM could selectively block the Toll-like receptor 2 (TLR2) signal of Gr-1(+) CD11b(+) MDSCs and increased their M1-type macrophage characteristics, such as producing IL-12, lowering expression of Arginase 1 and increasing expression of iNOS. Extensive study showed that Gr-1(+) CD11b(+) MDSCs by pAbM treatment had less ability to convert the CD4(+) CD25(-) cells into CD4(+) CD25(+) phenotype. Moreover, result from selective depletion of specific cell populations in xenograft mice model suggested that the anti-tumour effect of pAbM was dependent on Gr-1(+ ) CD11b(+) monocytes, nether CD8(+) T cells nor CD4(+) T cells. In addition to, pAbM did not inhibit tumour growth in TLR2(-/-) mice. All together, these results suggested that pAbM, a natural product commonly used for cancer treatment, was a specific TLR2 agonist and had potent anti-tumour effects through the opposite of the suppressive function of Gr-1(+) CD11b(+) MDSCs. © 2015 John Wiley & Sons Ltd.

  8. Penrose limits, pp waves, and deformed M2-branes

    International Nuclear Information System (INIS)

    Cvetic, M.; Lue, H.; Pope, C.N.

    2004-01-01

    Motivated by the recent discussions of the Penrose limit of AdS 5 xS 5 , we examine a more general class of supersymmetric pp-wave solutions of the type IIB theory, with a larger number of nonvanishing structures in the self-dual 5-form. One of the pp-wave solutions can be obtained as a Penrose limit of a D3-D3 intersection. In addition to 16 standard supersymmetries these backgrounds always allow for supernumerary supersymmetries. The latter are in one-to-one correspondence with the linearly realized world-sheet supersymmetries of the corresponding exactly solvable type IIB string action. The pp-waves provide new examples where supersymmetries will survive in a T-duality transformation on the x + coordinate. The T-dual solutions can be lifted to give supersymmetric deformed M2-branes in D=11. The deformed M2-brane is dual to a three-dimensional field theory whose renormalization group flow runs from the conformal fixed point in the infrared regime to a nonconformal theory as the energy increases. At a certain intermediate energy scale there is a phase transition associated with a naked singularity of the M2-brane. In the ultraviolet limit the theory is related by T duality to an exactly solvable massive type IIB string theory

  9. Effects of montelukast on M2-related cytokine and chemokine in M2 macrophages

    Directory of Open Access Journals (Sweden)

    Yi-Ching Lin

    2018-02-01

    Conclusion: Montelukast suppressed LPS-induced M2-related cytokines and chemokines in alternatively activated macrophages, and the effects might be mediated through the MAPK-p38 and NF-κB-p65 pathways.

  10. LOSA-M2 aerosol Raman lidar

    Science.gov (United States)

    Balin, Yu S.; Bairashin, G. S.; Kokhanenko, G. P.; Penner, I. E.; Samoilova, S. V.

    2011-10-01

    The scanning LOSA-M2 aerosol Raman lidar, which is aimed at probing atmosphere at wavelengths of 532 and 1064 nm, is described. The backscattered light is received simultaneously in two regimes: analogue and photon-counting. Along with the signals of elastic light scattering at the initial wavelengths, a 607-nm Raman signal from molecular nitrogen is also recorded. It is shown that the height range of atmosphere probing can be expanded from the near-Earth layer to stratosphere using two (near- and far-field) receiving telescopes, and analogue and photon-counting lidar signals can be combined into one signal. Examples of natural measurements of aerosol stratification in atmosphere along vertical and horizontal paths during the expeditions to the Gobi Desert (Mongolia) and Lake Baikal areas are presented.

  11. M2M Optimizations in Public Mobile Networks

    NARCIS (Netherlands)

    Norp, A.H.J.; Landais, B.

    2012-01-01

    Many M2M applications use public telecommunications networks to transfer data from M2M devices to an M2M server. These telecommunications networks will have to be adapted to cope with the traffic generated by the projected growth of M2M applications. In the near future, many more devices will be

  12. 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.

    Science.gov (United States)

    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.

  13. National Differences in Remission of Type 2 Diabetes Mellitus After Roux-en-Y Gastric Bypass Surgery-Subgroup Analysis of 2-Year Results of the Diabetes Surgery Study Comparing Taiwanese with Americans with Mild Obesity (BMI 30-35 kg/m2).

    Science.gov (United States)

    Chong, Keong; Ikramuddin, Sayeed; Lee, Wei-Jei; Billington, Charles J; Bantle, John P; Wang, Qi; Thomas, Avis J; Connett, John E; Leslie, Daniel B; Inabnet, William B; Jeffery, Robert W; Sarr, Michael G; Jensen, Michael D; Vella, Adrian; Ahmed, Leaque; Belani, Kumar; Schone, Joyce L; Olofson, Amy E; Bainbridge, Heather A; Laqua, Patricia S; Korner, Judith; Chuang, Lee-Ming

    2017-05-01

    The purpose of this study is to compare effects of different nations on Roux-en-Y gastric bypass (RYGB) vs. intensive medical management (IMM) in achieving remission of type 2 diabetes mellitus (T2DM). Between April 2008 and December 2011, this randomized, controlled clinical trial was conducted at four teaching hospitals in the United States and Taiwan involving 71 participants with mild obesity (BMI 30-35 kg/m 2 ). Thirty-six of 71 participants were randomly assigned to the RYGB group, and the others were in IMM group. Partial or complete remission of T2DM was defined as blood HbA1c diabetes remission. Adding RYGB to lifestyle and medical management was associated with a greater likelihood of remission of T2DM in both Taiwanese and American subjects with mild obesity with type 2 diabetes. Residual beta-cell function at baseline appears to be the major factor predicting remission of T2DM. Trial registry number: clinicaltrials.gov Identifier: NCT00641251.

  14. Main: 1M2Q [RPSD[Archive

    Lifescience Database Archive (English)

    Full Text Available 1M2Q トウモロコシ Corn Zea mays L. Casein Kinase Ii, Alpha Chain Name=Ack2; Zea Mays Mole...LVGRHSRKPWLKFMNADNQHLVSPEAIDFLDKLLRYDHQERLTALEAMTHPYFQQVRAAENSRTRA corn_1M2Q.jpg ...

  15. Mass-deformed M2 branes in Stenzel space

    Science.gov (United States)

    Dias, Óscar J. C.; Hartnett, Gavin S.; Niehoff, Benjamin E.; Santos, Jorge E.

    2017-11-01

    We obtain finite-temperature M2 black branes in 11-dimensional supergravity, in a G 4-flux background whose self-dual part approaches a solution of Cvetič, Gibbons, Lü, and Pope, based upon Stenzel's family of Ricci-flat Kähler deformed cones. Our solutions are asymptotically AdS 4 times a 7-dimensional Stiefel manifold V 5,2, and the branes are "smeared" to retain SO(5) symmetry in the internal space. The solutions represent a mass deformation of the corresponding dual CFT 3, whose full description is at this time only partially-understood. We investigate the possibility of a confinement/de-confinement phase transition analogous to the AdS 5 × S 5 case, and a possible Gregory-Laflamme type instability which could lead to polarised brane solutions which break SO(5). We discuss possible consequences for AdS/CFT and the KKLT cosmological uplift mechanism.

  16. 26 CFR 1.401(m)-2 - ACP test.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false ACP test. 1.401(m)-2 Section 1.401(m)-2 Internal... TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(m)-2 ACP test. (a) Actual contribution percentage (ACP) test—(1) In general—(i) ACP test formula. A plan satisfies the ACP test for a plan year only...

  17. Towards Horizontal Architecture for Autonomic M2M Service Networks

    Directory of Open Access Journals (Sweden)

    Juhani Latvakoski

    2014-05-01

    Full Text Available Today, increasing number of industrial application cases rely on the Machine to Machine (M2M services exposed from physical devices. Such M2M services enable interaction of physical world with the core processes of company information systems. However, there are grand challenges related to complexity and “vertical silos” limiting the M2M market scale and interoperability. It is here expected that horizontal approach for the system architecture is required for solving these challenges. Therefore, a set of architectural principles and key enablers for the horizontal architecture have been specified in this work. A selected set of key enablers called as autonomic M2M manager, M2M service capabilities, M2M messaging system, M2M gateways towards energy constrained M2M asset devices and creation of trust to enable end-to-end security for M2M applications have been developed. The developed key enablers have been evaluated separately in different scenarios dealing with smart metering, car sharing and electric bike experiments. The evaluation results shows that the provided architectural principles, and developed key enablers establish a solid ground for future research and seem to enable communication between objects and applications, which are not initially been designed to communicate together. The aim as the next step in this research is to create a combined experimental system to evaluate the system interoperability and performance in a more detailed manner.

  18. Wound administration of M2-polarized macrophages does not improve murine cutaneous healing responses.

    Directory of Open Access Journals (Sweden)

    Nadine Jetten

    Full Text Available Macrophages play a crucial role in all stages of cutaneous wound healing responses and dysregulation of macrophage function can result in derailed wound repair. The phenotype of macrophages is influenced by the wound microenvironment and evolves during healing from a more pro-inflammatory (M1 profile in early stages, to a less inflammatory pro-healing (M2 phenotype in later stages of repair. The aim of the current study was to investigate the potential of exogenous administration of M2 macrophages to promote wound healing in an experimental mouse model of cutaneous injury. Bone marrow derived macrophages were stimulated in-vitro with IL-4 or IL-10 to obtain two different subsets of M2-polarized cells, M2a or M2c respectively. Polarized macrophages were injected into full-thickness excisional skin wounds of either C57BL/6 or diabetic db/db mice. Control groups were injected with non-polarized (M0 macrophages or saline. Our data indicate that despite M2 macrophages exhibit an anti-inflammatory phenotype in-vitro, they do not improve wound closure in wild type mice while they delay healing in diabetic mice. Examination of wounds on day 15 post-injury indicated delayed re-epithelialization and persistence of neutrophils in M2 macrophage treated diabetic wounds. Therefore, topical application of ex-vivo generated M2 macrophages is not beneficial and contraindicated for cell therapy of skin wounds.

  19. EspM2 is a RhoA guanine nucleotide exchange factor.

    Science.gov (United States)

    Arbeloa, Ana; Garnett, James; Lillington, James; Bulgin, Richard R; Berger, Cedric N; Lea, Susan M; Matthews, Steve; Frankel, Gad

    2010-05-01

    We investigated how the type III secretion system WxxxE effectors EspM2 of enterohaemorrhagic Escherichia coli, which triggers stress fibre formation, and SifA of Salmonella enterica serovar Typhimurium, which is involved in intracellular survival, modulate Rho GTPases. We identified a direct interaction between EspM2 or SifA and nucleotide-free RhoA. Nuclear Magnetic Resonance Spectroscopy revealed that EspM2 has a similar fold to SifA and the guanine nucleotide exchange factor (GEF) effector SopE. EspM2 induced nucleotide exchange in RhoA but not in Rac1 or H-Ras, while SifA induced nucleotide exchange in none of them. Mutating W70 of the WxxxE motif or L118 and I127 residues, which surround the catalytic loop, affected the stability of EspM2. Substitution of Q124, located within the catalytic loop of EspM2, with alanine, greatly attenuated the RhoA GEF activity in vitro and the ability of EspM2 to induce stress fibres upon ectopic expression. These results suggest that binding of SifA to RhoA does not trigger nucleotide exchange while EspM2 is a unique Rho GTPase GEF.

  20. Syntheses and structures of the MOF-type series of metal 1,4,5,8,-naphthalenetetracarboxylates M 2(OH) 2[C 14O 8H 4] (Al, Ga, In) with infinite trans-connected M-OH-M chains (MIL-122)

    Science.gov (United States)

    Volkringer, Christophe; Loiseau, Thierry; Guillou, Nathalie; Férey, Gérard; Elkaïm, Erik

    2009-08-01

    Three new isostructural MOF-type compounds (named MIL-122) have been obtained from the hydrothermal reaction at 210 °C for 24 h of the 1,4,5,8-naphthalenetetracarboxylic acid with aluminum, gallium or indium source in water. The structures of the compounds M 2(OH) 2[C 14H 4O 8] (M = Al, Ga, In) have been solved ab initio from powder X-ray diffraction analysis using the synchrotron radiation (Soleil; station CRISTAL). The three-dimensional organic-inorganic framework exhibits infinite straight chains of metal-centered octahedra sharing trans corners linked to each other through the 1,4,5,8-naphthalenetetracarboxylate ligand. The cations Al, Ga or In, are coordinated by four oxygen atoms coming from the carboxyl groups and two bridging hydroxyl groups μ2-OH, located in trans position in the octahedral surrounding. The compounds characterized by thermogravimetric and thermodiffraction analyses are thermally stable up to 440, 460 and 380 °C, for Al, Ga and In, respectively. Crystal data: monoclinic cell; P2 1/ c (n°14); for MIL-122 (Al): a = 9.5174(2), b = 10.0706(1), c = 6.6465(2) Å, β = 91.2614(5)°, V = 636.878(2) Å 3, Z = 2; for MIL-122 (Ga): a = 9.6501(1), b = 10.0585(1), c = 6.75069(9) Å, β = 92.4786(9)°, V = 654.65(1) Å 3, Z = 2; for MIL-122 (In): a = 9.92359(5), b = 10.19765(7), c = 7.19357(4) Å, β = 727.034(8)°, V = 727.034(8)Å 3, Z = 2.

  1. A Survey on M2M Service Networks

    Directory of Open Access Journals (Sweden)

    Juhani Latvakoski

    2014-11-01

    Full Text Available The number of industrial applications relying on the Machine to Machine (M2M services exposed from physical world has been increasing in recent years. Such M2M services enable communication of devices with the core processes of companies. However, there is a big challenge related to complexity and to application-specific M2M systems called “vertical silos”. This paper focuses on reviewing the technologies of M2M service networks and discussing approaches from the perspectives of M2M information and services, M2M communication and M2M security. Finally, a discussion on technologies and approaches potentially enabling future autonomic M2M service networks are provided. According to our conclusions, it is seen that clear definition of the architectural principles is needed to solve the “vertical silo” problem and then, proceeding towards enabling autonomic capabilities for solving complexity problem appears feasible. Several areas of future research have been identified, e.g., autonomic information based services, optimization of communications with limited capability devices, real-time messaging, creation of trust and end to end security, adaptability, reliability, performance, interoperability, and maintenance.

  2. Partial pressure (or fugacity) of carbon dioxide, salinity and other variables collected from time series observations using Bubble type equilibrator for autonomous carbon dioxide (CO2) measurement, Carbon dioxide (CO2) gas analyzer and other instruments from MOORING_M2_164W_57N in the Bering Sea from 2013-05-06 to 2014-10-19 (NCEI Accession 0157599)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — NCEI Accession 0157599 includes chemical, meteorological, physical and time series data collected from MOORING_M2_164W_57N in the Bering Sea from 2013-05-06 to...

  3. Theoretical Assessment of 178m2Hf De-Excitation

    Energy Technology Data Exchange (ETDEWEB)

    Hartouni, E P; Chen, M; Descalle, M A; Escher, J E; Loshak, A; Navratil, P; Ormand, W E; Pruet, J; Thompson, I J; Wang, T F

    2008-10-06

    This document contains a comprehensive literature review in support of the theoretical assessment of the {sup 178m2}Hf de-excitation, as well as a rigorous description of controlled energy release from an isomeric nuclear state.

  4. A model of the human M2 muscarinic acetylcholine receptor

    Science.gov (United States)

    Jöhren, Kirstin; Höltje, Hans-Dieter

    2002-11-01

    The M2 muscarinic acetylcholine receptor belongs to the family of rhodopsin like G-Protein Coupled Receptors. This subtype of muscarinic receptors is of special interest because it bears, aside from an orthosteric binding site, also an allosteric binding site. Based on the X-ray structure of bovine rhodopsin a complete homology model of the human M2 receptor was developed. For the orthosteric binding site point mutations and binding studies with different agonists and antagonists are available. This knowledge was utilized for an initial verification of the M2 model. Allosteric modulation of activity is mediated by structurally different ligands such as gallamine, caracurine V salts or W84 (a hexamethonium-derivative). Caracurine V derivatives with different affinities to M2 were docked using GRID-fields. Subsequent molecular dynamics simulations yielded different binding energies based on diverse electrostatic and lipophilic interactions. The calculated affinities are in good agreement to experimentally determined affinities.

  5. Microbial metabolite butyrate facilitates M2 macrophage polarization and function.

    Science.gov (United States)

    Ji, Jian; Shu, Dingming; Zheng, Mingzhu; Wang, Jie; Luo, Chenglong; Wang, Yan; Guo, Fuyou; Zou, Xian; Lv, Xiaohui; Li, Ying; Liu, Tianfei; Qu, Hao

    2016-04-20

    Metabolites from intestinal microbes modulate the mucosal immune system by regulating the polarization and expansion of T cells. Whether the microbial metabolites influence macrophage polarization, however, is poorly understood. Here, we show that the large bowel microbial fermentation product, butyrate, facilitates M2 macrophage polarization, in vitro and in vivo. The supernatant from butyrate-treated M2 macrophage increased the migration and enhanced the wound closure rate of MLE-12 cells. Butyrate attenuated intestinal inflammation in mice with dextran sulfate sodium (DSS)-induced colitis, with a significant increase in colonic expression of the M2 macrophage-associated protein, Arg1. M2 macrophage treated with butyrate, had increased activation of the H3K9/STAT6 signaling pathway, suggesting a mechanism for butyrate facilitated M2 macrophage polarization. Collectively, our study indicated that commensal microbe-derived butyrate is a novel activator of STAT6-mediated transcription through H3K9 acetylation driving M2 macrophage polarization, and delineated new insights into the immune interplay underlying inflammatory bowel disease.

  6. Study of {sup 179}Hf{sup m2} excitation

    Energy Technology Data Exchange (ETDEWEB)

    Vishnevsky, I. N.; Zheltonozhsky, V. A., E-mail: zhelton@kinr.kiev.ua; Savrasov, A. N. [National Academy of Sciences of Ukraine, Institute for Nuclear Research (Ukraine); Mazur, V. M. [National Academy of Sciences of Ukraine, Institute of Electronic Physics (Ukraine)

    2016-12-15

    Isomeric ratios of {sup 179}Hf{sup m2,g} yields in the (γ, n) reaction and the cross section for the {sup 179}Hf{sup m2} population in the (α, p) reaction are measured for the first time at the end-point energies of 15.1 and 17.5 MeV for bremsstrahlung photons and 26 MeV for alpha particles. The results are σ = (1.1 ± 0.11) × 10{sup −27} cm{sup 2} for the {sup 176}Lu(α, p){sup 179}Hf{sup m2} reaction and Y{sub m2}/Y{sub g} = (6.1 ± 0.3) × 10{sup −6} and (3.7 ± 0.2) × 10{sup −6} for the {sup 180}Hf(γ, n){sup 179}Hf{sup m22} reaction at E{sub ep} =15.1 and 17.5 MeV, respectively. The experimental data on the relative {sup 179}Hf{sup m2} yield indicate a single-humped shape of the excitation function for the {sup 180}Hf(γ, n){sup 179}Hf{sup m2} reaction. Simulation is performed using the TALYS-1.4 and EMPIRE-3.2 codes.

  7. Phosphorylation of Human Metapneumovirus M2-1 Protein Upregulates Viral Replication and Pathogenesis.

    Science.gov (United States)

    Cai, Hui; Zhang, Yu; Lu, Mijia; Liang, Xueya; Jennings, Ryan; Niewiesk, Stefan; Li, Jianrong

    2016-08-15

    Human metapneumovirus (hMPV) is a major causative agent of upper- and lower-respiratory-tract infections in infants, the elderly, and immunocompromised individuals worldwide. Like all pneumoviruses, hMPV encodes the zinc binding protein M2-1, which plays important regulatory roles in RNA synthesis. The M2-1 protein is phosphorylated, but the specific role(s) of the phosphorylation in viral replication and pathogenesis remains unknown. In this study, we found that hMPV M2-1 is phosphorylated at amino acid residues S57 and S60. Subsequent mutagenesis found that phosphorylation is not essential for zinc binding activity and oligomerization, whereas inhibition of zinc binding activity abolished the phosphorylation and oligomerization of the M2-1 protein. Using a reverse genetics system, recombinant hMPVs (rhMPVs) lacking either one or both phosphorylation sites in the M2-1 protein were recovered. These recombinant viruses had a significant decrease in both genomic RNA replication and mRNA transcription. In addition, these recombinant viruses were highly attenuated in cell culture and cotton rats. Importantly, rhMPVs lacking phosphorylation in the M2-1 protein triggered high levels of neutralizing antibody and provided complete protection against challenge with wild-type hMPV. Collectively, these data demonstrated that phosphorylation of the M2-1 protein upregulates hMPV RNA synthesis, replication, and pathogenesis in vivo The pneumoviruses include many important human and animal pathogens, such as human respiratory syncytial virus (hRSV), hMPV, bovine RSV, and avian metapneumovirus (aMPV). Among these viruses, hRSV and hMPV are the leading causes of acute respiratory tract infection in infants and children. Currently, there is no antiviral or vaccine to combat these diseases. All known pneumoviruses encode a zinc binding protein, M2-1, which is a transcriptional antitermination factor. In this work, we found that phosphorylation of M2-1 is essential for virus

  8. Immunization with M2e-displaying T7 bacteriophage nanoparticles protects against influenza A virus challenge.

    Directory of Open Access Journals (Sweden)

    Hamidreza Hashemi

    Full Text Available Considering the emergence of highly pathogenic influenza viruses and threat of worldwide pandemics, there is an urgent need to develop broadly-protective influenza vaccines. In this study, we demonstrate the potential of T7 bacteriophage-based nanoparticles with genetically fused ectodomain of influenza A virus M2 protein (T7-M2e as a candidate universal flu vaccine. Immunization of mice with non-adjuvanted T7-M2e elicited M2e-specific serum antibody responses that were similar in magnitude to those elicited by M2e peptide administered in Freund's adjuvant. Comparable IgG responses directed against T7 phage capsomers were induced following vaccination with wild type T7 or T7-M2e. T7-M2e immunization induced balanced amounts of IgG(1 and IgG(2a antibodies and these antibodies specifically recognized native M2 on the surface of influenza A virus-infected mammalian cells. The frequency of IFN-γ-secreting T cells induced by T7-M2e nanoparticles was comparable to those elicited by M2e peptide emulsified in Freund's adjuvant. Emulsification of T7-M2e nanoparticles in Freund's adjuvant, however, induced a significantly stronger T cell response. Furthermore, T7-M2e-immunized mice were protected against lethal challenge with an H1N1 or an H3N2 virus, implying the induction of hetero-subtypic immunity in our mouse model. T7-M2e-immunized mice displayed considerable weight loss and had significantly reduced viral load in their lungs compared to controls. We conclude that display of M2e on the surface of T7 phage nanoparticles offers an efficient and economical opportunity to induce cross-protective M2e-based immunity against influenza A.

  9. M2-F1 on lakebed with pilot Milt Thompson

    Science.gov (United States)

    1963-01-01

    NASA Flight Research Pilot Milt Thompson, shown here on the lakebed with the M2-F1 lifting body, was an early backer of R. Dale Reed's lifting-body proposal. He urged Flight Research Center director Paul Bikle to approve the M2-F1's construction. Thompson also made the first glide flights in both the M2-F1 and its successor, the heavyweight M2-F2. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, NASA Flight Research Center (later Dryden Flight Research Center, Edwards, CA) management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved

  10. Dynamic Environmental/Economic Scheduling for Microgrid Using Improved MOEA/D-M2M

    Directory of Open Access Journals (Sweden)

    Xin Li

    2016-01-01

    Full Text Available The environmental/economic dynamic scheduling for microgrids (MGs is a complex multiobjective optimization problem, which usually has dynamic system parameters and constraints. In this paper, a biobjective optimization model of MG scheduling is established. And various types of microsources (like the conventional sources, various types of renewable sources, etc., electricity markets, and dynamic constraints are considered. A recently proposed MOEA/D-M2M framework is improved (I-MOEA/D-M2M to solve the real-world MG scheduling problems. In order to deal with the constraints, the processes of solutions sorting and selecting in the original MOEA/D-M2M are revised. In addition, a self-adaptive decomposition strategy and a modified allocation method of individuals are introduced to enhance the capability of dealing with uncertainties, as well as reduce unnecessary computational work in practice and meet the time requirements for the dynamic optimization tasks. Thereafter, the proposed I-MOEA/D-M2M is applied to the independent MG scheduling problems, taking into account the load demand variation and the electricity price changes. The simulation results by MATLAB show that the proposed method can achieve better distributed fronts in much less running time than the typical multiobjective evolutionary algorithms (MOEAs like the improved strength Pareto evolutionary algorithm (SPEA2 and the nondominated sorting genetic algorithm II (NSGAII. Finally, I-MOEA/D-M2M is used to solve a 24-hour MG dynamic operation scheduling problem and obtains satisfactory results.

  11. Characteristics and potential role of M2 macrophages in COPD

    Directory of Open Access Journals (Sweden)

    He S

    2017-10-01

    Full Text Available Shengyang He, Lihua Xie, Junjuan Lu, Shenghua SunDepartment of Respiratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China Background: COPD is a multi-pathogenesis disease mainly caused by smoking. A further understanding of the mechanism of smoking-related COPD might contribute to preventions and treatments of this disease in the early stages. This study was designed to identify the characteristics of M2 macrophages in COPD for a better understanding about their potential role.Materials and methods: COPD models were built in the C57BL/6 mouse by cigarette smoke (CS exposure combined with intraperitoneal injection of cigarette smoke extract (CSE. The modeling efficiency was evaluated by lung function and hematoxylin and eosin (H&E staining. The number of different macrophage phenotypes was detected by immunohistochemical staining (IHS of CD206, CD86 and CD68 on the lung tissue paraffin section. The RAW264.7 cells were polarized toward the M2 phenotype by interleukin IL-4 and confirmed by a flow cytometer. The gene expression levels of TGF-βRII, Smad2, Smad3 and Smad7 in CSE-treated M2 macrophages were detected by real-time reverse transcription polymerase chain reaction (RT-PCR. The expression levels of TGF-β/Smad pathway-related makers (TGF-βRII, p-Smad2, p-Smad3, Smad7 and TGF-β in alveolar M2 macrophages were detected by two consecutive paraffin section IHS.Results: The COPD model is well established, which is confirmed by the lung function test and lung H&E staining. The whole number of macrophages and the ratio of M2/M1 phenotype are both increased (p<0.05. The level of CD206+ cells in IL-4-stimulated RAW264.7 cells is up to 93.4%, which is confirmed by a flow cytometer. The gene expression of TGF-βRII, Smad2, Smad3 and Smad7 are all enhanced (p<0.05 in CES-treated M2 macrophages, which is detected by RT-PCR. The protein levels of TGF-β/Smad pathway-related markers are

  12. Hyperglycemia induces mixed M1/M2 cytokine profile in primary human monocyte-derived macrophages

    NARCIS (Netherlands)

    Moganti, Kondaiah; Li, Feng; Schmuttermaier, Christina; Riemann, Sarah; Klueter, Harald; Gratchev, Alexei; Harmsen, Martin C.; Kzhyshkowska, Julia

    2017-01-01

    Hyperglycaemia is a key factor in diabetic pathology. Macrophages are essential regulators of inflammation which can be classified into two major vectors of polarisation: classically activated macrophages (M1) and alternatively activated macrophages (M2). Both types of macrophages play a role in

  13. M2-F1 ejection seat test at South Edwards

    Science.gov (United States)

    1963-01-01

    The M2-F1 was fitted with an ejection seat before the airtow flights began. The project selected the seat used in the T-37 as modified by the Weber Company to use a rocket rather than a ballistic charge for ejection. To test the ejection seat, the Flight Research Center's Dick Klein constructed a plywood mockup of the M2-F1's top deck and canopy. On the first firings, the test was unsuccessful, but on the final test the dummy in the seat landed safely. The M2-F1 ejection seat was later used in the two Lunar Landing Research Vehicles and the three Lunar Landing Training Vehicles. Three of them crashed, but in each case the pilot ejected from the vehicle successfully. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with

  14. Multiple M2-branes and the embedding tensor

    NARCIS (Netherlands)

    Bergshoeff, Eric A.; de Roo, Mees; Hohm, Olaf

    2008-01-01

    We show that the Bagger-Lambert theory of multiple M2-branes fits into the general construction of maximally supersymmetric gauge theories using the embedding tensor technique. We apply the embedding tensor technique in order to systematically obtain the consistent gaugings of N = 8 superconformal

  15. M2-F1 in hangar with Pontiac tow vehicle

    Science.gov (United States)

    1963-01-01

    The M2-F1 Lifting Body is seen here in a hangar with its hotrod Pontiac convertible tow vehicle at the Flight Research Center (later the Dryden Flight Research Center), Edwards, California. The car was a 1963 Pontiac Catalina convertible, fitted with a 421-cubic-inch tripower engine like those being run at the Daytona 500 auto race. The vehicle also had a four-speed transmission and a heavy-duty suspension and cooling system. A roll bar was also added and the passenger seat turned around so an observer could watch the M2-F1 while it was being towed. The rear seat was removed and a second, side-facing seat installed. The lifting-body team used the Pontiac for all the ground-tow flights over the next three years. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey

  16. M2e-Based Universal Influenza A Vaccines

    Science.gov (United States)

    Deng, Lei; Cho, Ki Joon; Fiers, Walter; Saelens, Xavier

    2015-01-01

    The successful isolation of a human influenza virus in 1933 was soon followed by the first attempts to develop an influenza vaccine. Nowadays, vaccination is still the most effective method to prevent human influenza disease. However, licensed influenza vaccines offer protection against antigenically matching viruses, and the composition of these vaccines needs to be updated nearly every year. Vaccines that target conserved epitopes of influenza viruses would in principle not require such updating and would probably have a considerable positive impact on global human health in case of a pandemic outbreak. The extracellular domain of Matrix 2 (M2e) protein is an evolutionarily conserved region in influenza A viruses and a promising epitope for designing a universal influenza vaccine. Here we review the seminal and recent studies that focused on M2e as a vaccine antigen. We address the mechanism of action and the clinical development of M2e-vaccines. Finally, we try to foresee how M2e-based vaccines could be implemented clinically in the future. PMID:26344949

  17. Dimeric Complexes of Tryptophan with M2+ Metal Ions

    NARCIS (Netherlands)

    Dunbar, R. C.; Steill, J. D.; Polfer, N. C.; Oomens, J.

    2009-01-01

    IRMPD spectroscopy using the FELIX free electron laser and a Fourier transform ICR mass spectrometer was used to characterize the structures of electrosprayed dimer complexes M(2+)Trp(2) of tryptophan with a series of eight doubly charged metal ions, including alkaline earths Ca, Sr, and Ba, and

  18. M2DART: a real image rear-projection display

    Science.gov (United States)

    Best, Leonard G.; Wight, Don R.; Peppler, Philipp W.

    1999-08-01

    The Mobile Modular Display for Advanced Research and Training (M2DART) was designed and fabricated at the Air Force Research Laboratory (AFRL) Warfighter Training Research Facility. The M2DART is part of a long term development goal of AFRL to produce a display and imaging system combination with significantly improved visual acuity in a full field-of- view/field-of-regard environment. The M2DART is an eight- channel, state-of-the-art, real image, rear-projection visual display system. It is a full color, high resolution, wraparound display designed for use with single-seat cockpit simulators. Depending on the number of available image generator channels, the system allows for a wide instantaneous field-of-view, when used in conjunction with a magnetic head tracker and video router combination to provide a full field- of-regard. The display is designed to accommodate a variety of visual image generators and cockpit simulators. The system uses commercial off-the-shelf (COTS) BARCO CRT projectors to display the out-the-window (OTW) visual imagery to the pilot. The M2DART concept demonstrates that a rear-projected, real image approach is a viable means of providing full color imagery to flight simulators with improved brightness and resolution characteristics. The final design of the M2DART represents a balance between such considerations as training requirements, the number of available image generator channels, system resolution, field of view, brightness, image stability and maintainability. This paper will provide a system description, which includes design trade-off considerations, hardware configuration, screen geometry, field of view, and performance specifications.

  19. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction

    DEFF Research Database (Denmark)

    Burnett, A. K.; Russell, N. H.; Hills, R. K.

    2015-01-01

    Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45 mg/m(2), and has be...... = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535....

  20. Internal steel structure of M2-F1

    Science.gov (United States)

    1963-01-01

    The internal steel structure for the M2-F1 was built at the Flight Research Center (predecessor of the Dryden Flight Research Center, Edwards, CA) in a section of the calibration hangar dubbed 'Wright Bicycle Shop.' Visible are the stick, rudder pedals, and ejection seat. The external wooden shell was attached to the steel structure. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got the M2-F1 airborne to prove it could fly

  1. M2 macrophages participate in the biological tissue healing reaction to mineral trioxide aggregate.

    Science.gov (United States)

    Ito, Takafumi; Kaneko, Tomoatsu; Yamanaka, Yusuke; Shigetani, Yoshimi; Yoshiba, Kunihiko; Okiji, Takashi

    2014-03-01

    This study examined the protein and messenger RNA (mRNA) expression of molecules associated with M2 (wound healing) macrophages in mineral trioxide aggregate (MTA)-implanted rat subcutaneous tissue to elucidate the involvement of M2 macrophages in the connective tissue response to MTA. Silicone tubes containing freshly mixed MTA or a calcium hydroxide cement (Life; Kerr, Romulus, MI) were subcutaneously implanted into the backs of Wistar rats. Solid silicone rods implanted in different animals served as controls. The specimens were then double immunostained for ED1 (CD68, a general macrophage marker) and ED2 (CD163, an M2 macrophage marker). Immunostaining for CD34 (a marker for vascularization and wound healing) was also performed. Expression levels of CD34, CD163, and mannose receptor c type 1 (an M2 macrophage marker) mRNAs were determined with real-time polymerase chain reaction. MTA-implanted subcutaneous tissues showed significant increases in the density of ED1+ED2+ macrophages beneath the implantation site and expression levels of CD163 and MMR mRNAs compared with Life-implanted and control tissues. MTA-implanted subcutaneous tissues also showed a significant increase of CD34-immunostained areas and up-regulation of CD34 mRNAs compared with Life-implanted and control tissues. MTA implantation induced the accumulation of M2 macrophage marker (ED2)-expressing macrophages and enhanced the expression of M2 macrophage marker genes. MTA implantation also enhanced the expression of CD34, suggesting acceleration of the healing/tissue repair process. Taken together, biological connective tissue response to MTA may involve wound healing/tissue repair processes involving M2 macrophages. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  2. Dynamic Changes of Microglia/Macrophage M1 and M2 Polarization in Theiler's Murine Encephalomyelitis.

    Science.gov (United States)

    Herder, Vanessa; Iskandar, Cut Dahlia; Kegler, Kristel; Hansmann, Florian; Elmarabet, Suliman Ahmed; Khan, Muhammad Akram; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang; Ulrich, Reiner; Beineke, Andreas

    2015-11-01

    Microglia and macrophages play a central role for demyelination in Theiler's murine encephalomyelitis (TME) virus infection, a commonly used infectious model for chronic-progressive multiple sclerosis. In order to determine the dynamic changes of microglia/macrophage polarization in TME, the spinal cord of Swiss Jim Lambert (SJL) mice was investigated by gene expression profiling and immunofluorescence. Virus persistence and demyelinating leukomyelitis were confirmed by immunohistochemistry and histology. Electron microscopy revealed continuous myelin loss together with abortive myelin repair during the late chronic infection phase indicative of incomplete remyelination. A total of 59 genes out of 151 M1- and M2-related genes were differentially expressed in TME virus-infected mice over the study period. The onset of virus-induced demyelination was associated with a dominating M1 polarization, while mounting M2 polarization of macrophages/microglia together with sustained prominent M1-related gene expression was present during the chronic-progressive phase. Molecular results were confirmed by immunofluorescence, showing an increased spinal cord accumulation of CD16/32(+) M1-, arginase-1(+) M2- and Ym1(+) M2-type cells associated with progressive demyelination. The present study provides a comprehensive database of M1-/M2-related gene expression involved in the initiation and progression of demyelination supporting the hypothesis that perpetuating interaction between virus and macrophages/microglia induces a vicious circle with persistent inflammation and impaired myelin repair in TME. © 2014 International Society of Neuropathology.

  3. On relating multiple M2 and D2-branes

    International Nuclear Information System (INIS)

    Gran, U.; Nilsson, B.E.W; Petersson, C.

    2008-01-01

    Due to the difficulties of finding superconformal Lagrangian theories for multiple M2-branes, we will in this paper instead focus on the field equations. By relaxing the requirement of a Lagrangian formulation we can explore the possibility of having structure constants f ABC D satisfying the fundamental identity but which are not totally antisymmetric. We exemplify this discussion by making use of an explicit choice of a non-antisymmetric f ABC D constructed from the Lie algebra structure constants f ab c of an arbitrary gauge group. Although this choice of f ABC D does not admit an obvious Lagrangian description, it does reproduce the correct SYM theory for a stack of N D2-branes to leading order in g YM -1 upon reduction and, moreover, it sheds new light on the centre of mass coordinates for multiple M2-branes.

  4. State-of-the-art Model M-2 Maintenance System

    International Nuclear Information System (INIS)

    Herndon, J.N.; Martin, H.L.; Satterlee, P.E. Jr.; Jelatis, D.G.; Jennrich, C.E.

    1984-04-01

    The Model M-2 Maintenance System is part of an ongoing program within the Consolidated Fuel Reprocessing Program (CFRP) at Oak Ridge National Laboratory (ORNL) to improve remote manipulation technology for future nuclear fuel reprocessing and other remote applications. Techniques, equipment, and guidelines which can improve the efficiency of remote maintenance are being developed. The Model M-2 Maintenance System, installed in the Integrated Equipment Test (IET) Facility at ORNL, provides a complete, integrated remote maintenance system for the demonstration and development of remote maintenance techniques. The system comprises a pair of force-reflecting servomanipulator arms, television viewing, lighting, and auxiliary lifting capabilities, thereby allowing manlike maintenance operations to be executed remotely within the remote cell mockup area in the IET. The Model M-2 Maintenance System incorporates an upgraded version of the proven Central Research Laboratories' Model M servomanipulator. Included are state-of-the-art brushless dc servomotors for improved performance, remotely removable wrist assemblies, geared azimuth drive, and a distributed microprocessor-based digital control system. 5 references, 8 figures

  5. Molecular mechanisms that regulate the macrophage M1/M2 polarization balance

    Directory of Open Access Journals (Sweden)

    Nan eWang

    2014-11-01

    Full Text Available As an essential component of innate immunity, macrophages have multiple functions in both inhibiting or promoting cell proliferation and tissue repair. Diversity and plasticity are hallmarks of macrophages. Classical M1 and alternative M2 activation of macrophages, mirroring the Th1–Th2 polarization of T cells, represent two extremes of a dynamic changing state of macrophage activation. M1-type macrophages release cytokines that inhibit the proliferation of surrounding cells and damage contiguous tissue, and M2-type macrophages release cytokines that promote the proliferation of contiguous cells and tissue repair. M1-M2 polarization of macrophage is a tightly controlled process entailing a set of signaling pathways, transcriptional and posttranscriptional regulatory networks. An imbalance of macrophage M1-M2 polarization is often associated with various diseases or inflammatory conditions. Therefore identification of the molecules associated with the dynamic changes of macrophage polarization and understanding their interactions is crucial for elucidating the molecular basis of disease progression and designing novel macrophage-mediated therapeutic strategies.

  6. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua.

    Directory of Open Access Journals (Sweden)

    Karen C Wheeler

    Full Text Available It is increasingly evident that cytokines and growth factors produced in the decidua play a pivotal role in the regulation of the local immune microenvironment and the establishment of pregnancy. One of the major growth factors produced in the decidua is vascular endothelial growth factor (VEGF, which acts not only on endothelial cells, but also on multiple other cell types, including macrophages. We sought to determine whether decidua-derived VEGF affects macrophage recruitment and polarization using human endometrial/decidual tissue samples, primary human endometrial stromal cells (ESCs, and the human monocyte cell line THP1. In situ hybridization was used for assessment of local VEGF expression and immunohistochemistry was used for identification and localization of CD68-positive endometrial macrophages. Macrophage migration in culture was assessed using a transwell migration assay, and the various M1/M2 phenotypic markers and VEGF expression were assessed using quantitative real-time PCR (qRT-PCR. We found dramatic increases in both VEGF levels and macrophage numbers in the decidua during early pregnancy compared to the secretory phase endometrium (non-pregnant, with a significant increase in M2 macrophage markers, suggesting that M2 is the predominant macrophage phenotype in the decidua. However, decidual samples from preeclamptic pregnancies showed a significant shift in macrophage phenotype markers, with upregulation of M1 and downregulation of M2 markers. In THP1 cultures, VEGF treatment significantly enhanced macrophage migration and induced M1 macrophages to shift to an M2 phenotype. Moreover, treatment with conditioned media from decidualized ESCs induced changes in macrophage migration and polarization similar to that of VEGF treatment. These effects were abrogated by the addition of a potent VEGF inhibitor. Together these results suggest that decidual VEGF plays a significant role in macrophage recruitment and M2 polarization, and

  7. M2 polarization of monocytes in ankylosing spondylitis and relationship with inflammation and structural damage.

    Science.gov (United States)

    Zhao, Jinzhu; Yuan, Wei; Tao, Chunsheng; Sun, Peifeng; Yang, Zaixing; Xu, Weidong

    2017-12-01

    The aim of this study was to evaluate the polarization of peripheral blood monocytes in the patients with ankylosing spondylitis (AS) and to determine the correlations between monocyte polarization and inflammation and structural damage. A total of 120 AS patients, 50 rheumatoid arthritis (RA) patients and 100 healthy controls were enrolled in the study. M1 (CD68+CD192+) and M2 (CX3CR1+CD163+) monocytes were characterized by flow cytometry. Demographic, clinical, radiographic and laboratory data were collected and analyzed. A large increase in M2 (CX3CR1+CD163+) monocytes was observed in AS, and M2/M1 ratio was 7.18 ± 6.12, 2.54 ± 3.14 and 35.61 ± 20.04 in control, RA and AS, respectively. The M2/M1 ratio correlated with modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) (r = 0.565; p Ankylosing Spondylitis Disease Activity Index (BASDAI) (r = -0.201; p = 0.028). Anti-TNF-α therapy induced a significant reduction in the percentage of M1 monocyte, ESR, CRP and BASDAI in AS patients. The present results demonstrated that M2 type polarized monocytes are predominant in the peripheral blood in AS and the M2/M1 ratio is correlated with structural damage (mSASSS), inflammatory biomarkers (ESR and CRP) and BASDAI. © 2017 APMIS. Published by John Wiley & Sons Ltd.

  8. M2-Branes in N = 3 Harmonic Superspace

    Directory of Open Access Journals (Sweden)

    E. Ivanov

    2010-01-01

    Full Text Available We give a brief account of the recently proposed N = 3 superfield formulation of the N = 6, 3D superconformal theory of Aharony et al (ABJM describing a low-energy limit of the system of multiple M2-branes on the AdS4×S7/Zk background. This formulation is given in harmonic N = 3 superspace and reveals a number of surprising new features. In particular, the sextic scalar potential of ABJM arises at the on-shell component level as the result of eliminating appropriate auxiliary fields, while there is no explicit superpotential at the off-shell superfield level.

  9. Resultados tipo Bernstein em M2 x R

    OpenAIRE

    Jose Wilker de Lima Silva

    2007-01-01

    Apresentaremos uma fÃrmula para o Laplaciano da funÃÃo Θ = onde f : Sigma ^ {n} → M^{n } à R à uma imersÃo com codimensÃo um, Sigma ^{n}à uma hiperfÃcie two-sided, T à um campo conforme em Sigma ^{n} à R e n à um campo unitÃrio normal a Sigma ^{n} em M^{n} à R. Usaremos tal fÃrmula para obtermos alguns resultados tipo Bernstein em M2 à R.

  10. Lie 3-algebra and multiple M2-branes

    International Nuclear Information System (INIS)

    Ho, Pei-Ming; Hou, Ru-Chuen; Matsuo, Yutaka

    2008-01-01

    Motivated by the recent proposal of an N = 8 supersymmetric action for multiple M2-branes, we study the Lie 3-algebra in detail. In particular, we focus on the fundamental identity and the relation with Nambu-Poisson bracket. Some new algebras not known in the literature are found. Next we consider cubic matrix representations of Lie 3-algebras. We show how to obtain higher dimensional representations by tensor products for a generic 3-algebra. A criterion of reducibility is presented. We also discuss the application of Lie 3-algebra to the membrane physics, including the Basu-Harvey equation and the Bagger-Lambert model.

  11. Lie 3-Algebra and Multiple M2-branes

    OpenAIRE

    Ho, Pei-Ming; Hou, Ru-Chuen; Matsuo, Yutaka

    2008-01-01

    Motivated by the recent proposal of an N=8 supersymmetric action for multiple M2-branes, we study the Lie 3-algebra in detail. In particular, we focus on the fundamental identity and the relation with Nambu-Poisson bracket. Some new algebras not known in the literature are found. Next we consider cubic matrix representations of Lie 3-algebras. We show how to obtain higher dimensional representations by tensor products for a generic 3-algebra. A criterion of reducibility is presented. We also ...

  12. Experiments with an 834 m2 ring laser interferometer

    Science.gov (United States)

    Hurst, R. B.; Stedman, G. E.; Schreiber, K. U.; Thirkettle, R. J.; Graham, R. D.; Rabeendran, N.; Wells, J.-P. R.

    2009-06-01

    An ultralarge ring He-Ne ring laser gyroscope, UG-2, with area 834 m2 and dimensions 39.7×21 m2, has been built underground at Cashmere Cavern, Christchurch, New Zealand (latitude -43.575°). Earth rotation is sufficient to unlock it, giving a Sagnac frequency of 2.18 kHz. Supermirrors are used with transmission ˜0.18 parts per million (ppm) and optical loss unexpectedly high at ˜200 ppm per reflection. The cavity Q is 1.5×1012. Residual Sagnac frequency error caused by backscatter coupling is measured as 1000 s, mechanical movement of the mirror assemblies, which act to change the geometrical dimensions and tilt. At all averaging times the residual rotational noise is well above the limit imposed by quantum phase fluctuations. It is concluded from comparisons among many large ring lasers that the excess mirror losses arise from high order aberrations, and UG-2 may be larger than the optimum size.

  13. Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophage activation.

    Directory of Open Access Journals (Sweden)

    Mirjam Stahl

    Full Text Available Idiopathic pulmonary fibrosis is characterized by abundant collagen production and accumulation of alternatively activated macrophages (M2 in the lower respiratory tract. Mechanisms as to how alveolar macrophages are activated by collagen breakdown products are unknown. Alveolar macrophages were obtained by bronchoalveolar lavage from 30 patients with idiopathic pulmonary fibrosis (IPF and 37 healthy donors (HD. Alveolar macrophages were cultured in the presence of collagen type I, III, IV and V monomers w/wo a neutralizing antibody against scavenger receptor I class A (CD204. Culture supernatants were assayed for the M2 markers CCL18, CCL2, and interleukin-1 receptor antagonist (IL-1ra by ELISA. Furthermore, expression of phospho-Akt was measured using ELISA and expression of CD204 by RT-PCR and flow cytometry. Stimulation with collagen type I and III monomers significantly up-regulated CCL18, IL-1ra production of alveolar macrophages. Furthermore, expression of CCL2 and CD204 were up-regulated by collagen type I exposure. In addition, collagen type I stimulation increased pospho-Akt expression. Collagen type I effects were abrogated by neutralizing antiCD204 and a non-selective Phosphatidylinositide 3-kinase inhibitor (LY294002. Spontaneous CD204 expression of alveolar macrophages was significantly increased in patients with IPF. In conclusion, our findings demonstrate that monomeric collagen type I via CD204 induces phospho-Akt expression shifting alveolar macrophages to the profibrotic M2 type. Innate immune responses induced by collagen monomers might perpetuate pulmonary fibrosis.

  14. LTE-advanced random access mechanism for M2M communication: A review

    Science.gov (United States)

    Mustafa, Rashid; Sarowa, Sandeep; Jaglan, Reena Rathee; Khan, Mohammad Junaid; Agrawal, Sunil

    2016-03-01

    Machine Type Communications (MTC) enables one or more self-sufficient machines to communicate directly with one another without human interference. MTC applications include smart grid, security, e-Health and intelligent automation system. To support huge numbers of MTC devices, one of the challenging issues is to provide a competent way for numerous access in the network and to minimize network overload. In this article, the different control mechanisms for overload random access are reviewed to avoid congestion caused by random access channel (RACH) of MTC devices. However, past and present wireless technologies have been engineered for Human-to-Human (H2H) communications, in particular, for transmission of voice. Consequently the Long Term Evolution (LTE) -Advanced is expected to play a central role in communicating Machine to Machine (M2M) and are very optimistic about H2H communications. Distinct and unique characteristics of M2M communications create new challenges from those in H2H communications. In this article, we investigate the impact of massive M2M terminals attempting random access to LTE-Advanced all at once. We discuss and review the solutions to alleviate the overload problem by Third Generation Partnership Project (3GPP). As a result, we evaluate and compare these solutions that can effectively eliminate the congestion on the random access channel for M2M communications without affecting H2H communications.

  15. Macrophages during the fibrotic process: M2 as friend and foe.

    Directory of Open Access Journals (Sweden)

    Tarcio Teodoro Braga

    2015-11-01

    Full Text Available Macrophages play essential activities in homeostasis maintenance, tissue regeneration and wound healing. However, when the physiological process of wound healing is deregulated by persistent insults and chronic diseases, macrophages can participate actively in the development of fibrosis. In this regard, the exacerbation or resolution of fibrosis depends on the type of macrophages polarized and the severity and duration of the inflammatory insult. M1 macrophages use glycolytic metabolism to optimize oxygen consumption and activate myofibroblasts and fibrocytes. On the other hand, M2 macrophages, which use oxidative metabolism, have anti-inflammatory properties due to their capacity to produce and secrete IL-10, TGFβ and arginase that promotes tissue repair. However, when the primary insult is not controlled and there is a persistent M2 macrophage activity, these cells promote ECM deposition through the continuous production of TGFβ and growth factors. In this scenario, M2 macrophages act as a break point between normal wound healing and the pro-fibrotic process. Here, we review the aspects of tissue repair based on macrophage biology and we evidence scar formation is directly related to the degree of inflammation, but also with the appearance of M2 macrophages.

  16. Microglia M2A Polarization as Potential Link between Food Allergy and Autism Spectrum Disorders

    Directory of Open Access Journals (Sweden)

    Hans O. Kalkman

    2017-12-01

    Full Text Available Atopic diseases are frequently co-morbid with autism spectrum disorders (ASD. Allergic responses are associated with an activation of mast cells, innate lymphoid cells, and Th2 cells. These cells produce type-2 cytokines (IL4 and IL13, which stimulate microglia and macrophages to adopt a phenotype referred to as ‘alternative activation’ or ‘M2A’. M2A-polarized macrophages and microglia play a physiological role in tissue repair by secreting growth factors such as brain-derived neurotrophic factor (BDNF and insulin-like growth factor-1. In ASD there is evidence for increased type-2 cytokines, microglia activation, M2A polarization, and increased levels of growth factors. In neurons, these growth factors drive a signal transduction pathway that leads to activation of the enzyme mammalian Target of Rapamycin (mTOR, and thereby to the inhibition of autophagy. Activation of mTOR is an effect that is also common to several of the genetic forms of autism. In the central nervous system, redundant synapses are removed via an autophagic process. Activation of mTOR would diminish the pruning of redundant synapses, which in the context of ASD is likely to be undesired. Based on this line of reasoning, atopic diseases like food allergy, eczema or asthma would represent risk factors for autism spectrum disorders.

  17. Human metapneumovirus M2-2 protein inhibits innate immune response in monocyte-derived dendritic cells.

    Directory of Open Access Journals (Sweden)

    Junping Ren

    Full Text Available Human metapneumovirus (hMPV is a leading cause of lower respiratory infection in young children, the elderly and immunocompromised patients. Repeated hMPV infections occur throughout life. However, immune evasion mechanisms of hMPV infection are largely unknown. Recently, our group has demonstrated that hMPV M2-2 protein, an important virulence factor, contributes to immune evasion in airway epithelial cells by targeting the mitochondrial antiviral-signaling protein (MAVS. Whether M2-2 regulates the innate immunity in human dendritic cells (DC, an important family of immune cells controlling antigen presenting, is currently unknown. We found that human DC infected with a virus lacking M2-2 protein expression (rhMPV-ΔM2-2 produced higher levels of cytokines, chemokines and IFNs, compared to cells infected with wild-type virus (rhMPV-WT, suggesting that M2-2 protein inhibits innate immunity in human DC. In parallel, we found that myeloid differentiation primary response gene 88 (MyD88, an essential adaptor for Toll-like receptors (TLRs, plays a critical role in inducing immune response of human DC, as downregulation of MyD88 by siRNA blocked the induction of immune regulatory molecules by hMPV. Since M2-2 is a cytoplasmic protein, we investigated whether M2-2 interferes with MyD88-mediated antiviral signaling. We found that indeed M2-2 protein associated with MyD88 and inhibited MyD88-dependent gene transcription. In this study, we also identified the domains of M2-2 responsible for its immune inhibitory function in human DC. In summary, our results demonstrate that M2-2 contributes to hMPV immune evasion by inhibiting MyD88-dependent cellular responses in human DC.

  18. M2e-tetramer-specific memory CD4 T cells are broadly protective against influenza infection.

    Science.gov (United States)

    Eliasson, D G; Omokanye, A; Schön, K; Wenzel, U A; Bernasconi, V; Bemark, M; Kolpe, A; El Bakkouri, K; Ysenbaert, T; Deng, L; Fiers, W; Saelens, X; Lycke, N

    2018-01-01

    Matrix protein 2 ectodomain (M2e) is considered an attractive component of a broadly protective, universal influenza A vaccine. Here we challenge the canonical view that antibodies against M2e are the prime effectors of protection. Intranasal immunizations of Balb/c mice with CTA1-3M2e-DD-generated M2e-specific memory CD4 T cells that were I-A d restricted and critically protected against infection, even in the complete absence of antibodies, as observed in JhD mice. Whereas some M2e-tetramer-specific memory CD4 T cells resided in spleen and lymph nodes, the majority were lung-resident Th17 cells, that rapidly expanded upon a viral challenge infection. Indeed, immunized IL-17A -/- mice were significantly less well protected compared with wild-type mice despite exhibiting comparable antibody levels. Similarly, poor protection was also observed in congenic Balb/B (H-2 b ) mice, which failed to develop M2e-specific CD4 T cells, but exhibited comparable antibody levels. Lung-resident CD69 + CD103 low M2e-specific memory CD4 T cells were αβ TCR + and 50% were Th17 cells that were associated with an early influx of neutrophils after virus challenge. Adoptively transferred M2e memory CD4 T cells were strong helper T cells, which accelerated M2e- but more importantly also hemagglutinin-specific IgG production. Thus, for the first time we demonstrate that M2e-specific memory CD4 T cells are broadly protective.

  19. Irradiation Promotes an M2 Macrophage Phenotype in Tumor Hypoxia

    International Nuclear Information System (INIS)

    Chiang, Chi-Shiun; Fu, Sheng Yung; Wang, Shu-Chi; Yu, Ching-Fang; Chen, Fang-Hsin; Lin, Chi-Min; Hong, Ji-Hong

    2012-01-01

    Macrophages display different phenotypes with distinct functions and can rapidly respond to environmental changes. Previous studies on TRAMP-C1 tumor model have shown that irradiation has a strong impact on tumor microenvironments. The major changes include the decrease of microvascular density, the increase of avascular hypoxia, and the aggregation of tumor-associated macrophages in avascular hypoxic regions. Similar changes were observed no matter the irradiation was given to tissue bed before tumor implantation (pre-IR tumors), or to established tumors (IR tumors). Recent results on three murine tumors, TRAMP-C1 prostate adenocarcinoma, ALTS1C1 astrocytoma, and GL261 glioma, further demonstrate that different phenotypes of inflammatory cells are spatially distributed into different microenvironments in both IR and pre-IR tumors. Regions with avascular hypoxia and central necrosis have CD11b high /Gr-1+ neutrophils in the center of the necrotic area. Next to them are CD11b low /F4/80+ macrophages that sit at the junctions between central necrotic and surrounding hypoxic regions. The majority of cells in the hypoxic regions are CD11b low /CD68+ macrophages. These inflammatory cell populations express different levels of Arg I. This distribution pattern, except for neutrophils, is not observed in tumors receiving chemotherapy or an anti-angiogenesis agent which also lead to avascular hypoxia. This unique distribution pattern of inflammatory cells in IR tumor sites is interfered with by targeting the expression of a chemokine protein, SDF-1α, by tumor cells, and this also increases radiation-induced tumor growth delay. This indicates that irradiated-hypoxia tissues have distinct tumor microenvironments that favor the development of M2 macrophages and that is affected by the levels of tumor-secreted SDF-1α.

  20. Non-Neuronal Functions of the M2 Muscarinic Acetylcholine Receptor

    Directory of Open Access Journals (Sweden)

    Ritva Tikkanen

    2013-04-01

    Full Text Available Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal systems, it has become evident that acetylcholine also plays an important role in non-neuronal cells such as epithelial and immune cells. Furthermore, many cell types in the periphery are capable of synthesizing acetylcholine and express at least some of the receptors. In this review, we summarize the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of the M2 muscarinic receptor in epithelial cells. We will review the mechanisms of signaling by the M2 receptor but also the cellular trafficking and ARF6 mediated endocytosis of this receptor, which play an important role in the regulation of signaling events. In addition, we provide an overview of the M2 receptor in human pathological conditions such as autoimmune diseases and cancer.

  1. Alternatively Activated (M2 Macrophage Phenotype Is Inducible by Endothelin-1 in Cultured Human Macrophages.

    Directory of Open Access Journals (Sweden)

    Stefano Soldano

    contrasted by ETA/BRA treatment in both cultured cell types.ET-1 seems to induce the M2 phenotype in cultured human macrophages, a process apparently contrasted by the action of the ETA/BRA, suggesting possible clinical implications in those fibrotic diseases characterized by increased ET-1 concentrations, such as systemic sclerosis but also type 2 diabetes.

  2. Study on surface modification of M2 steel induced by Cu ions and Al ions implantation

    International Nuclear Information System (INIS)

    Wang Chao; Liu Zhengmin

    2001-01-01

    Changes of surface hardness and wear resistances in M2 type steel implanted by Cu Al ions were reported. The dependence of surface strengthening on ion species and dose was studied by X-ray diffraction (XRD) and Rutherford Backscattering Spectroscopy (RBS) for microhardness and wear resistances measurement. It is shown that both hardness and wear resistance increases apparently after ion implantation. XRD analysis indicates that different phases formed after Al Cu ions implanted. It is also suggested that Cu, Al ions have different role in surface strengthening

  3. Dy 3-activated M2SiO4 (M= Ba, Mg, Sr)-type phosphors

    Indian Academy of Sciences (India)

    ... i.e., mixing and grinding of solid form precursors followedby high-temperature heat treatments of several hours in furnaces, generally under open atmosphere and investigated by X-ray diffraction (XRD) to get phase properties and photoluminescence (PL) analysis to get luminescenceproperties. The thermal behaviours of ...

  4. A stringy origin of M2 brane Chern-Simons theories

    International Nuclear Information System (INIS)

    Aganagic, Mina

    2010-01-01

    We show that string duality relates M-theory on a local Calabi-Yau fourfold singularity X 4 to type IIA string theory on a Calabi-Yau threefold X 3 fibered over a real line, with RR 2-form fluxes turned on. The RR flux encodes how the M-theory circle is fibered over the IIA geometry. The theories on N D2 branes probing X 3 are the well-known quiver theories with N=2 supersymmetry in three dimensions. We show that turning on fluxes, and fibering the X 3 over a direction transverse to the branes, corresponds to turning on N=2 Chern-Simons couplings. String duality implies that, in the strong coupling limit, the N D2 branes on X 3 in this background become N M2 branes on X 4 . This provides a string theory derivation for the recently conjectured description of the M2 brane theories on Calabi-Yau fourfolds in terms of N=2 quiver Chern-Simons theories. We also provide a new N=2 Chern-Simons theory dual to AdS 4 xQ 1,1,1 . Type IIA/M-theory duality also relates IIA string theory on X 3 with only the RR fluxes turned on, to M-theory on a G 2 holonomy manifold. We show that this implies that the N M2 branes probing the G 2 manifold are described by the quiver Chern-Simons theory originating from the D2 branes probing X 3 , except that now Chern-Simons terms preserve only N=1 supersymmetry in three dimensions.

  5. Effect of Fe-chelating complexes on a novel M2FC performance with ferric chloride and ferricyanide catholytes.

    Science.gov (United States)

    Chung, Kyungmi; Lee, Ilgyu; Han, Jong-In

    2012-01-01

    As an effort to better utilize the microbial fuel cell (MFC) technology, we previously proposed an innovative MFC system named M2FC consisting of ferric-based MFC part and ferrous-based fuel cell (FC) part. In this reactor, ferric ion, the catholyte in the MFC part, was efficiently regenerated by the FC part with the generation of additional electricity. When both units were operated separately, the ferric-based MFC part produced approximately 1360 mW m(-2) of power density with FeCl(3) as catholyte and Fe-citrate as anolyte. The ferrous-based FC part with FeCl(3) as catholyte and Fe-EDTA as anolyte displayed the highest power density (1500 mW m(-2)), while that with ferricyanide as catholyte and Fe-noligand as anolyte had the lowest power density (380 mW m(-2)). The types of catholytes and chelating complexes as anolyte were found to play important roles in the reduction of ferric ions and oxidation of ferrous ion. Linear sweep voltammetry results supported that the cathode electrolytes were electrically active and these agreed well with the M2FC reactor performance. These results clearly showed that ligands played critical role in the efficiency and rate for recycling iron ion and thus the M2FC performance. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation.

    Science.gov (United States)

    Yue, Shi; Rao, Jianhua; Zhu, Jianjun; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Lu, Ling; Wang, Xuehao; Zhai, Yuan

    2014-06-01

    Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-α and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation. Copyright © 2014 by The American Association of Immunologists, Inc.

  7. Endovascular Therapy of M2 Occlusion in IMS III: Role of M2 Segment Definition and Location on Clinical and Revascularization Outcomes.

    Science.gov (United States)

    Tomsick, T A; Carrozzella, J; Foster, L; Hill, M D; von Kummer, R; Goyal, M; Demchuk, A M; Khatri, P; Palesch, Y; Broderick, J P; Yeatts, S D; Liebeskind, D S

    2017-01-01

    Uncertainty persists regarding the safety and efficacy of endovascular therapy of M2 occlusions following IV tPA. We reviewed the impact of revascularization on clinical outcomes in 83 patients with M2 occlusions in the Interventional Management of Stroke III trial according to specific M1-M2 segment anatomic features. Perfusion of any M2 branch distinguished M2-versus-M1 occlusion. Prespecified modified TICI and arterial occlusive lesion revascularization and clinical mRS 0-2 end points at 90 days for endovascular therapy-treated M2 occlusions were analyzed. Post hoc analyses of the relationship of outcomes to multiple baseline angiographic M2 and M1 subgroup characteristics were performed. Of 83 participants with M2 occlusion who underwent endovascular therapy, 41.0% achieved mRS 0-2 at 90 days, including 46.6% with modified TICI 2-3 reperfusion compared with 26.1% with modified TICI 0-1 reperfusion (risk difference, 20.6%; 95% CI, -1.4%-42.5%). mRS 0-2 outcome was associated with reperfusion for M2 trunk (n = 9) or M2 division (n = 42) occlusions, but not for M2 branch occlusions (n = 28). Of participants with trunk and division occlusions, 63.2% with modified TICI 2a and 42.9% with modified TICI 2b reperfusion achieved mRS 0-2 outcomes; mRS 0-2 outcomes for M2 trunk occlusions (33%) did not differ from distal (38.2%) and proximal (26.9%) M1 occlusions. mRS 0-2 at 90 days was dependent on reperfusion for M2 trunk but not for M2 branch occlusions. For M2 division occlusions, good outcome with modified TICI 2b reperfusion did not differ from that in modified TICI 2a. M2 segment definition and occlusion location may contribute to differences in revascularization and good outcome between Interventional Management of Stroke III and other endovascular therapy studies. © 2017 by American Journal of Neuroradiology.

  8. Activation of CECR1 in M2-like TAMs promotes paracrine stimulation-mediated glial tumor progression

    NARCIS (Netherlands)

    Zhu, Changbin; Mustafa, Dana; Zheng, Ping-Pin; van der Weiden, Marcel; Sacchetti, Andrea; Brandt, Maarten; Chrifi, Ihsan; Tempel, D.|info:eu-repo/dai/nl/413983471; Leenen, Pieter J M; Duncker, Dirk Jan; Cheng, Caroline|info:eu-repo/dai/nl/29115106X; Kros, Johan M

    2017-01-01

    Background.: The majority of glioma-associated microglia/macrophages have been identified as M2-type macrophages with immune suppressive and tumor supportive action. Recently, the extracellular adenosine deaminase protein Cat Eye Syndrome Critical Region Protein 1 (CECR1) was shown to regulate

  9. PPARγ ligands switched high fat diet-induced macrophage M2b polarization toward M2a thereby improving intestinal Candida elimination

    DEFF Research Database (Denmark)

    Lefèvre, Lise; Galès, Amandine; Olagnier, David

    2010-01-01

    of Candida albicans through the activation of alternative M2 macrophage polarization. Here, we evaluated the impact of high fat diet (HFD)-induced obesity and the effect of rosiglitazone (PPARγ ligand) or WY14643 (PPARα ligand) both on the phenotypic M1/M2 polarization of peritoneal and cecal tissue...

  10. N = 6 superconformal Chern-Simons-matter theories, M2-branes and their gravity duals

    International Nuclear Information System (INIS)

    Aharony, Ofer; Bergman, Oren; Maldacena, Juan; Jafferis, Daniel Louis

    2008-01-01

    We construct three dimensional Chern-Simons-matter theories with gauge groups U(N) x U(N) and SU(N) x SU(N) which have explicit N = 6 superconformal symmetry. Using brane constructions we argue that the U(N) x U(N) theory at level k describes the low energy limit of N M2-branes probing a C 4 /Z k singularity. At large N the theory is then dual to M-theory on AdS 4 x S 7 /Z k . The theory also has a 't Hooft limit (of large N with a fixed ratio N/k) which is dual to type IIA string theory on AdS 4 x CP 3 . For k = 1 the theory is conjectured to describe N M2-branes in flat space, although our construction realizes explicitly only six of the eight supersymmetries. We give some evidence for this conjecture, which is similar to the evidence for mirror symmetry in d = 3 gauge theories. When the gauge group is SU(2) x SU(2) our theory has extra symmetries and becomes identical to the Bagger-Lambert theory.

  11. Reliable Radio Access for Massive Machine-to-Machine (M2M) Communication

    DEFF Research Database (Denmark)

    Madueño, Germán Corrales

    as the preferable solution for M2M, no mechanisms are in place to guarantee reliable M2M access. Contrary to mainstream solutions that focus on preventing overload, we introduce mechanisms to provide reliable M2M service. We also investigate what cellular networks can do about upcoming smart metering traffic...

  12. Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein

    DEFF Research Database (Denmark)

    Andersson, Anne-Marie Carola; Håkansson, Kjell Ove; Jensen, Benjamin Anderschou Holbech

    2012-01-01

    by diverse influenza A viruses, a vaccine (M2e-NSP4) was constructed linking M2e (in its consensus sequence) to the rotavirus fragment NSP4(98-135); due to its coiled-coil region this fragment is known to form tetramers in aqueous solution and in this manner we hoped to mimick the natural configuration of M2...

  13. Esophageal xanthoma: presence of M2 macrophages suggests association with late inflammatory and reparative processes

    Directory of Open Access Journals (Sweden)

    Uehara Karina

    2017-10-01

    Full Text Available Esophageal xanthoma is a rare lesion which is an asymptomatic small yellowish polyp, and most of the reported cases were solitary lesion. Histologically, aggregations of foam cells are found under the papillary hypertrophic squamous epithelium and the foam cells express CD68. The etiology of esophageal xanthoma is unknown. The focal irritation of the esophageal mucosa and infiltrated inflammatory cells are presumed to contribute to its pathogenesis. Although the pathogenesis may be associated with inflammation, the type and nature of the macrophages remain unclear. Here we report a 46-year-old male with esophageal xanthoma, which was incidentally found by endoscopy. Histologically, acute inflammation was not noted, and immunohistochemistry revealed that the foam cells seen in this case of esophageal xanthoma expressed increased levels of M2 macrophage markers. These findings suggest that esophageal xanthoma is associated with late inflammatory and reparative processes long after the initial inflammation of esophageal squamous epithelium.

  14. M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway

    DEFF Research Database (Denmark)

    Madsen, Daniel H; Leonard, Daniel; Masedunskas, Andrius

    2013-01-01

    Tissue remodeling processes critically depend on the timely removal and remodeling of preexisting collagen scaffolds. Nevertheless, many aspects related to the turnover of this abundant extracellular matrix component in vivo are still incompletely understood. We therefore took advantage of recent...... advances in optical imaging to develop an assay to visualize collagen turnover in situ and identify cell types and molecules involved in this process. Collagen introduced into the dermis of mice underwent cellular endocytosis in a partially matrix metalloproteinase-dependent manner and was subsequently...... routed to lysosomes for complete degradation. Collagen uptake was predominantly executed by a quantitatively minor population of M2-like macrophages, whereas more abundant Col1a1-expressing fibroblasts and Cx3cr1-expressing macrophages internalized collagen at lower levels. Genetic ablation...

  15. M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1/M2 Monocytes to Osteoclastogenesis

    Directory of Open Access Journals (Sweden)

    Shoichi Fukui

    2018-01-01

    Full Text Available ObjectivesWe investigated the relationships among M1 monocytes, M2 monocytes, osteoclast (OC differentiation ability, and clinical characteristics in patients with rheumatoid arthritis (RA.MethodsPeripheral blood mononuclear cells (PBMCs were isolated from RA patients and healthy donors, and we then investigated the number of M1 monocytes or M2 monocytes by fluorescence-activated cell sorting. We also obtained and cultured CD14-positive cells from PBMCs from RA patients and healthy donors to investigate OC differentiation in vitro.ResultsForty RA patients and 20 healthy donors were included. Twenty-two patients (55% were anticitrullinated protein antibody (ACPA positive. The median M1/M2 ratio was 0.59 (0.31–1.11, interquartile range. There were no significant differences between the RA patients and healthy donors. There was a positive correlation between the M1/M2 ratio and the differentiated OC number in vitro in RA patients (ρ = 0.81, p < 0.001. The ACPA-positive patients had significantly higher M1/M2 ratios in vivo (p = 0.028 and significantly greater numbers of OCs in vitro (p = 0.005 than the ACPA-negative patients. Multivariable regression analysis revealed that the M1/M2 ratio was the sole significant contribution factor to in vitro osteoclastogenesis. RA patients with M1/M2 ratios >1 (having relatively more M1 monocytes had higher C-reactive protein and erythrocyte sedimentation rates than RA patients with M1/M2 ratios ≤1. M1-dominant monocytes in vitro produced higher concentrations of interleukin-6 upon stimulation with lipopolysaccharide than M2 monocytes.ConclusionM1/M2 monocytes imbalance strongly contributes to osteoclastogenesis of RA patients. Our findings cast M1 and M2 monocyte subsets in a new light as a new target of treatments for RA to prevent progression of osteoclastic bone destruction.

  16. Characterization of the M2 autoantigen of central nervous system (CNS) myelin as a glycoproteins(s) also expressed on oligodendrocyte membrane

    Energy Technology Data Exchange (ETDEWEB)

    Lebar, R.; Lubetzki, C.; Vincent, C.; Lombrail, P.; Boutry, J.M.

    1986-03-01

    Guinea pigs immunized with homologous brain tissue develop an acute experimental allergic encephalomyelitis and their sera contain demyelinating antibodies. These antibodies were used to characterize the target: the unidentified autoantigen M2. Using both the Dot immunobinding technique and autoradiography of immunoprecipitates formed with radiolabelled guinea-pig myelin and analyzed in SDS acrylamide gel electrophoresis, M2 was found to be a component of CNS myelin and not peripheral nervous system (PNS) myelin. In the Dot technique anti-M2 serum did not react with myelin basic protein (BP), proteolipid and galactocerebroside (GC). On electrophoresis, in reducing and non reducing conditions, M2 appeared as two CNS myelin protein bands at the 27,000 and 54,000 molecular weight levels, distinct from the CNS myelin major protein bands of proteolipid protein and BP. Affinity chromatography of CNS myelin on wheat germ agglutinin Sepharose showed that M2 bands were of glycoprotein nature. The same M2 bands were formed with guinea pig antibodies and rat, rabbit or bovine CNS myelin. The same type of anti-M2 antibodies were induced in rabbits immunized with homologous CNS tissue. As a component of myelin, M2 was present in white matter tracts of CNS tissue sections tested by immunofluorescence. Furthermore, M2 was expressed on rat oligodendrocyte membrane in one day and 8 day in vitro cultures.

  17. Reexamination of M2,3 atomic level widths and L1M2,3 transition energies of elements 69≤Z≤95

    Science.gov (United States)

    Fennane, K.; Berset, M.; Dousse, J.-Cl.; Hoszowska, J.; Raboud, P.-A.; Campbell, J. L.

    2013-11-01

    We report on high-resolution measurements of the photoinduced L1M2 and L1M3 x-ray emission lines of 69Tm, 70Yb, 71Lu, 73Ta, 74W, 75Re, 77Ir, 81Tl, 83Bi, and 95Am. From the linewidths of the measured transitions an accurate set of M2 and M3 level widths is determined assuming for the L1 level widths the values reported by Raboud [P.-A. Raboud et al., Phys. Rev. APLRAAN1050-294710.1103/PhysRevA.65.022512 65, 022512 (2002)]. Furthermore, the present experimental M2,3 data set is extended to 80Hg, 90Th, and 92U, using former L1M2,3 high-resolution x-ray emission spectroscopy measurements performed by our group. A detailed comparison of the M2 and M3 level widths determined in the present work with those recommended by Campbell and Papp [J. L. Campbell and T. Papp, At. Data Nucl. Data TablesADNDAT0092-640X10.1006/adnd.2000.0848 77, 1 (2001)] and other available experimental data as well as theoretical predictions is done. The observed abrupt changes of the M2,3 level widths versus atomic number Z can be explained satisfactorily by the cutoffs and onsets of the M2M4N1, respectively M3M4N3,4,5 and M3M5N2,3 Coster-Kronig transitions deduced from the semiempirical (Z+1) approximation. As a spin-off result of this study, precise L1M2 and L1M3 transition energies are obtained for the investigated elements. A very good agreement with transition energies calculated within the many-body perturbation theory is found.

  18. Effects of bimetallic doping on small cyclic and tubular boron clusters: B7M2 and B14M2 structures with M = Fe, Co.

    Science.gov (United States)

    Pham, Hung Tan; Nguyen, Minh Tho

    2015-07-14

    Using density functional theory with the TPSSh functional and the 6-311+G(d) basis set, we extensively searched for the global minima of two metallic atoms doped boron clusters B6M2, B7M2, B12M2 and B14M2 with transition metal element M being Co and Fe. Structural identifications reveal that B7Co2, B7Fe2 and B7CoFe clusters have global minima in a B-cyclic motif, in which a perfectly planar B7 is coordinated with two metallic atoms placed along the C7 axis. The B6 cluster is too small to form a cycle with the presence of two metals. Similarly, the B12 cluster is not large enough to stabilize the metallic dimer within a double ring 2 × B6 tube. The doped B14M2 clusters including B14Co2, B14Fe2 and B14CoFe have a double ring 2 × B7 tubular shape in which one metal atom is encapsulated by the B14 tube and the other is located at an exposed position. Dissociation energies demonstrate that while bimetallic cyclic cluster B7M2 prefers a fragmentation channel that generates the B7 global minimum plus metallic dimer, the tubular structure B14M2 tends to dissociate giving a bimetallic cyclic structure B7M2 and a B@B6 cluster. The enhanced stability of the bimetallic doped boron clusters considered can be understood from the stabilizing interactions between the anti-bonding MOs of metal-metal dimers and the levels of a disk aromatic configuration (for bimetallic cyclic structures), or the eigenstates of the B14 tubular form (in case of bimetallic tubular structure).

  19. Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

    Directory of Open Access Journals (Sweden)

    Tamás Rőszer

    2015-01-01

    Full Text Available The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed.

  20. Immunological Assessment of Three Tandem Repeat of Influenza Virus M2 Extracellular Domain with Adjuvant in Balb/c Mice Model

    Directory of Open Access Journals (Sweden)

    Hadiseh Shokouhi

    2016-04-01

    Full Text Available Abstract Background: Influenza A viruses are globally important respiratory pathogens which cause a high degree of morbidity and mortality during annual epidemics. M2 protein which expressed on the viral surface facilitates virus entry to the host cells. The extracellular domain of M2 protein (M2e consists of N-terminal 24 residue which shows remarkable conservation among all subtypes of influenza A viruses. In this study, we evaluated the immunogenicity of three tandem repeats of M2e along with different adjuvants in BALB/C mice model. Materials and Methods: Recombinant protein (3M2e was expressed in Escherichia coli and purified. Six weeks old BALB/c mice were immunized interdermally with three doses of 3M2e alone or supplemented with Alum/CpG motif as adjuvant. Control group was injected with PBS. Two weeks after the last immunization, specific anti-M2 was measured using ELISA method and finally mice were challenged with one lethal dose (LD90 of PR8 virus. Results: The results showed that 3M2e can induce specific antibody alone. However, 3M2e protein supplemented with Alum-CpG induced higher level of specific antibodies, so that, there was a significant difference with 3M2e group (p<0.05. Anti-M2 antibodies mostly consisted of IgG2a subclass which considered as activity index of TH1 Cells. Moreover, this group showed enhanced protection against wild-type virus (survival rate=60%. Conclusion: Applying Alum-CpG as a complex adjuvant may play a crucial role in integrating innate and acquisitive immunity. We increased density of M2e in combination with complex adjuvant and showed that this vaccine induced power immune responses and semi-protected mice against lethal challenge.

  1. Transcriptome analysis of IL-10-stimulated (M2c) macrophages by next-generation sequencing.

    Science.gov (United States)

    Lurier, Emily B; Dalton, Donald; Dampier, Will; Raman, Pichai; Nassiri, Sina; Ferraro, Nicole M; Rajagopalan, Ramakrishan; Sarmady, Mahdi; Spiller, Kara L

    2017-07-01

    Alternatively activated "M2" macrophages are believed to function during late stages of wound healing, behaving in an anti-inflammatory manner to mediate the resolution of the pro-inflammatory response caused by "M1" macrophages. However, the differences between two main subtypes of M2 macrophages, namely interleukin-4 (IL-4)-stimulated "M2a" macrophages and IL-10-stimulated "M2c" macrophages, are not well understood. M2a macrophages are characterized by their ability to inhibit inflammation and contribute to the stabilization of angiogenesis. However, the role and temporal profile of M2c macrophages in wound healing are not known. Therefore, we performed next generation sequencing (RNA-seq) to identify biological functions and gene expression signatures of macrophages polarized in vitro with IL-10 to the M2c phenotype in comparison to M1 and M2a macrophages and an unactivated control (M0). We then explored the expression of these gene signatures in a publicly available data set of human wound healing. RNA-seq analysis showed that hundreds of genes were upregulated in M2c macrophages compared to the M0 control, with thousands of alternative splicing events. Following validation by Nanostring, 39 genes were found to be upregulated by M2c macrophages compared to the M0 control, and 17 genes were significantly upregulated relative to the M0, M1, and M2a phenotypes (using an adjusted p-value cutoff of 0.05 and fold change cutoff of 1.5). Many of the identified M2c-specific genes are associated with angiogenesis, matrix remodeling, and phagocytosis, including CD163, MMP8, TIMP1, VCAN, SERPINA1, MARCO, PLOD2, PCOCLE2 and F5. Analysis of the macrophage-conditioned media for secretion of matrix-remodeling proteins showed that M2c macrophages secreted higher levels of MMP7, MMP8, and TIMP1 compared to the other phenotypes. Interestingly, temporal gene expression analysis of a publicly available microarray data set of human wound healing showed that M2c-related genes were

  2. m2 « -m2

    Indian Academy of Sciences (India)

    . We shall focus in this talk on the horizontal U(1) symmetry [19,21], which is the simplest version of the generalized 'alignment' mechanism and has an interesting link to the D-term supersymmtry breaking. We shall consider U(1) models with ...

  3. X-ray spectra, chemical bonding, and electron structure of ScM2Si2 (M = Fe, Co, Ni)

    International Nuclear Information System (INIS)

    Shcherba, I.D.; Kotur, B.Ya.

    1990-01-01

    In a study of the interaction of the components in the ternary systems Sc-M-Si (where M is a 3d transition metal) it was established that there are compounds of the empirical formula ScM 2 Si 2 (M = Fe, Co, Ni). They crystallize in two structural types, HfFe 2 Si 2 (the compound ScFe 2 Si 2 ) and CeGa 2 Al 2 (ScCo 2 Si 2 and ScNi 2 Si 2 ) (ref. 1), leading to different coordination environment of the atoms in the structures of the compounds. With the aim of investigating the electron structure and the type ofin these compounds, they authors made a systematic x-ray spectral investigation with simultaneous analysis of the crystal structures of ScM 2 Si 2

  4. Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages

    Science.gov (United States)

    2014-01-01

    -6 and tumor necrosis factor α were evaluated using enzyme-linked immunosorbent assay. Furthermore, macrophage-depleted mice with intramuscular injection of glycerol were subjected to a single injection of different types of RAW 264.7 macrophages. Mice infused with M0 and M1 macrophages suffered a more severe histological and functional injury, while mice transfused with MSC-educated M2 macrophages showed reduced kidney injury. Conclusions Our findings suggested that MSCs can ameliorate rhabdomyolysis-induced AKI via the activation of macrophages to a trophic M2 phenotype, which supports the transition from tubule injury to tubule repair. PMID:24961539

  5. Disruption of the M2 gene of murine gammaherpesvirus 68 alters splenic latency following intranasal, but not intraperitoneal, inoculation.

    Science.gov (United States)

    Jacoby, Meagan A; Virgin, Herbert W; Speck, Samuel H

    2002-02-01

    Infection of mice with murine gammaherpesvirus 68 (gamma HV68; also referred to as MHV68) provides a tractable small-animal model with which to address the requirements for the establishment and maintenance of gammaherpesvirus infection in vivo. The M2 gene of gamma HV68 is a latency-associated gene that encodes a protein lacking discernible homology to any known viral or cellular proteins. M2 gene transcripts have been detected in latently infected splenocytes (S. M. Husain, E. J. Usherwood, H. Dyson, C. Coleclough, M. A. Coppola, D. L. Woodland, M. A. Blackman, J. P. Stewart, and J. T. Sample, Proc. Natl. Acad. Sci. USA 96:7508-7513, 1999; H. W. Virgin IV, R. M. Presti, X. Y. Li, C. Liu, and S. H. Speck, J. Virol. 73:2321-2332, 1999) and peritoneal exudate cells (H. W. Virgin IV, R. M. Presti, X. Y. Li, C. Liu, and S. H. Speck, J. Virol. 73:2321-2332, 1999), as well as in a latently gamma HV68-infected B-lymphoma cell line (S. M. Husain, E. J. Usherwood, H. Dyson, C. Coleclough, M. A. Coppola, D. L. Woodland, M. A. Blackman, J. P. Stewart, and J. T. Sample, Proc. Natl. Acad. Sci. USA 96:7508-7513, 1999). Here we describe the generation of gamma HV68 mutants with disruptions in the M2 gene. Mutation of the M2 gene did not affect the ability of the virus to replicate in tissue culture, nor did it affect gamma HV68 virulence in B6.Rag1 deficient mice. However, we found that M2 was differentially required for acute replication in vivo. While mutation of M2 did not affect acute phase of virus replication in the lungs of mice following intranasal inoculation, acute-phase virus replication in the spleen was decreased compared to that of the wild-type and marker rescue viruses following intraperitoneal inoculation. Upon intranasal inoculation, M2 mutant viruses exhibited a significant decrease in the establishment of latency in the spleen on day 16 postinfection, as measured by the frequency of viral genome-positive cells. In addition, M2 mutant viral genome

  6. M2 macrophages exhibit higher sensitivity to oxLDL-induced lipotoxicity than other monocyte/macrophage subtypes

    Directory of Open Access Journals (Sweden)

    Isa Suleiman A

    2011-12-01

    Full Text Available Abstract Background In obesity, phenotypic switches occur in macrophage populations such that the predominantly M2-polarised anti-inflammatory state seen in lean individuals changes to a predominantly M1-polarised pro-inflammatory state in those who are obese. However, the mechanisms by which these phenotypic shifts occur have not yet been fully elucidated. Results The effects of oxLDL (1-40 μg/ml; 24 h on several parameters relevant to the Unfolded Protein Response (UPR-mediated lipotoxic effects of oxLDL (disruption of ER Ca2+ handling; activation of the UPR transcription factor XBP-1; upregulation of the UPR target genes BiP and CHOP; apoptosis; cell viability were investigated in human primary monocyte-derived macrophages, and also in monocyte-macrophages derived from the THP-1 monocytic cell line. A consistent pattern was observed: M2-polarised macrophages were more sensitive to the lipotoxic effects of oxLDL than either non-polarised macrophages or non-differentiated monocytic cells. Specifically, M2-polarised macrophages were the only cell type to undergo significantly increased apoptosis (Primary cells: 1.23 ± 0.01 basal; THP-1-derived: 1.97 ± 0.12 basal; P P Conclusions We propose that the enhanced susceptibility of M2-polarised macrophages to lipotoxicity seen in the present in vitro study could, over time, contribute to the phenotypic shift seen in obese individuals in vivo. This is because a higher degree of oxLDL-induced lipotoxic cell death within M2 macrophages could contribute to a decrease in numbers of M2 cells, and thus a relative increase in proportion of non-M2 cells, within macrophage populations. Given the pro-inflammatory characteristics of a predominantly M1-polarised state, the data presented here may constitute a useful contribution to our understanding of the origin of the pro-inflammatory nature of obesity, and of the pathogenesis of obesity-associated inflammatory disorders such as Type 2 Diabetes and

  7. Infiltration of M2 Tumor-Associated Macrophages in Oral Squamous Cell Carcinoma Correlates with Tumor Malignancy

    Energy Technology Data Exchange (ETDEWEB)

    Mori, Kazumasa [Division of Oral and Maxillofacial Surgery, Department of Diagnosis and Therapeutics, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283 (Japan); Hiroi, Miki [Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283 (Japan); Shimada, Jun [Division of Oral and Maxillofacial Surgery, Department of Diagnosis and Therapeutics, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283 (Japan); Ohmori, Yoshihiro, E-mail: ohmori@dent.meikai.ac.jp [Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283 (Japan)

    2011-09-28

    Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment of many solid tumors. The functional competence of TAMs varies depending on the type of tumors and their respective microenvironments. The classically activated M1 macrophages exhibit antitumor functions, whereas the alternatively activated M2 macrophages exhibit protumor functions that contribute to tumor development and progression. Although TAMs have been detected in oral squamous cell carcinoma (OSCC), little is known about their phenotype. In the present study, we performed an immunohistochemical analysis to identify TAMs in surgically resected specimens from 50 patients with OSCC and evaluated the relationship between infiltrated TAMs and the pathological grade of OSCC. Positive staining for CD163, which has been used as a marker for M2 macrophages, was observed in OSCC specimens, and the percentages of CD163{sup +} cells were significantly increased based on the pathological grade. CD163{sup +} cells were detected in the tumor stroma in grade I tumors, whereas an increase in the CD163{sup +} cells in the tumor nest was observed in higher grades of tumors. Although infiltrated CD4{sup +} and CD8{sup +} T cells were detected in all pathological grades of OSCC, no correlation between the infiltrated T cells and the CD163{sup +} TAMs was observed. These results indicate that the infiltrated TAMs in OSCC have an M2 phenotype and that the M2 macrophages may participate in the development of OSCC.

  8. Comparison of Plasma Tu-M2-PK and CA19-9 in Pancreatic Cancer

    DEFF Research Database (Denmark)

    Joergensen, Maiken Thyregod; Heegaard, Niels H H; Schaffalitzky de Muckadell, Ove B

    2009-01-01

    alone. The presence of chronic pancreatitis or jaundice causes increased levels of CA19-9 but does not influence Tu-M2-PK. CONCLUSIONS:: Tu-M2-PK was inferior to CA19-9 as marker of PDAC. Tu-M2-PK may have a role in diagnosing PDAC because it is not affected by cholestasis or Lewis phenotype. Neither...

  9. A new sarasinoside congener, sarasinoside M2, from a marine sponge collected in the Solomon Islands.

    Science.gov (United States)

    Puilingi, Clyde Gorapava; Kudo, Yuta; Cho, Yuko; Konoki, Keiichi; Yotsu-Yamashita, Mari

    2017-02-01

    A new sarasinoside congener (sarasinoside M 2 ) and known sarasinoside B 1 were obtained from a marine sponge. Sarasinoside M 2 was suggested to have the same aglycon as sarasinoside M although the internal glucose in its sugar moiety is replaced by xylose. Sarasinosides B 1 and M 2 showed moderate cytotoxicity (approximate IC 50 5-18 μM) toward Neuro-2a and HepG2 cell lines.

  10. Distributed Energy-Efficient Topology Control Algorithm in Home M2M Networks

    OpenAIRE

    Lee, Chao-Yang; Yang, Chu-Sing

    2012-01-01

    Because machine-to-machine (M2M) technology enables machines to communicate with each other without human intervention, it could play a big role in sensor network systems. Through wireless sensor network (WSN) gateways, various information can be collected by sensors for M2M systems. For home M2M networks, this study proposes a distributed energy-efficient topology control algorithm for both topology construction and topology maintenance. Topology control is an effective method of enhancing e...

  11. M2-F1 lifting body and Paresev 1B on ramp

    Science.gov (United States)

    1963-01-01

    In this photo of the M2-F1 lifting body and the Paresev 1B on the ramp, the viewer sees two vehicles representing different approaches to building a research craft to simulate a spacecraft able to land on the ground instead of splashing down in the ocean as the Mercury capsules did. The M2-F1 was a lifting body, a shape able to re-enter from orbit and land. The Paresev (Paraglider Research Vehicle) used a Rogallo wing that could be (but never was) used to replace a conventional parachute for landing a capsule-type spacecraft, allowing it to make a controlled landing on the ground. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop

  12. Roles of alternatively activated M2 macrophages in allergic contact dermatitis

    Directory of Open Access Journals (Sweden)

    Kotaro Suzuki

    2017-07-01

    Full Text Available Alternatively activated macrophages (M2 macrophages play key roles in the suppression of Th1 cell responses and the orchestration of tissue repair. However, recent studies have shown that M2 macrophages have potentials to produce high levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, suggesting that M2 macrophages may exacerbate inflammation in some settings. In this regard, we have recently shown that large numbers of M2 macrophages accumulate in the sites of hapten-induced contact hypersensitivity (CHS, an animal model of allergic contact dermatitis, and that M2 macrophages exacerbate hapten-induced CHS by producing matrix metalloproteinase 12 (MMP12. We have also shown that suppressor of cytokine signaling-3 (SOCS3, a member of SOCS family proteins that are cytokine-inducible negative regulators of the JAK/STAT signaling pathways, is highly and preferentially expressed in M2 macrophages in hapten-induced CHS and that SOCS3 expressed in M2 macrophages is involved in the attenuation of CHS by suppressing MMP12 production. These findings underscore the importance of M2 macrophage-derived MMP12 in the development of CHS, and suggest that inhibition of M2 macrophages or MMP12 could be a potential therapeutic strategy for the treatment of allergic contact dermatitis.

  13. Reliable Reporting for Massive M2M Communications with Periodic Resource Pooling

    DEFF Research Database (Denmark)

    Madueño, Germán Corrales; Stefanovic, Cedomir; Popovski, Petar

    2014-01-01

    This letter considers a wireless M2M communication scenario with a massive number of M2M devices. Each device needs to send its reports within a given deadline and with certain reliability, e.g., 99.99%. A pool of resources available to all M2M devices is periodically available for transmission...... to guarantee the desired reliability of the report delivery within the deadline. The fact that the pool of resources is used by a massive number of devices allows to base the dimensioning on the central limit theorem. The results are interpreted in the context of LTE, but they are applicable to any M2M...... communication system....

  14. Safety and immunogenicity of a recombinant M2e-flagellin influenza vaccine (STF2.4xM2e) in healthy adults.

    Science.gov (United States)

    Turley, Christine B; Rupp, Richard E; Johnson, Casey; Taylor, David N; Wolfson, Julie; Tussey, Lynda; Kavita, Uma; Stanberry, Lawrence; Shaw, Alan

    2011-07-18

    The ectodomain of matrix protein 2 (M2e) is a promising candidate for a broadly protective influenza A vaccine because it is highly conserved and antibodies to M2e are protective in animal models. STF2.4xM2e (VAX102) is a recombinant fusion protein that links four tandem copies of the M2e antigen to Salmonella typhimurium flagellin, a TLR5 ligand used as an adjuvant. The objectives of this first-in-human study were to assess the safety and immunogenicity of VAX102 given as a prime-boost regimen to healthy adults. Sixty subjects 18-49 years old were enrolled in a multicenter, double-blind, randomized, placebo-controlled trial (Study 1). Based on pre-clincial data, initial design included doses starting at 10 μg, with an escalation plan. After reactogenicity was noted at the 10 μg dose, the trial was redesigned to evaluate 0.3, 1.0, and 3 μg doses. Following this study, 16 subjects were enrolled in Study 2, an open label, low dose study, to evaluate doses of 0.03 and 0.1 μg. In both trials, vaccine or placebo was given intramuscularly (i.m.) at 0 and 28 days. Clinical and laboratory safety assessments took place 1 and 7 days after immunization. Immune responses to M2e and flagellin were assessed by ELISA at 7, 14 and 28 days after each dose. Seroconversion was defined as a serum IgG anti-M2e antibody value ≥0.174 μg/ml and a fourfold rise in concentration. Doses of 0.03-1 μg were safe and well tolerated in all subjects. Doses of 0.03 and 0.1 μg produced limited immunogenicity (38% and 75% respectively), after the second dose of vaccine. Doses of 0.3 and 1.0 μg were immunogenic in 18 (75%) of 24 vaccinees after the first dose and 23 (96%) after the second dose. In the 1.0 μg group, the geometric mean M2e antibody concentration was 0.4 μg/ml after the first dose and 1.7 μg/ml after the booster dose. M2e antibody concentrations and seroconversion rates were not significantly different at higher doses (p>0.05). Immune response to flagellin was robust but did

  15. Characteristics of Suppressor Macrophages Induced by Mycobacterial and Protozoal Infections in relation to Alternatively Activated M2 Macrophages

    Directory of Open Access Journals (Sweden)

    Haruaki Tomioka

    2012-01-01

    Full Text Available In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity. Notably, this type of immune conversion is occasionally associated with the generation of certain types of suppressor macrophage populations. During the course of Mycobacterium tuberculosis (MTB and Mycobacterium avium-intracellulare complex (MAC infections, the generation of macrophages which possess strong suppressor activity against host T- and B-cell functions is frequently encountered. This paper describes the immunological properties of M1- and M2-type macrophages generated in tumor-bearing animals and those generated in hosts with certain microbial infections. In addition, this paper highlights the immunological and molecular biological characteristics of suppressor macrophages generated in hosts with mycobacterial infections, especially MAC infection.

  16. Models for financial crisis detection in Indonesia based on M1, M2 per foreign exchange reverse, and M2 multiplier indicators

    Science.gov (United States)

    Sugiyanto; Zukhronah, Etik; Pratiwi, Esteti Sophia

    2017-12-01

    Indonesia has been hit by financial crisis in the middle of 1997. The financial crisis that has occurred gives a severe impact to the economy of Indonesia resulting the needs for a detection system of financial crisis. Crisis can be detected based on several indicators such as M1, M2 per foreign exchange reserves, and M2 multiplier. These three indicators can affect the exchange rate stability and may further affect the financial stability so that it can be one of the causes of the financial crisis. This research aims to determine the appropriate model that can detect the financial crisis in Indonesia. Markov switching is an alternative model that can be approach and used often for detecting financial crisis. We can determine the combination of volatility and Markov switching model with AR and volatility model are determined first. The results of this research are that M1 can be modelled by SWARCH (3, 1) while M2 per foreign research exchange reserves and M2 multiplier can be modelled by SWARCH(3,2).

  17. Aggregation and Trunking of M2M Traffic via D2D Connections

    DEFF Research Database (Denmark)

    Rigazzi, Giovanni; Kiilerich Pratas, Nuno; Popovski, Petar

    2015-01-01

    Machine-to-Machine (M2M) communications is one of the key enablers of the Internet of Things (IoT). Billions of devices are expected to be deployed in the near future for novel M2M applications demanding ubiquitous access and global connectivity. In order to cope with the massive number of machines...

  18. Kinetics of Proton Transport into Influenza Virions by the Viral M2 Channel

    NARCIS (Netherlands)

    Ivanovic, Tijana; Rozendaal, Rutger; Floyd, Daniel L.; Popovic, Milos; Oijen, Antoine M. van; Harrison, Stephen C.

    2012-01-01

    M2 protein of influenza A viruses is a tetrameric transmembrane proton channel, which has essential functions both early and late in the virus infectious cycle. Previous studies of proton transport by M2 have been limited to measurements outside the context of the virus particle. We have developed

  19. Establishing a Research Center: The Minority Male Community College Collaborative (M2C3)

    Science.gov (United States)

    Wood, J. Luke; Urias, Marissa Vasquez; Harris, Frank, III

    2016-01-01

    This chapter describes the establishment of the Minority Male Community College Collaborative (M2C3), a research and practice center at San Diego State University. M2C3 partners with community colleges across the United States to enhance access, achievement, and success among men of color. This chapter begins with a description of the national…

  20. 12 CFR Appendix M2 to Part 226 - Actual Repayment Disclosures

    Science.gov (United States)

    2010-01-01

    ... Part 226 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM TRUTH IN LENDING (REGULATION Z) Pt. 226, App. M2 Appendix M2 to Part 226—Actual Repayment... nearest whole year if the estimate contains a fractional year less than 0.5, and rounded up to the nearest...

  1. Identification of Trichoderma Strain M2 and Related Growth Promoting Effects on Brassica chinensis L.

    Directory of Open Access Journals (Sweden)

    XING Fang-fang

    2017-01-01

    Full Text Available The research took Trichoderma strain as tested strains which isolated from the rhizosphere of healthy and high yield pepper, M2 was classified and identified by combining morphological classification with molecular identification means(rDNA-ITS sequence analysis, whose effect on growth of Brassica chinensis L. was explored, in order to provide superior strains for bio-fertilizer development. After solid fermentation of Trichoderma M2, under the condition of the greenhouse, took some research on the growth promoting effect on Brassica chi nensis L. of Trichoderma M2. The results showed that the strain M2 was identified as Trichoderma harzianum strain. M2 had obvious effects on promoting growth, the SPAD and edible leaf number of Brassica chinensis L. Adding of 5.0×109 cfu M2 had the best effect on increasing the biological yield. Compared with CK, fresh weight and dry weight was increased by 30.26%and 20.08%respectively. Followed by inocula tion of 5.0×108 cfu M2, fresh weight and dry weight was increased by 18.33% and 12.46% respectively. Therefore, M2 showed evident promoting effect on Brassica chinensis L., and had potential application value.

  2. Evaluation of secure capability-based access control in the M2M local cloud platform

    DEFF Research Database (Denmark)

    Anggorojati, Bayu; Prasad, Neeli R.; Prasad, Ramjee

    2016-01-01

    delegation. Recently, the capability based access control has been considered as method to manage access in the Internet of Things (IoT) or M2M domain. In this paper, the implementation and evaluation of a proposed secure capability based access control in the M2M local cloud platform is presented......Managing access to and protecting resources is one of the important aspect in managing security, especially in a distributed computing system such as Machine-to-Machine (M2M). One such platform known as the M2M local cloud platform, referring to BETaaS architecture [1], which conceptually consists...... of multiple distributed M2M gateways, creating new challenges in the access control. Some existing access control systems lack in scalability and flexibility to manage access from users or entity that belong to different authorization domains, or fails to provide fine grained and flexible access right...

  3. Open multiple M2-branes I: quantum geometry of the M5-brane in a C-field

    Science.gov (United States)

    Chu, Chong-Sun; Smith, Douglas J.

    2011-09-01

    We show that the Nahm equation and the Basu-Harvey equation which provide the fuzzy funnel description can be understood as the boundary condition of the F1-strings or M2-branes probing the intersecting branes system. In particular the noncommutative geometry of a D3-brane in the presence of a constant B-field can be identified with a constant shift in the B-field modified Nahm equation. Since the C-field modified Basu-Harvey equation can be derived from the known behaviour of the system in the Bion description, in order for this modification to be consistent with the boundary condition of the M2-branes, we derive a new type of quantum geometry on the M5-brane worldvolume. Unlike the D-brane case, this is naturally expressed in terms of a relation between a 3-bracket of the M5-brane worldvolume coordinates and the C-field.

  4. Heterologous expression of Ralp3 in Streptococcus pyogenes M2 and M6 strains affects the virulence characteristics.

    Directory of Open Access Journals (Sweden)

    Nikolai Siemens

    Full Text Available BACKGROUND: Ralp3 is a transcriptional regulator present in a serotype specific fashion on the chromosome of the human pathogen Streptococcus pyogenes (group A streptococci, GAS. In serotypes harbouring the ralp3 gene either positive or negative effects on important metabolic and virulence genes involved in colonization and immune evasion in the human host were observed. A previous study revealed that deletion of ralp3 in a GAS M49 serotype significantly attenuated many virulence traits and caused metabolic disadvantages. This leads to two questions: (i which kind of consequences could Ralp3 expression have in GAS serotypes naturally lacking this gene, and (ii is Ralp3 actively lost during evolution in these serotypes. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the role of Ralp3 in GAS M2 and M6 pathogenesis. Both serotypes lack ralp3 on their chromosome. The heterologous expression of ralp3 in both serotypes resulted in reduced attachment to and internalization into the majority of tested epithelial cells. Both ralp3 expression strains showed a decreased ability to survive in human blood and exclusively M2::ralp3 showed decreased survival in human serum. Both mutants secreted more active SpeB in the supernatant, resulting in a higher activity compared to wild type strains. The respective M2 and M6 wild type strains outcompeted the ralp3 expression strains in direct metabolic competition assays. The phenotypic changes observed in the M2:ralp3 and M6:ralp3 were verified on the transcriptional level. Consistent with the virulence data, tested genes showed transcript level changes in the same direction. CONCLUSIONS/SIGNIFICANCE: Together these data suggest that Ralp3 can take over transcriptional control of virulence genes in serotypes lacking the ralp3 gene. Those serotypes most likely lost Ralp3 during evolution since obviously expression of this gene is disadvantageous for metabolism and pathogenesis.

  5. Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Grabarz, Felipe; Aguiar, Cristhiane Favero; Correa-Costa, Matheus; Braga, Tárcio Teodoro; Hyane, Meire I; Andrade-Oliveira, Vinícius; Landgraf, Maristella Almeida; Câmara, Niels Olsen Saraiva

    2018-04-01

    Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (Jα18 -/- ) were subjected to the protocol of bleomycin-induced pulmonary fibrosis with or without treatment with NKT cell agonists α-galactosylceramide and sulfatide. The participation of different cell populations, collagen deposition, and protein levels of different cytokines involved in inflammation and fibrosis was evaluated. The results indicate a benign role of NKT cells in Jα18 -/- mice and in wild-type α-galactosylceramide-sulfatide-treated groups. These animals presented lower levels of collagen deposition, fibrogenic molecules such as TGF-β and vimentin and improved survival rates. In contrast, WT mice developed a Th2-driven response augmenting IL-4, 5, and 13 protein synthesis and increased collagen deposition. Furthermore, the arginase-1 metabolic pathway was downregulated in wild-type NKT-activated and knockout mice indicating lower activity of M2 macrophages in lung tissue. Hence, our data suggest that NKT cells play a protective role in this experimental model by down modulating the Th2 milieu, inhibiting M2 polarization and finally preventing fibrosis.

  6. A humanized anti-M2 scFv shows protective in vitro activity against influenza

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M [Los Alamos National Laboratory; Velappan, Nileena [Los Alamos National Laboratory; Schmidt, Jurgen G [Los Alamos National Laboratory

    2008-01-01

    M2 is one of the most conserved influenza proteins, and has been widely prospected as a potential universal vaccine target, with protection predominantly mediated by antibodies. In this paper we describe the creation of a humanized single chain Fv from 14C2, a potent monoclonal antibody against M2. We show that the humanized scFv demonstrates similar activity to the parental mAb: it is able to recognize M2 in its native context on cell surfaces and is able to show protective in vitro activity against influenza, and so represents a potential lead antibody candidate for universal prophylactic or therapeutic intervention in influenza.

  7. Beta3 adrenoceptors substitute the role of M(2) muscarinic receptor in coping with cold stress in the heart: evidence from M(2)KO mice.

    Science.gov (United States)

    Benes, Jan; Novakova, Martina; Rotkova, Jana; Farar, Vladimir; Kvetnansky, Richard; Riljak, Vladimir; Myslivecek, Jaromir

    2012-07-01

    We investigated the role of beta3-adrenoceptors (AR) in cold stress (1 or 7 days in cold) in animals lacking main cardioinhibitive receptors-M2 muscarinic receptors (M(2)KO). There was no change in receptor number in the right ventricles. In the left ventricles, there was decrease in binding to all cardiostimulative receptors (beta1-, and beta2-AR) and increase in cardiodepressive receptors (beta3-AR) in unstressed KO in comparison to WT. The cold stress in WT animals resulted in decrease in binding to beta1- and beta2-AR (to 37%/35% after 1 day in cold and to 27%/28% after 7 days in cold) while beta3-AR were increased (to 216% of control) when 7 days cold was applied. MR were reduced to 46% and 58%, respectively. Gene expression of M2 MR in WT was not changed due to stress, while M3 was changed. The reaction of beta1- and beta2-AR (binding) to cold was similar in KO and WT animals, and beta3-AR in stressed KO animals did not change. Adenylyl cyclase activity was affected by beta3-agonist CL316243 in cold stressed WT animals but CL316243 had almost no effects on adenylyl cyclase activity in stressed KO. Nitric oxide activity (NOS) was not affected by BRL37344 (beta3-agonist) both in WT and KO animals. Similarly, the stress had no effects on NOS activity in WT animals and in KO animals. We conclude that the function of M2 MR is substituted by beta3-AR and that these effects are mediated via adenylyl cyclase rather than NOS.

  8. The Predictive Factors for Diabetic Remission in Chinese Patients with BMI > 30 kg/m2 and BMI < 30 kg/m2 Are Different.

    Science.gov (United States)

    Liang, Hui; Cao, Qing; Liu, Huan; Guan, Wei; Wong, Claudia; Tong, Daniel

    2018-01-15

    Roux-en-Y gastric bypass has been proven to be beneficial for patients with obesity and type 2 diabetes mellitus (T2DM). In less-obese patient (BMI 30-35 kg/m 2 ), surgical treatment is indicated when medication fails to control the T2DM. Asian develops diabetes at a lower BMI. For lower-BMI patients, the rate of diabetes amelioration varies significantly with patients of higher BMI after surgical treatment. The factors that contribute to the post-operative diabetes response rate in lower-BMI patients have not been elucidated. Between 2010 and 2014, a total of 144 patients who underwent gastric bypass for the treatment of T2DM were included for study. Patients were divided into two groups for subgroup analysis, namely BMI > 30 kg/m 2 and BMI BMI group (BMI > 30 kg/m 2 ) was 80% (n = 90) whereas for the lower BMI (BMI BMI group, low HbA1c and high fasting C-peptide are predictive factors whereas for lower-BMI group, along with elevated C-peptide level, disease duration is the positive predictive factor for DM remission. Patients with BMI > 30 kg/m 2 and those with BMI BMI patients while duration of diabetes is for high-low-BMI patients. C-peptide is a predictor of remission in both groups. Further large-scale studies are required to define the predictors of diabetes remission after gastric bypass in low- and high-BMI patients.

  9. Dysfunctional Presynaptic M2 Receptors in the Presence of Chronically High Acetylcholine Levels: Data from the PRiMA Knockout Mouse.

    Science.gov (United States)

    Mohr, Franziska; Krejci, Eric; Zimmermann, Martina; Klein, Jochen

    2015-01-01

    The muscarinic M2 receptor (M2R) acts as a negative feedback regulator in central cholinergic systems. Activation of the M2 receptor limits acetylcholine (ACh) release, especially when ACh levels are increased because acetylcholinesterase (AChE) activity is acutely inhibited. Chronically high ACh levels in the extracellular space, however, were reported to down-regulate M2R to various degrees. In the present study, we used the PRiMA knockout mouse which develops severely reduced AChE activity postnatally to investigate ACh release, and we used microdialysis to investigate whether the function of M2R to reduce ACh release in vivo was impaired in adult PRiMA knockout mice. We first show that striatal and hippocampal ACh levels, while strongly increased, still respond to AChE inhibitors. Infusion or injection of oxotremorine, a muscarinic M2 agonist, reduced ACh levels in wild-type mice but did not significantly affect ACh levels in PRiMA knockout mice or in wild-type mice in which ACh levels were artificially increased by infusion of neostigmine. Scopolamine, a muscarinic antagonist, increased ACh levels in wild-type mice receiving neostigmine, but not in wild-type mice or in PRiMA knockout mice. These results demonstrate that M2R are dysfunctional and do not affect ACh levels in PRiMA knockout mice, likely because of down-regulation and/or loss of receptor-effector coupling. Remarkably, this loss of function does not affect cognitive functions in PRiMA knockout mice. Our results are discussed in the context of AChE inhibitor therapy as used in dementia.

  10. Trypsin, Tryptase, and Thrombin Polarize Macrophages towards a Pro-Fibrotic M2a Phenotype.

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    Michael J V White

    Full Text Available For both wound healing and the formation of a fibrotic lesion, circulating monocytes enter the tissue and differentiate into fibroblast-like cells called fibrocytes and pro-fibrotic M2a macrophages, which together with fibroblasts form scar tissue. Monocytes can also differentiate into classically activated M1 macrophages and alternatively activated M2 macrophages. The proteases thrombin, which is activated during blood clotting, and tryptase, which is released by activated mast cells, potentiate fibroblast proliferation and fibrocyte differentiation, but their effect on macrophages is unknown. Here we report that thrombin, tryptase, and the protease trypsin bias human macrophage differentiation towards a pro-fibrotic M2a phenotype expressing high levels of galectin-3 from unpolarized monocytes, or from M1 and M2 macrophages, and that these effects appear to operate through protease-activated receptors. These results suggest that proteases can initiate scar tissue formation by affecting fibroblasts, fibrocytes, and macrophages.

  11. Marine microbial biodiversity, bioinformatics and biotechnology (M2B3) data reporting and service standards.

    Science.gov (United States)

    Ten Hoopen, Petra; Pesant, Stéphane; Kottmann, Renzo; Kopf, Anna; Bicak, Mesude; Claus, Simon; Deneudt, Klaas; Borremans, Catherine; Thijsse, Peter; Dekeyzer, Stefanie; Schaap, Dick Ma; Bowler, Chris; Glöckner, Frank Oliver; Cochrane, Guy

    2015-01-01

    Contextual data collected concurrently with molecular samples are critical to the use of metagenomics in the fields of marine biodiversity, bioinformatics and biotechnology. We present here Marine Microbial Biodiversity, Bioinformatics and Biotechnology (M2B3) standards for "Reporting" and "Serving" data. The M2B3 Reporting Standard (1) describes minimal mandatory and recommended contextual information for a marine microbial sample obtained in the epipelagic zone, (2) includes meaningful information for researchers in the oceanographic, biodiversity and molecular disciplines, and (3) can easily be adopted by any marine laboratory with minimum sampling resources. The M2B3 Service Standard defines a software interface through which these data can be discovered and explored in data repositories. The M2B3 Standards were developed by the European project Micro B3, funded under 7(th) Framework Programme "Ocean of Tomorrow", and were first used with the Ocean Sampling Day initiative. We believe that these standards have value in broader marine science.

  12. Turbulence Models: Shock Boundary Layer Interaction at M=2.05

    Data.gov (United States)

    National Aeronautics and Space Administration — Exp: Shock Boundary Layer Interaction at M=2.05. This web page provides data from experiments that may be useful for the validation of turbulence models. This...

  13. HF183/BFDrev and HumM2 qPCR data

    Data.gov (United States)

    U.S. Environmental Protection Agency — Concentration estimates for HF183/BFDrev and HumM2 qPCR genetic markers in raw sewage collected from 54 geographic locations across the United States. This dataset...

  14. Porous Photocatalytic Membrane Microreactor (P2M2): A new reactor concept for photochemistry

    NARCIS (Netherlands)

    Aran, H.C.; Salamon, David; Rijnaarts, Timon; Rijnaarts, T.; Mul, Guido; Wessling, Matthias; Lammertink, Rob G.H.

    2011-01-01

    In this study, a new membrane microreactor concept for multiphase photocatalytic reactions is demonstrated. Microfabrication, photocatalyst immobilization and surface modification steps were performed to develop a Porous Photocatalytic Membrane Microreactor (P2M2). This concept benefits from a

  15. Service-Oriented Radio Architecture: A Novel M2M Network Architecture for Cognitive Radio Systems

    OpenAIRE

    Dong, Xu; Wei, Shengqun; Li, Ying; Wang, Lifeng; Bai, Lin

    2012-01-01

    In future cognitive radio networks, a number of spectrum sensors can be distributedly deployed to monitor the surrounding wireless environment, where the machine-to-machine (M2M) technology is considered to provide the interactions among sensors, cognitive engines, and other system modules. Thus, a flexible M2M network architecture is desired to develop cognitive radio networks. As a distributed system framework, service-oriented architecture (SOA) has been well studied to provide the loose c...

  16. Melanoma exosomes promote mixed M1 and M2 macrophage polarization.

    Science.gov (United States)

    Bardi, Gina T; Smith, Mary Ann; Hood, Joshua L

    2018-05-01

    Macrophages are key participants in melanoma growth and survival. In general, macrophages can be classified as M1 or M2 activation phenotypes. Increasing evidence demonstrates that melanoma exosomes also facilitate tumor survival and metastasis. However, the role of melanoma exosomes in directly influencing macrophage function is poorly understood. Herein, we investigated the hypothesis that natural melanoma exosomes might directly influence macrophage polarization. To explore this hypothesis, ELISA, RT-qPCR, and macrophage functional studies were performed in vitro using an established source of melanoma exosomes (B16-F10). ELISA results for melanoma exosome induction of common M1 and M2 cytokines in RAW 264.7 macrophages, revealed that melanoma exosomes do not polarize macrophages exclusively in the M1 or M2 direction. Melanoma exosomes induced the M1 and M2 representative cytokines TNF-α and IL-10 respectively. Further assessment, using an RT-qPCR array with RAW 264.7 and primary macrophages, confirmed and extended the ELISA findings. Upregulation of markers common to both M1 and M2 polarization phenotypes included CCL22, IL-12B, IL-1β, IL-6, i-NOS, and TNF-α. The M2 cytokine TGF-β was upregulated in primary but not RAW 264.7 macrophages. Pro-tumor functions have been attributed to each of these markers. Macrophage functional assays demonstrated a trend toward increased i-NOS (M1) to arginase (M2) activity. Collectively, the results provide the first evidence that melanoma exosomes can induce a mixed M1 and M2 pro-tumor macrophage activation phenotype. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Presenting Influenza A M2e Antigen on Recombinant Spores of Bacillus subtilis.

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    Tomasz Łęga

    Full Text Available Effective vaccination against influenza virus infection is a serious problem mainly due to antigenic variability of the virus. Among many of investigated antigens, the extracellular domain of the M2 protein (M2e features high homology in all strains of influenza A viruses and antibodies against M2e and is protective in animal models; this makes it a potential candidate for generation of a universal influenza vaccine. However, due to the low immunogenicity of the M2e, formulation of a vaccine based on this antigen requires some modification to induce effective immune responses. In this work we evaluated the possible use of Bacillus subtilis spores as a carrier of the Influenza A M2e antigen in mucosal vaccination. A tandem repeat of 4 consensus sequences coding for human-avian-swine-human M2e (M2eH-A-S-H peptide was fused to spore coat proteins and stably exposed on the spore surface, as demonstrated by the immunostaining of intact, recombinant spores. Oral immunization of mice with recombinant endospores carrying M2eH-A-S-H elicited specific antibody production without the addition of adjuvants. Bacillus subtilis endospores can serve as influenza antigen carriers. Recombinant spores constructed in this work showed low immunogenicity although were able to induce antibody production. The System of influenza antigen administration presented in this work is attractive mainly due to the omitting time-consuming and cost-intensive immunogen production and purification. Therefore modification should be made to increase the immunogenicity of the presented system.

  18. Delivery strategies to control inflammatory response: Modulating M1-M2 polarization in tissue engineering applications

    OpenAIRE

    Alvarez, Mario Moisés; Liu, Julie C.; Santiago, Grissel Trujillo-de; Cha, Byung-Hyun; Vishwakarma, Ajaykumar; Ghaemmaghami, Amir; Khademhosseini, Ali

    2016-01-01

    Macrophages are key players in many physiological scenarios including tissue homeostasis. In response to injury, typically the balance between macrophage sub-populations shifts from an M1 phenotype (pro-inflammatory) to an M2 phenotype (anti-inflammatory). In tissue engineering scenarios, after implantation of any device, it is desirable to exercise control on this M1-M2 progression and to ensure a timely and smooth transition from the inflammatory to the healing stage. In this review, we bri...

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

    Science.gov (United States)

    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.

  20. α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

    Science.gov (United States)

    Ohue-Kitano, Ryuji; Yasuoka, Yumiko; Goto, Tsuyoshi; Kitamura, Nahoko; Park, Si-Bum; Kishino, Shigenobu; Kimura, Ikuo; Kasubuchi, Mayu; Takahashi, Haruya; Li, Yongjia; Yeh, Yu-Sheng; Jheng, Huei-Fen; Iwase, Mari; Tanaka, Masashi; Masuda, Shinya; Inoue, Takayuki; Yamakage, Hajime; Kusakabe, Toru; Tani, Fumito; Shimatsu, Akira; Takahashi, Nobuyuki; Ogawa, Jun; Satoh-Asahara, Noriko; Kawada, Teruo

    2018-01-01

    Among dietary fatty acids with immunologic effects, ω-3 polyunsaturated fatty acids, such as α-linolenic acid (ALA), have been considered as factors that contribute to the differentiation of M2-type macrophages (M2 macrophages). In this study, we examined the effect of ALA and its gut lactic acid bacteria metabolites 13-hydroxy-9( Z ),15( Z )-octadecadienoic acid (13-OH) and 13-oxo-9( Z ),15( Z )-octadecadienoic acid (13-oxo) on the differentiation of M2 macrophages from bone marrow-derived cells (BMDCs) and investigated the underlying mechanisms. BMDCs were stimulated with ALA, 13-OH, or 13-oxo in the presence of IL-4 or IL-13 for 24 h, and significant increases in M2 macrophage markers CD206 and Arginase-1 (Arg1) were observed. In addition, M2 macrophage phenotypes were less prevalent following cotreatment with GPCR40 antagonists or inhibitors of PLC-β and MEK under these conditions, suggesting that GPCR40 signaling is involved in the regulation of M2 macrophage differentiation. In further experiments, remarkable M2 macrophage accumulation was observed in the lamina propria of the small intestine of C57BL/6 mice after intragastric treatments with ALA, 13-OH, or 13-oxo at 1 g/kg of body weight per day for 3 d. These findings suggest a novel mechanism of M2 macrophage differentiation involving fatty acids from gut lactic acid bacteria and GPCR40 signaling.-Ohue-Kitano, R., Yasuoka, Y., Goto, T., Kitamura, N., Park, S.-B., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., Yeh, Y.-S., Jheng, H.-F., Iwase, M., Tanaka, M., Masuda, S., Inoue, T., Yamakage, H., Kusakabe, T., Tani, F., Shimatsu, A., Takahashi, N., Ogawa, J., Satoh-Asahara, N., Kawada, T. α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40. © FASEB.

  1. Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model.

    Directory of Open Access Journals (Sweden)

    Yi-Rang Na

    Full Text Available Tumor cells are often associated with abundant macrophages that resemble the alternatively activated M2 subset. Tumor-associated macrophages (TAMs inhibit anti-tumor immune responses and promote metastasis. Cyclooxygenase-2 (COX-2 inhibition is known to prevent breast cancer metastasis. This study hypothesized that COX-2 inhibition affects TAM characteristics potentially relevant to tumor cell metastasis. We found that the specific COX-2 inhibitor, etodolac, inhibited human M2 macrophage differentiation, as determined by decreased CD14 and CD163 expressions and increased TNFα production. Several key metastasis-related mediators, such as vascular endothelial growth factor-A, vascular endothelial growth factor-C, and matrix metalloproteinase-9, were inhibited in the presence of etodolac as compared to untreated M2 macrophages. Murine bone marrow derived M2 macrophages also showed enhanced surface MHCII IA/IE and CD80, CD86 expressions together with enhanced TNFα expressions with etodolac treatment during differentiation. Using a BALB/c breast cancer model, we found that etodolac significantly reduced lung metastasis, possibly due to macrophages expressing increased IA/IE and TNFα, but decreased M2 macrophage-related genes expressions (Ym1, TGFβ. In conclusion, COX-2 inhibition caused loss of the M2 macrophage characteristics of TAMs and may assist prevention of breast cancer metastasis.

  2. Monocyte Differentiation towards Protumor Activity Does Not Correlate with M1 or M2 Phenotypes

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    G. Karina Chimal-Ramírez

    2016-01-01

    Full Text Available Macrophages facilitate breast cancer progression. Macrophages were initially classified as M1 or M2 based on their distinct metabolic programs and then expanded to include antitumoral (M1 and protumoral (M2 activities. However, it is still uncertain what markers define the pro- and antitumoral phenotypes and what conditions lead to their formation. In this study, monocytic cell lines and primary monocytes were subjected to commonly reported protocols of M1/M2 polarization and conditions known to engage monocytes into protumoral functions. The results showed that only IDO enzyme and CD86 M1 markers were upregulated correlating with M1 polarization. TNF-α, CCR7, IL-10, arginase I, CD36, and CD163 were expressed indistinguishably from M1 or M2 polarization. Similarly, protumoral engaging resulted in upregulation of both M1 and M2 markers, with conditioned media from the most aggressive breast cancer cell line promoting the greatest changes. In spite of the mixed phenotype, M1-polarized macrophages exhibited the highest expression/secretion of inflammatory mediators, many of which have previously been associated with breast cancer aggressiveness. These data argue that although the existence of protumoral macrophages is unquestionable, their associated phenotypes and the precise conditions driving their formation are still unclear, and those conditions may need both M1 and M2 stimuli.

  3. Induction of murine macrophage M2 polarization by cigarette smoke extract via the JAK2/STAT3 pathway.

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    Fengjiao Yuan

    Full Text Available Cigarette smoking is a major pathogenic factor in lung cancer. Macrophages play an important role in host defense and adaptive immunity. These cells display diverse phenotypes for performing different functions. M2 type macrophages usually exhibit immunosuppressive and tumor-promoting characteristics. Although macrophage polarization toward the M2 phenotype has been observed in the lungs of cigarette smokers, the molecular basis of the process remains unclear. In this study, we evaluated the possible mechanisms for the polarization of mouse macrophages that are induced by cigarette smoking (CS or cigarette smoke extract (CSE. The results showed that exposure to CSE suppressed the production of reactive oxygen species (ROS and nitric oxide (NO and down-regulated the phagocytic ability of Ana-1 cells. The CD163 expressions on the surface of macrophages from different sources were significantly increased in in vivo and in vitro studies. The M1 macrophage cytokines TNF-α, IL-12p40 and enzyme iNOS decreased in the culture supernatant, and their mRNA levels decreased depending on the time and concentration of CSE. In contrast, the M2 phenotype macrophage cytokines IL-10, IL-6, TGF-β1 and TGF-β2 were up-regulated. Moreover, phosphorylation of JAK2 and STAT3 was observed after the Ana-1 cells were treated with CSE. In addition, pretreating the Ana-1 cells with the STAT3 phosphorylation inhibitor WP1066 inhibited the CSE-induced CD163 expression, increased the mRNA level of IL-10 and significantly decreased the mRNA level of IL-12. In conclusion, we demonstrated that the M2 polarization of macrophages induced by CS could be mediated through JAK2/STAT3 pathway activation.

  4. Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides.

    Science.gov (United States)

    Pannell, Maria; Labuz, Dominika; Celik, Melih Ö; Keye, Jacqueline; Batra, Arvind; Siegmund, Britta; Machelska, Halina

    2016-10-07

    During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain. Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4. The macrophage phenotypes were verified using flow cytometry for surface marker analysis and cytokine bead array for cytokine profile assessment. Opioid peptide levels were measured by radioimmunoassay and enzyme immunoassay. As a model of neuropathic pain, a chronic constriction injury (CCI) of the sciatic nerve was employed. Polarized M0, M1, and M2 macrophages (5 × 10 5 cells) were injected perineurally twice, on days 14 and 15 following CCI or sham surgery. Mechanical and heat sensitivity were measured using the von Frey and Hargreaves tests, respectively. To track the injected macrophages, we also transferred fluorescently stained polarized cells and analyzed the surface marker profile of endogenous and injected cells in the nerves ex vivo. Compared to M0 and M1 cells, M2 macrophages contained and released higher amounts of opioid peptides, including Met-enkephalin, dynorphin A (1-17), and β-endorphin. M2 cells transferred perineurally at the nerve injury site reduced mechanical, but not heat hypersensitivity following the second injection. The analgesic effect was reversed by the perineurally applied opioid receptor antagonist naloxone methiodide. M2 cells did not affect sensitivity following sham surgery. Neither M0 nor M1 cells altered mechanical and heat sensitivity in CCI or sham-operated animals. Tracing the

  5. Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo.

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    Shweta Joshi

    Full Text Available Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the α4β1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis.

  6. Unraveling a molecular determinant for clathrin-independent internalization of the M2 muscarinic acetylcholine receptor

    Science.gov (United States)

    Wan, Min; Zhang, Wenhua; Tian, Yangli; Xu, Chanjuan; Xu, Tao; Liu, Jianfeng; Zhang, Rongying

    2015-01-01

    Endocytosis and postendocytic sorting of G-protein-coupled receptors (GPCRs) is important for the regulation of both their cell surface density and signaling profile. Unlike the mechanisms of clathrin-dependent endocytosis (CDE), the mechanisms underlying the control of GPCR signaling by clathrin-independent endocytosis (CIE) remain largely unknown. Among the muscarinic acetylcholine receptors (mAChRs), the M4 mAChR undergoes CDE and recycling, whereas the M2 mAChR is internalized through CIE and targeted to lysosomes. Here we investigated the endocytosis and postendocytic trafficking of M2 mAChR based on a comparative analysis of the third cytoplasmic domain in M2 and M4 mAChRs. For the first time, we identified that the sequence 374KKKPPPS380 servers as a sorting signal for the clathrin-independent internalization of M2 mAChR. Switching 374KKKPPPS380 to the i3 loop of the M4 mAChR shifted the receptor into lysosomes through the CIE pathway; and therefore away from CDE and recycling. We also found another previously unidentified sequence that guides CDE of the M2 mAChR, 361VARKIVKMTKQPA373, which is normally masked in the presence of the downstream sequence 374KKKPPPS380. Taken together, our data indicate that endocytosis and postendocytic sorting of GPCRs that undergo CIE could be sequence-dependent. PMID:26094760

  7. Prophylactic and therapeutic activity of fully human monoclonal antibodies directed against Influenza A M2 protein

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    Gwerder Myriam

    2009-12-01

    Full Text Available Abstract Influenza virus infection is a prevalent disease in humans. Antibodies against hemagglutinin have been shown to prevent infection and hence hemagglutinin is the major constituent of current vaccines. Antibodies directed against the highly conserved extracellular domain of M2 have also been shown to mediate protection against Influenza A infection in various animal models. Active vaccination is generally considered the best approach to combat viral diseases. However, passive immunization is an attractive alternative, particularly in acutely exposed or immune compromized individuals, young children and the elderly. We recently described a novel method for the rapid isolation of natural human antibodies by mammalian cell display. Here we used this approach to isolate human monoclonal antibodies directed against the highly conserved extracellular domain of the Influenza A M2 protein. The identified antibodies bound M2 peptide with high affinities, recognized native cell-surface expressed M2 and protected mice from a lethal influenza virus challenge. Moreover, therapeutic treatment up to 2 days after infection was effective, suggesting that M2-specific monoclonals have a great potential as immunotherapeutic agents against Influenza infection.

  8. Negative Immune Regulator TIPE2 Promotes M2 Macrophage Differentiation through the Activation of PI3K-AKT Signaling Pathway.

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    Ruiling Liu

    Full Text Available Macrophages play important roles in the regulation of the innate and adaptive immune responses. Classically activated macrophages and alternatively activated macrophages are the two major forms of macrophages and have opposing functionalities. Tumor necrosis factor-α-induced protein 8-2 is expressed primarily by immune cells and negatively regulates type 1 innate and adaptive immune responses to maintain immune tolerance. While previous studies indicate that TIPE2 promotes M2 but inhibits M1 macrophage differentiation, the underlying molecular mechanism by which TIPE2 promotes M2 macrophage differentiation remains unclear. Our current study shows that TIPE2-deficient bone-marrow cells are defective in IL-4 induced M2 macrophage differentiation in vitro. Mechanistic studies revealed that TIPE2 promotes phosphoinositide metabolism and the activation of the down-stream AKT signaling pathway, which in turn leads to the expression of markers specific for M2 macrophages. In addition, our results showed that Tipe2-deficiency does not affect the activation of the JAK-STAT6 signaling pathway that also plays an important role during M2 macrophage differentiation. Taken together, these results indicate that TIPE2 promotes M2 macrophage differentiation through the activation of PI3K-AKT signaling pathway, and may play an important role during the resolution of inflammation, parasite control, as well as tissue repair.

  9. High-virulence CMY-2- and CTX-M-2-producing avian pathogenic Escherichia coli strains isolated from commercial turkeys.

    Science.gov (United States)

    da Silva, Ketrin Cristina; Cunha, Marcos Paulo Vieira; Cerdeira, Louise; de Oliveira, Maria Gabriela Xavier; de Oliveira, Mirela Caroline Vilela; Gomes, Cleise Ribeiro; Lincopan, Nilton; Knöbl, Terezinha; Moreno, Andrea Micke

    2017-01-01

    This study reports the high-virulence phylogenetic backgrounds of CMY-2- and CTX-M-2-producing avian pathogenic Escherichia coli strains isolated from turkeys sent to slaughter and condemned by airsacculitis in Brazil. Among 300 air sac samples, seven E. coli strains produced plasmid-mediated CMY-2-type AmpC, of which three carried also the bla CTX-M-2 Extended Spectrum Beta-Lactamase encoding gene. Interestingly, the transfer of the bla CMY-2 gene was positive for three E. coli strains, being associated with the presence of IncI1 plasmids. The complete sequence of the representative pJB10 plasmid revealed that the bla CMY-2 gene was within a transposon-like element in the classical genetic environment consisting of tnpA-bla CMY-2 -blc-sugE structure. This plasmid with 94-kb belonged to the sequence type (ST) 12 among IncI1 plasmids, which has been associated with the worldwide spread of bla CMY-2 among Salmonella enterica and E. coli. Furthermore, to the best of our knowledge, this is the first complete sequence of a CMY-2-encoding plasmid derived from an Escherichia coli isolated from food-producing animals in Latin America. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Mycobacterium bovis Bacillus Calmette–Guérin Alters Melanoma Microenvironment Favoring Antitumor T Cell Responses and Improving M2 Macrophage Function

    Directory of Open Access Journals (Sweden)

    Ricardo D. Lardone

    2017-08-01

    Full Text Available Intralesional Mycobacterium bovis bacillus Calmette–Guérin (BCG has long been a relatively inexpensive therapy for inoperable cutaneous metastatic melanoma (CMM, although intralesional BCG skin mechanisms remain understudied. We analyzed intralesional BCG-treated CMM lesions combined with in vitro studies to further investigate BCG-altered pathways. Since macrophages play a pivotal role against both cancer and mycobacterial infections, we hypothesized BCG regulates macrophages to promote antitumor immunity. Tumor-associated macrophages (M2 infiltrate melanomas and impair antitumor immunity. BCG-treated, in vitro-polarized M2 (M2-BCG showed transcriptional changes involving inflammation, immune cell recruitment, cross talk, and activation pathways. Mechanistic network analysis indicated M2-BCG potential to improve interferon gamma (IFN-γ responses. Accordingly, frequency of IFN-γ-producing CD4+ T cells responding to M2-BCG vs. mock-treated M2 increased (p < 0.05. Moreover, conditioned media from M2-BCG vs. M2 elevated the frequency of granzyme B-producing CD8+ tumor-infiltrating lymphocytes (TILs facing autologous melanoma cell lines (p < 0.01. Furthermore, transcriptome analysis of intralesional BCG-injected CMM relative to uninjected lesions showed immune function prevalence, with the most enriched pathways representing T cell activation mechanisms. In vitro-infected MM-derived cell lines stimulated higher frequency of IFN-γ-producing TIL from the same melanoma (p < 0.05. Our data suggest BCG favors antitumor responses in CMM through direct/indirect effects on tumor microenvironment cell types including macrophages, T cells, and tumor itself.

  11. VANAM multi-compartment aerosol depletion test M2* with insoluble aerosol material

    International Nuclear Information System (INIS)

    Kanzleiter, T.

    1993-07-01

    This report presents the experimental data of VANAM experiment M2'. It was performed with an insoluble aerosol material (SnO 2 ) like the previous experiment M2 but under a modified test procedure and with an improved instrumentation. The modified test procedure of M2' which led to more distinct results, should be chosen also for the subsequent VANAM tests with other aerosol materials. The most important results are: Significantly different aerosol depletion rates in a ''dry'' steam-air atmosphere (saturated or slightly superheated conditions) or in a ''wet'' atmosphere (supersaturated conditions, fog formation). Due to diverse depletion rates, local aerosol concentration differences within the multi-compartment containment geometry develop during the experiment, reaching two orders of magnitude. (orig./HP) [de

  12. M2IRAGE: Management of measurements during radiological interventions geographically assisted in the environment

    International Nuclear Information System (INIS)

    Gerphagnon, O.; Roche, H.; Lelache, H.; Guelin, M.; Fauquant, J.M.; Kacenelen, Y.; Armand, Y.

    2010-01-01

    This report presents the M 2 IRAGE software, a data processing tool designed to share radioactivity measurements and to give a schematised view of a radiological situation and of its evolution, while respecting different legal frameworks, notably the obligation to produce a radiological measurement programme. After a simplified recall of the crisis management organisation, the authors describe the M 2 IRAGE software and hardware architecture, the functions of its main modules (presentation of radioprotection information during field intervention, field mission management, data browsing, and data transmission to field teams). While giving some display examples, the authors describe how an event is managed and processed by this tool: event creation, measurement acquisition, aid to decision, team management. They report and discuss the results of a national exercise which took place in September 2009 in Saclay with a prototype version of M 2 IRAGE

  13. Holographic cosmology from a system of M2–M5 branes

    Energy Technology Data Exchange (ETDEWEB)

    Sepehri, Alireza, E-mail: alireza.sepehri@uk.ac.ir [Faculty of Physics, Shahid Bahonar University, P.O. Box 76175, Kerman (Iran, Islamic Republic of); Research Institute for Astronomy and Astrophysics of Maragha (RIAAM), Maragha (Iran, Islamic Republic of); Faizal, Mir, E-mail: f2mir@uwaterloo.ca [Department of Physics and Astronomy, University of Waterloo, Waterloo, ON, N2L 3G1 (Canada); Setare, Mohammad Reza, E-mail: rezakord@ipm.ir [Department of Science, Campus of Bijar, University of Kurdistan, Bijar (Iran, Islamic Republic of); Ali, Ahmed Farag, E-mail: afali@fsu.edu [Department of Physics, Florida State University, Tallahassee, FL 32306 (United States); Department of Physics, Faculty of Science, Benha University, Benha 13518 (Egypt)

    2016-05-15

    In this paper, we analyze the holographic cosmology using a M2–M5 brane configuration. In this configuration, a M2-brane will be placed in between a M5-brane and an anti-M5-brane. The M2-brane will act as a channel for energy to flow from an anti-M5-brane to a M5-brane, and this will increase the degrees of freedom on the M5-brane causing inflation. The inflation will end when the M5-brane and anti-M5-brane get separated. However, at a later stage the distance between the M5-brane and the anti-M5-bran can reduce and this will cause the formation of tachyonic states. These tachyonic states will again open a bridge between the M5-branes and the anti-M5-branes, which will cause further acceleration of the universe.

  14. Holographic cosmology from a system of M2–M5 branes

    International Nuclear Information System (INIS)

    Sepehri, Alireza; Faizal, Mir; Setare, Mohammad Reza; Ali, Ahmed Farag

    2016-01-01

    In this paper, we analyze the holographic cosmology using a M2–M5 brane configuration. In this configuration, a M2-brane will be placed in between a M5-brane and an anti-M5-brane. The M2-brane will act as a channel for energy to flow from an anti-M5-brane to a M5-brane, and this will increase the degrees of freedom on the M5-brane causing inflation. The inflation will end when the M5-brane and anti-M5-brane get separated. However, at a later stage the distance between the M5-brane and the anti-M5-bran can reduce and this will cause the formation of tachyonic states. These tachyonic states will again open a bridge between the M5-branes and the anti-M5-branes, which will cause further acceleration of the universe.

  15. M2 FILTER FOR SPECKLE NOISE SUPPRESSION IN BREAST ULTRASOUND IMAGES

    Directory of Open Access Journals (Sweden)

    E.S. Samundeeswari

    2016-11-01

    Full Text Available Breast cancer, commonly found in women is a serious life threatening disease due to its invasive nature. Ultrasound (US imaging method plays an effective role in screening early detection and diagnosis of Breast cancer. Speckle noise generally affects medical ultrasound images and also causes a number of difficulties in identifying the Region of Interest. Suppressing speckle noise is a challenging task as it destroys fine edge details. No specific filter is designed yet to get a noise free BUS image that is contaminated by speckle noise. In this paper M2 filter, a novel hybrid of linear and nonlinear filter is proposed and compared to other spatial filters with 3×3 kernel size. The performance of the proposed M2 filter is measured by statistical quantity parameters like MSE, PSNR and SSI. The experimental analysis clearly shows that the proposed M2 filter outperforms better than other spatial filters by 2% high PSNR values with regards to speckle suppression.

  16. Quantification and localization of M2 macrophages in human kidneys with acute tubular injury

    Directory of Open Access Journals (Sweden)

    Palmer MB

    2014-11-01

    Full Text Available Matthew B Palmer,1 Alfred A Vichot,2 Lloyd G Cantley,2 Gilbert W Moeckel1 1Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; 2Department of Medicine, Yale University School of Medicine, New Haven, CT, USA Abstract: This study addresses for the first time the question whether there is significant macrophage population in human kidney sections from patients with acute tubular injury (ATI. We examined therefore the interstitial macrophage population in human kidney tissue with biopsy-proven diagnosis of ATI, minimal change disease (MCD, and MCD with ATI. Kidney biopsies from patients with the above diagnoses were stained with antibodies directed against CD68 (general macrophage marker, CD163 (M2 marker, and HLA-DR (M1 marker and their respective electron microscopy samples were evaluated for the presence of interstitial macrophages. Our study shows that patients with ATI have significantly increased numbers of interstitial CD68+ macrophages, with an increase in both HLA-DR+ M1 macrophages and CD163+ M2 macrophages as compared to patients with MCD alone. Approximately 75% of macrophages were M2 (CD163+ whereas only 25% were M1 (HLA-DR+. M2 macrophages, which are believed to be critical for wound healing, were found to localize close to the tubular basement membrane of injured proximal tubule cells. Ultra structural examination showed close adherence of macrophages to the basement membrane of injured tubular epithelial cells. We conclude that macrophages accumulate around injured tubules following ATI and exhibit predominantly an M2 phenotype. We further speculate that macrophage-mediated repair may involve physical contact between the M2 macrophage and the injured tubular epithelial cell. Keywords: macrophages, acute kidney injury, CD163, HLA-DR, CD68, electron microscopy

  17. Plant-produced recombinant influenza A vaccines based on the M2e peptide.

    Science.gov (United States)

    Mardanova, Eugenia S; Ravin, Nikolai V

    2018-03-09

    Influenza is a widely distributed infection that almost annually causes seasonal epidemics. The current egg-based platforms for influenza vaccine production are facing a number of challenges and are failing to satisfy the global demand in the case of pandemics due to the long production time. Recombinant vaccines are an alternative that can be quickly produced in high quantities in standard expression systems. Plants may become a promising biofactory for the large-scale production of recombinant proteins due to low cost, scalability, and safety. Plant-based expression systems have been used to produce recombinant vaccines against influenza based on two targets; the major surface antigen hemagglutinin and the transmembrane protein M2. Different forms of recombinant hemagglutinin were successfully expressed in plants, and some plant-produced vaccines based on hemagglutinin were successfully tested in clinical trials. However, these vaccines remain strain specific, while the highly conserved extracellular domain of M2 protein (M2e) could be used for the development of a universal influenza vaccine. In this review, the state of the art in developing plant-produced influenza vaccines based on M2e is presented and placed in perspective. A number of strategies to produce M2e in an immunogenic form in plants have been reported, including its presentation on the surface of plant viruses or virus-like particles formed by capsid proteins, linkage to bacterial flagellin, and targeting to protein bodies. Some M2e-based vaccine candidates were produced at high levels (up to 1 mg/g of fresh plant tissue) and were shown to be capable of stimulating broad-range protective immunity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Critical illness induces alternative activation of M2 macrophages in adipose tissue.

    Science.gov (United States)

    Langouche, Lies; Marques, Mirna B; Ingels, Catherine; Gunst, Jan; Derde, Sarah; Vander Perre, Sarah; D'Hoore, André; Van den Berghe, Greet

    2011-01-01

    We recently reported macrophage accumulation in adipose tissue of critically ill patients. Classically activated macrophage accumulation in adipose tissue is a known feature of obesity, where it is linked with increasing insulin resistance. However, the characteristics of adipose tissue macrophage accumulation in critical illness remain unknown. We studied macrophage markers with immunostaining and gene expression in visceral and subcutaneous adipose tissue from healthy control subjects (n = 20) and non-surviving prolonged critically ill patients (n = 61). For comparison, also subcutaneous in vivo adipose tissue biopsies were studied from 15 prolonged critically ill patients. Subcutaneous and visceral adipose tissue biopsies from non-surviving prolonged critically ill patients displayed a large increase in macrophage staining. This staining corresponded with elevated gene expression of "alternatively activated" M2 macrophage markers arginase-1, IL-10 and CD163 and low levels of the "classically activated" M1 macrophage markers tumor necrosis factor (TNF)-α and inducible nitric-oxide synthase (iNOS). Immunostaining for CD163 confirmed positive M2 macrophage staining in both visceral and subcutaneous adipose tissue biopsies from critically ill patients. Surprisingly, circulating levels and tissue gene expression of the alternative M2 activators IL-4 and IL-13 were low and not different from controls. In contrast, adipose tissue protein levels of peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor required for M2 differentiation and acting downstream of IL-4, was markedly elevated in illness. In subcutaneous abdominal adipose tissue biopsies from surviving critically ill patients, we could confirm positive macrophage staining with CD68 and CD163. We also could confirm elevated arginase-1 gene expression and elevated PPARγ protein levels. Unlike obesity, critical illness evokes adipose tissue accumulation of alternatively activated M2

  19. Control software architecture and operating modes of the Model M-2 maintenance system

    International Nuclear Information System (INIS)

    Satterlee, P.E. Jr.; Martin, H.L.; Herndon, J.N.

    1984-04-01

    The Model M-2 maintenance system is the first completely digitally controlled servomanipulator. The M-2 system allows dexterous operations to be performed remotely using bilateral force-reflecting master/slave techniques, and its integrated operator interface takes advantage of touch-screen-driven menus to allow selection of all possible operating modes. The control system hardware for this system has been described previously. This paper describes the architecture of the overall control system. The system's various modes of operation are identified, the software implementation of each is described, system diagnostic routines are described, and highlights of the computer-augmented operator interface are discussed. 3 references, 5 figures

  20. Control software architecture and operating modes of the Model M-2 maintenance system

    Energy Technology Data Exchange (ETDEWEB)

    Satterlee, P.E. Jr.; Martin, H.L.; Herndon, J.N.

    1984-04-01

    The Model M-2 maintenance system is the first completely digitally controlled servomanipulator. The M-2 system allows dexterous operations to be performed remotely using bilateral force-reflecting master/slave techniques, and its integrated operator interface takes advantage of touch-screen-driven menus to allow selection of all possible operating modes. The control system hardware for this system has been described previously. This paper describes the architecture of the overall control system. The system's various modes of operation are identified, the software implementation of each is described, system diagnostic routines are described, and highlights of the computer-augmented operator interface are discussed. 3 references, 5 figures.

  1. Almost optimal distributed M2M multicasting in wireless mesh networks

    DEFF Research Database (Denmark)

    Xin, Qin; Manne, Fredrik; Zhang, Yan

    2012-01-01

    Wireless Mesh Networking (WMN) is an emerging communication paradigm to enable resilient, cost-efficient and reliable services for the future-generation wireless networks. In this paper, we study the problem of multipoint-to- multipoint (M2M) multicasting in a WMN which aims to use the minimum...... number of time slots to exchange messages among a group of k mesh nodes in a multi-hop WMN with n mesh nodes. We study the M2M multicasting problem in a distributed environment where each participant only knows that there are k participants and it does not know who are other k-1 participants among n mesh...

  2. Segal–Bargmann transform and Paley–Wiener theorems on M(2 )

    Indian Academy of Sciences (India)

    S1) to. L2(S1) by. ˆf (ξ ) = ∫. M(2) f (g)Uξ g dg. Moreover, the group Fourier transform ˆf (ξ ), for ξ ∈ R2 of f ∈ L1(M(2)) is an integral operator with the kernel kf (ξ, e iα, e iβ) where kf (ξ, e iα, e iβ) = ˜f(e iβξ, e i(β−α)), and ˜f is the Euclidean Fourier ...

  3. Modelling the enigmatic Late Pliocene Glacial Event - Marine Isotope Stage M2

    Science.gov (United States)

    Dolan, Aisling M.; Haywood, Alan M.; Hunter, Stephen J.; Tindall, Julia C.; Dowsett, Harry J.; Hill, Daniel J.; Pickering, Steven J.

    2015-01-01

    The Pliocene Epoch (5.2 to 2.58 Ma) has often been targeted to investigate the nature of warm climates. However, climate records for the Pliocene exhibit significant variability and show intervals that apparently experienced a cooler than modern climate. Marine Isotope Stage (MIS) M2 (~ 3.3 Ma) is a globally recognisable cooling event that disturbs an otherwise relatively (compared to present-day) warm background climate state. It remains unclear whether this event corresponds to significant ice sheet build-up in the Northern and Southern Hemisphere. Estimates of sea level for this interval vary, and range from modern values to estimates of 65 m sea level fall with respect to present day. Here we implement plausible M2 ice sheet configurations into a coupled atmosphere–ocean climate model to test the hypothesis that larger-than-modern ice sheet configurations may have existed at M2. Climate model results are compared with proxy climate data available for M2 to assess the plausibility of each ice sheet configuration. Whilst the outcomes of our data/model comparisons are not in all cases straight forward to interpret, there is little indication that results from model simulations in which significant ice masses have been prescribed in the Northern Hemisphere are incompatible with proxy data from the North Atlantic, Northeast Arctic Russia, North Africa and the Southern Ocean. Therefore, our model results do not preclude the possibility of the existence of larger ice masses during M2 in the Northern or Southern Hemisphere. Specifically they are not able to discount the possibility of significant ice masses in the Northern Hemisphere during the M2 event, consistent with a global sea-level fall of between 40 m and 60 m. This study highlights the general need for more focused and coordinated data generation in the future to improve the coverage and consistency in proxy records for M2, which will allow these and future M2 sensitivity tests to be interrogated

  4. M2-F1 lifting body aircraft on a flatbed truck

    Science.gov (United States)

    1997-01-01

    After the grounding of the M2-F1 in 1966, it was kept in outside storage on the Dryden complex. After several years, its fabric and plywood structure was damaged by the sun and weather. Restoration of the vehicle began in February 1994 under the leadership of NASA retiree Dick Fischer, with other retirees who had originally worked on the M2-F1's construction and flight research three decades before also participating. The photo shows the now-restored M2-F1 returning to the site of its flight research, now called the Dryden Flight Research Center, on 22 August 1997. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, NASA Flight Research Center (later Dryden Flight Research Center, Edwards, CA) management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available

  5. A Survey on M2M Systems for mHealth: A Wireless Communications Perspective

    Directory of Open Access Journals (Sweden)

    Elli Kartsakli

    2014-09-01

    Full Text Available In the new era of connectivity, marked by the explosive number of wireless electronic devices and the need for smart and pervasive applications, Machine-to-Machine (M2M communications are an emerging technology that enables the seamless device interconnection without the need of human interaction. The use of M2M technology can bring to life a wide range of mHealth applications, with considerable benefits for both patients and healthcare providers. Many technological challenges have to be met, however, to ensure the widespread adoption of mHealth solutions in the future. In this context, we aim to provide a comprehensive survey on M2M systems for mHealth applications from a wireless communication perspective. An end-to-end holistic approach is adopted, focusing on different communication aspects of the M2M architecture. Hence, we first provide a systematic review ofWireless Body Area Networks (WBANs, which constitute the enabling technology at the patient’s side, and then discuss end-to-end solutions that involve the design and implementation of practical mHealth applications. We close the survey by identifying challenges and open research issues, thus paving the way for future research opportunities.

  6. Kinetics of proton transport into influenza virions by the viral M2 channel.

    Directory of Open Access Journals (Sweden)

    Tijana Ivanovic

    Full Text Available M2 protein of influenza A viruses is a tetrameric transmembrane proton channel, which has essential functions both early and late in the virus infectious cycle. Previous studies of proton transport by M2 have been limited to measurements outside the context of the virus particle. We have developed an in vitro fluorescence-based assay to monitor internal acidification of individual virions triggered to undergo membrane fusion. We show that rimantadine, an inhibitor of M2 proton conductance, blocks the acidification-dependent dissipation of fluorescence from a pH-sensitive virus-content probe. Fusion-pore formation usually follows internal acidification but does not require it. The rate of internal virion acidification increases with external proton concentration and saturates with a pK(m of ∼4.7. The rate of proton transport through a single, fully protonated M2 channel is approximately 100 to 400 protons per second. The saturating proton-concentration dependence and the low rate of internal virion acidification derived from authentic virions support a transporter model for the mechanism of proton transfer.

  7. Solidification microstructure of M2 high speed steel by different casting technologies

    Directory of Open Access Journals (Sweden)

    Zhou Xuefeng

    2011-08-01

    Full Text Available The present work investigated the solidification microstructure of AISI M2 high speed steel manufactured by different casting technologies, namely iron mould casting and continuous casting. The results revealed that the as-cast structure of the steel was composed of the iron matrix and the M2C eutectic carbide networks, which were greatly refined in the ingot made by continuous casting process, compared with that by the iron mould casting process. M2C eutectic carbides presented variation in their morphologies and growth characteristics in the ingots by both casting methods. In the ingot by iron mould casting, they have a plate-like morphology and grow anisotropically. However, in the ingot made by continuous casting, the carbides evolved into the fiber-like shape that exhibited little characteristics of anisotropic growth. It was noticed that the fiber-like M2C was much easier to decompose and spheroidize after heated, as a result, the carbides refined remarkably, compared with the case of plate-like carbides in the iron mould casting ingot.

  8. Efficient LTE Access with Collision Resolution for Massive M2M Communications

    DEFF Research Database (Denmark)

    Madueño, Germán Corrales; Stefanovic, Cedomir; Popovski, Petar

    2014-01-01

    outage. In this work we propose a LTE RACH scheme tailored for delay-sensitive M2M services with synchronous traffic arrivals. The key idea is, upon detection of a RACH overload, to apply a collision resolution algorithm based on splitting trees. The solution is implemented on top of the existing LTE...

  9. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Haga, Kazuko; Kruse, Andrew C.; Asada, Hidetsugu; Yurugi-Kobayashi, Takami; Shiroishi, Mitsunori; Zhang, Cheng; Weis, William I.; Okada, Tetsuji; Kobilka, Brian K.; Haga, Tatsuya; Kobayashi, Takuya (Stanford-MED); (Kyoto); (Gakushuin); (Kyushu)

    2012-03-15

    The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

  10. M2-F1 in flight over lakebed on tow line

    Science.gov (United States)

    1963-01-01

    After initial ground-tow flights of the M2-F1 using the Pontiac as a tow vehicle, the way was clear to make air tows behind a C-47. The first air tow took place on 16 August 1963. Pilot Milt Thompson found that the M2-F1 flew well, with good control. This first flight lasted less than two minutes from tow-line release to touchdown. The descent rate was 4,000 feet per minute. The wingless, lifting body aircraft design was initially concieved as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got

  11. Proposed Ames M2-F1, M1-L half-cone, and Langley lenticular bodies.

    Science.gov (United States)

    1962-01-01

    Dale Reed, who inaugurated the lifting-body flight research at NASA's Flight Research Center (later, Dryden Flight Research Center, Edwards, CA), originally proposed that three wooden outer shells be built. These would then be attached to the single internal steel structure. The three shapes were (viewer's left to right) the M2-F1, the M1-L, and a lenticular shape. Milt Thompson, who supported Reed's advocacy for a lifting-body research project, recommended that only the M2-F1 shell be built, believing that the M1-L shape was 'too radical,' while the lenticular one was 'too exotic.' Although the lenticular shape was often likened to that of a flying saucer, Reed's wife Donna called it the 'powder puff.' The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey

  12. Wooden shell of M2-F1 being assembled at El Mirage

    Science.gov (United States)

    1962-01-01

    Wooden shell of the M2-F1 being assembled at El Mirage, CA. While Flight Research Center technicians built the internal steel structure of the M2-F1, sailplane builder Gus Briegleb built the vehicle's outer wooden shell. Its skin was 3/32-inch mahogany plywood, with 1/8-inch mahogany rib sections reinforced with spruce. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got the M2-F1 airborne to prove it could fly safely and to

  13. M2-F1 mounted in NASA Ames Research Center 40x80 foot wind tunnel

    Science.gov (United States)

    1962-01-01

    After the first attempted ground-tow tests of the M2-F1 in March 1963, the vehicle was taken to the Ames Research Center, Mountain View, CA, for wind-tunnel testing. During these tests, Milt Thompson and others were in the M2-F1 to position the control surfaces for each test. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got the M2-F1 airborne to prove it could fly safely and to train pilots before they were towed behind a C

  14. Evidence for M2 macrophages in granulomas from pulmonary sarcoidosis : a new aspect of macrophage heterogeneity

    NARCIS (Netherlands)

    Shamaei, Masoud; Mortaz, Esmaeil; Pourabdollah, Mihan; Garssen, Johan; Tabarsi, Payam; Velayati, Aliakbar; Adcock, Ian M

    BACKGROUND: Sarcoidosis is a granulomatous disease of unknown etiology. Macrophages play a key role in granuloma formation with the T cells, having a significant impact on macrophage polarization (M1 and M2) and the cellular composition of the granuloma. This study evaluates macrophage polarization

  15. Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor.

    Science.gov (United States)

    Schrage, R; Seemann, W K; Klöckner, J; Dallanoce, C; Racké, K; Kostenis, E; De Amici, M; Holzgrabe, U; Mohr, K

    2013-05-01

    Artificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such 'superagonism' has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a 'superagonist'. Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies. In CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi /Gs signalling competence. In the orthosteric loss-of-function mutant M2 -Y104(3.33) A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. 'Superagonism' is preserved in the physiological cellular context of MRC-5 human lung fibroblasts. Structure-signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that 'superagonism' of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points. Supraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR 'superagonism' is provided. We suggest that iperoxo-like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  16. Functional motifs responsible for human metapneumovirus M2-2-mediated innate immune evasion.

    Science.gov (United States)

    Chen, Yu; Deng, Xiaoling; Deng, Junfang; Zhou, Jiehua; Ren, Yuping; Liu, Shengxuan; Prusak, Deborah J; Wood, Thomas G; Bao, Xiaoyong

    2016-12-01

    Human metapneumovirus (hMPV) is a major cause of lower respiratory infection in young children. Repeated infections occur throughout life, but its immune evasion mechanisms are largely unknown. We recently found that hMPV M2-2 protein elicits immune evasion by targeting mitochondrial antiviral-signaling protein (MAVS), an antiviral signaling molecule. However, the molecular mechanisms underlying such inhibition are not known. Our mutagenesis studies revealed that PDZ-binding motifs, 29-DEMI-32 and 39-KEALSDGI-46, located in an immune inhibitory region of M2-2, are responsible for M2-2-mediated immune evasion. We also found both motifs prevent TRAF5 and TRAF6, the MAVS downstream adaptors, to be recruited to MAVS, while the motif 39-KEALSDGI-46 also blocks TRAF3 migrating to MAVS. In parallel, these TRAFs are important in activating transcription factors NF-kB and/or IRF-3 by hMPV. Our findings collectively demonstrate that M2-2 uses its PDZ motifs to launch the hMPV immune evasion through blocking the interaction of MAVS and its downstream TRAFs. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Formation of the high-spin Hf-179m2 isomer in reactor irradiations

    Czech Academy of Sciences Publication Activity Database

    Karamian, S. A.; Carroll, J. J.; Adam, Jindřich; Kulagin, EN.; Shabalin, EP.

    2004-01-01

    Roč. 14, č. 4 (2004), s. 438-441 ISSN 1054-660X R&D Projects: GA MŠk(CZ) ME 134 Keywords : reactor irradiation * high-spin Hf-179m2 Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 0.836, year: 2004

  18. Massive M2M Access with Reliability Guarantees in LTE Systems

    DEFF Research Database (Denmark)

    Madueño, Germán Corrales; Kiilerich Pratas, Nuno; Stefanovic, Cedomir

    2015-01-01

    Machine-to-Machine (M2M) communications are one of the major drivers of the cellular network evolution towards 5G systems. One of the key challenges is on how to provide reliability guarantees to each accessing device in a situation in which there is a massive number of almost-simultaneous arriva...

  19. Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages

    Science.gov (United States)

    Waqas, Syed F. Hassnain; Hoang, Anh Cuong; Ampem, Grace; Azegrouz, Hind; Balogh, Lajos; Thuróczy, Julianna; Gerling, Ivan C.; Nam, Sorim; Lim, Jong-Seok; Martinez-Ibañez, Juncal; Real, José T.; Paschke, Stephan; Quillet, Raphaëlle; Ayachi, Safia; Simonin, Frédéric; Schneider, E. Marion; Brinkman, Jacqueline A.; Seroogy, Christine M.

    2017-01-01

    The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet–fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage–associated genes IL-4 receptor α (Il4ra), arginase 1 (Arg1), IL-10 (Il10), and alkylglycerol monooxygenase (Agmo). NPFF induced ATM proliferation concomitantly with the increase in N-Myc downstream-regulated gene 2 (Ndrg2) expression and suppressed the transcription of Ifi200 cell-cycle inhibitor family members and MAF bZIP transcription factor B (Mafb), a negative regulator of macrophage proliferation. NPFF thus plays an important role in supporting healthy adipose tissue via the maintenance of metabolically beneficial ATMs. PMID:28581443

  20. Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages.

    Science.gov (United States)

    Waqas, Syed F Hassnain; Hoang, Anh Cuong; Lin, Ya-Tin; Ampem, Grace; Azegrouz, Hind; Balogh, Lajos; Thuróczy, Julianna; Chen, Jin-Chung; Gerling, Ivan C; Nam, Sorim; Lim, Jong-Seok; Martinez-Ibañez, Juncal; Real, José T; Paschke, Stephan; Quillet, Raphaëlle; Ayachi, Safia; Simonin, Frédéric; Schneider, E Marion; Brinkman, Jacqueline A; Lamming, Dudley W; Seroogy, Christine M; Röszer, Tamás

    2017-06-30

    The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet-fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage-associated genes IL-4 receptor α (Il4ra), arginase 1 (Arg1), IL-10 (Il10), and alkylglycerol monooxygenase (Agmo). NPFF induced ATM proliferation concomitantly with the increase in N-Myc downstream-regulated gene 2 (Ndrg2) expression and suppressed the transcription of Ifi200 cell-cycle inhibitor family members and MAF bZIP transcription factor B (Mafb), a negative regulator of macrophage proliferation. NPFF thus plays an important role in supporting healthy adipose tissue via the maintenance of metabolically beneficial ATMs.

  1. Tramadol differentially regulates M1 and M2 macrophages from human umbilical cord blood.

    Science.gov (United States)

    Zhang, Jun; Chen, Liang; Sun, Yunyun; Li, Yuanhai

    2017-03-17

    Tramadol is an analgesic drug and relieves pain through activating μ-opioid receptors and inhibiting serotonin and noradrenaline reuptake. Emerging evidence shows that it also stimulates immune cells, including NK cells, splenocytes, and lymphocytes, and elevates IL-2 production. However, it remains unknown whether and how tramadol directly affects macrophages. To answer these questions, we collected human umbilical cord blood, isolated macrophages, and examined their responses to tramadol. Although tramadol did not alter resting macrophages and the antigen-presenting function in lipopolysaccharide-activated macrophages, it regulated M1 and M2 macrophages, which are, respectively, transformed by IFN-γ and IL-4. Interestingly, tramadol inhibits production and secretion of cytokines in M1 macrophages, but facilitates the production of inflammation-responding molecules, synthesized in M2 macrophages. We also found that STAT6 cascade pathway in M2 macrophages was significantly enhanced by tramadol. Therefore, this study reveals that tramadol regulates inflammation by inhibiting M1 macrophages (killing process), but promoting the function of M2 macrophages (healing process).

  2. Multiple promoters drive tissue-specific expression of the human M2 muscarinic acetylcholine receptor gene

    Czech Academy of Sciences Publication Activity Database

    Krejčí, Alena; Bruce, A. W.; Doležal, Vladimír; Tuček, Stanislav; Buckley, N. J.

    2004-01-01

    Roč. 91, č. 1 (2004), s. 88-98 ISSN 0022-3042 R&D Projects: GA AV ČR IAA5011306 Institutional research plan: CEZ:AV0Z5011922 Keywords : M2 muscarinic receptor * neuron-restrictive silence factor * promoter Subject RIV: ED - Physiology Impact factor: 4.824, year: 2004

  3. Initial search for triggered gamma emission from Hf-178(m2) using the YSU miniball array

    Czech Academy of Sciences Publication Activity Database

    Carroll, J. J.; Burnett, J.; Drummond, T.; Lepak, J.; Propri, R.; Smith, D.; Karamian, S. A.; Adam, Jindřich; Stedile, F.; Agee, FJ.

    2002-01-01

    Roč. 143, 1, 2, 3, 4 (2002), s. 37-54 ISSN 0304-3843 Institutional research plan: CEZ:AV0Z1048901 Keywords : triggered gamma emission * Hf-178(m2) * nuclear batteries Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 0.533, year: 2002

  4. Serine is a natural ligand and allosteric activator of pyruvate kinase M2

    NARCIS (Netherlands)

    Chaneton, Barbara; Hillmann, Petra; Zheng, Liang; Martin, Agnes C. L.; Maddocks, Oliver D. K.; Chokkathukalam, Achuthanunni; Coyle, Joseph E.; Jankevics, Andris; Holding, Finn P.; Vousden, Karen H.; Frezza, Christian; O'Reilly, Marc; Gottlieb, Eyal

    2012-01-01

    Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation(1). Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of

  5. M2-F1 on lakebed with Pontiac convertible tow vehicle

    Science.gov (United States)

    1963-01-01

    The M2-F1 lifting body, dubbed the 'flying bathtub' by the media, was the precursor of a remarkable series of wingless flying vehicles that contributed data used in the space shuttle and the X-38 Technology Demonstrator for crew return from the International Space Station. The early tow tests were done using the 1963 Pontiac Catalina convertible modified for the purpose. The first flight attempt occurred on 1 March 1963 but was unsuccessful due to control-system problems. It was not until 5 April 1963, after tests in the Ames Research Center wind tunnel, that Milt Thompson made the first M2-F1 tow flight. Based on the ideas and basic design of Alfred J. Eggers and others at the Ames Aeronautical Laboratory (now the Ames Research Center), Mountain View, Calif., in the mid-1950s, the M2-F1 came to be built over a four-month period in 1962-63 for a cost of only about $30,000 plus perhaps an additional $8,000-$10,000 for an ejection seat and $10,000 for solid-propellant rockets to add time to the landing flare. Engineers and technicians at the NASA Flight Research Center (now NASA Dryden) kept costs low by designing and fabricating it partly in-house, with the plywood shell constructed by a local sailplane builder. Someone at the time estimated that it would have cost a major aircraft company $150,000 to build the same vehicle. Unlike the later lifting bodies, the M2-F1 was unpowered and was initially towed until it was airborne by a souped-up Pontiac convertible. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina

  6. Bariatric surgery in 1119 patients with preoperative body mass index<35 (kg/m(2)): results at 1 year.

    Science.gov (United States)

    Maiz, Cristóbal; Alvarado, Juan; Quezada, Nicolás; Salinas, José; Funke, Ricardo; Boza, Camilo

    2015-01-01

    The use of body mass index (BMI) as the only criterion to indicate bariatric surgery is currently under discussion. There is growing evidence that supports bariatric surgery in carefully selected patients with lower BMI. To report our experience in bariatric surgery in>1000 patients with BMI<35 kg/m(2) and their results at 1 year. University hospital (censored). A retrospective analysis was performed in patients who underwent laparoscopic Roux-en-Y gastric bypass (LRYGB) or sleeve gastrectomy (SG) with preoperative BMI<35 kg/m(2) from January 2008 to December 2011. Demographic and anthropometric data, preoperative co-morbidities, and perioperative variables were retrieved. Weight loss and co-morbidities progression were analyzed 1 year after surgery and compared among procedures. A P value<.05 was considered significant. We identified 1119 patients: mean age 38.8±11.4, 951 (85%) women, preoperative weight 87.5±9.3 kg and BMI 33.1 (31.9-34.1) kg/m(2). Preoperatively, 11.7% had type 2 diabetes mellitus, 25.9% arterial hypertension, 55.6% insulin resistance, and 53.2% dyslipidemia. In total, 283 patients (25.2%) underwent LRYGB and 836 (74.8%) SG. One year after surgery (follow-up: 66.67%) patients reached 24.5 (22.8-26.4) BMI and the percentage of excess of weight loss (%EWL) was 107.9±36.6%. Diabetes, hypertension, insulin resistance, and dyslipidemia remission/improvement rates were 54/39%, 58/29%, 72/17%, and 54/30%, respectively. Bariatric surgery in selected class I obesity patients can safely be performed. We have observed good results in terms of weight loss and co-morbidity improvement/remission. Long-term follow-up is required. Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  7. M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria-Associated Sepsis in Alcoholics.

    Science.gov (United States)

    Tsuchimoto, Yusuke; Asai, Akira; Tsuda, Yasuhiro; Ito, Ichiaki; Nishiguchi, Tomoki; Garcia, Melanie C; Suzuki, Sumihiro; Kobayashi, Makiko; Higuchi, Kazuhide; Suzuki, Fujio

    2015-12-01

    Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. γ-irradiated NOD-SCID IL-2Rγ(null) mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12(+)IL-10(-)CD163(-)CD14(+) cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1(+)CD163(+)CD14(+) cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to M1 monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12(-)IL-10(-)CCL1(-)CD163(-)CD14(+) cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M1 monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria-associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes. Copyright © 2015 by The American Association of Immunologists, Inc.

  8. Study on phylogenetic relationships, variability, and correlated mutations in M2 proteins of influenza virus A.

    Directory of Open Access Journals (Sweden)

    Ly Le

    Full Text Available M2 channel, an influenza virus transmembrane protein, serves as an important target for antiviral drug design. There are still discordances concerning the role of some residues involved in proton transfer as well as the mechanism of inhibition by commercial drugs. The viral M2 proteins show high conservativity; about 3/4 of the positions are occupied by one residue in over 95%. Nine M2 proteins from the H3N2 strain and possibly two proteins from H2N2 strains make a phylogenic cluster closely related to 2RLF. The variability range is limited to 4 residues/position with one exception. The 2RLF protein stands out by the presence of 2 serines at the positions 19 and 50, which are in most other M2 proteins occupied by cysteines. The study of correlated mutations shows that there are several positions with significant mutational correlation that have not been described so far as functionally important. That there are 5 more residues potentially involved in the M2 mechanism of action. The original software used in this work (Consensus Constructor, SSSSg, Corm, Talana is freely accessible as stand-alone offline applications upon request to the authors. The other software used in this work is freely available online for noncommercial purposes at public services on bioinformatics such as ExPASy or NCBI. The study on mutational variability, evolutionary relationship, and correlated mutation presented in this paper is a potential way to explain more completely the role of significant factors in proton channel action and to clarify the inhibition mechanism by specific drugs.

  9. Unprimed, M1 and M2 Macrophages Differentially Interact with Porphyromonas gingivalis.

    Directory of Open Access Journals (Sweden)

    Roselind S Lam

    Full Text Available Porphyromonas gingivalis is a keystone pathogen in the development of chronic periodontitis. Tissue macrophages are amongst the first immune cells to respond to bacteria and depending on the cytokine profile at the infection site, macrophages are primed to react to infection in different ways. Priming of naive macrophages with IFN-γ produces a classical pro-inflammatory, antibacterial M1 macrophage after TLR ligation, whereas priming with IL-4 induces an anti-inflammatory tissue-repair M2 phenotype. Previous work has shown that M1 are preferentially generated in gingival tissue following infection with P. gingivalis. However, few studies have investigated the interactions of macrophage subsets with P. gingivalis cells. The aim of this study was to determine the ability of naive, M1 and M2 macrophages to phagocytose P. gingivalis and investigate how this interaction affects both the bacterial cell and the macrophage. M1 and M2 macrophages were both found to have enhanced phagocytic capacity compared with that of naive macrophages, however only the naive and M1 macrophages were able to produce a respiratory burst in order to clear the bacteria from the phagosome. P. gingivalis was found to persist in naive and M2, but not M1 macrophages for 24 hours. Phagocytosis of P. gingivalis also induced high levels of TNF-α, IL-12 and iNOS in M1 macrophages, but not in naive or M2 macrophages. Furthermore, infection of macrophages with P. gingivalis at high bacteria to macrophage ratios, while inducing an inflammatory response, was also found to be deleterious to macrophage longevity, with high levels of apoptotic cell death found in macrophages after infection. The activation of M1 macrophages observed in this study may contribute to the initiation and maintenance of a pro-inflammatory state during chronic periodontitis.

  10. Construction of Δm2--sin2 2θ plots

    International Nuclear Information System (INIS)

    Snyder, R.

    1991-01-01

    In the two-flavor approximation, the probability for a neutrino to oscillate from one flavor to the other is given by Ρ νa → νb = sin 2 2θ sin 2 (1.27 Δm 2 L/E ν ) where θ is the mixing angle, Δm 2 = |m νa 2 - m νb 2 | is measured in (eV/c 2 ) 2 , L, the distance from the source, is measured in km, and E, the beam energy, is measured in GeV. If either Δm 2 or sin 2 2Θ is zero, there is no oscillation. They might also have small, non-zero values, causing the oscillations to be so small as to be unobservable in a particular experiment. They may also have values which allow us to determine the probability of oscillation, but so far no compelling evidence for oscillation exists. The universal method of portraying what region of parameter space is explored by a neutrino oscillation experiment is to mark off an area on a Δm 2 vs. sin 2 2θ plot. Typically, a line is graphed, with the claim that if the experiment finds not evidence of oscillation, one can, for example, be 90% certain that Δm 2 and sin 2 2θ lie within the region below and to the left of the line. Since these plots are so widely used, it is useful to understand the process by which they are created

  11. M2-F1 in flight during low-speed car tow

    Science.gov (United States)

    1963-01-01

    The M2-F1 shown in flight during a low-speed car tow runs across the lakebed. Such tests allowed about two minutes to test the vehicle's handling in flight. NASA Flight Research Center (later redesignated the Dryden Flight Research Center) personnel conducted as many as 8 to 14 ground-tow flights in a single day either to test the vehicle in preparation for air tows or to train pilots to fly the vehicle before they undertook air tows. The wingless, lifting body aircraft design was initially concieved as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30

  12. M2-F1 fabrication by Grierson Hamilton, Bob Green, and Ed Browne

    Science.gov (United States)

    1962-01-01

    Flight Research Center discretionary funds paid for the M2-F-1's construction. NASA mechanics, sheet-metal smiths, and technicians did much of the work in a curtained-off area of a hangar called the 'Wright Bicycle Shop.' The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got the M2-F1 airborne to prove it could fly safely and to train pilots before they were towed behind a C-47 aircraft and released. These initial car-tow tests

  13. Liquid Chromatography-Mass Spectrometry-Based Rapid Secondary-Metabolite Profiling of Marine Pseudoalteromonas sp. M2

    Directory of Open Access Journals (Sweden)

    Woo Jung Kim

    2016-01-01

    Full Text Available The ocean is a rich resource of flora, fauna, and food. A wild-type bacterial strain showing confluent growth on marine agar with antibacterial activity was isolated from marine water, identified using 16S rDNA sequence analysis as Pseudoalteromonas sp., and designated as strain M2. This strain was found to produce various secondary metabolites including quinolone alkaloids. Using high-resolution mass spectrometry (MS and nuclear magnetic resonance (NMR analysis, we identified nine secondary metabolites of 4-hydroxy-2-alkylquinoline (pseudane-III, IV, V, VI, VII, VIII, IX, X, and XI. Additionally, this strain produced two novel, closely related compounds, 2-isopentylqunoline-4-one and 2-(2,3-dimetylbutylqunoline-4-(1H-one, which have not been previously reported from marine bacteria. From the metabolites produced by Pseudoalteromonas sp. M2, 2-(2,3-dimethylbutylquinolin-4-one, pseudane-VI, and pseudane-VII inhibited melanin synthesis in Melan-A cells by 23.0%, 28.2%, and 42.7%, respectively, wherein pseudane-VII showed the highest inhibition at 8 µg/mL. The results of this study suggest that liquid chromatography (LC-MS/MS-based metabolite screening effectively improves the efficiency of novel metabolite discovery. Additionally, these compounds are promising candidates for further bioactivity development.

  14. Preferred M2 Polarization by ASC-Based Hydrogel Accelerated Angiogenesis and Myogenesis in Volumetric Muscle Loss Rats

    Directory of Open Access Journals (Sweden)

    Hong Huang

    2017-01-01

    Full Text Available Volumetric muscle loss (VML injury resulted from massive muscle defects and diseases for which there are still no effective therapeutic treatments. This study aimed to investigate the effects of rat adipose-derived mesenchymal stem cells (rASCs and rASCs-conditioned medium- (CM- based type I collagen hydrogel on macrophage (MP transition, myogenesis, and vascularization in the rat VML model. Laser Doppler results demonstrated much higher blood flow in the rASC- and CM-based hydrogel groups. qRT-PCR, hematoxylin and eosin, immunofluorescence, and Sirius Red staining manifested that both rASCs and CM-based hydrogel implantation accelerated muscle repair with upregulated angiogenesis and myogenesis, attenuated inflammation while facilitating M2 transition, and decreased the collagen deposition compared with the hydrogel group. In vitro experiments indicated that factors secreted from polarized M2 MPs could accelerate the migration and tube formation capacities of HUVECs. These results suggested that rASCs exerted immunomodulatory effects on MPs which further enhanced the proangiogenic potential on ECs to promote myogenesis and angiogenesis during muscle repair. These fundamental results support further clinical applications of ASCs for muscle loss injury.

  15. Electrospun poly(hydroxybutyrate) scaffolds promote engraftment of human skin equivalents via macrophage M2 polarization and angiogenesis.

    Science.gov (United States)

    Castellano, Delia; Sanchis, Ana; Blanes, María; Pérez Del Caz, Mª Dolores; Ruiz-Saurí, Amparo; Piquer-Gil, Marina; Pelacho, Beatriz; Marco, Bruno; Garcia, Nahuel; Ontoria-Oviedo, Imelda; Cambra, Vicente; Prosper, Felipe; Sepúlveda, Pilar

    2018-02-01

    Human dermo-epidermal skin equivalents (DE) comprising in vitro expanded autologous keratinocytes and fibroblasts are a good option for massive burn treatment. However, the lengthy expansion time required to obtain sufficient surface to cover an extensive burn together with the challenging surgical procedure limits their clinical use. The integration of DE and biodegradable scaffolds has been proposed in an effort to enhance their mechanical properties. Here, it is shown that poly(hydroxybutyrate) electrospun scaffolds (PHB) present good biocompatibility both in vitro and in vivo and are superior to poly-ε-caprolactone electrospun scaffolds as a substrate for skin reconstruction. Implantation of PHB scaffolds in healthy rats polarized macrophages to an M2-type that promoted constructive in vivo remodelling. Moreover, implantation of DE-PHB composites in a NOD/SCID mouse xenograft model resulted in engraftment accompanied by an increase in angiogenesis that favoured the survival of the human graft. Thus, PHB scaffolds are an attractive substrate for further exploration in skin reconstruction procedures, probably due in part to their greater angiogenic and M2 macrophage polarization properties. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  16. Endovascular thrombectomy for M2 occlusions: comparison between forced arterial suction thrombectomy and stent retriever thrombectomy.

    Science.gov (United States)

    Kim, Yong-Won; Son, Seungnam; Kang, Dong-Hun; Hwang, Yang-Ha; Kim, Yong-Sun

    2017-07-01

    To date there has been no direct comparison of two frequently used endovascular thrombectomy (EVT) methods (forced arterial suction thrombectomy (FAST) and stent retriever thrombectomy) in M2 occlusions. We review our experiences with EVT performed using FAST and stent retriever thrombectomy in such cases. The subjects comprised 41 patients with an M2 occlusion who underwent EVT (25 with FAST, 16 with stent retriever thrombectomy). The patients' data were retrospectively analyzed to evaluate the technical characteristics and angiographic outcome of the two EVT techniques. Thrombolysis In Cerebral Infarction (TICI) grades 2b-3 using the first chosen technique did not differ significantly between the two techniques (FAST 64.0% vs stent retriever thrombectomy 81.2%, p=0.305). Time from groin puncture to reperfusion was significantly shorter for stent retriever thrombectomy (53.0 vs 38.5 min; p=0.045). Distal embolization occurred in three cases (12.0%) in the FAST group and in four (26.7%) in the stent retriever group (p=0.362). However, the two techniques did not differ significantly in the final TICI 2b-3 rate (72.0% vs 87.5%; p=0.441). A frequent angiographic finding regarding the failure of FAST was that the M2 occlusion was located immediately after severe acute angulation between M1 and M2. Stent retriever thrombectomy may provide faster reperfusion than FAST, while the FAST technique might be associated with lower distal embolization and a higher reperfusion rate for the first thrombectomy attempt, but without any significant difference in clinical outcome. When choosing the EVT method for M2 occlusions, consideration of the location of the occlusion and tortuosity between M1 and M2 might be helpful to achieve a better angiographic outcome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  17. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages.

    Directory of Open Access Journals (Sweden)

    Mário Henrique M Barros

    Full Text Available Macrophage polarization is increasingly recognised as an important pathogenetic factor in inflammatory and neoplastic diseases. Proinflammatory M1 macrophages promote T helper (Th 1 responses and show tumoricidal activity. M2 macrophages contribute to tissue repair and promote Th2 responses. CD68 and CD163 are used to identify macrophages in tissue sections. However, characterisation of polarised macrophages in situ has remained difficult. Macrophage polarisation is regulated by transcription factors, pSTAT1 and RBP-J for M1, and CMAF for M2. We reasoned that double-labelling immunohistochemistry for the detection of macrophage markers together with transcription factors may be suitable to characterise macrophage polarisation in situ. To test this hypothesis, we have studied conditions associated with Th1- and Th2-predominant immune responses: infectious mononucleosis and Crohn's disease for Th1 and allergic nasal polyps, oxyuriasis, wound healing and foreign body granulomas for predominant Th2 response. In all situations, CD163+ cells usually outnumbered CD68+ cells. Moreover, CD163+ cells, usually considered as M2 macrophages, co-expressing pSTAT1 and RBP-J were found in all conditions examined. The numbers of putative M1 macrophages were higher in Th1- than in Th2-associated diseases, while more M2 macrophages were seen in Th2- than in Th1 related disorders. In most Th1-related diseases, the balance of M1 over M2 cells was shifted towards M1 cells, while the reverse was observed for Th2-related conditions. Hierarchical cluster analysis revealed two distinct clusters: cluster I included Th1 diseases together with cases with high numbers of CD163+pSTAT1+, CD68+pSTAT1+, CD163+RBP-J+ and CD68+RBP-J+ macrophages; cluster II comprised Th2 conditions together with cases displaying high numbers of CD163+CMAF+ and CD68+CMAF+ macrophages. These results suggest that the detection of pSTAT1, RBP-J, and CMAF in the context of CD68 or CD163 expression is a

  18. The modulatory role of M2 muscarinic receptor on apomorphine-induced yawning and genital grooming.

    Science.gov (United States)

    Gamberini, Maria Thereza; Bolognesi, Maria Laura; Nasello, Antonia Gladys

    2012-12-07

    The interaction between dopaminergic and cholinergic pathways in the induction of behavioral responses has been previously established. In the brain, M2 receptors are found predominantly in presynaptic cholinergic neurons as autoreceptors, and in dopaminergic neurons as heteroceptors, suggesting a control role of acetylcholine and dopamine release, respectively. Our aim was to investigate the role of M2 receptors on the yawning and genital grooming of rats induced by apomorphine, a dopaminergic receptor agonist, focusing on the interaction between cholinergic and dopaminergic pathways. Initially, the effect of atropine, a non-selective muscarinic antagonist, on yawning and genital grooming induced by apomorphine (100 μg/kg s.c.) was analyzed. Atropine doses of 0.5, 1 and 2 mg/kg i.p. were administered to Wistar rats 30 min before induction of the behavioral responses by apomorphine. Number of yawns and time spent genital grooming were quantified over a 60 min period. Apomorphine-induced yawning was increased by low dose (0.5 mg/kg i.p.) but not by high doses (1 and 2 mg/kg, i.p.) of atropine. Genital grooming was antagonized by 2 mg/kg i.p. of atropine and showed no changes at the other doses tested. Tripitramine, a selective M2 cholinergic antagonist, was used as a tool for distinguishing between M2 and all other muscarinic receptor subtypes in yawning and genital grooming. Tripitramine doses of 0.01, 0.02 and 0.04 μmol/kg i.p. were administered to Wistar rats 30 min before apomorphine (100 μg/kg s.c.). Number of yawns and time spent genital grooming were also quantified over a 60 min period. Tripitramine 0.01 μmol/kg increased all parameters. Higher doses, which possibly block all subtypes of muscarinic receptor, did not modify the response of apomorphine, suggesting a non-selective effect of tripitramine at these doses. Given that low doses of tripitramine increased the behavioral responses induced by apomorphine and that the main distribution of the M2

  19. Potent neutralization of influenza A virus by a single-domain antibody blocking M2 ion channel protein.

    Directory of Open Access Journals (Sweden)

    Guowei Wei

    Full Text Available Influenza A virus poses serious health threat to humans. Neutralizing antibodies against the highly conserved M2 ion channel is thought to offer broad protection against influenza A viruses. Here, we screened synthetic Camel single-domain antibody (VHH libraries against native M2 ion channel protein. One of the isolated VHHs, M2-7A, specifically bound to M2-expressed cell membrane as well as influenza A virion, inhibited replication of both amantadine-sensitive and resistant influenza A viruses in vitro, and protected mice from a lethal influenza virus challenge. Moreover, M2-7A showed blocking activity for proton influx through M2 ion channel. These pieces of evidence collectively demonstrate for the first time that a neutralizing antibody against M2 with broad specificity is achievable, and M2-7A may have potential for cross protection against a number of variants and subtypes of influenza A viruses.

  20. BioM2MetDisease: a manually curated database for associations between microRNAs, metabolites, small molecules and metabolic diseases.

    Science.gov (United States)

    Xu, Yanjun; Yang, Haixiu; Wu, Tan; Dong, Qun; Sun, Zeguo; Shang, Desi; Li, Feng; Xu, Yingqi; Su, Fei; Liu, Siyao; Zhang, Yunpeng; Li, Xia

    2017-01-01

    BioM2MetDisease is a manually curated database that aims to provide a comprehensive and experimentally supported resource of associations between metabolic diseases and various biomolecules. Recently, metabolic diseases such as diabetes have become one of the leading threats to people’s health. Metabolic disease associated with alterations of multiple types of biomolecules such as miRNAs and metabolites. An integrated and high-quality data source that collection of metabolic disease associated biomolecules is essential for exploring the underlying molecular mechanisms and discovering novel therapeutics. Here, we developed the BioM2MetDisease database, which currently documents 2681 entries of relationships between 1147 biomolecules (miRNAs, metabolites and small molecules/drugs) and 78 metabolic diseases across 14 species. Each entry includes biomolecule category, species, biomolecule name, disease name, dysregulation pattern, experimental technique, a brief description of metabolic disease-biomolecule relationships, the reference, additional annotation information etc. BioM2MetDisease provides a user-friendly interface to explore and retrieve all data conveniently. A submission page was also offered for researchers to submit new associations between biomolecules and metabolic diseases. BioM2MetDisease provides a comprehensive resource for studying biology molecules act in metabolic diseases, and it is helpful for understanding the molecular mechanisms and developing novel therapeutics for metabolic diseases. http://www.bio-bigdata.com/BioM2MetDisease/. © The Author(s) 2017. Published by Oxford University Press.

  1. Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization.

    Science.gov (United States)

    Ye, Yibiao; Xu, Yunxiuxiu; Lai, Yu; He, Wenguang; Li, Yanshan; Wang, Ruomei; Luo, Xinxi; Chen, Rufu; Chen, Tao

    2018-03-01

    Macrophages have been shown to demonstrate a high level of plasticity, with the ability to undergo dynamic transition between M1 and M2 polarized phenotypes. We investigate long non-coding RNA (lncRNA) cox-2 in macrophage polarization and the regulatory mechanism functions in hepatocellular carcinoma (HCC). Lipopolysaccharide (LPS) was used to induce RAW264.7 macrophages into M1 type, and IL-4 was to induce RAW264.7 macrophages into M2 type. We selected mouse hepatic cell line Hepal-6 and hepatoma cell line HepG2 for co-incubation with M1 or M2 macrophages. Quantitative real-time PCR was used to detect the expressions of lncRNA cox-2 and mRNAs. ELISA was conducted for testing IL-12 and IL-10 expressions; Western blotting for epithelial mesenchymal transition related factors (E-cadherin and Vimentin). An MTT, colony formation assay, flow cytometry, transwell assay, and stretch test were conducted to test cell abilities. The M1 macrophages had higher lncRNA cox-2 expression than that in the non-polarized macrophages and M2 macrophages. The lncRNA cox-2 siRNA decreased the expression levels of IL-12, iNOS, and TNF-α in M1 macrophages, increased the expression levels of IL-10, Arg-1, and Fizz-1 in M2 macrophages (all P evasion and tumor growth by inhibiting the polarization of M2 macrophages. © 2017 Wiley Periodicals, Inc.

  2. Melanoma-initiating cells exploit M2 macrophage TGFβ and arginase pathway for survival and proliferation

    Science.gov (United States)

    Tham, Muly; Tan, Kar Wai; Keeble, Jo; Wang, Xiaojie; Hubert, Sandra; Barron, Luke; Tan, Nguan Soon; Kato, Masashi; Prevost-Blondel, Armelle; Angeli, Veronique; Abastado, Jean-Pierre

    2014-01-01

    M2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34− but not CD34+ tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34− TICs from chemotherapy in vitro. In vivo, while inhibition of CD115 suppressed the macrophage-dependent CD34− TIC population, chemotherapy accelerated its development. The ability of TICs to respond to TAMs was acquired during melanoma progression and immediately preceded a surge in metastatic outgrowth. TAM-derived transforming growth factor-β (TGFβ) and polyamines produced via the Arginase pathway were critical for stimulation of TICs and synergized to promote their growth. PMID:25294815

  3. EcoM2 web portal: Collecting empirical data and supporting companies' ecodesign implementation and management

    DEFF Research Database (Denmark)

    Pigosso, Daniela Cristina Antelmi; McAloone, Tim C.; Rozenfeld, Henrique

    2013-01-01

    to that a comprehensive framework has been developed, with the aim of ensuring systematic management, implementation and continuous improvement of the ecodesign process. The framework, called Ecodesign Maturity Model (EcoM2), enables the diagnosis of the company’s ecodesign maturity profile; the identification......Despite the recognition of the potential benefits of ecodesign, a promising approach to integrate environmental concerns into the product development process, its application has failed to reach large numbers of companies and sectors worldwide due to managerial difficulties. In response...... of strengths and limitations; and the establishment of strategic roadmaps for improved ecodesign implementation. This paper describes the development of the EcoM2 web portal, which will allow for the framework to be tested on greater numbers of companies and at the same time to provide a quick diagnosis...

  4. Microstructural characterization of laser surface melted AISI M2 tool steel.

    Science.gov (United States)

    Arias, J; Cabeza, M; Castro, G; Feijoo, I; Merino, P; Pena, G

    2010-09-01

    We describe the microstructure of Nd:YAG continuous wave laser surface melted high-speed steel, namely AISI M2, treated with different laser scanning speeds and beam diameters on its surface. Microstructural characterization of the remelted surface layer was performed using light optical and scanning electron microscopy and X-ray diffraction. The combination of the three techniques provided new insights into the substantial changes induced by laser surface melting of the steel surface layer. The advantage of the method is that it avoids the difficult and tedious work of preparing samples of this hard material for transmission electron microscopy, which is the technique normally used to study these fine microstructures. A melted zone with a dendritic structure and a partially melted zone with a heterogeneous cellular structure were observed. M(2)C carbides with different morphologies were identified in the resolidified surface layer after laser melting.

  5. Azithromycin protects mice against ischemic stroke injury by promoting macrophage transition towards M2 phenotype.

    Science.gov (United States)

    Amantea, Diana; Certo, Michelangelo; Petrelli, Francesco; Tassorelli, Cristina; Micieli, Giuseppe; Corasaniti, Maria Tiziana; Puccetti, Paolo; Fallarino, Francesca; Bagetta, Giacinto

    2016-01-01

    To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood-brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7 days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24-48 h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Wilson loops on three-manifolds and their M2-brane duals

    International Nuclear Information System (INIS)

    Farquet, Daniel; Sparks, James

    2014-01-01

    We compute the large N limit of Wilson loop expectation values for a broad class of N=2 supersymmetric gauge theories defined on a general class of background three-manifolds M 3 , diffeomorphic to S 3 . We find a simple closed formula which depends on the background geometry only through a certain supersymmetric Killing vector field. The supergravity dual of such a Wilson loop is an M2-brane wrapping the M-theory circle, together with a complex curve Σ 2 in a self-dual Einstein manifold M 4 , whose conformal boundary is M 3 . We show that the regularized action of this M2-brane also depends only on the supersymmetric Killing vector, precisely reproducing the large N field theory computation.

  7. Soft X-Ray Magneto-optical Faraday Effect around Ni M2,3 Edges

    International Nuclear Information System (INIS)

    Kai, Chen; Ming-Qi, Cui; Fen, Yan; Li-Juan, Sun; Lei, Zheng; Chen-Yan, Ma; Shi-Bo, Xi; Yi-Dong, Zhao; Jia, Zhao

    2008-01-01

    We present magneto-optical (MO) Faraday spectra measured around the M 2,3 edges (60–70eV) of Ni films at the Beijing Synchrotron Radiation Facility (BSRF). A polarization analysis of the final state of the transmitted radiation from the Ni film is employed to determine the Faraday rotation at the edges. The MO effect becomes resonantly enhanced at the M 2,3 edges, and accordingly large values for the rotation angle β of 1.85 ± 0.19° for this ferromagnetic Ni film with thickness of 31 nm are measured. Without the magnetic field, the azimuthal angles do not shift; with parallel and antiparallel magnetic field the rotation angles shift in the opposite way and they are symmetrical. The uncertainty of Faraday rotation angles mainly comes from the data fitting and the state change of the beamline when the angles are measured

  8. Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord

    OpenAIRE

    Lankford, Karen L.; Arroyo, Edgardo J.; Nazimek, Katarzyna; Bryniarski, Krzysztof; Askenase, Philip W.; Kocsis, Jeffery D.

    2018-01-01

    In a previous report we showed that intravenous infusion of bone marrow-derived mesenchymal stem cells (MSCs) improved functional recovery after contusive spinal cord injury (SCI) in the non-immunosuppressed rat, although the MSCs themselves were not detected at the spinal cord injury (SCI) site [1]. Rather, the MSCs lodged transiently in the lungs for about two days post-infusion. Preliminary studies and a recent report [2] suggest that the effects of intravenous (IV) infusion of MSCs could ...

  9. Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes

    DEFF Research Database (Denmark)

    Svendsen, Pia; Graversen, Jonas H.; Etzerodt, Anders

    2017-01-01

    Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation...

  10. CD16+ monocytes and skewed macrophage polarization toward M2 type hallmark heart transplant acute cellular rejection

    NARCIS (Netherlands)

    T.P.P. van den Bosch (Thierry); K. Caliskan (Kadir); M.D. Kraaij (Marina); A.A. Constantinescu (Alina); O.C. Manintveld (Olivier); P.J. Leenen (Pieter); J. von der Thusen (Jan); M.C. Clahsen-van Groningen (Marian); C.C. Baan (Carla); A.T. Rowshani (Ajda)

    2017-01-01

    textabstractBackground: During acute heart transplant rejection, infiltration of lymphocytes and monocytes is followed by endothelial injury and eventually myocardial fibrosis. To date, no information is available on monocyte-macrophage-related cellular shifts and their polarization status during

  11. CD16+ Monocytes and Skewed Macrophage Polarization toward M2 Type Hallmark Heart Transplant Acute Cellular Rejection

    OpenAIRE

    van den Bosch, Thierry P. P.; Caliskan, Kadir; Kraaij, Marina D.; Constantinescu, Alina A.; Manintveld, Olivier C.; Leenen, Pieter J. M.; von der Th?sen, Jan H.; Clahsen-van Groningen, Marian C.; Baan, Carla C.; Rowshani, Ajda T.

    2017-01-01

    textabstractBackground: During acute heart transplant rejection, infiltration of lymphocytes and monocytes is followed by endothelial injury and eventually myocardial fibrosis. To date, no information is available on monocyte-macrophage-related cellular shifts and their polarization status during rejection. Here, we aimed to define and correlate monocyte-macrophage endomyocardial tissue profiles obtained at rejection and time points prior to rejection, with corresponding serial blood samples ...

  12. ON THE FAMILY OF ELLIPTIC CURVES y2 = x3 − m2x + p 1 ...

    Indian Academy of Sciences (India)

    12

    Abstract. In this paper we study the torsion subgroup and rank of elliptic curves for the subfamilies of Em,p : y2 = x3 − m2x + p2, where m is a positive integer and p is a prime. We prove that for any prime p, the torsion subgroup of Em,p(Q) is trivial for both the cases. {m ≥ 1, m ≡ 0 (mod 3)} and {m ≥ 1, m ≡ 0 (mod 3), with ...

  13. Φ1,2 deformation of the M2,2n+1 conformal minimal models

    International Nuclear Information System (INIS)

    Koubek, A.; Mussardo, G.

    1991-05-01

    The spectrum and the factorizable S-matrices of the massive excitations of the Φ 1.2 deformation of the nonunitary minimal models M 2,2n+1 is given. These models present no kinks as asymptotic states, as follows from the reduction of the Zhiber-Mikhailov-Shabat model with respect to the quantum group SL(2) q , found by Smirnov. An interesting situation of zeros and poles overlapping in the physical amplitudes is also discussed. (orig.)

  14. Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13.

    Science.gov (United States)

    Gao, Shanshan; Zhou, Juan; Liu, Na; Wang, Lijun; Gao, Qiyue; Wu, Yan; Zhao, Qiang; Liu, Peining; Wang, Shun; Liu, Yan; Guo, Ning; Shen, Yan; Wu, Yue; Yuan, Zuyi

    2015-08-01

    To address the underlying mechanisms by which curcumin facilitates M2 phenotype polarization of macrophages and its roles in the protective effects during experimental autoimmune myocarditis (EAM). The expression of classic M2 markers, including macrophage mannose receptor (MMR), arginase-1 (Arg-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ) was upregulated in curcumin-treated Raw264.7 macrophages. Curcumin increased interleukin-4 (IL-4) and interleukin-13 (IL-13) mRNA expression and protein secretion. Curcumin notably increased STAT6 phosphorylation. Leflunomide, a STAT6 inhibitor, and IL-4 and/or IL-13 neutralizing antibodies antagonized the induction of MMR, Arg-1 and PPAR-γ by curcumin in Raw264.7 cells. In vivo, 6-week old male Lewis rats were used to induce EAM and orally administrated with curcumin or corn oil for 3weeks after myosin injection. Cardiac functional parameters, including left ventricular fractional shortening (LVFS), ejection fraction (EF), left ventricular end-systolic diameter (LVEDs) and heart rate (HR) were significantly improved by curcumin treatment. Curcumin also reduced the inflammatory cell infiltration and myocardial mRNA levels of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS). Meanwhile, the myocardial mRNA levels of MMR and Arg-1 were markedly up-regulated by curcumin. Immunofluorescence assay showed that the number of CD68(+) MMR(+) and CD68(+) Arg-1(+) double positive macrophages in curcumin-treated myocardial tissue was significantly higher than untreated control. The number of CD68(+) iNOS(+) double positive macrophages was increased obviously in EAM group, but decreased markedly by curcumin treatment. Taken together, these results show that curcumin induces macrophage M2 polarization by secretion of IL-4 and/or IL-13. Curcumin ameliorates EAM by reducing infiltration inflammatory macrophages and by polarizing M0 and M1 macrophages to M2 phenotype. Copyright © 2015 Elsevier Ltd. All rights

  15. Synthesis and crystal structure of trans-[Ni(pyzdcH)M 2 (H 2 O) 2 ...

    African Journals Online (AJOL)

    Synthesis and crystal structure of trans-[Ni(pyzdcH)M 2 (H 2 O) 2 ] based on pyrazine-2,3-dicarboxylic acid. ... Bulletin of the Chemical Society of Ethiopia ... The determined structure of the title compound C24H20Ni2N8O20 consists of the mononuclear trans-[Ni(pyzdc)2(H2O)2], (pyzdc = pyrazine-2,3- dicarboxylate).

  16. Genetic variability for different quantitative traits in M2 generations of opium poppy (Papaver somniferum L.)

    International Nuclear Information System (INIS)

    Chatterjee, A.; Shukla, S.; Singh, S.P.

    2004-01-01

    An experiment on induced mutation in two varieties of opium poppy was laid out to create new genetic variability for isolation of high yielding genotypes. Varieties NBRI-1 and NBRI-5 were subjected to irradiation for five doses of gamma rays and NBRI-5 was also treated with four doses of EMS and 20 mixed doses of EMS plus gamma rays. The data were recorded on 15 plants/treatment for 10 polygenic characters as pooled in M1 and M2 generations separately as well as in each dose-wise in M2 population. The results indicated that GCV, heritability and genetic advance were higher in M1 than M2 in both the varieties for all the traits except for opium and seed yield. The genetic advance was consistently high for opium yield, seed yield and capsule weight in all the doses for both the varieties with some exception. The dose level of kR10 and kR30 in NBRI-1 revealed high GCV, heritability and genetic advance for seed weight. These treatment levels also had high values of all these three genetic parameters for capsules per plant, capsule size and capsule weight. The values of these three parameters were also high for all the doses in M2 generations of both the varieties for opium yield, seed weight, capsule weight and capsule size in comparison to control. The GCV, heritability and genetic advance were consistently high for all the mixed doses in NBRI-5 for opium yield, seed weight and capsule weight, with some exception [it

  17. M2Align: parallel multiple sequence alignment with a multi-objective metaheuristic.

    Science.gov (United States)

    Zambrano-Vega, Cristian; Nebro, Antonio J; García-Nieto, José; Aldana-Montes, José F

    2017-10-01

    Multiple sequence alignment (MSA) is an NP-complete optimization problem found in computational biology, where the time complexity of finding an optimal alignment raises exponentially along with the number of sequences and their lengths. Additionally, to assess the quality of a MSA, a number of objectives can be taken into account, such as maximizing the sum-of-pairs, maximizing the totally conserved columns, minimizing the number of gaps, or maximizing structural information based scores such as STRIKE. An approach to deal with MSA problems is to use multi-objective metaheuristics, which are non-exact stochastic optimization methods that can produce high quality solutions to complex problems having two or more objectives to be optimized at the same time. Our motivation is to provide a multi-objective metaheuristic for MSA that can run in parallel taking advantage of multi-core-based computers. The software tool we propose, called M2Align (Multi-objective Multiple Sequence Alignment), is a parallel and more efficient version of the three-objective optimizer for sequence alignments MO-SAStrE, able of reducing the algorithm computing time by exploiting the computing capabilities of common multi-core CPU clusters. Our performance evaluation over datasets of the benchmark BAliBASE (v3.0) shows that significant time reductions can be achieved by using up to 20 cores. Even in sequential executions, M2Align is faster than MO-SAStrE, thanks to the encoding method used for the alignments. M2Align is an open source project hosted in GitHub, where the source code and sample datasets can be freely obtained: https://github.com/KhaosResearch/M2Align. antonio@lcc.uma.es. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  18. Industry 4.0, M2m, Iot&S - All Equal?

    Science.gov (United States)

    Dobrin, Carmen

    2014-11-01

    Similarity between Industry 4.0, M2M, IOT&S. Advantages and disadvantages obtained using this three important methods. Decreasing costs while components are getting smaller and smaller in a world with better networking. Influence of business management applications integrated in smart factory logistic. The most important impacts in merging virtual and real production world, with the improvement of best processes having the same goal: creating value by open innovation

  19. Modifications to 25m2 target-aligned research Heliostat mirror panels

    CSIR Research Space (South Africa)

    Roos, TH

    2009-09-01

    Full Text Available (2007), A 25m 2 Target-Aligned Heliostat With Closed-Loop Control, Presented at ISES SWC2007, Beijing [2] G. J. Kolb, S. A. Jones, M. W. Donnelly, D Gorman, R. Thomas, R. Davenport, R Lumia (2007), Heliostat Cost Reduction Study, Sandia Report SAND...2007-3293 [3] J. W. Strachan, R. M. Houser (1993), Testing and Evaluation of Large-Area Heliostats for Solar Thermal Applications, Sandia Report SAND92-1381, Albuquerque, New Mexico. ...

  20. ON THE FAMILY OF ELLIPTIC CURVES y2 = x3 − m2x + p 1 ...

    Indian Academy of Sciences (India)

    12

    subfamilies of Em,p : y2 = x3 − m2x + p2, where m is a positive integer and p is a prime. We prove that for any ... be a family of elliptic curves, where m is a positive integer such that m ≡ 0 (mod 3) and m ≡ 2 (mod 32) with p ... In other words, the above condition is equivalent to the cubic equation x3 + ax + b = 0, having three ...

  1. M2-like macrophage polarization in high lactic acid-producing head and neck cancer.

    Science.gov (United States)

    Ohashi, Toshimitsu; Aoki, Mitsuhiro; Tomita, Hiroyuki; Akazawa, Takashi; Sato, Katsuya; Kuze, Bunya; Mizuta, Keisuke; Hara, Akira; Nagaoka, Hitoshi; Inoue, Norimitsu; Ito, Yatsuji

    2017-06-01

    Reprogramming of glucose metabolism in tumor cells is referred to as the Warburg effect and results in increased lactic acid secretion into the tumor microenvironment. We have previously shown that lactic acid has important roles as a pro-inflammatory and immunosuppressive mediator and promotes tumor progression. In this study, we examined the relationship between the lactic acid concentration and expression of LDHA and GLUT1, which are related to the Warburg effect, in human head and neck squamous cell carcinoma (HNSCC). Tumors expressing lower levels of LDHA and GLUT1 had a higher concentration of lactic acid than those with higher LDHA and GLUT1 expression. Lactic acid also suppressed the expression of LDHA and GLUT1 in vitro. We previously reported that lactic acid enhances expression of an M2 macrophage marker, ARG1, in murine macrophages. Therefore, we investigated the relationship between the lactic acid concentration and polarization of M2 macrophages in HNSCC by measuring the expression of M2 macrophage markers, CSF1R and CD163, normalized using a pan-macrophage marker, CD68. Tumors with lower levels of CD68 showed a higher concentration of lactic acid, whereas those with higher levels of CSF1R showed a significantly higher concentration of lactic acid. A similar tendency was observed for CD163. These results suggest that tumor-secreted lactic acid is linked to the reduction of macrophages in tumors and promotes induction of M2-like macrophage polarization in human HNSCC. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  2. Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2

    OpenAIRE

    Shankar Babu, Mani; Mahanta, Sailendra; Lakhter, Alexander J.; Hato, Takashi; Paul, Subhankar; Naidu, Samisubbu R.

    2018-01-01

    Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhib...

  3. Granulin exacerbates lupus nephritis via enhancing macrophage M2b polarization.

    Directory of Open Access Journals (Sweden)

    Xi Chen

    Full Text Available BACKGROUND AND AIMS: Lupus nephritis (LN, with considerable morbidity and mortality, is one of the most severe manifestations of systemic lupus erythematosus (SLE. Yet, the pathogenic mechanisms of LN have not been clearly elucidated, and efficient therapies are still in great need. Granulin (GRN, a multifunctional protein linked to inflammatory diseases, has recently been reported to correlate with the disease activity of autoimmune diseases. However, the role of GRN in the pathogenic process of LN still remains obscure. In this study, we explored its potential role and underlying mechanism in the pathogenesis of LN. METHODOLOGY/PRINCIPAL FINDINGS: We found that serum GRN levels were significantly up-regulated and were positively correlated with the severity of LN. Overexpression of GRN in vivo by transgenic injection remarkably exacerbated LN, whereas down-regulation of GRN with shRNA ameliorated LN, firmly demonstrating the critical role of GRN in the pathogenesis of LN. Notably, macrophage phenotype analysis revealed that overexpression of GRN could enhance macrophage polarization to M2b, a key mediator of the initiation and progression of LN. On the contrary, down-regulation of GRN resulted in impaired M2b differentiation, thus ameliorating LN. Moreover, we found that MAPK signals were necessary for the effect of GRN on macrophage M2b polarization. CONCLUSION/SIGNIFICANCE: We first demonstrated that GRN could aggravate lupus nephritis (LN via promoting macrophage M2b polarization, which might provide insights into the pathogenesis of LN as well as potential therapeutic strategies against LN.

  4. M2 macrophage is the predominant phenotype in airways inflammatory lesions in patients with granulomatosis with polyangiitis

    NARCIS (Netherlands)

    Silva de Souza, Alexandre Wagner; van Timmeren, Mirjan; Sanders, Jan-Stephan; Stegeman, Coen; Heeringa, Peter; Kallenberg, Cees G. M.; Westra, Johanna

    2017-01-01

    Background: Macrophages may present two distinct phenotypes indicated as M1 and M2 under different stimuli. M1 and M2 macrophages have divergent functions that range from enhancement of inflammation for M1 to tissue repair and remodeling for M2 macrophages. The objective of this study was to

  5. Analysis of Two-Worm Interaction Model in Heterogeneous M2M Network

    Directory of Open Access Journals (Sweden)

    Jinhua Ma

    2015-10-01

    Full Text Available With the rapid development of M2M (Machine-to-Machine networks, the damages caused by malicious worms are getting more and more serious. By considering the influences of the network heterogeneity on worm spreading, we are the first to study the complex interaction dynamics between benign worms and malicious worms in heterogeneous M2M network. We analyze and compare three worm propagation models based on different immunization schemes. By investigating the local stability of the worm-free equilibrium, we obtain the basic reproduction number R0 . Besides, by using suitable Lyapunov functions, we prove that the worm-free equilibrium is globally asymptotically stable if R0 ≤ 1 , otherwise unstable. The dynamics of worm models is completely determined by R0 . In the absence of birth, death and users’ treatment, we obtain the final size formula of worms. This study shows that the nodes with higher node degree are more susceptible to be infected than those with lower node degree. In addition, the effects of various immunization schemes are studied. Numerical simulations verify our theoretical results. The research results are meaningful for us to further understand the spread of worms in heterogeneous M2M network, and enact effectual control tactics.

  6. RESTful M2M Gateway for Remote Wireless Monitoring for District Central Heating Networks

    Directory of Open Access Journals (Sweden)

    Bo Cheng

    2014-11-01

    Full Text Available In recent years, the increased interest in energy conservation and environmental protection, combined with the development of modern communication and computer technology, has resulted in the replacement of distributed heating by central heating in urban areas. This paper proposes a Representational State Transfer (REST Machine-to-Machine (M2M gateway for wireless remote monitoring for a district central heating network. In particular, we focus on the resource-oriented RESTful M2M gateway architecture, and present an uniform devices abstraction approach based on Open Service Gateway Initiative (OSGi technology, and implement the resource mapping mechanism between resource address mapping mechanism between RESTful resources and the physical sensor devices, and present the buffer queue combined with polling method to implement the data scheduling and Quality of Service (QoS guarantee, and also give the RESTful M2M gateway open service Application Programming Interface (API set. The performance has been measured and analyzed. Finally, the conclusions and future work are presented.

  7. TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology

    Science.gov (United States)

    Entwistle, Lewis J.; Khoury, Hania; Papoutsopoulou, Stamatia; Mahmood, Radma; Mansour, Nuha R.; Ching-Cheng Huang, Stanley; Pearce, Edward J.; Pedro S. de Carvalho, Luiz; Ley, Steven C.

    2016-01-01

    Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8 –/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8 –/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID:27487182

  8. Extracellular mycobacterial DnaK polarizes macrophages to the M2-like phenotype.

    Directory of Open Access Journals (Sweden)

    Rafael L Lopes

    Full Text Available Macrophages are myeloid cells that play an essential role in inflammation and host defense, regulating immune responses and maintaining tissue homeostasis. Depending on the microenvironment, macrophages can polarize to two distinct phenotypes. The M1 phenotype is activated by IFN-γ and bacterial products, and displays an inflammatory profile, while M2 macrophages are activated by IL-4 and tend to be anti-inflammatory or immunosupressive. It was observed that DnaK from Mycobacterium tuberculosis has immunosuppressive properties, inducing a tolerogenic phenotype in dendritic cells and MDSCs, contributing to graft acceptance and tumor growth. However, its role in macrophage polarization remains to be elucidated. We asked whether DnaK was able to modulate macrophage phenotype. Murine macrophages, derived from bone marrow, or from the peritoneum, were incubated with DnaK and their phenotype compared to M1 or M2 polarized macrophages. Treatment with DnaK leads macrophages to present higher arginase I activity, IL-10 production and FIZZ1 and Ym1 expression. Furthermore, DnaK increased surface levels of CD206. Importantly, DnaK-treated macrophages were able to promote tumor growth in an allogeneic melanoma model. Our results suggest that DnaK polarizes macrophages to the M2-like phenotype and could constitute a virulence factor and is an important immunomodulator of macrophage responses.

  9. Voltage affects the dissociation rate constant of the m2 muscarinic receptor.

    Directory of Open Access Journals (Sweden)

    Yair Ben Chaim

    Full Text Available G-protein coupled receptors (GPCRs comprise the largest protein family and mediate the vast majority of signal transduction processes in the body. Until recently GPCRs were not considered to be voltage dependent. Newly it was shown for several GPCRs that the first step in GPCR activation, the binding of agonist to the receptor, is voltage sensitive: Voltage shifts the receptor between two states that differ in their binding affinity. Here we show that this shift involves the rate constant of dissociation. We used the m2 muscarinic receptor (m2R a prototypical GPCR and measured directly the dissociation of [(3H]ACh from m2R expressed Xenopus oocytes. We show, for the first time, that the voltage dependent change in affinity is implemented by voltage shifting the receptor between two states that differ in their rate constant of dissociation. Furthermore, we provide evidence that suggest that the above shift is achieved by voltage regulating the coupling of the GPCR to its G protein.

  10. Seamless communication in supply chains based on M2M technology

    Directory of Open Access Journals (Sweden)

    Walid Moneimne

    2016-12-01

    Full Text Available Background: Access to information is the key element in the successful and efficient organization of transport & logistic processes. The importance of real-time access to information is confirmed by a panel workshop carried out with support of design thinking methodology. There are two ways of gaining access to the right information - manual, where human agency is needed and fully automatic, where new M2M technology is implemented. Implementation of such technology improves seamless communication during transport execution and allows real-time access to needed information. The aim of the paper is to evaluate the influence of the effectiveness of using M2M technology and traditional way of communication as well as data gathering in order to ensure seamless communication in the supply chain. Methods: Survey, design thinking, desk research and real case study results were used in the paper. Results and conclusions: Seamless communication and implementation of M2M technology within the whole supply (including modes of transport and transport units chain is a backbone of the lean and reliable digital supply chain.

  11. β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer.

    Science.gov (United States)

    Yu, Xiaomu; Xu, Maoyi; Li, Na; Li, Zongjuan; Li, Hongye; Shao, Shujuan; Zou, Kun; Zou, Lijuan

    2017-08-19

    Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. RESTful M2M gateway for remote wireless monitoring for district central heating networks.

    Science.gov (United States)

    Cheng, Bo; Wei, Zesan

    2014-11-27

    In recent years, the increased interest in energy conservation and environmental protection, combined with the development of modern communication and computer technology, has resulted in the replacement of distributed heating by central heating in urban areas. This paper proposes a Representational State Transfer (REST) Machine-to-Machine (M2M) gateway for wireless remote monitoring for a district central heating network. In particular, we focus on the resource-oriented RESTful M2M gateway architecture, and present an uniform devices abstraction approach based on Open Service Gateway Initiative (OSGi) technology, and implement the resource mapping mechanism between resource address mapping mechanism between RESTful resources and the physical sensor devices, and present the buffer queue combined with polling method to implement the data scheduling and Quality of Service (QoS) guarantee, and also give the RESTful M2M gateway open service Application Programming Interface (API) set. The performance has been measured and analyzed. Finally, the conclusions and future work are presented.

  13. Measurement of M2-Curve for Asymmetric Beams by Self-Referencing Interferometer Wavefront Sensor

    Directory of Open Access Journals (Sweden)

    Yongzhao Du

    2016-11-01

    Full Text Available For asymmetric laser beams, the values of beam quality factor M x 2 and M y 2 are inconsistent if one selects a different coordinate system or measures beam quality with different experimental conditionals, even when analyzing the same beam. To overcome this non-uniqueness, a new beam quality characterization method named as M2-curve is developed. The M2-curve not only contains the beam quality factor M x 2 and M y 2 in the x-direction and y-direction, respectively; but also introduces a curve of M x α 2 versus rotation angle α of coordinate axis. Moreover, we also present a real-time measurement method to demonstrate beam propagation factor M2-curve with a modified self-referencing Mach-Zehnder interferometer based-wavefront sensor (henceforth SRI-WFS. The feasibility of the proposed method is demonstrated with the theoretical analysis and experiment in multimode beams. The experimental results showed that the proposed measurement method is simple, fast, and a single-shot measurement procedure without movable parts.

  14. Buprenorphine differentially affects M1- and M2-polarized macrophages from human umbilical cord blood.

    Science.gov (United States)

    Sun, Juan; Guo, Wei; Du, Xingguang

    2017-06-01

    As a partial μ-opioid receptor agonist with long half-life time, buprenorphine has been widely used to relieve chronic cancer and nonmalignant pain. The maintenance of chronic pain involves inflammation; however whether buprenorphine has anti-inflammation property remains unclear. Macrophages, the immune cells that initiate and maintain inflammation, were isolated from human umbilical cord blood, and were polarized into M1 or M2 macrophages with IFN-γ in the presence of lipopolysaccharide (LPS) or IL-4, respectively. Quantitative PCR, ELISA, Western blotting analysis, and chromatin immunoprecipitation assays were employed to characterize M1 and M2 macrophages. 1) Buprenorphine did not change not only the apoptosis, survival, and morphology of resting macrophages, but also the antigen-presenting function of macrophages. 2) Buprenorphine inhibited the levels of mRNA and protein of several cytokines in M1 macrophages, and enhanced the expression of Ym1 and Fizz1 in M2 macrophages. 3) Buprenorphine did not affect the modulation of NF-κB and MAPK cascades by LPS in M1 macrophages. 4) Buprenorphine inhibited the expression of IRF5 and reduced binding of DNA to IRF5. Buprenorphine may downregulate IRF5 pathway and limit M1 macrophage phenotype. These effects may contribute to its therapeutic benefit for chronic neuropathic pain.

  15. Solution structure of the quaternary MutT-M2+-AMPCPP-M2+ complex and mechanism of its pyrophosphohydrolase action.

    Science.gov (United States)

    Lin, J; Abeygunawardana, C; Frick, D N; Bessman, M J; Mildvan, A S

    1997-02-11

    The MutT enzyme (129 residues) catalyzes the hydrolysis of nucleoside triphosphates (NTP) by substitution at the rarely attacked beta-P, to yield NMP and pyrophosphate. It requires two divalent cations, forming an active E-M2+-NTP-M2+ complex. The solution structure of the free enzyme consists of a five-stranded mixed beta-sheet connected by loop I-alpha-helix I-loop II, by two tight turns, and by loop III and terminated by loop IV-alpha-helix II [Abeygunawardana, C., et al. (1995) Biochemistry 34, 14997-15005]. Assignments of backbone 15N and NH resonances and side chain 15N and NH2 resonances of the quaternary complex were made by 1H-15N HSQC titrations of the free enzyme with MgCl2 followed by equimolar AMPCPP/MgCl2. H(alpha) assignments were made by 1H-15N 3D TOCSY HSQC, and 1H-13C CT-HSQC spectra and backbone and side chain 1H and 13C assignments were made by 3D HCCH TOCSY experiments. Ligands donated by the protein to the enzyme-bound divalent cation, identified by paramagnetic effects of Co2+ and Mn2+ on CO(C)H spectra, are the carboxylate groups of Glu-56, -57, and -98 and the amide carbonyl of Gly-38. The solution structure of the complex was computed with XPLOR using a total of 2168 NOE and 83 phi restraints for the protein, 11 intramolecular NOEs for bound Mg2+ AMPCPP, 22 intermolecular NOEs between MutT and AMPCPP, and distances from the enzyme-bound Co2+ to the three phosphorus atoms of Co3+(NH3)4AMPCPP from paramagnetic effects of Co2+ on their T1 values. The fold of the MutT enzyme in the complex is very similar to that of the free enzyme, with minor changes in the metal and substrate binding sites. The adenine ring binds in a hydrophobic cleft, interacting with Leu-4 and Ile-6 on beta-strand A and with Ile-80 on beta-strand D. The 6-NH2 group of adenine approaches the side chain NH2 of Asn-119. This unfavorable interaction is consistent with the stronger binding by MutT of guanine nucleotides, which have a 6-keto group. The ribose binds with its

  16. M2-F3 In-flight Launch from B-52

    Science.gov (United States)

    1971-01-01

    This photo shows the M2-F3 Lifting Body being launched from NASA's B-52 mothership at the NASA Flight Research Center (FRC--now the Dryden Flight Research Center), Edwards, California. A fleet of lifting bodies flown at the FRC from 1963 to l975 demonstrated the ability of pilots to maneuver and safely land a wingless vehicle designed to fly back to Earth from space and be landed like an aircraft at a pre-determined site. Early flight testing of the M2-F1 and M2-F2 lifting body reentry configurations had validated the concept of piloted lifting body reentry from space. When the M2-F2 crashed on May 10, 1967, valuable information had already been obtained and was contributing to new designs. NASA pilots said the M2-F2 had lateral control problems, so when the M2-F2 was rebuilt at Northrop and redesignated the M2-F3, it was modified with an additional third vertical fin -- centered between the tip fins -- to improve control characteristics. First flight of the M2-F3, with NASA pilot Bill Dana at the controls, was June 2, 1970. The modified vehicle exhibited much better lateral stability and control characteristics than before, and only three glide flights were necessary before the first powered flight on Nov. 25, 1970. Over the next 26 missions, the M2-F3 reached a top speed of l,064 mph (Mach 1.6). Highest altitude reached by vehicle was 7l,500 feet on Dec. 20, 1972, the date of its last flight, with NASA pilot John Manke at the controls. NASA donated The M2-F3 vehicle to the Smithsonian Institute in December 1973. It is currently hanging in the Air and Space Museum along with the X-15 aircraft number 1, which was its hangar partner from 1965 to 1969. NASA B-52, Tail Number 008, is an air launch carrier aircraft, 'mothership,' as well as a research aircraft platform that has been used on a variety of research projects. The aircraft, a 'B' model built in 1952 and first flown on June 11, 1955, is the oldest B-52 in flying status and has been used on some of the most

  17. Classification of acute myeloid leukemia subtypes M1, M2 and M3 using active contour without edge segmentation and momentum backpropagation artificial neural network

    Directory of Open Access Journals (Sweden)

    Harjoko Agus

    2018-01-01

    Full Text Available Acute Myeloid Leukemia (AML is a type of cancer which attacks white blood cells from myeloid. AML has eight subtypes, namely: M0, M1, M2, M3, M4, M5, M6, and M7. AML subtypes M1, M2 and M3 are affected by the same type of cells, myeloblast, making it needs more detailed analysis to distinguish. To overcome these obstacles, this research is applying digital image processing with Active Contour Without Edge (ACWE and Momentum Backpropagation artificial neural network for AML subtypes M1, M2 and M3 classification based on the type of the cell. Six features required as training parameters from every cell obtained by using feature extraction. The features are: cell area, perimeter, circularity, nucleus ratio, mean and standard deviation. The results show that ACWE can be used for segmenting white blood cells with 83.789% success percentage of 876 total cell objects. The whole AML slides had been identified according to the cell types predicted number through training with momentum backpropagation. Five times testing calibration with the best parameter generated averages value of 84.754% precision, 75.887% sensitivity, 95.090% specificity and 93.569% accuracy.

  18. M2 macrophages and inflammatory cells in oral lesions of chronic paracoccidioidomycosis.

    Science.gov (United States)

    de Carli, Marina Lara; Miyazawa, Marta; Nonogaki, Suely; Shirata, Neuza Kasumi; Oliveira, Denise Tostes; Pereira, Alessandro Antônio Costa; Hanemann, João Adolfo Costa

    2016-02-01

    Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by Paracoccidioides brasiliensis (Pb) and associated with deficient cellular immune response, which is modulated by inflammatory cells, mainly macrophages, and cytokines. Recently, the comprehension of the macrophage polarization mediated by Th1 and Th2 cytokines has contributed to elucidate the immune response that takes part in some diseases. Thus, the aim of this study was to assess the presence of Th1- and Th2-immune response and also Pb counting in oral lesions of chronic PCM. Forty-eight cases of chronic PCM oral lesions were included. All cases were classified as loose or dense granulomas. S100 protein, IL-1β, IL-6, TNF-α, CD163 and CD68 immunoexpressions, and Pb localization were evaluated. The fungi present in the tissue were quantified by anti-Pb antibody. Most patients were white men with mean age of 47 years old and showed higher incidence of multiple lesions. Loose granulomas were predominant and exhibited a great amount of M2 macrophages, which were visualized with anti-CD163 antibody. The expression for CD163 and CD68 was similar (P = 0.05), highlighting the predominance of M2 macrophages in PCM. IL-1β, IL-6, and TNF-α immunoexpression did not significantly change with CD163, CD68, and S100 protein. The number of fungi was significantly higher in cases with intense IL-1β immunoexpression (P = 0.003). M2-activated macrophages were the majority among inflammatory cells in chronic PCM, characterizing the action of a Th2-immune response. Nevertheless, Th1 cytokines were also found; mainly IL-1β, which was associated with fungi counting in oral lesions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Towards Efficient Mobile M2M Communications: Survey and Open Challenges

    Science.gov (United States)

    Pereira, Carlos; Aguiar, Ana

    2014-01-01

    Machine-to-Machine (M2M) communications enable networked devices and services to exchange information and perform actions seamlessly without the need for human intervention. They are viewed as a key enabler of the Internet of Things (IoT) and ubiquitous applications, like mobile healthcare, telemetry, or intelligent transport systems. We survey existing work on mobile M2M communications, we identify open challenges that have a direct impact on performance and resource usage efficiency, especially the impact on energy efficiency, and we review techniques to improve communications. We review the ETSI standard and application protocols, and draw considerations on the impact of their use in constrained mobile devices. Nowadays, smartphones are equipped with a wide range of embedded sensors, with varied local and wide area connectivity capabilities, and thus they offer a unique opportunity to serve as mobile gateways for other more constrained devices with local connectivity. At the same time, they can gather context data about users and environment from the embedded sensors. These capabilities may be crucial for mobile M2M applications. Finally, in this paper, we consider a scenario where smartphones are used as gateways that collect and aggregate data from sensors in a cellular network. We conclude that, in order for their use to the feasible in terms of a normal depletion time of a smartphone's battery, it is a good advice to maximize the collection of data necessary to be transmitted from nearby sensors, and maximize the intervals between transmissions. More research is required to devise energy efficient transmission methods that enable the use of smartphones as mobile gateways. PMID:25333291

  20. Pharmacological effects of mitraphylline from Uncaria tomentosa in primary human monocytes: Skew toward M2 macrophages.

    Science.gov (United States)

    Montserrat-de la Paz, S; de la Puerta, R; Fernandez-Arche, A; Quilez, A M; Muriana, F J G; Garcia-Gimenez, M D; Bermudez, B

    2015-07-21

    Uncaria tomentosa (Willdenow ex Roemer & Schultes) DC. (Rubiaceae) is a Peruvian thorny liana, commonly known as "cat׳s claw", and traditionally used in folk medicine to deal with several inflammatory diseases. Mitraphylline (MTP) is the most abundant pentacyclic oxindolic alkaloid (POA) from U. Tomentosa and has been reported to modify the inflammatory response. Herein, we have sought to identify the mechanisms underlying this modulatory effect of MTP on primary human monocytes and its ability to regulate differentiation processes on human primary monocyte and monocyte-derived macrophages. In vitro studies with human primary monocytes and monocyte-derived macrophages were performed. Monocytes and M0 macrophages were exposed to MTP (25μM) and LPS (100ng/mL). M0 macrophages were polarized to M1 and M2 phenotypes in the absence or presence of MTP. The activation state of monocytes/macrophages was assessed by flow cytometry, gene expression and protein analysis of different specific markers. In human primary monocytes, the incubation of MTP for 24h reduced the number of classical (CD14(++)CD16(-)) and intermediate (CD14(++)CD16(+)) subsets when compared to untreated or LPS-treated cells. MTP also reduced the chemotactic capacity of human primary monocytes. In addition, MTP promoted the polarization of M0 macrophages toward an anti-inflammatory M2 phenotype, the abrogation of the release of pro-inflammatory cytokines such as TNFα, IL-6 or IL-1β, as well as the restoration of markers for M2 macrophages in LPS-treated M1 macrophages. Our results suggest that MTP may be a key modulator for regulating the plasticity of monocytes/macrophages and the attenuation of the inflammatory response. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  1. Bile acid-induced arrhythmia is mediated by muscarinic M2 receptors in neonatal rat cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Siti H Sheikh Abdul Kadir

    Full Text Available BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP is a common disease affecting up to 5% of pregnancies and which can cause fetal arrhythmia and sudden intrauterine death. We previously demonstrated that bile acid taurocholate (TC, which is raised in the bloodstream of ICP, can acutely alter the rate and rhythm of contraction and induce abnormal calcium destabilization in cultured neonatal rat cardiomyocytes (NRCM. Apart from their hepatic functions bile acids are ubiquitous signalling molecules with diverse systemic effects mediated by either the nuclear receptor FXR or by a recently discovered G-protein coupled receptor TGR5. We aim to investigate the mechanism of bile-acid induced arrhythmogenic effects in an in-vitro model of the fetal heart. METHODS AND RESULTS: Levels of bile acid transporters and nuclear receptor FXR were studied by quantitative real time PCR, western blot and immunostaining, which showed low levels of expression. We did not observe functional involvement of the canonical receptors FXR and TGR5. Instead, we found that TC binds to the muscarinic M(2 receptor in NRCM and serves as a partial agonist of this receptor in terms of inhibitory effect on intracellular cAMP and negative chronotropic response. Pharmacological inhibition and siRNA-knockdown of the M(2 receptor completely abolished the negative effect of TC on contraction, calcium transient amplitude and synchronisation in NRCM clusters. CONCLUSION: We conclude that in NRCM the TC-induced arrhythmia is mediated by the partial agonism at the M(2 receptor. This mechanism might serve as a promising new therapeutic target for fetal arrhythmia.

  2. Three Lifting Bodies on Lakebed (X-24A, M2-F3, HL-10)

    Science.gov (United States)

    1969-01-01

    The wingless, lifting body aircraft sitting on Rogers Dry Lake at what is now NASA's Dryden Flight Research Center, Edwards, California, from left to right are the X-24A, M2-F3 and the HL-10.The lifting body aircraft studied the feasibility of maneuvering and landing an aerodynamic craft designed for reentry from space. These lifting bodies were air launched by a B-52 mother ship, then flew powered by their own rocket engines before making an unpowered approach and landing. They helped validate the concept that a space shuttle could make accurate landings without power. The X-24A flew from April 17, 1969 to June 4, 1971. The M2-F3 flew from June 2, 1970 until December 20, 1972. The HL-10 flew from December 22, 1966 until July 17, 1970 and logged the highest and fastest records in the lifting body program. The X-24 was one of a group of lifting bodies flown by the NASA Flight Research Center (now Dryden Flight Research Center), Edwards, California, in a joint program with the U.S. Air Force at Edwards Air Force Base from 1963 to 1975. The lifting bodies were used to demonstrate the ability of pilots to maneuver and safely land wingless vehicles designed to fly back to Earth from space and be landed like an airplane at a predetermined site. Lifting bodies' aerodynamic lift, essential to flight in the atmosphere, was obtained from their shape. The addition of fins and control surfaces allowed the pilots to stabilize and control the vehicles and regulate their flight paths. Built by Martin Aircraft Company, Maryland, for the U.S. Air Force, the X-24A was a bulbous vehicle shaped like a teardrop with three vertical fins at the rear for directional control. It weighed 6,270 pounds, was 24.5 feet long and 11.5 feet wide (measuring just the fuselage, not the distance between the tips of the outboard fins). Its first unpowered glide flight was on April 17, 1969, with Air Force Maj. Jerauld Gentry at the controls. Gentry also piloted its first powered flight on March 19

  3. Towards Efficient Mobile M2M Communications: Survey and Open Challenges

    Directory of Open Access Journals (Sweden)

    Carlos Pereira

    2014-10-01

    Full Text Available Machine-to-Machine (M2M communications enable networked devices and services to exchange information and perform actions seamlessly without the need for human intervention. They are viewed as a key enabler of the Internet of Things (IoT and ubiquitous applications, like mobile healthcare, telemetry, or intelligent transport systems. We survey existing work on mobile M2M communications, we identify open challenges that have a direct impact on performance and resource usage efficiency, especially the impact on energy efficiency, and we review techniques to improve communications. We review the ETSI standard and application protocols, and draw considerations on the impact of their use in constrained mobile devices. Nowadays, smartphones are equipped with a wide range of embedded sensors, with varied local and wide area connectivity capabilities, and thus they offer a unique opportunity to serve as mobile gateways for other more constrained devices with local connectivity. At the same time, they can gather context data about users and environment from the embedded sensors. These capabilities may be crucial for mobile M2M applications. Finally, in this paper, we consider a scenario where smartphones are used as gateways that collect and aggregate data from sensors in a cellular network. We conclude that, in order for their use to the feasible in terms of a normal depletion time of a smartphone’s battery, it is a good advice to maximize the collection of data necessary to be transmitted from nearby sensors, and maximize the intervals between transmissions. More research is required to devise energy efficient transmission methods that enable the use of smartphones as mobile gateways.

  4. Uptake of BSH in M2R melanoma cells monitored by NMR spectroscopy

    International Nuclear Information System (INIS)

    Koudinova, N.; Elhanati, G.; Salomon, Y.; Bendel, P.

    2000-01-01

    The accumulation ratio of BSH, relative to that of boric acid, in M2R mouse melanoma cells, was measured using 11 B NMR of the cell extracts. The cells were incubated in growth medium for up to 24 h, in the presence of 0.8 mM boric acid and 0.25-1.5 mM BSH. The aqueous phase of the cellular extracts was re-suspended for NMR spectroscopy. The relative accumulation ratio of BSH/boric acid determined from 9 separate experiments was 0.45±0.09. (author)

  5. Putative M2 muscarinic receptors of rat heart have high affinity for organophosphorus anticholinesterases

    International Nuclear Information System (INIS)

    Silveira, C.L.; Eldefrawi, A.T.; Eldefrawi, M.E.

    1990-01-01

    The M2 subtype of muscarinic receptor is predominant in heart, and such receptors were reported to be located in muscles as well as in presynaptic cholinergic and adrenergic nerve terminals. Muscarinic receptors of rat heart were identified by the high affinity binding of the agonist (+)-[3H]cis-methyldioxolane ([3H]CD), which has been used to label a high affinity population of M2 receptors. A single population of sites was detected and [3H]CD binding was sensitive to the M2 antagonist himbacine but much less so to pirenzepine, the M1 antagonist. These cardiac receptors had different sensitivities to NiCl2 and N-ethylmaleimide from brain muscarinic receptors, that were also labeled with [3H]CD and considered to be of the M2 subtype. Up to 70% of the [3H]CD-labeled cardiac receptors had high affinities for several organophosphate (OP) anticholinesterases. [3H]CD binding was inhibited by the nerve agents soman, VX, sarin, and tabun, with K0.5 values of 0.8, 2, 20, and 50 nM, respectively. It was also inhibited by echothiophate and paraoxon with K0.5 values of 100 and 300 nM, respectively. The apparent competitive nature of inhibition of [3H]CD binding by both sarin and paraoxon suggests that the OPs bind to the acetylcholine binding site of the muscarinic receptor. Other OP insecticides had lower potencies, inhibiting less than 50% of 5 nM [3H]CD binding by 1 microM of EPN, coumaphos, dioxathion, dichlorvos, or chlorpyriphos. There was poor correlation between the potencies of the OPs in reversibly inhibiting [3H]CD binding, and their anticholinesterase activities and toxicities. Acetylcholinesterases are the primary targets for these OP compounds because of the irreversible nature of their inhibition, which results in building of acetylcholine concentrations that activate muscarinic and nicotinic receptors and desensitize them, thereby inhibiting respiration

  6. Proyecto estructural e instalaciones de edificio industrial de 1200 m2 situada en Picassent

    OpenAIRE

    FALOMIR ESTARELLES, MIREIA

    2015-01-01

    [ES] El trabajo consistirá en la elección de un proceso industrial, su diseño y dimensionado, y la elección de la arquitectura adecuada del edificio/s que lo albergarán, así como posiblemente el diseño de algunas de las instalaciones necesarias para cumplir tanto con las necesidades del sistema productivo como con la normativa vigente. Falomir Estarelles, M. (2014). Proyecto estructural e instalaciones de edificio industrial de 1200 m2 situada en Picassent. http://hdl.handle.net/10251/4982...

  7. Proyecto estructural de edificio industrial de 2160 m2 situada en Alcala Xivert

    OpenAIRE

    HIGUERO TORRES, IVÁN

    2015-01-01

    [ES] El trabajo consistirá en la elección de un proceso industrial, su diseño y dimensionado, y la elección de la arquitectura adecuada del edificio/s que lo albergarán, así como posiblemente el diseño de algunas de las instalaciones necesarias para cumplir tanto con las necesidades del sistema productivo como con la normativa vigente. Higuero Torres, I. (2014). Proyecto estructural de edificio industrial de 2160 m2 situada en Alcala Xivert. http://hdl.handle.net/10251/49822. TFGM

  8. Proyecto estructural de edificio industrial de 2240 m2 situada en Altea

    OpenAIRE

    OLIVER SÁNCHEZ, ANTONIO

    2015-01-01

    [ES] El trabajo consistirá en la elección de un proceso industrial, su diseño y dimensionado, y la elección de la arquitectura adecuada del edificio/s que lo albergarán, así como posiblemente el diseño de algunas de las instalaciones necesarias para cumplir tanto con las necesidades del sistema productivo como con la normativa vigente. Oliver Sánchez, A. (2014). Proyecto estructural de edificio industrial de 2240 m2 situada en Altea. http://hdl.handle.net/10251/49857. TFGM

  9. Fibroblast growth factor-9 enhances M2 macrophage differentiation and attenuates adverse cardiac remodeling in the infarcted diabetic heart.

    Directory of Open Access Journals (Sweden)

    Dinender K Singla

    Full Text Available Inflammation has been implicated as a perpetrator of diabetes and its associated complications. Monocytes, key mediators of inflammation, differentiate into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages upon infiltration of damaged tissue. However, the inflammatory cell types, which propagate diabetes progression and consequential adverse disorders, remain unclear. The current study was undertaken to assess monocyte infiltration and the role of fibroblast growth factor-9 (FGF-9 on monocyte to macrophage differentiation and cardioprotection in the diabetic infarcted heart. Db/db diabetic mice were assigned to sham, myocardial infarction (MI, and MI+FGF-9 groups. MI was induced by permanent coronary artery ligation and animals were subjected to 2D transthoracic echocardiography two weeks post-surgery. Immunohistochemical and immunoassay results from heart samples collected suggest significantly increased infiltration of monocytes (Mean ± SEM; MI: 2.02% ± 0.23% vs. Sham 0.75% ± 0.07%; p<0.05 and associated pro-inflammatory cytokines (TNF-α, MCP-1, and IL-6, adverse cardiac remodeling (Mean ± SEM; MI: 33% ± 3.04% vs. Sham 2.2% ± 0.33%; p<0.05, and left ventricular dysfunction (Mean ± SEM; MI: 35.4% ± 1.25% vs. Sham 49.19% ± 1.07%; p<0.05 in the MI group. Importantly, treatment of diabetic infarcted myocardium with FGF-9 resulted in significantly decreased monocyte infiltration (Mean ± SEM; MI+FGF-9: 1.39% ± 0.1% vs. MI: 2.02% ± 0.23%; p<0.05, increased M2 macrophage differentiation (Mean ± SEM; MI+FGF-9: 4.82% ± 0.86% vs. MI: 0.85% ± 0.3%; p<0.05 and associated anti-inflammatory cytokines (IL-10 and IL-1RA, reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs. MI: 33% ± 3.04%; p<0.05, and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs. MI: 35.4% ± 1.25%; p<0.05. In conclusion, our data suggest FGF-9 possesses novel therapeutic potential in its

  10. Mini-magnetospheric plasma propulsion (M2P2): High speed propulsion sailing the solar wind

    International Nuclear Information System (INIS)

    Winglee, Robert; Slough, John; Ziemba, Tim; Goodson, Anthony

    2000-01-01

    Mini-Magnetospheric Plasma Propulsion (M2P2) seeks the creation of a magnetic wall or bubble (i.e. a magnetosphere) that will intercept the supersonic solar wind which is moving at 300-800 km/s. In so doing, a force of about 1 N will be exerted on the spacecraft by the spacecraft while only requiring a few mN of force to sustain the mini-magnetosphere. Equivalently, the incident solar wind power is about 1 MW while about 1 kW electrical power is required to sustain the system, with about 0.25-0.5 kg being expended per day. This nominal configuration utilizing only solar electric cells for power, the M2P2 will produce a magnetic barrier approximately 15-20 km in radius, which would accelerate a 70-140 kg payload to speeds of about 50-80 km/s. At this speed, missions to the heliopause and beyond can be achieved in under 10 yrs. Design characteristics for a prototype are also described

  11. An improved radiosynthesis of the muscarinic M2 radiopharmaceutical, [{sup 18}F]FP-TZTP

    Energy Technology Data Exchange (ETDEWEB)

    Oosten, Erik M. van [Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada); PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Wilson, Alan A.; Stephenson, Karin A. [PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Mamo, David C. [PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Geriatric Mental Health Program, Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, Ontario, M6J 1H4 (Canada); Pollock, Bruce G.; Mulsant, Benoit H. [Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Geriatric Mental Health Program, Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, Ontario, M6J 1H4 (Canada); Yudin, Andrei K. [Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada); Houle, Sylvain [PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Vasdev, Neil [PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada)], E-mail: neil.vasdev@camhpet.ca

    2009-04-15

    The radioligand 3-(4-(3-[{sup 18}F]fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5, 6-tetrahydropyridine ([{sup 18}F]FP-TZTP) is an agonist with specificity towards subtype 2 of muscarinic acetylcholine (M2) receptors. It is currently the only radiotracer available for imaging M2 receptors in human subjects with positron emission tomography. The present study reports on an improved method for the synthesis of [{sup 18}F]FP-TZTP, automated using a GE TRACERlab{sup TM} FX{sub FN} radiosynthesis module. A key facet was the use of a new precursor, 3-(4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-3-ylthio) propyl 4-methylbenzenesulfonate. The precursor was fluorinated via nucleophilic displacement of the tosyloxy group by potassium cryptand [{sup 18}F]fluoride (K[{sup 18}F]/K{sub 222}) in CH{sub 3}CN at 80 deg. C for 5 min, and purified by HPLC. Formulated [{sup 18}F]FP-TZTP was prepared in an uncorrected radiochemical yield of 29{+-}4%, with a specific activity of 138{+-}41 GBq/{mu}mol (3732{+-}1109 mCi/{mu}mol) at the end of synthesis (35 min; n=3). This methodology offers higher yields, faster synthesis times, an optimized precursor, and simpler automation than previously reported.

  12. ISOMP: An Instant Service-Orchestration Mobile M2M Platform

    Directory of Open Access Journals (Sweden)

    Cholhong Im

    2016-01-01

    Full Text Available Smartphones have greater computing power than ever before, providing convenient applications to improve our lives. In general, people find it difficult to locate suitable applications and implementing new applications often requires professional skills. In this paper, we propose a new service platform that facilitates the implementation of new applications by composing prebuilt components that provide the context information of mobile devices such as location and contacts. Our platform introduces an innovative concept named context collaboration, in which smartphones exchange context information with each other, which in turn is used to deduct useful inferences. The concept is realized by instant orchestration, which assembles some components and implements a composite component. The interactive communication interface helps a mobile device to communicate with other devices using open APIs, such as SOAP and HTTP (REST. The platform also works in heterogeneous environments, for example, between Android and iOS operating systems. Throughout the platform, mobile devices can act as smart M2M machines with context awareness, enabling intelligent tasks on behalf of users. Our platform will open up a new and innovative pathway for both enhanced mobile context awareness and M2M, which is expected to be a fundamental feature of the next generation of mobile devices.

  13. Anti-Inflammatory Strategy for M2 Microglial Polarization Using Retinoic Acid-Loaded Nanoparticles

    Directory of Open Access Journals (Sweden)

    Marta Machado-Pereira

    2017-01-01

    Full Text Available Inflammatory mechanisms triggered by microglial cells are involved in the pathophysiology of several brain disorders, hindering repair. Herein, we propose the use of retinoic acid-loaded polymeric nanoparticles (RA-NP as a means to modulate microglia response towards an anti-inflammatory and neuroprotective phenotype (M2. RA-NP were first confirmed to be internalized by N9 microglial cells; nanoparticles did not affect cell survival at concentrations below 100 μg/mL. Then, immunocytochemical studies were performed to assess the expression of pro- and anti-inflammatory mediators. Our results show that RA-NP inhibited LPS-induced release of nitric oxide and the expression of inducible nitric oxide synthase and promoted arginase-1 and interleukin-4 production. Additionally, RA-NP induced a ramified microglia morphology (indicative of M2 state, promoting tissue viability, particularly neuronal survival, and restored the expression of postsynaptic protein-95 in organotypic hippocampal slice cultures exposed to an inflammatory challenge. RA-NP also proved to be more efficient than the free equivalent RA concentration. Altogether, our data indicate that RA-NP may be envisioned as a promising therapeutic agent for brain inflammatory diseases.

  14. Characterizing detergent mediated reconstitution of viral protein M2 in large unilamellar vesicles

    Science.gov (United States)

    Freyre, Mariel; Grossman, Carl; Crouch, Catherine; Howard, Kathleen

    2015-03-01

    Influenza M2 is a model membrane protein whose function is to induce curvature and vesicle formation in the process of viral infection. To study embedded M2 in synthetic phospholipid vesicles (large unilamellar vesicles or LUVs), a concentration of detergent and buffer is optimized to balance protein solubility, proteolipid concentration, and LUV stability. Adding detergent also causes the LUVs to partially disassemble and form micelles, which warrants detergent removal to restore LUV integrity. We explore methods of measuring the coexistence of detergent micelles and LUVs to track the different phases of the system as detergent is removed. A combination of Fluorescence Correlation Spectroscopy, Dynamic Light Scattering, and chemical analysis are used to measure the properties of this system. With detergent/LUV number densities as high as 5 we find coexistence of micelles and LUVs at 50% to 60%. As the detergent is removed, the micelle concentration drops to lower than 30% while detergent levels drop to nearly zero. These results may indicate a polydispersed LUV size distribution after detergent mediated reconstitution. Supported by HHMI and Swarthmore College.

  15. M2Di: MATLAB 2D Stokes solvers using the Finite Difference method

    Science.gov (United States)

    Räss, Ludovic; Duretz, Thibault; Schmalholz, Stefan; Podladchikov, Yury

    2017-04-01

    The study of coupled processes in Earth Sciences leads to the development of multiphysics modelling tools. Mechanical solvers represent the essential ingredient of any of these tools such that their performance and robustness is generally dictated by that of the mechanical solver. Here, we present M2Di, a collection of MATLAB routines designed for studying 2D linear and power law incompressible viscous flow using Finite Difference discretisation. The scripts are written in a concise vectorised MATLAB fashion and rely on fast and robust linear and non-linear solvers (Picard and Newton iterations). As a result, time to solution of 22 seconds for linear viscous flow with 104 viscosity jump on 10002 grid points can be achieved on a standard personal computer. We will present a numerous example of applications that span from high resolution crystal-melt dynamics, deformation of heterogeneous power law viscous fluids, instantaneous mantle flow patterns in cylindrical coordinates, and calculation of pressure gradients around inclusions using variable grid spacing. We use analytical solution for linear viscous flow with highly variable viscosity to validate the linear flow solver. Validation of the non-linear solver is achieved by comparing numerical solution to analytic and benchmark solutions of power law viscous folding and necking. The M2Di codes are open source and can hence be used for research or educational purposes.

  16. Posttranslational Modifications of Pyruvate Kinase M2: Tweaks that Benefit Cancer

    Directory of Open Access Journals (Sweden)

    Gopinath Prakasam

    2018-02-01

    Full Text Available Cancer cells rewire metabolism to meet biosynthetic and energetic demands. The characteristic increase in glycolysis, i.e., Warburg effect, now considered as a hallmark, supports cancer in various ways. To attain such metabolic reshuffle, cancer cells preferentially re-express the M2 isoform of pyruvate kinase (PKM2, M2-PK and alter its quaternary structure to generate less-active PKM2 dimers. The relatively inactive dimers cause the accumulation of glycolytic intermediates that are redirected into anabolic pathways. In addition, dimeric PKM2 also benefits cancer cells through various non-glycolytic moonlight functions, such as gene transcription, protein kinase activity, and redox balance. A large body of data have shown that several distinct posttranslation modifications (PTMs regulate PKM2 in a way that benefits cancer growth, e.g., formation of PKM2 dimers. This review discusses the recent advancements in our understanding of various PTMs and the benefits they impart to the sustenance of cancer. Understanding the PTMs in PKM2 is crucial to assess their therapeutic potential and to design novel anticancer strategies.

  17. Development and evaluation of intelligent machine tools based on knowledge evolution in M2M environment

    International Nuclear Information System (INIS)

    Kim, Dong Hoon; Song, Jun Yeob; Lee, Jong Hyun; Cha, Suk Keun

    2009-01-01

    In the near future, the foreseen improvement in machine tools will be in the form of a knowledge evolution-based intelligent device. The goal of this study is to develop intelligent machine tools having knowledge-evolution capability in Machine to Machine (M2M) wired and wireless environment. The knowledge evolution-based intelligent machine tools are expected to be capable of gathering knowledge autonomously, producing knowledge, understanding knowledge, applying reasoning to knowledge, making new decisions, dialoguing with other machines, etc. The concept of the knowledge-evolution intelligent machine originated from the process of machine control operation by the sense, dialogue and decision of a human expert. The structure of knowledge evolution in M2M and the scheme for a dialogue agent among agent-based modules such as a sensory agent, a dialogue agent and an expert system (decision support agent) are presented in this paper, and work-offset compensation from thermal change and recommendation of cutting condition are performed on-line for knowledge-evolution verification

  18. An improved radiosynthesis of the muscarinic M2 radiopharmaceutical, [18F]FP-TZTP

    International Nuclear Information System (INIS)

    Oosten, Erik M. van; Wilson, Alan A.; Stephenson, Karin A.; Mamo, David C.; Pollock, Bruce G.; Mulsant, Benoit H.; Yudin, Andrei K.; Houle, Sylvain; Vasdev, Neil

    2009-01-01

    The radioligand 3-(4-(3-[ 18 F]fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5, 6-tetrahydropyridine ([ 18 F]FP-TZTP) is an agonist with specificity towards subtype 2 of muscarinic acetylcholine (M2) receptors. It is currently the only radiotracer available for imaging M2 receptors in human subjects with positron emission tomography. The present study reports on an improved method for the synthesis of [ 18 F]FP-TZTP, automated using a GE TRACERlab TM FX FN radiosynthesis module. A key facet was the use of a new precursor, 3-(4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-3-ylthio) propyl 4-methylbenzenesulfonate. The precursor was fluorinated via nucleophilic displacement of the tosyloxy group by potassium cryptand [ 18 F]fluoride (K[ 18 F]/K 222 ) in CH 3 CN at 80 deg. C for 5 min, and purified by HPLC. Formulated [ 18 F]FP-TZTP was prepared in an uncorrected radiochemical yield of 29±4%, with a specific activity of 138±41 GBq/μmol (3732±1109 mCi/μmol) at the end of synthesis (35 min; n=3). This methodology offers higher yields, faster synthesis times, an optimized precursor, and simpler automation than previously reported

  19. VizieR Online Data Catalog: Magellan/M2FS spectroscopy of Abell 267 (Tucker+, 2017)

    Science.gov (United States)

    Tucker, E.; Walker, M. G.; Mateo, M.; Olszewski, E. W.; Bailey, J. I.; Crane, J. D.; Shectman, S. A.

    2018-02-01

    We select targets for Michigan/Magellan Fiber System (M2FS) observations by identifying galaxies detected in SDSS images (Data Release 12; Alam et al.2015, Cat. V/147) that are projected along the line of sight to Abell 267 and are likely to be quiescent cluster members. We observed 223 individual galaxy spectra on 2013 November 30 on the Clay Magellan Telescope using M2FS. We used the low-resolution grating on M2FS and chose a coverage range of 4600-6400Å with a resolution of R~2000. The detector used with M2FS consists of two 4096*4112 pixel CCDs. (1 data file).

  20. High-spin nuclear target of 178m2Hf: creation and nuclear reaction studies

    International Nuclear Information System (INIS)

    Oganessyan, Yu.Ts.; Karamyan, S.A.; Gangrskij, Yu.P.

    1993-01-01

    A long-lived (31 years) four-quasiparticle isomer 178m 2 Hf(I,K π =16,16 + ) was produced in microweight quantities using the nuclear reaction 176 Yb( 4 He, 2n). Methods of precision chemistry and mass-separation for the purification of the produced Hf material have been developed. Thin targets of isomeric hafnium-178 on carbon backings were prepared and used in experiments on a neutron, proton and deuteron beams. First results on nuclear reactions on a high-spin exotic target were obtained. Experiments on electromagnetic interactions of the isomeric hafnium using methods of the collinear laser spectroscopy as well as of the nuclear orientation of hafnium implanted into a crystalline media were started. 11 refs.; 11 figs.; 2 tabs

  1. The evolution of M 2-9 from 2000 to 2010

    Science.gov (United States)

    Corradi, R. L. M.; Balick, B.; Santander-García, M.

    2011-05-01

    Context. Understanding the formation of collimated outflows is one of the most debated and controversial topics in the study of the late stages of stellar evolution. Aims: M 2-9 is an outstanding representative of extreme aspherical flows. It presents unique features such as a pair of high-velocity dusty polar blobs and a mirror-symmetric rotating pattern in the inner lobes. Their study provides important information on the nature of the poorly understood central source of M 2-9 and its nebula. Methods: Imaging monitoring at sub-arcsec resolution of the evolution of the nebula in the past decade is presented. Spectroscopic data provide complementary information. Results: We determine the proper motions of the dusty blobs, which infer a new distance estimate of 1.3 ± 0.2 kpc, a total nebular size of 0.8 pc, a speed of 147 km s-1, and a kinematical age of 2500 yr. The corkscrew geometry of the inner rotating pattern is confirmed and quantified. Different recombination timescales for different ions explain the observed surface brightness distribution. According to the images taken after 1999, the pattern rotates with a period of 92 ± 4 years. On the other hand, the analysis of images taken between 1952 and 1977 measures a faster angular velocity. If the phenomenon were related to orbital motion, this would correspond to a modest orbital eccentricity (e = 0.10 ± 0.05), and a slightly shorter period (86 ± 5 years). New features have appeared after 2005 on the west side of the lobes and at the base of the pattern. Conclusions: The geometry and travelling times of the rotating pattern support our previous proposal that the phenomenon is produced by a collimated spray of high velocity particles (jet) from the central source, which excites the walls of the inner cavity of M 2-9, rather than by a ionizing photon beam. The speed of such a jet would be remarkable: between 11 000 and 16 000 km s-1. The rotating-jet scenario may explain the formation and excitation of most

  2. Structure and Abrasive Wear of Composite HSS M2/WC Coating

    Directory of Open Access Journals (Sweden)

    S. F. Gnyusov

    2012-01-01

    Full Text Available Features of phase-structure formation and abrasive wear resistance of composite coatings “WC-M2 steel” worn against tungsten monocarbide have been investigated. It was established that adding 20 wt.% WC to the deposited powder mixture leads to the increase in M6C carbide content. These carbides show a multimodal size distribution consisting of ~5.9 μm eutectic carbides along the grain boundaries, ~0.25 μm carbides dispersed inside the grains. Also a greater amount of metastable austenite (~88 vol.% is found. The high abrasive wear resistance of these coatings is provided by γ→α′-martensitic transformation and multimodal size distribution of reinforcing particles.

  3. The mutual dependence of M1 fertility and M2 mutations in rice

    International Nuclear Information System (INIS)

    Gopinathan Nair, V.

    1982-01-01

    The mutual dependence of M 1 fertility and M 2 mutations in rice was studied after treatment with gamma rays and EMS. The frequency of chlorophyll mutations increased with decrease in seed fertility when M 1 ears were selected at random. However, at the lowest fertility class the mutation frequency was low. This reduction is attributed to the elimination of mutants in the high sterility class. The mutation yield can therefore be significantly enhanced by selecting M 1 ears of low fertility. The segregation ratio of mutants increased as fertility decreased. Mutation spectrum was however not influenced by M 1 fertility. This makes selection for fertility quite ineffective in altering the mutation spectrum. (author)

  4. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed.

    Science.gov (United States)

    Cherry, Jonathan D; Olschowka, John A; O'Banion, M Kerry

    2014-06-03

    The concept of multiple macrophage activation states is not new. However, extending this idea to resident tissue macrophages, like microglia, has gained increased interest in recent years. Unfortunately, the research on peripheral macrophage polarization does not necessarily translate accurately to their central nervous system (CNS) counterparts. Even though pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states, the specific functions of these states is still an area of intense debate. This review examines the multiple possible activation states microglia can be polarized to. This is followed by a detailed description of microglial polarization and the functional relevance of this process in both acute and chronic CNS disease models described in the literature. Particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.

  5. Thermoelectric Performance of the MXenes M2CO2 (M = Ti, Zr, or Hf)

    KAUST Repository

    Gandi, Appala

    2016-02-21

    We present the first report in which the thermoelectric properties of two-dimensional MXenes are calculated by considering both the electron and phonon transport. Specifically, we solve the transport equations of the electrons and phonons for three MXenes, M2CO2, where M = Ti, Zr, or Hf, in order to evaluate the effect of the metal M on the thermoelectric performance. The lattice contribution to the thermal conductivity, obtained from the phonon life times, is found to be lowest in Ti2CO2 and highest in Hf2CO2 in the temperature range from 300 K to 700 K. The highest figure of merit is predicted for Ti2CO2 . The heavy mass of the electrons due to flat conduction bands results in a larger thermopower in the case of n-doping in these compounds.

  6. The Creation and Destruction of Hf-178m2 Isomer by Neutron Interaction

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Hsiao-Hua [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); TechSource, Inc. Los Alamos, NM (United States); Talbert, Willard L. [TechSource, Inc. Los Alamos, NM (United States); Ward, Tom [TechSource, Inc. Los Alamos, NM (United States)

    2017-03-06

    The property of the isomer state in 178m2Hf was an interesting topic in nuclear structure studies during the time period 1970 to 1980. The state at 2.446 MeV with spin and parity Kπ = 16+, has a half-life of 31 years. The isomer is described as a four-quasi-particle state. The K forbidden deexcitatiion by gamma emission is the reason for long half-life. During 1980, the isomer became a troublesome issue for radiation safety workers, because this isomer can also be produced in the first wall of a fussion reactor containing tungsten and also in a tungsten beam stop of a high-energy accelerator.

  7. The relaxed three-algebras: their matrix representation and implications for multi M2-brane theory

    International Nuclear Information System (INIS)

    Ali-Akbari, M.; Sheikh-Jabbari, M.M.; Simon, J.

    2008-01-01

    We argue that one can relax the requirements of the non-associative three-algebras recently used in constructing D = 3, N = 8 superconformal field theories, and introduce the notion of 'relaxed three-algebras'. We present a specific realization of the relaxed three-algebras in terms of classical Lie algebras with a matrix representation, endowed with a non-associative four-bracket structure which is prescribed to replace the three-brackets of the three-algebras. We show that both the so(4)-based solutions as well as the cases with non-positive definite metric find a uniform description in our setting. We discuss the implications of our four-bracket representation for the D = 3, N = 8 and multi M2-brane theory and show that our setup can shed light on the problem of negative kinetic energy degrees of freedom of the Lorentzian case.

  8. Solar thermal barometer. More than 2 million m2 installed in 2005

    International Nuclear Information System (INIS)

    Anon.

    2006-01-01

    With 22,8% growth, the european union solar thermal market (glazed, vacuum and unglazed collectors) has passed the 2 million m 2 benchmark corresponding to installed capacity of approximately 1450 MWth. This growth can be explained by the very good performance of the three leading EU solar thermal markets: Germany, Austria and Greece and the increase in importance of the French and Spanish markets. Statistical data are provided for the european union on the annually installed surfaces, breakdown by technologies of the solar thermal market, the solar thermal capacity in operation, the representative companies of the thermal solar sector and a comparison of current trend with the white book objectives. (A.L.B.)

  9. Access Control in IoT/M2M - Cloud Platform

    DEFF Research Database (Denmark)

    Anggorojati, Bayu

    Billions of devices are connected to the Internet nowadays, and the number will continue to grow in the future thanks to the advances in the electronics and telecommunication technology developments. Its application in broad aspects of human’s life brings a lot of benefits by improving productivity...... and quality of life. This paradigm, which is often called Internet of Things (IoT) or Machine-to-Machine (M2M), will provide an unprecedented opportunity to create applications and services that go far beyond the mere purpose of each participant. Many studies on the both technical and social aspects of Io...... of a system can be accessed by other parties by means of a set of access policies. For an IoT system such as Radio Frequency Identification (RFID) that collects huge amounts of RFID events data and may store it in the cloud storage for tracking purpose, access control to such data becomes a critical point...

  10. Microwave and magnetic (M2 proteomics of a mouse model of mild traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Teresa M. Evans

    2014-06-01

    Full Text Available Short-term increases in oxidative stress and decreases in motor function, including debilitating effects on balance and motor control, can occur following primary mild traumatic brain injuries (mTBI. However, the long-term effects on motor unit impairment and integrity as well as the molecular mechanisms underlying secondary injuries are poorly understood. We hypothesized that changes in central nervous system-specific protein (CSP expression might correlate to these long-term effects. To test our hypothesis, we longitudinally assessed a closed-skull mTBI mouse model, vs. sham control, at 1, 7, 30, and 120 days post-injury. Motor impairment was determined by rotarod and grip strength performance measures, while motor unit integrity was determined using electromyography. Relative protein expression was determined by microwave and magnetic (M2 proteomics of ipsilateral brain tissue, as previously described. Isoprostane measurements were performed to confirm a primary oxidative stress response. Decoding the relative expression of 476 ± 56 top-ranked proteins for each specimen revealed statistically significant changes in the expression of two well-known CSPs at 1, 7 and 30 days post-injury: P < 0.001 for myelin basic protein (MBP and p < 0.05 for myelin associated glycoprotein (MAG. This was confirmed by Western blot. Moreover, MAG, αII-spectrin (SPNA2 and neurofilament light (NEFL expression at 30 days post-injury were directly related to grip strength (p < 0.05. While higher-powered studies of larger cohorts merit further investigation, this study supports the proof-of-concept that M2 proteomics is a rapid method to quantify putative protein biomarkers and therapeutic targets of mTBI and suggests the feasibility of CSP expression correlations to long-term effects on motor impairment.

  11. Tidal surge in the M2 proton channel, sensed by 2D IR spectroscopy.

    Science.gov (United States)

    Ghosh, Ayanjeet; Qiu, Jade; DeGrado, William F; Hochstrasser, Robin M

    2011-04-12

    The M2 proton channel from influenza A virus transmits protons across membranes via a narrow aqueous pore lined by water and a proton sensor, His37. Near the center of the membrane, a water cluster is stabilized by the carbonyl of Gly34 and His37, the properties of which are modulated by protonation of His37. At low pH (5-6), where M2 conducts protons, this region undergoes exchange processes on the microsecond to second timescale. Here, we use 2D IR to examine the instantaneous conformational distribution and hydration of G34, and the evolution of the ensemble on the femtosecond to picosecond timescale. The channel water is strongly pH dependent as gauged by 2D IR which allows recording of the vibrational frequency autocorrelation function of a (13)C = (18)O Gly34 probe. At pH 8, where entry and exit of protons within the channel are very slow, the carbonyl groups appear to adopt a single conformation/environment. The high-pH conformer does not exhibit spectral dynamics near the Gly34, and water in the channel must form a relatively rigid ice-like structure. By contrast, two vibrational forms of G34 are seen at pH 6.2, neither of which is identical to the high-pH form. In at least one of these low-pH forms, the probe is immersed in a very mobile, bulk-like aqueous environment having a correlation time ca. 1.3 ps at pH 6.2. Thus, protonation of His37 at low pH causes liquid-like water molecules to flow into the neighborhood of the Gly34.

  12. β1/2 or M2/3 Receptors Are Required for Different Gastrointestinal Motility Responses Induced by Acupuncture at Heterotopic or Homotopic Acupoints

    Science.gov (United States)

    Yu, Xiaochun; Cui, Changxiang; Yang, Zhaokun; Shi, Hong; Jing, Xianghong; Zhu, Bing

    2016-01-01

    Acupuncture at homotopic acupoints or heterotopic acupoints is known to either inhibit or facilitate gastrointestinal motility, depending on the acupoint location. However, little effort has been made to investigate the roles of specific receptors (such as adrenergic and muscarinic acetylcholine receptors) in mediating the effects of acupuncture at heterotopic and homotopic acupoints. Different adrenergic receptor subtypes or cholinergic receptor subtypes are predominantly expressed in various sections of the gut, resulting in variations between the effects of acupuncture at heterotopic or homotopic acupoints on gastrointestinal motility. Here, we investigated the role of β1/β2 receptors and M2/M3 receptors in gastrointestinal motility regulated by acupuncture at ST37, a heterotopic acupoint, and ST25, a homotopic acupoint, by simultaneously recording intraluminal pressures in the distal colon and stomach or jejunum and examining fecal phenol red excretion in β1/2 receptor-knockout mice and M2/3 receptor-knockout mice. We found that knockout of the M2/3 receptor significantly inhibited ST37 acupuncture-induced enhancement of gastric motility, jejunal motility, and colonic motility. Additionally, knocking out of the β1/2 receptor significantly diminished the ST25 acupuncture-induced inhibition of gastric motility and jejunal motility without significantly altering the enhancement of colonic motility induced by acupuncture at ST25. Acupuncture at ST37 significantly accelerated gastrointestinal transition in β1/2 receptor-knockout mice and their wild-type littermates. However, this acceleration of gastrointestinal transition was markedly diminished in M2/3 receptor-knockout mice relative to their wild-type littermates. Acupuncture at ST25 significantly increased gastrointestinal transition in β1/2 receptor-knockout mice and significantly decreased gastrointestinal transition in M2/3 receptor-knockout mice without altering gastrointestinal transition in wild-type

  13. Deletion of the M2-2 gene from avian metapneumovirus subgroup C impairs virus replication and immunogenicity in Turkeys.

    Science.gov (United States)

    Yu, Qingzhong; Estevez, Carlos N; Roth, Jason P; Hu, Haixia; Zsak, Laszlo

    2011-06-01

    The second matrix (M2) gene of avian metapneumovirus subgroup C (aMPV-C) contains two overlapping open reading frames (ORFs), encoding two putative proteins, M2-1 and M2-2. Both proteins are believed to be involved in viral RNA transcription or replication. To further characterize the function of the M2-2 protein in virus replication, the non-overlapping region of the M2-2 ORF was deleted from an infectious cDNA clone of the aMPV-C strain, and a viable virus was rescued by using reverse genetics technology. The recombinant virus, raMPV-C ΔM2-2, was characterized in vitro and in vivo. In Vero cells, raMPV-C ΔM2-2 replicated slightly less efficiently than the parental virus, 10-fold reduction at 48-h post-infection. The raMPV-C ΔM2-2 virus induced typical cytopathic effects (CPE) that were indistinguishable from those seen with the parental virus infection. In specific-pathogen-free (SPF) turkeys, raMPV-C ΔM2-2 was attenuated and caused no clinical signs of disease. Less than 20% of the inoculated birds shed detectable virus in tracheal tissue during the first 5 days post-infection, and no virus shedding was detected afterward. Forty percent of infected birds produced a weak antibody response at 14 days post-infection. Upon challenge with a virulent aMPV-C strain, more than 80% of the raMPV-C ΔM2-2-inoculated birds showed typical disease signs and virus shedding in tracheal tissue. These results suggest that the M2-2 protein of aMPV-C virus is not essential for virus replication in vitro, but is required for sufficient virus replication to maintain pathogenicity and immunogenicity in the natural host.

  14. Diversification of the vacAs1m1 and vacAs2m2 strains of Helicobacter pylori in Meriones unguiculatus

    Directory of Open Access Journals (Sweden)

    Sandra Mendoza Elizalde

    2016-11-01

    Full Text Available The bacterium Helicobacter pylori exhibits great genetic diversity, and the pathogenic roles of its virulence factors have been widely studied. However, the evolutionary dynamics of H. pylori strains during stomach colonization are not well characterized. Here, we analyzed the microevolutionary dynamics of the toxigenic strain vacAs1m1, the non-toxigenic strain vacAs2m2, and a combination of both strains in an animal model over time. Meriones unguiculatus were inoculated with the following bacteria: group 1–toxigenic strain vacAs1m1/cagA+/cagE+/babA2+; ST181, group 2–non-toxigenic strain vacAs2m2/ cagA+/ cagE+/ babA2+; ST2901, and group 3–both strains. The gerbils were euthanized at different time points (3, 6, 12 and 18 months. In group 1, genetic alterations were observed at 6 and 12 months. With the combination of both strains, group 3 also exhibited genetic alterations at 3 and 18 months; moreover, a chimera, vacA m1-m2, was detected. Additionally, four new sequence types (STs were reported in the PubMLST database for H. pylori. Synonymous and non-synonymous mutations were analyzed and associated with alterations in amino acids. Microevolutionary analysis of the STs (PHYLOViZ identified in each group revealed many mutational changes in the toxigenic (vacAs1m1 and non-toxigenic (vacAs2m2 strains. Phylogenetic assessments (eBURST did not reveal clonal complexes. Our findings indicate that the toxigenic strain, vacAs1m1, and a combination of toxigenic and non-toxigenic strains acquired genetic material by recombination. The allelic combination, vacAs2m1, displayed the best adaptation in the animal model over time, and a chimera, m1-m2, was also identified, which confirmed previous reports.

  15. Muscarinic M2 and M4 receptors in anterior cingulate cortex: relation to neuropsychiatric symptoms in dementia with Lewy bodies.

    Science.gov (United States)

    Teaktong, Thanasak; Piggott, Margaret A; Mckeith, Ian G; Perry, Robert H; Ballard, Clive G; Perry, Elaine K

    2005-06-20

    Alterations in cholinergic functions have been reported to be associated with neuropsychiatric symptoms in dementia. Increased M1 muscarinic receptor binding in temporal cortex is associated with delusions in dementia with Lewy bodies (DLB) patients and increased M2/M4 receptor binding with psychosis in Alzheimer's disease. However, the relation between M2 and M4 muscarinic receptor and psychotic symptoms in DLB is unknown. The aim of this study was to measure M2 and M4 receptors in the anterior cingulate cortex in DLB and to correlate the neurochemical findings with neuropsychiatric symptoms. Muscarinic M2 and M4 receptor levels in the anterior cingulate cortex and adjacent cortex (Brodmann's area [BA] 32) were measured separately by using a radioligand binding protocol based on binding of [(3)H]AF-DX 384 in the presence and absence of dicyclomine, a potent M4 receptor antagonist. M2 receptor binding was significantly increased, while M4 receptor binding was unchanged in the cingulate cortex and BA32 of DLB patients compared with age-matched controls. Impaired consciousness was significantly associated with increased M4 binding and delusions were significantly associated with increased M2 binding. Increased M2 and M4 receptor binding in DLB was also associated with visual hallucinations. Upregulation of M2 and M4 muscarinic receptors in cingulate and adjacent cortex may thus contribute to the development of psychosis in DLB, with potential implications for treatments with drugs acting on these receptors.

  16. HLA-B27M1M2 and high immune responsiveness to Shigella flexneri in post-dysenteric arthritis

    NARCIS (Netherlands)

    van Bohemen, C. G.; Nabbe, A. J.; Landheer, J. E.; Grumet, F. C.; Mazurkiewicz, E. S.; Dinant, H. J.; Lionarons, R. J.; van Bodegom, P. C.; Zanen, H. C.

    1986-01-01

    The heterogeneous HLA-B27 antigen is closely associated with post-infectious or reactive arthritis (ReA) and is comprised of two serologically defined variants: B27M1+M2+ and B27M1+M2-. An outbreak of dysentery (n = 120) caused by a Shigella flexneri 2a strain, which possessed cell envelope antigens

  17. Studies on Nanoparticle Based Avian Influenza Vaccines to Present Immunogenic Epitopes of the Virus with Concentration on Ectodomain of Matrix 2 (M2e) Protein

    Science.gov (United States)

    Babapoor Dighaleh, Sankhiros

    2011-12-01

    Avian influenza is an infectious disease of avian species caused by type A influenza viruses with a significant economic impact on the poultry industry. Vaccination is the main prevention strategy in many countries worldwide. However, available vaccines elicit antibodies against two major surface protein of the virus hemagglutinin (HA) and neuraminidase (NA), where they constantly change by point mutations. Influenza viruses can also easily undergo gene reassortment. Therefore, to protect chickens against new strain of avian influenza virus, as well as control and prevent virus spread among farms, new vaccines needed to be designed which is a tedious, time consuming and expensive. Recently, conserved regions of the influenza genome have been evaluated as possible universal vaccines to eliminate constant vaccine updates based on circulating virus. In this study, peptide nanotechnology was used to generate vaccine nanoparticles that carry the highly conserved external domain of matrix 2 protein (M2e). These nanoparticles presented M2e in monomeric or tetrameric forms, designated as PSC-M2e-CH and BNSC-M2eN-CH. respectively. First, to demonstrate immunogenicity of these nanoparticles, we measured anti-M2e antibody in chickens, particularly when a high dose was applied. Prior to vaccination-challenge study, the challenge dose were determined by oculonasal inoculation of 10 6 EID50 or 107.7 EID50 of low pathogenicity AI virus HSN2 followed by measuring cloacal and tracheal virus shedding. A biphasic virus shedding pattern was observed with two peaks of virus shedding at days 4 and 8 for both tracheal and cloacal swabs. The chickens infected with 107.7 EID50 had significant virus shedding as compared with 106 EID50. Based on results of mentioned studies, a vaccination-challenge study was conducted by using 75mug of each vaccine construct per inoculation (with and without adjuvant) and higher dose of virus for challenge. BN5C-M2e-CH with adjuvant significantly reduced the

  18. Phase transformations, ionic conductivity and dipole ordering of NASICON-like double phosphates Na3M2(PO4)3 (M-Sc,Fe,Cr)

    International Nuclear Information System (INIS)

    Kalinin, V.B.

    1990-01-01

    Experimental data obtained using ceramic samples of Na 3 M 2 (PO 4 ) 3 and solid solutions on their basis have been analyzed and generalized. It is shown that isostoichiometry of Na 3 M 2 (PO 4 ) 3 compounds and different types of dipole ordering in their α-phases stimulate investigations of subsolidus regions in the systems Na 3 Sc 2 (PO 4 ) 3 -Na 3 Fe 2 (PO 4 ) 3 , Na 3 Sc 2 (PO 4 ) 3 -Na 3 Cr 2 (PO 4 ) 3 , Na 3 Fe 2 (PO 4 ) 3 -Na 3 Cr 2 (PO 4 ) 3 .It proved possible to detect changes of the properties in case of ferroelectric-antiferroelectric, antiferroelectric-antiferroelectric transitions

  19. Pyruvate kinase M2 overexpression and poor prognosis in solid tumors of digestive system: evidence from 16 cohort studies.

    Science.gov (United States)

    Wu, Jiayuan; Hu, Liren; Chen, Manyu; Cao, Wenjun; Chen, Haicong; He, Taiping

    2016-01-01

    The expression of pyruvate kinase M2 (PKM2) has been linked to tumor formation and invasion. Specifically, the relationship between high PKM2 expression and prognosis has been evaluated in solid tumors of digestive system. However, the prognostic value of PKM2 remains controversial. A literature search of PubMed, Embase, and Cochrane databases was conducted until October 2015. The end point focused on overall survival (OS). The pooled hazard ratio (HR) or odds ratio and the 95% confidence intervals were calculated to correlate PKM2 overexpression with OS and clinicopathological characteristics by employing fixed- or random-effects models, depending on the heterogeneity of the included studies. We identified 18 cohorts in 16 studies involving 2,812 patients for this meta-analysis. Overall, the combined HR for OS in all tumor types was 1.74 (1.44-2.11; Pdigestive system, thereby suggesting that PKM2 might be an indicator of poor prognosis in digestive system cancers.

  20. A new 2D monolayer BiXene, M2C (M = Mo, Tc, Os).

    Science.gov (United States)

    Sun, Weiwei; Li, Yunguo; Wang, Baotian; Jiang, Xue; Katsnelson, Mikhail I; Korzhavyi, Pavel; Eriksson, Olle; Di Marco, Igor

    2016-08-25

    The existence of BiXenes, a new family of 2D monolayers, is hereby predicted. Theoretically, BiXenes have 1H symmetry (P6[combining macron]m2) and can be formed from the 4d/5d binary carbides. As the name suggests, they are close relatives of MXenes, which instead have 1T symmetry (P3[combining macron]m1). The newly found BiXenes, as well as some new MXenes, are shown to have formation energies close to that of germanene, which suggests that these materials should be possible to be synthesised. Among them, we illustrate that 1H-Tc2C and 1T-Mo2C are dynamically stable at 0 K, while 1H-Mo2C, 1T-Tc2C, 1H-Os2C, and 1T-Rh2C are likely to be stabilised via strain or temperature. In addition, the nature of the chemical bonding is analysed, emphasizing that the covalency between the transition metal ions and carbon is much stronger in BiXenes than in MXenes. The emergence of BiXenes can not only open up a new era of conducting 2D monolayers, but also provide good candidates for carrier materials aimed at energy storage and spintronic devices that have already been unveiled in MXenes.

  1. Refining the microstructure of an AISI M2 tool steel by high-energy milling

    International Nuclear Information System (INIS)

    Postiglioni, R.V.; Alamino, A.E; Vurobi Junior, S.

    2009-01-01

    Samples of AISI M2 steel were produced by high-energy milling from chips of machining in Spex high energy mill, compaction and sintering of the powder obtained. The powder was analyzed by X-ray diffraction, and then compressed in discs of 8mm in diameter. The specimens have sintering at 1200 deg C for 1 hour under vacuum atmosphere, followed by annealing, quenching and tempering for 1 hour at 315 deg C and 540°C. Along with each disc, a sample of as-received steel was subjected to the same heat treatments to compare the final microstructure. After standard metallographic preparation, samples were etched with Beraha's reagent, characterized by optical microscopy, quantitative metallography, scanning electron microscopy with micro analysis and mapping by EDS, besides Vickers hardness. The steel produced by high-energy milling presented more refined carbide and better distribution in the microstructure. There was also reduction in the size of prior austenitic grains. (author)

  2. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Anastasiou, Dimitrios; Yu, Yimin; Israelsen, William J.; Jiang, Jian-Kang; Boxer, Matthew B.; Hong, Bum Soo; Tempel, Wolfram; Dimov, Svetoslav; Shen, Min; Jha, Abhishek; Yang, Hua; Mattaini, Katherine R.; Metallo, Christian M.; Fiske, Brian P.; Courtney, Kevin D.; Malstrom, Scott; Khan, Tahsin M.; Kung, Charles; Skoumbourdis, Amanda P.; Veith, Henrike; Southall, Noel; Walsh, Martin J.; Brimacombe, Kyle R.; Leister, William; Lunt, Sophia Y.; Johnson, Zachary R.; Yen, Katharine E.; Kunii, Kaiko; Davidson, Shawn M.; Christofk, Heather R.; Austin, Christopher P.; Inglese, James; Harris, Marian H.; Asara, John M.; Stephanopoulos, Gregory; Salituro, Francesco G.; Jin, Shengfang; Dang, Lenny; Auld, Douglas S.; Park, Hee-Won; Cantley, Lewis C.; Thomas, Craig J.; Vander Heiden, Matthew G.

    2012-08-26

    Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. This data supports the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

  3. Distributed net-centric architecture of m2m acquisition units with optical GVA

    Science.gov (United States)

    Guha, Dipnarayan; Choi, Jun; Hassan, Mashfique

    2005-05-01

    This paper describes the architecture of a low-latency symmetric multiprocessing optical soft memory system to cluster computing inside the core of an adaptive optical signal processor with the aid of soft decision algebraic polynomial algorithms. The optical system hardware is shown to evolve along with the iterator instantiations of the soft algorithm that forms the core of the memory map. The system enables efficient cache coherence protocols used in unit multiprocessors to be run across a homogeneous cluster in optical soft memory systems. We define a structure called the Optical Generalized Viterbi Algorithm Data Structure (Optical GVA DS) that makes up the system map for adaptive optical signal processing. The system executes transforms where algorithms for handling the entire data vector is processed, shortening the computational complexity effectively. Thus the optical soft memory system as described by the evolving Optical GVA DS iterator instantiates enables the design of parallel processors to handle modulated data in the optical domain. This is of importance in the realization of distributed netcentric architectures and forms the basis of large-scale real-time data processing and acquisition in m2m units.

  4. The Lichens experiment at Foton M-2 mission: Survival capacity in space

    Science.gov (United States)

    de La Torre, R.; Horneck, G.; Garcia-Sancho, L.

    Lichens are one of the most resistant organisms at Earth They live at very extreme environments in deserts Atacama desert high mountains Himalaya Antarctica Dry Valleys etc This is possible due to the symbiotic relationship between both constituents the algae and the fungui and to their poikilohidric nature characteristic that allows them to survive latent when environmental conditions are very extreme i e when UV radiation is very high temperatures are extreme and dryness exists If humidity returns and temperature tendencies turn near the optimum around 10 C dormant lichens starts to photosynthetice We have selected two epilithic lichen species for the LICHENS experiment which was included at the ESA Biopan-facility located at the outer shell of the satellite Foton M-2 launched into low Earth orbit the 31th of Mai 2005 from Baikonur Russia On of this species was Rhizocarpon geographicum a bipolar epilithic lichen which grows at high mountain regions e g Sierra de Gredos Central Spain with continental climate has been systematically studied in the natural environment Plataforma de Gredos at 2000 m altitude as well as under simulated space conditions at the space simulation facilities of the DLR The sensitivity of the photosynthetic system PSII to the different environmental conditions dryness including vacuum treatment high temperature fluctuations high UV intensity was fluorometrically measured with a MINI PAM Walz Germany The lichen Rhizocarpon geographicum was

  5. On homology modeling of the M2 muscarinic acetylcholine receptor subtype

    Science.gov (United States)

    Jakubík, Jan; Randáková, Alena; Doležal, Vladimír

    2013-06-01

    Twelve homology models of the human M2 muscarinic receptor using different sets of templates have been designed using the Prime program or the modeller program and compared to crystallographic structure (PDB:3UON). The best models were obtained using single template of the closest published structure, the M3 muscarinic receptor (PDB:4DAJ). Adding more (structurally distant) templates led to worse models. Data document a key role of the template in homology modeling. The models differ substantially. The quality checks built into the programs do not correlate with the RMSDs to the crystallographic structure and cannot be used to select the best model. Re-docking of the antagonists present in crystallographic structure and relative binding energy estimation by calculating MM/GBSA in Prime and the binding energy function in YASARA suggested it could be possible to evaluate the quality of the orthosteric binding site based on the prediction of relative binding energies. Although estimation of relative binding energies distinguishes between relatively good and bad models it does not indicate the best one. On the other hand, visual inspection of the models for known features and knowledge-based analysis of the intramolecular interactions allows an experimenter to select overall best models manually.

  6. CYP1A1 m1 and m2 polymorphisms: genetic susceptibility to lung cancer

    Directory of Open Access Journals (Sweden)

    Paula Mota

    2010-01-01

    Full Text Available Lung cancer is considered an environment-related disease that develops as a consequence of exposure to mutagenic agents, namely those present in tobacco. The CYP1A1 gene codifies the phase I enzyme aryl hydrocarbon hydroxilase (AHH belonging to the cytochrome P450 system that plays a major role in the bio-activation of tobacco procarcinogenes. Two CYP1A1 polymorphisms, m1 (T6235C transition and m2 (A4889G transition, are associated with greater enzymatic activity and have been described as genetic susceptibility factors for lung cancer.The aim of this study was to verify if this association holds true in blood samples of 175 lung cancer patients and 217 non-cancer patients from Portugal's midlands region. The samples were studied by restriction fragment length polymorphism (RFLP assay.The allelic frequencies of the mutant alleles were 0.12 for allele C and 1.14 for allele G in the control population. The results were not statistically different from those alleles in the patient population. There was also no statistically significant difference in genotype distribution in lung cancer patients and controls even when combining high risk genotypes. In our control sample, as in other populations of different ethnic origin, both polymorphisms also seem to be in linkage disequilibrium. We conclude that in this sample of the Portuguese population, CYP1A1 m1 and m2 polymorphisms are too rare to be of clinical relevance, and do not seem to be associated with susceptibility to lung cancer. Resumo: O cancro do pulmão é considerado uma doença relacionada com o meio ambiente, consequência da exposição a agentes mutagénicos, nomeadamente os presentes no fumo do tabaco. O gene CYP1A1 codifica a enzima aril hidrocarboneto hidroxilase (AHH, da fase I, do sistema multienzimático do citocromo P450, que desempenha uma função preponderante na bioactivação dos procarcinogénios do tabaco. Dois polimorfismos do CYP1A1, m1 (transi

  7. M2-F2 Lifting Body being Carried Aloft by B-52 Mothership

    Science.gov (United States)

    1966-01-01

    The M2-F2 Lifting Body is shown here being carried aloft by the Air Force's B-52 (tail number 003) prior to a research launch. The success of Dryden's 'homebuilt' M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies--the M2-F2 and the HL-10, both built by the Northrop Corporation. The 'M' refers to 'manned' and 'F' refers to 'flight' version. 'HL' comes from 'horizontal landing.' The first flight of the M2-F2--which looked much like the 'F1'--was on July 12, 1966. Milt Thompson was the pilot. NASA B-52, Tail Number 008, is an air launch carrier aircraft, 'mothership,' as well as a research aircraft platform that has been used on a variety of research projects. The aircraft, a 'B' model built in 1952 and first flown on June 11, 1955, is the oldest B-52 in flying status and has been used on some of the most significant research projects in aerospace history. Some of the significant projects supported by B-52 008 include the X-15, the lifting bodies, HiMAT (highly maneuverable aircraft technology), Pegasus, validation of parachute systems developed for the space shuttle program (solid-rocket-booster recovery system and the orbiter drag chute system), and the X-38. The B-52 served as the launch vehicle on 106 X-15 flights and flew a total of 159 captive-carry and launch missions in support of that program from June 1959 to October 1968. Information gained from the highly successful X-15 program contributed to the Mercury, Gemini, and Apollo human spaceflight programs as well as space shuttle development. Between 1966 and 1975, the B-52 served as the launch aircraft for 127 of the 144 wingless lifting body flights. In the 1970s and 1980s, the B-52 was the launch aircraft for several aircraft at what is now the Dryden Flight Research Center, Edwards, California, to study spin-stall, high-angle-of attack, and maneuvering characteristics. These included the 3/8-scale F-15/spin research vehicle (SRV), the HiMAT (Highly Maneuverable

  8. Analysis of Cell Proliferation in Newt (Pleurodeles waltl) Tissue Regeneration during Spaceflight in Foton M-2

    Science.gov (United States)

    Almeida, E. A. C.; Roden, C.; Phillips, J. A.; Yusuf, R.; Globus, R. K.; Searby, N.; Vercoutere, W.; Morey-Holton, E.; Tairbekov, M.; Grigoryan, N.; hide

    2006-01-01

    Terrestrial organisms exposed to microgravity during spaceflight expe rience musculoskeletal degeneration. It is still not understood if lo nger-term exposures to microgravity induce degeneration in other tiss ues, and if these effects are also observed in neutrally buoyant aqu atic organisms that may be pre-adapted to mechanical unloading. The " Regeneration" experiment conducted collaboratively between Russian an d US scientists for 16 days in the Russian Foton M-2 spaceflight soug ht to test the hypothesis that microgravity alters the proliferation of cells in regenerating tail tissue of the newt Pleurodeles waltl. Our initial results indicate that we successfUlly delivered the proli feration marker 5-bromo-2'-deoxy Uridine (BrdU) during spaceflight, and that it was incorporated in the nuclei of cells in regenerating tis sues. Cells in spaceflight tail regenerates proliferated at a slight ly slower rate and were more undifferentiated than those in ground sy nchronous controls. In addition, the size of regenerating tails from spaceflight was smaller than synchronous controls. However, onboard temperature recordings show that the temperature in spaceflight was a bout 2 C lower than ground synchronous controls, possibly explaining the observed differences. Additional post-facto ground controls at ma tched temperatures will correctly determine the effects of spaceflig ht on regenerative cell proliferation in the newt.

  9. Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2.

    Directory of Open Access Journals (Sweden)

    Mani Shankar Babu

    Full Text Available Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2 is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhibition of glycolysis and a corresponding increase in oxygen consumption. Accordingly, in silico studies revealed a high affinity-binding pocket for lapachol on PKM2 structure. Lapachol inhibited PKM2 activity of purified enzyme as well as in melanoma cell extracts. Blockade of glycolysis by lapachol in melanoma cells led to decreased ATP levels and inhibition of cell proliferation. Furthermore, perturbation of glycolysis in melanoma cells with lapachol sensitized cells to mitochondrial protonophore and promoted apoptosis. These results present lapachol as an inhibitor of PKM2 to interrogate metabolic plasticity in tumor cells.

  10. Switching of pyruvate kinase isoform L to M2 promotes metabolic reprogramming in hepatocarcinogenesis.

    Directory of Open Access Journals (Sweden)

    Carmen Chak-Lui Wong

    Full Text Available Hepatocellular carcinoma (HCC is an aggressive tumor, with a high mortality rate due to late symptom presentation and frequent tumor recurrences and metastasis. It is also a rapidly growing tumor supported by different metabolic mechanisms; nevertheless, the biological and molecular mechanisms involved in the metabolic reprogramming in HCC are unclear. In this study, we found that pyruvate kinase M2 (PKM2 was frequently over-expressed in human HCCs and its over-expression was associated with aggressive clinicopathological features and poor prognosis of HCC patients. Furthermore, knockdown of PKM2 suppressed aerobic glycolysis and cell proliferation in HCC cell lines in vitro. Importantly, knockdown of PKM2 hampered HCC growth in both subcutaneous injection and orthotopic liver implantation models, and reduced lung metastasis in vivo. Of significance, PKM2 over-expression in human HCCs was associated with a down-regulation of a liver-specific microRNA, miR-122. We further showed that miR-122 interacted with the 3UTR of the PKM2 gene. Re-expression of miR-122 in HCC cell lines reduced PKM2 expression, decreased glucose uptake in vitro, and suppressed HCC tumor growth in vivo. Our clinical data and functional studies have revealed a novel biological mechanism involved in HCC metabolic reprogramming.

  11. M2 Internal Tides and Their Observed Wavenumber Spectra from Satellite Altimetry*

    Science.gov (United States)

    Ray, R. D.; Zaron, E. D.

    2015-01-01

    A near-global chart of surface elevations associated with the stationary M2 internal tide is empirically constructed from multi-mission satellite altimeter data. An advantage of a strictly empirical mapping approach is that results are independent of assumptions about ocean wave dynamics and, in fact, can be used to test such assumptions. A disadvantage is that present-day altimeter coverage is only marginally adequate to support mapping such short-wavelength features. Moreover, predominantly north-south ground-track orientations and contamination from nontidal oceanographic variability can lead to deficiencies in mapped tides. Independent data from Cryosphere Satellite-2 (CryoSat-2) and other altimeters are used to test the solutions and show positive reduction in variance except in regions of large mesoscale variability. The tidal fields are subjected to two-dimensional wavenumber spectral analysis, which allows for the construction of an empirical map of modal wavelengths. Mode-1 wavelengths show good agreement with theoretical wavelengths calculated from the ocean's mean stratification, with a few localized exceptions (e.g., Tasman Sea). Mode-2 waves are detectable in much of the ocean, with wavelengths in reasonable agreement with theoretical expectations, but their spectral signatures grow too weak to map in some regions.

  12. Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2.

    Science.gov (United States)

    Shankar Babu, Mani; Mahanta, Sailendra; Lakhter, Alexander J; Hato, Takashi; Paul, Subhankar; Naidu, Samisubbu R

    2018-01-01

    Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhibition of glycolysis and a corresponding increase in oxygen consumption. Accordingly, in silico studies revealed a high affinity-binding pocket for lapachol on PKM2 structure. Lapachol inhibited PKM2 activity of purified enzyme as well as in melanoma cell extracts. Blockade of glycolysis by lapachol in melanoma cells led to decreased ATP levels and inhibition of cell proliferation. Furthermore, perturbation of glycolysis in melanoma cells with lapachol sensitized cells to mitochondrial protonophore and promoted apoptosis. These results present lapachol as an inhibitor of PKM2 to interrogate metabolic plasticity in tumor cells.

  13. Structural impact of creep in tungsten monoblock divertor target at 20 MW/m2

    Directory of Open Access Journals (Sweden)

    Muyuan Li

    2018-01-01

    Full Text Available In order to increase erosion lifetime of the divertor target, in the 2nd design phase of R&D work package ‘Divertor’ for European DEMO, armor thickness of tungsten monoblock divertor target is increased from 5 mm to 8 mm. By increasing armor thickness, surface temperature increases nearly linearly, which makes effect of creep no longer negligible at slow transients of 20 MW/m2. In this work, structural impact of creep in tungsten monoblock divertor target is for the first time quantitatively analyzed with the aid of finite element method. The numerical simulations have revealed that creep results in an increase of inelastic strain accumulation. With increasing armor thickness, tensile surface stress along x-axis (the longer edge at the plasma-facing surface of tungsten monoblock reduces, while surface stress along z-axis (axial direction of the cooling tube changes from tensile to compressive. Creep will accelerate this change. With increasing grain size, creep strain accumulation at loading surface increases due to higher creep rates, while plastic strain accumulation decreases. Creep can mitigate the risk of deep cracking by reducing the driving force for crack opening, and has a positive impact for preventing the contact between the upper parts of neighboring monoblocks in high heat flux tests.

  14. Machining tools in AISI M2 high-speed steel obtained by spray forming process

    International Nuclear Information System (INIS)

    Jesus, Edilson Rosa Barbosa de.

    2004-01-01

    The aim of the present work was the obtention of AISI M2 high-speed steel by spray forming technique and the material evaluation when used as machining tool. The obtained material was hot rolled at 50% and 72% reduction ratios, and from which it was manufactured inserts for machining tests. The performance of inserts made of the spray formed material was compared to inserts obtained from conventional and powder metallurgy (MP) processed materials. The spray formed material was chemical, physical, mechanical and microstructural characterised. For further characterisation, the materials were submitted to machining tests for performance evaluation under real work condition. The results of material characterisation highlight the potential of the spray forming technique, in the obtention of materials with good characteristics and properties. Under the current processing, hot rolling and heat treatments condition, the analysis of the results of the machining tests revealed a very similar behaviour among the tested materials. Proceeding a criterious analysis of the machining results tests, it was verified that the performance presented by the powder metallurgy material (MP) was slight superior, followed by conventional obtained material (MConv), which presented a insignificant advantage over the spray formed and hot rolled (72% reduction ratio) material. The worst result was encountered for the spray forming and hot rolled (50% reduction ratio) material that presented the highest wear values. (author)

  15. Filtered Rayleigh scattering velocimetry—accuracy investigation in a M=2.2 axisymmetric jet

    Science.gov (United States)

    Gustavsson, J. P. R.; Segal, C.

    2005-01-01

    The present study is a quantitative evaluation of filtered Rayleigh scattering (FRS) axial velocity measurements in a M=2.2 axisymmetric jet. The FRS setup used a frequency-doubled, injection-seeded Nd:YAG laser, an iodine vapor cell and two intensified CCD cameras. The goal was to evaluate the FRS accuracy in a practical flow case and assess the relative uncertainty contributions of different sources. Despite the use of dried air and co-flow, water condensation produced uneven seeding of the flow, making particle scattering dominate over molecular scattering. The time-averaged velocity measurements showed fair agreement between the FRS and pressure probe data acquired in the same setup with deviations of up to 50 m/s. The analysis of uncertainty sources showed that laser drift dominated with an estimated contribution of 35 m/s. Several other sources, shot noise, iodine cell calibration, image misalignment and non-monochromatic scattered light were found to contribute O(10 m/s) each, bringing the total uncertainty estimate to ±50 m/s, in agreement with the experimental data.

  16. Component, Context, and Manufacturing Model Library (C2M2L)

    Science.gov (United States)

    2012-11-01

    corrosion by the remaining zinc on the surface. Types of galvanizing include: electrochemical, electrode positional, hot-dip continuous line (the most...applications. The reinforcement can be made from textile yarn, wire, or stainless steel. Types of extruded rubber hose include; low-pressure (non-reinforced...unlimited The process for EDM includes: sinker EDM- the process can call for the use of different electrodes . The design of the work piece (complex shapes

  17. The M2 Proton Channel of Influenza Virus: How Does It Work?

    Science.gov (United States)

    Pohorille, Andrew; Wilson, Michael; Schweighofer, Karl; Fonda, Mark (Technical Monitor)

    2002-01-01

    The transport of protons across membranes is an essential process for both bioenergetics of modem cells and the origins of cellular life. All living systems make use of proton gradients across cell walls to convert environmental energy into a high-energy chemical compound, adenosine triphosphate (ATR), synthesized from adenosine diphosphate. ATR, in turn, is used as a source of energy to drive many cellular reactions. The ubiquity of this process in biology suggests that even the earliest cellular systems were relying on proton gradient for harvesting environmental energy needed to support their survival and growth. In contemporary cells, proton transfer is assisted by large, complex proteins embedded in membranes. The issue addressed in this study was: how the same process can be accomplished with the aid of similar, but much simpler molecules that could have existed in the protobiological milieu? The model system used in the study contained a bilayer membrane made of phospholipid, dimyristoylphosphatidylcholine (DMPC), which is a good model of the biological membranes focusing cellular boundaries. Both sides of the bilayer were surrounded by water which simulated the environment inside and outside the cell. Embedded in the membrane was a fragment of the Influenza-A M2 protein and enough sodium counterions to maintain system neutrality. This protein has been shown to exhibit remarkably high rates of proton transport and, therefore, is an excellent model to study the formation of proton gradients across membranes. The Influenza M2 protein is 97 amino acids in length, but a fragment 25 amino acids long, which contains a transmembrane domain of 19 amino acids flanked by 3 amino acids on each side, is sufficient to transport protons. Four identical protein fragments, each folded into a helix, aggregate to form small channels spanning the membrane. Protons are conducted through a narrow pore in the middle of the channel in response to applied voltage. This channel is

  18. M2-F2 Mated to B-52 Mothership on Ramp

    Science.gov (United States)

    1965-01-01

    A head-on view of the M2-F2 lifting body mounted on the wing pylon of its B-52 mothership in 1965. This was for a captive flight made the following month. The M2-F2 remained attached to the B-52 throughout the flight to test its on-board systems. NASA B-52, Tail Number 008, is an air launch carrier aircraft, 'mothership,' as well as a research aircraft platform that has been used on a variety of research projects. The aircraft, a 'B' model built in 1952 and first flown on June 11, 1955, is the oldest B-52 in flying status and has been used on some of the most significant research projects in aerospace history. Some of the significant projects supported by B-52 008 include the X-15, the lifting bodies, HiMAT (highly maneuverable aircraft technology), Pegasus, validation of parachute systems developed for the space shuttle program (solid-rocket-booster recovery system and the orbiter drag chute system), and the X-38. The B-52 served as the launch vehicle on 106 X-15 flights and flew a total of 159 captive-carry and launch missions in support of that program from June 1959 to October 1968. Information gained from the highly successful X-15 program contributed to the Mercury, Gemini, and Apollo human spaceflight programs as well as space shuttle development. Between 1966 and 1975, the B-52 served as the launch aircraft for 127 of the 144 wingless lifting body flights. In the 1970s and 1980s, the B-52 was the launch aircraft for several aircraft at what is now the Dryden Flight Research Center, Edwards, California, to study spin-stall, high-angle-of attack, and maneuvering characteristics. These included the 3/8-scale F-15/spin research vehicle (SRV), the HiMAT (Highly Maneuverable Aircraft Technology) research vehicle, and the DAST (drones for aerodynamic and structural testing). The aircraft supported the development of parachute recovery systems used to recover the space shuttle solid rocket booster casings. It also supported eight orbiter (space shuttle) drag chute

  19. Structure of vanadium oxosulfato complexes in V2O5-M2S2O7-M2SO4 (M = K, Cs) melts. A high temperature spectroscopic study

    DEFF Research Database (Denmark)

    Boghosian, S.; Chrissanthopoulos, A.; Fehrmann, Rasmus

    2002-01-01

    The V-V and V-IV oxosulfato complexes formed in V2O5-M2S2O7-M2SO4 (M = K, Cs) melts under SO2(g) or O-2(g) atmosphere have been studied by electronic absorption (VIS/NIR) and Raman spectroscopy at 450 degreesC. VIS/NIR spectra have been obtained at 450 degreesC for V2O5-K2S2O7 molten mixtures in SO...

  20. miR-181a Induces Macrophage Polarized to M2 Phenotype and Promotes M2 Macrophage-mediated Tumor Cell Metastasis by Targeting KLF6 and C/EBPα

    Directory of Open Access Journals (Sweden)

    Jia Bi

    2016-01-01

    Full Text Available Macrophages can acquire a variety of polarization status and functions: classically activated macrophages (M1 macrophages; alternatively activated macrophages (M2 macrophages. However, the molecular basis of the process is still unclear. Here, this study addresses that microRNA-181a (miR-181a is a key molecule controlling macrophage polarization. We found that miR-181a is overexpressed in M2 macrophages than in M1 macrophages. miR-181a expression was decreased when M2 phenotype converted to M1, whereas it increased when M1 phenotype converted to M2. Overexpression of miR-181a in M1 macrophages diminished M1 phenotype expression while promoting polarization to the M2 phenotype. In contrast, knockdown of miR-181a in M2 macrophages promoted M1 polarization and diminished M2 phenotype expression. Mechanistically, Bioinformatic analysis revealed that Kruppel-like factor 6 (KLF6 and CCAAT/enhancer binding protein-α (C/EBPα is a potential target of miR-181a and luciferase assay confirmed that KLF6 and C/EBPα translation is suppressed by miR-181a through interaction with the 3′UTR of KLF6 and C/EBPα mRNA. Further analysis showed that induction of miR-181a suppressed KLF6 and C/EBPα protein expression. Importantly, miR-181a also diminishes M2 macrophages-mediated migration and invasion capacity of tumor cells. Collectively, our results suggest that miR-181a plays a significant role in regulating macrophage polarization through directly target KLF6 and C/EBPα.

  1. M2-branes on orbifolds of the cone over Q1,1,1

    International Nuclear Information System (INIS)

    Franco, Sebastian; Klebanov, Igor R.; RodrIguez-Gomez, Diego

    2009-01-01

    We study the N = 2 supersymmetric Chern-Simons quiver gauge theory recently introduced in arXiv:0809.3237 to describe M2-branes on a cone over the well-known Sasaki-Einstein manifold Q 1,1,1 . For Chern-Simons levels (k,k,-k,-k) we argue that this theory is dual to AdS 4 x Q 1,1,1 /Z k . We derive the Z k orbifold action and show that it preserves geometrical symmetry U(1) R x SU(2) x U(1), in agreement with the symmetry of the gauge theory. We analyze the simplest gauge invariant chiral operators, and show that they match Kaluza-Klein harmonics on AdS 4 x Q 1,1,1 /Z k . This provides a test of the gauge theory, and in particular of its sextic superpotential which plays an important role in restricting the spectrum of chiral operators. We proceed to study other quiver gauge theories corresponding to more complicated orbifolds of Q 1,1,1 . In particular, we propose two U(N) 4 Chern-Simons gauge theories whose quiver diagrams are the same as in the 4d theories describing D3-branes on a complex cone over F 0 , a Z 2 orbifold of the conifold (in 4d the two quivers are related by the Seiberg duality). The manifest symmetry of these gauge theories is U(1) R x SU(2) x SU(2). We argue that these gauge theories at levels (k,k,-k,-k) are dual to AdS 4 x Q 2,2,2 /Z k . We exhibit calculations of the moduli space and of the chiral operator spectrum which provide support for this conjecture. We also briefly discuss a similar correspondence for AdS 4 x M 3,2 /Z k . Finally, we discuss resolutions of the cones and their dual gauge theories.

  2. Excess circulating alternatively activated myeloid (M2 cells accelerate ALS progression while inhibiting experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Ilan Vaknin

    Full Text Available Circulating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs, representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease.We tested this working hypothesis in amyotrophic lateral sclerosis (ALS and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2 cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1 mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE, which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS, revealed a two-fold increase in the percentage of circulating MDSCs (LIN(-/LowHLA-DR(-CD33(+ compared to controls.Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might

  3. Molecular Cloning, Characterization, and Expression of Cuc m 2, a Major Allergen in Cucumis melo

    Directory of Open Access Journals (Sweden)

    Mojtaba Sankian

    2013-05-01

    Full Text Available Background: Several studies reported the clinical features of IgE-mediated hypersensitivity after ingestion of melon. Melon allergy is a common IgE-mediated fruit allergy in Iran. This prompted us to investigate immunochemical and molecular properties of the major allergen in melon fruit, to compare the IgE-binding capacity of the natural protein with the recombinant allergen, and to determine cross-reactivity of the major allergen with closely-related allergens from other plants displaying clinical cross-reactivity with melon. Methods: Identification and molecular characterization of the major melon allergen were performed using IgE immunoblotting, allergen-specific ELISA, affinity-based purifications, cross-inhibition assays, cloning, and expression of the allergen in Escherichia coli. Results: Melon profilin was identified and isolated as a major IgE-binding component and designated as Cuc m 2. Sequencing corresponding cDNA revealed an open reading frame of 363 bp coding for 131 amino acid residues and two fragments of 171 bp and 383 bps for the 5’and 3’ UTRs, respectively. Significant cross-reactivity was found between melon profilin and Cynodon dactylon, tomato, peach, and grape profilins in cross-inhibition assays. Although the highest degree of amino acid identity was revealed with watermelon profilin, there was no significant cross-reactivity between melon and watermelon profilins. Conclusion: Melon profilin is the major IgE-binding component in melon extract, and the recombinant and natural forms exhibited similar IgE-binding capacities. A part of the fruit-fruit and pollen-fruit cross-reactions could be explained by the presence of this conserved protein; however, sequence homology provides insufficient information to predict IgE cross-reactivity of profilins.

  4. miR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Angela M Liu

    Full Text Available In contrast to normal differentiated cells that depend on mitochondrial oxidative phosphorylation for energy production, cancer cells have evolved to utilize aerobic glycolysis (Warburg's effect, with benefit of providing intermediates for biomass production. MicroRNA-122 (miR-122 is highly expressed in normal liver tissue regulating a wide variety of biological processes including cellular metabolism, but is reduced in hepatocellular carcinoma (HCC. Overexpression of miR-122 was shown to inhibit cancer cell proliferation, metastasis, and increase chemosensitivity, but its functions in cancer metabolism remains unknown. The present study aims to identify the miR-122 targeted genes and to investigate the associated regulatory mechanisms in HCC metabolism. We found the ectopic overexpression of miR-122 affected metabolic activities of HCC cells, evidenced by the reduced lactate production and increased oxygen consumption. Integrated gene expression analysis in a cohort of 94 HCC tissues revealed miR-122 level tightly associated with a battery of glycolytic genes, in which pyruvate kinase (PK gene showed the strongest anti-correlation coefficient (Pearson r = -0.6938, p = <0.0001. In addition, reduced PK level was significantly associated with poor clinical outcomes of HCC patients. We found isoform M2 (PKM2 is the dominant form highly expressed in HCC and is a direct target of miR-122, as overexpression of miR-122 reduced both the mRNA and protein levels of PKM2, whereas PKM2 re-expression abrogated the miR-122-mediated glycolytic activities. The present study demonstrated the regulatory role of miR-122 on PKM2 in HCC, having an implication of therapeutic intervention targeting cancer metabolic pathways.

  5. Dynamic Resource Allocation and Access Class Barring Scheme for Delay-Sensitive Devices in Machine to Machine (M2M) Communications.

    Science.gov (United States)

    Li, Ning; Cao, Chao; Wang, Cong

    2017-06-15

    Supporting simultaneous access of machine-type devices is a critical challenge in machine-to-machine (M2M) communications. In this paper, we propose an optimal scheme to dynamically adjust the Access Class Barring (ACB) factor and the number of random access channel (RACH) resources for clustered machine-to-machine (M2M) communications, in which Delay-Sensitive (DS) devices coexist with Delay-Tolerant (DT) ones. In M2M communications, since delay-sensitive devices share random access resources with delay-tolerant devices, reducing the resources consumed by delay-sensitive devices means that there will be more resources available to delay-tolerant ones. Our goal is to optimize the random access scheme, which can not only satisfy the requirements of delay-sensitive devices, but also take the communication quality of delay-tolerant ones into consideration. We discuss this problem from the perspective of delay-sensitive services by adjusting the resource allocation and ACB scheme for these devices dynamically. Simulation results show that our proposed scheme realizes good performance in satisfying the delay-sensitive services as well as increasing the utilization rate of the random access resources allocated to them.

  6. Experiment on an Integrated Ricefish Polyculture System (6 Species, 1- 2 fish/m2 in the Mekong Delta

    Directory of Open Access Journals (Sweden)

    Lan, LM.

    2002-01-01

    Full Text Available Our ricefish polyculture (6 species results at two stocking densities (1 and 2 fish/m2 show that: The water quality in a ricefish polyculture system, such as water temperature (29.1 – 29.0 °C, water pH (6.6 – 6.7, water transparency (18.0 – 20.8 cm, dissolved O2 (4.7 – 4.6 ppm, CO2 (22.8 – 23.1 ppm, COD (11.9 – 12.7 ppm, are similar at both densities and acceptable for the 6 tropical fish species. Ammonium and phosphorus concentrations are statistically higher at 1 fish/m2 (0.4 and 0.2 ppm. The primary productivity is similar for both densities (6.5 – 6.8 g O2/m3/day and suitable for fish culture. The phytoplankton biodiversity is relatively high and at the same level for both treatments (74 – 63 taxa, but the densities of phytoplankton, of zooplankton, and the biomass of zoobenthos are lower at the highest density (2 fish/m2, probably due to a higher predation by fish.The fish yield (808 kg/ha at 2 fish/m2 is higher than at 1 fish/m2 (482 kg/ha. The cost ratio benefit (1.84 and the cost ratio profit (1.81 for farm households at 1 fish/m2 are lower than those values at 2 fish/m2 (2.1 and 2.05 respectively. Regarding the aquaculture extension program, the model of the ricefish polyculture (6 species system with the stocking density of 2 fish/m2 could be extended in the rice fields to improve farmer's income in the Mekong delta.

  7. Systemic and Cardiac Depletion of M2 Macrophage through CSF-1R Signaling Inhibition Alters Cardiac Function Post Myocardial Infarction.

    Directory of Open Access Journals (Sweden)

    Anne-Laure Leblond

    Full Text Available The heart hosts tissue resident macrophages which are capable of modulating cardiac inflammation and function by multiple mechanisms. At present, the consequences of phenotypic diversity in macrophages in the heart are incompletely understood. The contribution of cardiac M2-polarized macrophages to the resolution of inflammation and repair response following myocardial infarction remains to be fully defined. In this study, the role of M2 macrophages was investigated utilising a specific CSF-1 receptor signalling inhibition strategy to achieve their depletion. In mice, oral administration of GW2580, a CSF-1R kinase inhibitor, induced significant decreases in Gr1lo and F4/80hi monocyte populations in the circulation and the spleen. GW2580 administration also induced a significant depletion of M2 macrophages in the heart after 1 week treatment as well as a reduction of cardiac arginase1 and CD206 gene expression indicative of M2 macrophage activity. In a murine myocardial infarction model, reduced M2 macrophage content was associated with increased M1-related gene expression (IL-6 and IL-1β, and decreased M2-related gene expression (Arginase1 and CD206 in the heart of GW2580-treated animals versus vehicle-treated controls. M2 depletion was also associated with a loss in left ventricular contractile function, infarct enlargement, decreased collagen staining and increased inflammatory cell infiltration into the infarct zone, specifically neutrophils and M1 macrophages. Taken together, these data indicate that CSF-1R signalling is critical for maintaining cardiac tissue resident M2-polarized macrophage population, which is required for the resolution of inflammation post myocardial infarction and, in turn, for preservation of ventricular function.

  8. Activation cross section measurement for the 179Hf(n,2n)178m2Hf reaction

    International Nuclear Information System (INIS)

    Yu Weixiang; Lu Hanlin; Zhao Wenrong

    1992-01-01

    As an important data for a fusion reactor there are not any experimental results for the cross section of the 179 Hf(n,2n) 178m2 Hf reaction. So the cross section was measured in this work at neutron energy of 14 MeV. Meanwhile, we also gave the data for the cross section of the 180 Hf(n,2n) 179m2 Hf reaction. (author). 5 refs, 4 figs, 5 tabs

  9. Magellan/M2FS Spectroscopy of the Reticulum 2 Dwarf Spheroidal Galaxy

    Science.gov (United States)

    Walker, Matthew G.; Mateo, Mario; Olszewski, Edward W.; Bailey, John I., III; Koposov, Sergey E.; Belokurov, Vasily; Evans, N. Wyn

    2015-08-01

    We present results from spectroscopic observations with the Michigan/Magellan Fiber System (M2FS) of 182 stellar targets along the line of sight (LOS) to the newly discovered “ultrafaint” object Reticulum 2 (Ret 2). For 37 of these targets, the spectra are sufficient to provide simultaneous estimates of LOS velocity ({v}{los}, median random error {δ }{v{los}}=1.4 km s-1), effective temperature ({T}{eff}, {δ }{T{eff}}=478 K), surface gravity ({log}g, {δ }{logg}=0.63 dex), and iron abundance ([{Fe}/{{H}}], {δ }[{Fe/{{H}}]}=0.47 dex). We use these results to confirm 17 stars as members of Ret 2. From the member sample we estimate a velocity dispersion of {σ }{v{los}}= {3.6}-0.7+1.0 km s-1 about a mean of = {64.3}-1.2+1.2 km s-1 in the solar rest frame (˜ -90.9 km s-1 in the Galactic rest frame), and a metallicity dispersion of {σ }[{Fe/{{H}}]} = {0.49}-0.14+0.19 dex about a mean of = -{2.58}-0.33+0.34. These estimates marginalize over possible velocity and metallicity gradients, which are consistent with zero. Our results place Ret 2 on chemodynamical scaling relations followed by the Milky Way’s dwarf-galactic satellites. Under assumptions of dynamic equilibrium and negligible contamination from binary stars—both of which must be checked with deeper imaging and repeat spectroscopic observations—the estimated velocity dispersion suggests a dynamical mass of M({R}{{h}})≈ 5{R}{{h}}{σ }{v{los}}{}2/(2G) = {2.4}-0.8+1.4× {10}5 {M}⊙ enclosed within projected halflight radius {R}{{h}}˜ 32 pc, with mass-to-light ratio ≈ 2M({R}{{h}})/{L}V = {467}-168+286 in solar units. This paper presents data gathered with the Magellan Telescopes at Las Campanas Observatory, Chile.

  10. Mechanisms of pyruvate kinase M2 isoform inhibits cell motility in hepatocellular carcinoma cells.

    Science.gov (United States)

    Chen, Yan-Ling; Song, Jun-Jiao; Chen, Xiao-Chun; Xu, Wei; Zhi, Qiang; Liu, Yun-Peng; Xu, Hong-Zhi; Pan, Jin-Shui; Ren, Jian-Lin; Guleng, Bayasi

    2015-08-14

    To investigate biological mechanisms underlying pyruvate kinase M2 isoform (PKM2) regulation of cell migration and invasion in hepatocellular carcinoma cells. HepG2 and Huh-7 hepatocellular carcinoma cell lines were stably transfected and cultured in DMEM (HyClone, Logan, UT, United States). To investigate the effects of PKM2 on cellular proliferation, hepatocellular carcinoma cells were subjected to the Cell Counting Kit-8 (Dojindo, Kamimashiki-gun, Kumamoto, Japan). And investigate the effects of PKM2 on cell signal pathway related with migration and invasion, Western immunoblotting were used to find out the differential proteins. All the antibody used was purchaseed from Cell Signal Technology. In order to explore cell motility used Transwell invasion and wound healing assays. The transwell plate with 0.5 mg/mL collagen type I (BD Bioscience, San Jose, CA)-coated filters. The wound-healing assay was performed in 6-well plates. Total RNA was extracted using TRIzol reagent (Invitrogen, CA, United States) and then reverse transcription was conducted. Quantitative reverse transcription-polymerase chain reaction (PCR) analysis was performed with the ABI 7500 real-time PCR system (Applied Biosystems). We further use digital gene expression tag profiling and identification of differentially expressed genes. The cells seeded in four 96-well plates were measured OD450 by conducted Cell Counting Kit-8. From this conduction we observed that both HepG2 and Huh-7 hepatocellular carcinoma cells with silenced PKM2 turn on a proliferate inhibition; however, cell migration and invasion were enhanced compared with the control upon stimulation with epidermal growth factor (EGF). Our results indicate that the knockdown of PKM2 decreased the expression of E-cadherin and enhanced the activity of the EGF/EGFR signaling pathway, furthermore up-regulate the subsequent signal molecular the PLCγ1 and extracellular signal-regulated kinase 1/2 expression in the hepatocellular carcinoma

  11. Plastic restriction of HIV-1 replication in human macrophages derived from M1/M2 polarized monocytes.

    Science.gov (United States)

    Graziano, Francesca; Vicenzi, Elisa; Poli, Guido

    2016-11-01

    M1/M2 cytokine-dependent polarization of primary human MDMs has been shown to contain CCR5-dependent (R5) HIV-1 replication. In this study, a similar effect was achieved when monocytes were first polarized toward M1 or M2 and were infected 7 d after their differentiation into MDMs, regardless of whether the cytokines were removed 18 h after cell stimulation or were left in culture. Unlike polarized MDMs, no significant down-regulation of CD4 from the cell surface was observed in MDMs derived from M1/M2-polarized monocytes. A second stimulation of MDMs differentiated from M1/M2 monocytes with the opposite polarizing cytokines converted the virus replication profile according to the new stimuli. The expression of M1 and M2 markers (i.e., APOBEC3A and DC-SIGN, respectively) was induced by MDM stimulation with the opposite cytokines, although it also persisted in cells according to their first stimulatory condition. Thus, stimulation of monocytes with M1- and M2-inducing cytokines leads to a restriction of HIV-1 replication when these cells are infected several days later as differentiated MDMs. These observations imply that activation of circulating monocytes significantly influences their capacity to either support or restrict HIV-1 replication, once extravasated, and eventually to become infected as tissue macrophages. © Society for Leukocyte Biology.

  12. Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications.

    Science.gov (United States)

    Rogenhofer, Nina; Nienaber, Lara R M; Amshoff, Lea C; Bogdanova, Nadia; Petroff, David; Wieacker, Peter; Thaler, Christian J; Markoff, Arseni

    2018-01-01

    The aim of this study was to confirm the associated M2/ANXA5 carrier risk in women with placenta-mediated pregnancy complications (PMPC) and to test their male partners for such association. Further analysis evaluated the influence of maternal vs. paternal M2 alleles on miscarriage. Two hundred eighty-eight couples with preeclampsia (PE), intrauterine growth restriction (IUGR), or premature birth (PB) were recruited (n = 96 of each phenotype). The prevalence of the M2 haplotype was compared to two control cohorts. They included a group of women with a history of normal pregnancy without gestational pathology (Munich controls, n = 94) and a random population sample (PopGen controls, n = 533). Significant association of M2 haplotype and pregnancy complications was confirmed for women and for couples, where prevalence was elevated from 15.4 to 23.8% (p pregnancy complication. M2/ANXA5 appears to be a risk factor for adverse pregnancy outcomes related, but not limited to miscarriages, with similar prevalence in women and their male partners. These findings support the proposed physiological function of ANXA5 as an embryonic anticoagulant that appears deficient in contiguous specter of thrombophilia-related pregnancy complications culminating more frequently in miscarriage in a maternal M2 carrier background.

  13. Effect of M1–M2 Polarization on the Motility and Traction Stresses of Primary Human Macrophages

    Science.gov (United States)

    Hind, Laurel E.; Lurier, Emily B.; Dembo, Micah; Spiller, Kara L.; Hammer, Daniel A.

    2016-01-01

    Macrophages become polarized by cues in their environment and this polarization causes a functional change in their behavior. Two main subsets of polarized macrophages have been described. M1, or “classically activated” macrophages, are pro-inflammatory and M2, or “alternatively activated” macrophages, are anti-inflammatory. In this study, we investigated the motility and force generation of primary human macrophages polarized down the M1 and M2 pathways using chemokinesis assays and traction force microscopy on polyacrylamide gels. We found that M1 macrophages are significantly less motile and M2 macrophages are significantly more motile than unactivated M0 macrophages. We also showed that M1 macrophages generate significantly less force than M0 or M2 macrophages. We further found that M0 and M2, but not M1, macrophage force generation is dependent on ROCK signaling, as identified using the chemical inhibitor Y27632. Finally, using the chemical inhibitor blebbistatin, we found that myosin contraction is required for force generation by M0, M1, and M2 macrophages. This study represents the first investigation of the changes in the mechanical motility mechanisms used by macrophages after polarization. PMID:28458726

  14. Effect of M1-M2 Polarization on the Motility and Traction Stresses of Primary Human Macrophages.

    Science.gov (United States)

    Hind, Laurel E; Lurier, Emily B; Dembo, Micah; Spiller, Kara L; Hammer, Daniel A

    2016-09-01

    Macrophages become polarized by cues in their environment and this polarization causes a functional change in their behavior. Two main subsets of polarized macrophages have been described. M1, or "classically activated" macrophages, are pro-inflammatory and M2, or "alternatively activated" macrophages, are anti-inflammatory. In this study, we investigated the motility and force generation of primary human macrophages polarized down the M1 and M2 pathways using chemokinesis assays and traction force microscopy on polyacrylamide gels. We found that M1 macrophages are significantly less motile and M2 macrophages are significantly more motile than unactivated M0 macrophages. We also showed that M1 macrophages generate significantly less force than M0 or M2 macrophages. We further found that M0 and M2, but not M1, macrophage force generation is dependent on ROCK signaling, as identified using the chemical inhibitor Y27632. Finally, using the chemical inhibitor blebbistatin, we found that myosin contraction is required for force generation by M0, M1, and M2 macrophages. This study represents the first investigation of the changes in the mechanical motility mechanisms used by macrophages after polarization.

  15. Chemoradiotherapy with weekly cisplatin 40 mg/m2 in 103 head-and-neck cancer patients. A cumulative dose-effect analysis

    International Nuclear Information System (INIS)

    Bremer, Michael; Steinmann, Diana; Cerny, Bettina; Karstens, Johann Hinrich

    2009-01-01

    Background and purpose: in patients with head-and-neck cancer treated with chemoradiotherapy (CRT), a cisplatin-based regimen is often used. Several treatment schedules are accepted with a cumulative cisplatin dose of 200 mg/m 2 (CisCD200) given during radiotherapy. The aim of this analysis was to investigate feasibility and efficacy of a weekly cisplatin 40 mg/m 2 regimen. Patients and methods: during 08/2001 and 12/2006, 103 patients with squamous head-and-neck cancer received concurrent CRT with intended weekly cisplatin 40 mg/m 2 and were analyzed retrospectively. CRT was definitive for a newly diagnosed primary in 62, postoperative in 16, and for recurrence in 25 patients. Most patients had carcinoma of the hypo- and oropharynx (81%). Patients received a median total dose of 70 Gy (range, 42-71.2 Gy). Results: only 42 patients (41%) received a CisCD200 predominantly due to hematotoxicity. Actuarial 12- and 18-month overall survival (OS) for patients with and without CisCD200 was 83.3% versus 72.1% (p = 0.19) and 66.7% versus 67.2% (p = 0.86), the 12- and 18-month locoregional control (LRC) 66.7% versus 78.7% (p = 0.325) and 59.5% versus 78.7% (p = 0.109), respectively. Multivariate analysis revealed only type of CRT (definitive vs. recurrent) and T-classification as significant variables predicting OS and LRC. Conclusion: feasibility and efficacy of CRT with weekly cisplatin 40 mg/m 2 were suboptimal in this analysis. However, the prospects of weekly cisplatin may be its more suitable integration into emerging trimodality concepts combining CRT with molecularly targeted agents. (orig.)

  16. Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2+γδ T cell cytotoxicity in a perforin-dependent manner.

    Science.gov (United States)

    Fowler, Daniel W; Copier, John; Dalgleish, Angus G; Bodman-Smith, Mark D

    2017-09-01

    Vδ2 + T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2 + T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2 + T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C-C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2 + T cell cytotoxicity. Vδ2 + T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive-at least in part-to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2 + T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy.

  17. Research Pilot Milt Thompson in M2-F2 Aircraft Attached to B-52 Mothership

    Science.gov (United States)

    1966-01-01

    NASA research pilot Milt Thompson sits in the M2-F2 'heavyweight' lifting body research vehicle before a 1966 test flight. The M2-F2 and the other lifting-body designs were all attached to a wing pylon on NASA's B-52 mothership and carried aloft. The vehicles were then drop-launched and, at the end of their flights, glided back to wheeled landings on the dry lake or runway at Edwards AFB. The lifting body designs influenced the design of the Space Shuttle and were also reincarnated in the design of the X-38 in the 1990s. NASA B-52, Tail Number 008, is an air launch carrier aircraft, 'mothership,' as well as a research aircraft platform that has been used on a variety of research projects. The aircraft, a 'B' model built in 1952 and first flown on June 11, 1955, is the oldest B-52 in flying status and has been used on some of the most significant research projects in aerospace history. Some of the significant projects supported by B-52 008 include the X-15, the lifting bodies, HiMAT (highly maneuverable aircraft technology), Pegasus, validation of parachute systems developed for the space shuttle program (solid-rocket-booster recovery system and the orbiter drag chute system), and the X-38. The B-52 served as the launch vehicle on 106 X-15 flights and flew a total of 159 captive-carry and launch missions in support of that program from June 1959 to October 1968. Information gained from the highly successful X-15 program contributed to the Mercury, Gemini, and Apollo human spaceflight programs as well as space shuttle development. Between 1966 and 1975, the B-52 served as the launch aircraft for 127 of the 144 wingless lifting body flights. In the 1970s and 1980s, the B-52 was the launch aircraft for several aircraft at what is now the Dryden Flight Research Center, Edwards, California, to study spin-stall, high-angle-of attack, and maneuvering characteristics. These included the 3/8-scale F-15/spin research vehicle (SRV), the HiMAT (Highly Maneuverable Aircraft

  18. Latency Analysis of Systems with Multiple Interfaces for Ultra-Reliable M2M Communication

    DEFF Research Database (Denmark)

    Nielsen, Jimmy Jessen; Popovski, Petar

    2016-01-01

    One of the ways to satisfy the requirements of ultra-reliable low latency communication for mission critical Machine-type Communications (MTC) applications is to integrate multiple communication interfaces. In order to estimate the performance in terms of latency and reliability of such an integr......One of the ways to satisfy the requirements of ultra-reliable low latency communication for mission critical Machine-type Communications (MTC) applications is to integrate multiple communication interfaces. In order to estimate the performance in terms of latency and reliability...... of such an integrated communication system, we propose an analysis framework that combines traditional reliability models with technology-specific latency probability distributions. In our proposed model we demonstrate how failure correlation between technologies can be taken into account. We show for the considered...

  19. Carbon and nitrogen abundances of stellar populations in the globular cluster M 2

    Science.gov (United States)

    Lardo, C.; Pancino, E.; Mucciarelli, A.; Milone, A. P.

    2012-12-01

    We present CH and CN index analysis and C and N abundance calculations based on the low-resolution blue spectra of red giant branch (RGB) stars in the Galactic globular cluster NGC 7089 (M 2). Our main goal is to investigate the C-N anticorrelation for this intermediate metallicity cluster. The data were collected with DOLORES, the multiobject, low-resolution facility at the Telescopio Nazionale Galileo. We first looked for CH and CN band strength variations and bimodalities in a sample of RGB stars with 17.5 ≤ V ≤ 14.5. Thus we derived C and N abundances under LTE assumption by comparing observed spectra with synthetic models from the spectral features at 4300 Å (G-band) and at ~3883 Å (CN). Spectroscopic data were coupled with UV photometry obtained during the spectroscopic run. We found a considerable star-to-star variation in both A(C) and A(N) at all luminosities for our sample of 35 targets. These abundances appear to be anticorrelated, with a hint of bimodality in the C content for stars with luminosities below the RBG bump (V ~ 15.7), while the range of variations in N abundances is very large and spans almost ~2 dex. We find additional C depletion as the stars evolve off the RGB bump, in fairly good agreement with theoretical predictions for metal-poor stars in the course of normal stellar evolution. We isolated two groups with N-rich and N-poor stars and found that N abundance variations correlate with the (U - V) color in the DOLORES color-magnitude diagram (CMD). The V, (U - V) CMD for this cluster shows an additional RGB sequence, located at the red of the main RGB and amounting to a small fraction of the total giant population. We identified two CH stars detected in previous studies in our U,V images. These stars, which are both cluster members, fall on this redder sequence, suggesting that the anomalous RGB should have a peculiar chemical pattern. Unfortunately, no additional spectra were obtained for stars in this previously unknown RGB branch

  20. Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay.

    Directory of Open Access Journals (Sweden)

    Aruna D Balgi

    Full Text Available The M2 proton channel of the influenza A virus is the target of the anti-influenza drugs amantadine and rimantadine. The effectiveness of these drugs has been dramatically limited by the rapid spread of drug resistant mutations, mainly at sites S31N, V27A and L26F in the pore of the channel. Despite progress in designing inhibitors of V27A and L26F M2, there are currently no drugs targeting these mutated channels in clinical trials. Progress in developing new drugs has been hampered by the lack of a robust assay with sufficient throughput for discovery of new active chemotypes among chemical libraries and sufficient sensitivity to provide the SAR data essential for their improvement and development as drugs. In this study we adapted a yeast growth restoration assay, in which expression of the M2 channel inhibits yeast growth and exposure to an M2 channel inhibitor restores growth, into a robust and sensitive high-throughput screen for M2 channel inhibitors. A screen of over 250,000 pure chemicals and semi-purified fractions from natural extracts identified 21 active compounds comprising amantadine, rimantadine, 13 related adamantanes and 6 non-adamantanes. Of the non-adamantanes, hexamethylene amiloride and a triazine derivative represented new M2 inhibitory chemotypes that also showed antiviral activity in a plaque reduction assay. Of particular interest is the fact that the triazine derivative was not sufficiently potent for detection as an inhibitor in the traditional two electrode voltage clamp assay for M2 channel activity, but its discovery in the yeast assay led to testing of analogues of which one was as potent as amantadine.

  1. Sequence analysis and expression of the M1 and M2 matrix protein genes of hirame rhabdovirus (HIRRV)

    Science.gov (United States)

    Nishizawa, T.; Kurath, G.; Winton, J.R.

    1997-01-01

    We have cloned and sequenced a 2318 nucleotide region of the genomic RNA of hirame rhabdovirus (HIRRV), an important viral pathogen of Japanese flounder Paralichthys olivaceus. This region comprises approximately two-thirds of the 3' end of the nucleocapsid protein (N) gene and the complete matrix protein (M1 and M2) genes with the associated intergenic regions. The partial N gene sequence was 812 nucleotides in length with an open reading frame (ORF) that encoded the carboxyl-terminal 250 amino acids of the N protein. The M1 and M2 genes were 771 and 700 nucleotides in length, respectively, with ORFs encoding proteins of 227 and 193 amino acids. The M1 gene sequence contained an additional small ORF that could encode a highly basic, arginine-rich protein of 25 amino acids. Comparisons of the N, M1, and M2 gene sequences of HIRRV with the corresponding sequences of the fish rhabdoviruses, infectious hematopoietic necrosis virus (IHNV) or viral hemorrhagic septicemia virus (VHSV) indicated that HIRRV was more closely related to IHNV than to VHSV, but was clearly distinct from either. The putative consensus gene termination sequence for IHNV and VHSV, AGAYAG(A)(7), was present in the N-M1, M1-M2, and M2-G intergenic regions of HIRRV as were the putative transcription initiation sequences YGGCAC and AACA. An Escherichia coli expression system was used to produce recombinant proteins from the M1 and M2 genes of HIRRV. These were the same size as the authentic M1 and M2 proteins and reacted with anti-HIRRV rabbit serum in western blots. These reagents can be used for further study of the fish immune response and to test novel control methods.

  2. Benznidazole Therapy Modulates Interferon-γ and M2 Muscarinic Receptor Autoantibody Responses in Trypanosoma cruzi-Infected Children

    Science.gov (United States)

    Cutrullis, Romina A.; Moscatelli, Guillermo F.; Moroni, Samanta; Volta, Bibiana J.; Cardoni, Rita L.; Altcheh, Jaime M.; Corral, Ricardo S.; Freilij, Héctor L.; Petray, Patricia B.

    2011-01-01

    Objective The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs) as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benznidazole (BZ) could modify both response patterns. Methods This study comprised 30 T. cruzi-infected children (mean age: 13.8 years) and 19 uninfected controls (mean age: 12.7 years). Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. Results At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs+ patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7–88.1% decrease at T2. IFN-γ circulating levels also declined by T2. Conclusion Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses. PMID:22066031

  3. Benzonidazole therapy modulates interferon-γ and M2 muscarinic receptor autoantibody responses in Trypanosoma cruzi-infected children.

    Directory of Open Access Journals (Sweden)

    Romina A Cutrullis

    Full Text Available OBJECTIVE: The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benzonidazole (BZ could modify both response patterns. METHODS: This study comprised 30 T. cruzi-infected children (mean age: 13.8 years and 19 uninfected controls (mean age: 12.7 years. Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. RESULTS: At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs(+ patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7-88.1% decrease at T2. IFN-γ circulating levels also declined by T2. CONCLUSION: Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses.

  4. Chronic experimental autoimmune encephalomyelitis in the guinea pig. Presence of anti-M2 antibodies in central nervous system tissue and the possible role of M2 autoantigen in the induction of the disease.

    Science.gov (United States)

    Lebar, R; Baudrimont, M; Vincent, C

    1989-04-01

    Experimental autoimmune encephalomyelitis (EAE) can be transferred adoptively with T cells sensitized to the basic protein of myelin (BP). However, in the guinea pig, the chronic form of EAE has not been found to be inducible with BP alone, nor has it been adoptively transferred. An antibody response to the central nervous system (CNS) myelin autoantigens was looked for in serum and target CNS tissue in S13 guinea pigs with isologous CNS tissue-induced chronic EAE. Antibody activity was estimated by an immunoenzymatic technique and by autoradiography, using immunoprecipitated and electrophoresed relevant radiolabelled antigens. In serum, IgG antibody response to BP and M2 reached its maximum level 30 to 40 d after immunization and then declined progressively until it became undetectable. On the other hand, while anti-BP antibodies were seldom detected in CNS tissue acid extract, anti-M2 IgG antibodies were always present in CNS tissue of chronic EAE animals, and the amount of these antibodies were related to the severity of symptoms and lesions. No antibody response to proteolipid or to galactocerebroside was detected in serum or CNS tissue. BP-immunized controls showed no chronic EAE and no response to M2 in their serum or CNS tissue. Inasmuch as M2 has been shown to be a glycoprotein of CNS myelin, and anti-M2 antibodies to have a demyelinating property, the latter would be responsible for CNS tissue demyelination in chronic EAE. A shared role of BP and M2 in the induction of chronic EAE in the guinea pig is suggested.

  5. Amplification of the rat m2 muscarinic receptor gene by the polymerase chain reaction: Functional expression of the M sub 2 muscarinic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lai, J.; Bloom, J.W.; Yamamura, H.I.; Roeske, W.R. (Univ. of Arizona Health Sciences Center, Tucson (USA))

    1990-01-01

    A selective amplification of the coding sequence of the rat M{sub 2} muscarinic receptor gene was achieved by the polymerase chain reaction. The error rate of this amplification system under conditions specified was 1 nucleotide substitution in 841 base pairs. In vitro expression of this gene in murine fibroblasts (B82) via the eukaryotic expression vector, pH{beta}APr-1-neo, resulted in high level expression of specific ({sup 3}H)(-)MQNB binding in transfected B82 cell lines. One of these clones, M2LKB2-2, showed a stable expression of ({sup 3}H)(-)MQNB binding with a K{sub d} value of 265 pM and a B{sub max} value of 411{plus minus}50 fmol/10{sup 6} cells. Cardiac selective muscarinic antagonists such as himbacine and AF-DX 116 show high affinities for this binding site in the M2LKB2-2 cells. The rank order of potency of several antagonists in inhibiting ({sup 3}H)(-)MQNB binding in these cells conformed to the characteristics of an M{sub 2} type muscarinic receptor. Carbachol showed a single affinity state for the receptors in the M2LKB2-2 cells with a K{sub i} value of 2.0 {mu}M. This receptor appeared to be inversely coupled to adenylate cyclase via a pertussis toxin sensitive G-protein. Carbachol also had a slight stimulatory effect on the hydrolysis of inositol lipids. The polymerase chain reaction proves highly effective in cloning genes from genomic material, as demonstrated by the first in vitro functional expression of the rat M{sub 2} type muscarinic receptor.

  6. Role of Microglial M1/M2 Polarization in Relapse and Remission of Psychiatric Disorders and Diseases

    Directory of Open Access Journals (Sweden)

    Yutaka Nakagawa

    2014-11-01

    Full Text Available Psychiatric disorders such as schizophrenia and major depressive disorder were thought to be caused by neurotransmitter abnormalities. Patients with these disorders often experience relapse and remission; however the underlying molecular mechanisms of relapse and remission still remain unclear. Recent advanced immunological analyses have revealed that M1/M2 polarization of macrophages plays an important role in controlling the balance between promotion and suppression in inflammation. Microglial cells share certain characteristics with macrophages and contribute to immune-surveillance in the central nervous system (CNS. In this review, we summarize immunoregulatory functions of microglia and discuss a possible role of microglial M1/M2 polarization in relapse and remission of psychiatric disorders and diseases. M1 polarized microglia can produce pro-inflammatory cytokines, reactive oxygen species, and nitric oxide, suggesting that these molecules contribute to dysfunction of neural network in the CNS. Alternatively, M2 polarized microglia express cytokines and receptors that are implicated in inhibiting inflammation and restoring homeostasis. Based on these aspects, we propose a possibility that M1 and M2 microglia are related to relapse and remission, respectively in psychiatric disorders and diseases. Consequently, a target molecule skewing M2 polarization of microglia may provide beneficial therapies for these disorders and diseases in the CNS.

  7. Avian metapneumovirus M2:2 protein inhibits replication in Vero cells: modification facilitates live vaccine development.

    Science.gov (United States)

    Clubbe, Jayne; Naylor, Clive J

    2011-11-28

    Throughout the world, avian metapneumovirus (AMPV) infection of subtype A is principally controlled by two live vaccines both derived from UK field strain #8544. Improvements of those vaccines by use of reverse genetics technology was found to be hampered by the inability of #8544 to replicate in the commonly exploited Vero cell based reverse genetics system. A systematic reverse genetics based genome modification of a DNA copy of #8544, employing sequence data from a Vero grown, #8544 derived, live vaccine; was used to determine mutations required to facilitate virus recovery and replication in Vero cells. This identified a single coding substitution in the M2:2 reading frame as responsible. Furthermore, ablation of M2:2 was found to elicit the same outcome. M2:2 sequence analysis of seven AMPVs found Vero cell adaption to be associated with non similar amino acid changes in M2:2. The study shows that M2:2 modification of field virus #8544 will enable research leading to improved vaccines. This may have more general application to other AMPV field strains. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Macrophages Undergo M1-to-M2 Transition in Adipose Tissue Regeneration in a Rat Tissue Engineering Model.

    Science.gov (United States)

    Li, Zhijin; Xu, Fangfang; Wang, Zhifa; Dai, Taiqiang; Ma, Chao; Liu, Bin; Liu, Yanpu

    2016-10-01

    Macrophages are involved in the full processes of tissue healing or regeneration and play an important role in the regeneration of a variety of tissues. Although recent evidence suggests the role of different macrophage phenotypes in adipose tissue expansion, metabolism, and remodeling, the spectrum of macrophage phenotype in the adipose tissue engineering field remains unknown. The present study established a rat model of adipose tissue regeneration using a tissue engineering chamber. Macrophage phenotypes were assessed during the regenerative process in the model. Neo-adipose tissue was generated 6 weeks after implantation. Macrophages were obvious in the chamber constructs 3 days after implantation, peaked at day 7, and significantly decreased thereafter. At day 3, macrophages were predominantly M1 macrophages (CCR7+), and there were few M2 macrophages (CD206+). At day 7, the percentage of M2 macrophages significantly increased and remained stable at day 14. M2 macrophages became the predominant macrophage population at 42 days. Enzyme-linked immunosorbent assay demonstrated transition of cytokines from pro-inflammatory to anti-inflammatory, which was consistent with the transition of macrophage phenotype from M1 to M2. These results showed distinct transition of macrophage phenotypes from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 in adipose tissue regeneration in our tissue engineering model. This study provides new insight into macrophage phenotype transition in the regeneration of adipose tissue. © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  9. Chemical obtaining of LiMO2 and LiM2O4 (M=Co, Mn) oxides, for cathodic applications in Li-ion batteries

    Science.gov (United States)

    Y Neira-Guio, A.; Gómez Cuaspud, J. A.; López, E. Vera; Pineda Triana, Y.

    2017-12-01

    This paper describes the synthesis and characterization of two spinel and olivine-type multicomponent oxides based on LiMO2 and LiM2O4 systems (M=Co and Mn), which represent the current state of the art in the development of cathodes for Li-ion batteries. A simple combustion synthesis process was employed to obtain the nanometric oxides in powder form (crystal sizes around 5-8nm), with a number of improved surface characteristics. The characterization by X-Ray Diffraction (XRD), Scanning and Transmission Electron Microscopy (SEM, TEM) and X-Ray Fluorescence (XRF), allowed to evaluate the morphology and the stoichiometric compositions of solids, obtaining a concordant pure crystalline phase of LiCoO2 and LiMn2O4 oxides identified in a rhombohedral and cubic phase with punctual group R-3m (1 6 6) and Fm-3m (2 2 5) respectively. The electrical characterization of materials developed by impedance spectroscopy solid state, allowed to determine a p-type semiconducting behaviour with conductivity values of 6.2×10-3 and 2.7×10-7 S for LiCoO2 and LiMn2O4 systems, consistent with the state of the art for such materials.

  10. Simulation and experiment studies of aberration effects on the measurement of laser beam quality factor (M2)

    Science.gov (United States)

    Meng, Lingqiang; Huang, Zheqiang; Han, Zhigang; Shen, Hua; Zhu, Rihong

    2018-01-01

    In the measurement system of beam quality factor, M2, wave-front and intensity aberrations caused by optical elements, thermal effects, residual pump light, etc., influence the measurement results. The influence was analyzed using the angular spectrum and the finite element methods. Simulation of the impact of different aberrations, thermal effects and residual pump light on the measurement of the M2 is provided. The M2 of a high-power fiber laser is measured by a beam quality analyzer when the laser transmits through a high absorption red glass with different output power. The results from the experiment and the simulation have good consistency. The simulation and experiment results can be applied for the designs of high-power laser, laser beam quality measurement, and laser-launching systems.

  11. Selective-field-ionization dynamics of a lithium m=2 Rydberg state: Landau-Zener model versus quantal approach

    International Nuclear Information System (INIS)

    Foerre, M.; Hansen, J.P.

    2003-01-01

    The selective-field-ionization (SFI) dynamics of a Rydberg state of lithium with magnetic quantum number m=2 is studied in detail based on two different theoretical models: (1) a close coupling integration of the Schroedinger equation and (2) the multichannel (incoherent) Landau-Zener (MLZ) model. The m=2 states are particularly interesting, since they define a border zone between fully adiabatic (m=0,1) and fully diabatic (m>2) ionization dynamics. Both sets of calculations are performed up to, and above, the classical ionization limit. It is found that the MLZ model is excellent in the description of the fully diabatic dynamics while certain discrepancies between the time dependent quantal amplitudes appear when the dynamics become involved. Thus, in this region, the analysis of experimental SFI spectra should be performed with care

  12. Wireless Device-to-Device (D2D) Links for Machine-to-Machine (M2M) Communication

    DEFF Research Database (Denmark)

    Pratas, Nuno; Popovski, Petar

    2017-01-01

    Device-to-Device (D2D) communications will play an important role in the fifth generation (5G) cellular networks, by increasing the spatial reuse of spectrum resources and enabling communication links with low latency. D2D is composed of two fundamental building blocks: proximity discovery...... and direct communication between nearby users. Another emerging trend in wireless cellular systems is Machine-to-Machine (M2M) communications, often characterized by fixed, low transmission rates. In this chapter we motivate the synergy between D2D and M2M, and present technologies that enable M2M-via-D2D...... communication to operate as an underlay to the ordinary cellular transmissions....

  13. The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage

    Directory of Open Access Journals (Sweden)

    Kotal M

    2008-08-01

    Full Text Available Abstract Background The "out of Africa" model postulating single "southern route" dispersal posits arrival of "Anatomically Modern Human" to Indian subcontinent around 66–70 thousand years before present (kyBP. However the contributions and legacy of these earliest settlers in contemporary Indian populations, owing to the complex past population dynamics and later migrations has been an issue of controversy. The high frequency of mitochondrial lineage "M2" consistent with its greater age and distribution suggests that it may represent the phylogenetic signature of earliest settlers. Accordingly, we attempted to re-evaluate the impact and contribution of earliest settlers in shaping the genetic diversity and structure of contemporary Indian populations; using our newly sequenced 72 and 4 published complete mitochondrial genomes of this lineage. Results The M2 lineage, harbouring two deep rooting subclades M2a and M2b encompasses approximately one tenth of the mtDNA pool of studied tribes. The phylogeographic spread and diversity indices of M2 and its subclades among the tribes of different geographic regions and linguistic phyla were investigated in detail. Further the reconstructed demographic history of M2 lineage as a surrogate of earliest settlers' component revealed that the demographic events with pronounced regional variations had played pivotal role in shaping the complex net of populations phylogenetic relationship in Indian subcontinent. Conclusion Our results suggest that tribes of southern and eastern region along with Dravidian and Austro-Asiatic speakers of central India are the modern representatives of earliest settlers of subcontinent. The Last Glacial Maximum aridity and post LGM population growth mechanised some sort of homogeneity and redistribution of earliest settlers' component in India. The demic diffusion of agriculture and associated technologies around 3 kyBP, which might have marginalized hunter-gatherer, is

  14. Annexin A5 Promoter Haplotype M2 Is Not a Risk Factor for Recurrent Pregnancy Loss in Northern Europe

    DEFF Research Database (Denmark)

    Nagirnaja, Liina; Nõmmemees, Diana; Rull, Kristiina

    2015-01-01

    and recurrent pregnancy loss (RPL), however with inconclusive results. STUDY SUBJECTS AND METHODS: A retrospective case-control study combining resequencing and restriction fragment length polymorphism (RFLP) analysis was undertaken in 313 women with unexplained RPL and 214 fertile women from Estonia...... compared to controls both in Estonia (8.1% vs 15.2%, respectively) and Denmark (9.7% vs 12.6%). The high M2 prevalence in fertile controls was consistent with estimations for European and East Asian populations (9.6%-16.0%). CONCLUSIONS: This study cautions to consider the M2 haplotype as a deterministic...

  15. Generation of New M2e-HA2 Fusion Chimeric Peptide to Development of a Recombinant Fusion Protein Vaccine

    OpenAIRE

    Ameghi, Ali; Baradaran, Behzad; Aghaiypour, Khosrow; Barzegar, Abolfazl; Pilehvar-Soltanahmadi, Yones; Moghadampour, Masood; Taghizadeh, Morteza; Zarghami, Nosratollah

    2015-01-01

    Purpose: The purpose was to design a new construction containing influenza virus (H1N1) M2e gene and HA2 gene by bioinformatics approach, cloning the construct in to Escherichia coli and produce M2e-HA2 peptide. Methods: The procedure was done by virus cultivation in SPF eggs, hemagglutination assay (HA), RNA isolation, RT-PCR, primers designed (DNAMAN 4 and Oligo7), virtual fusion construction translation (ExPASy), N-Glycosylated sites prediction (Ensemblegly-Iowa), c...

  16. M2-Polarized Macrophages Compose Lupus Vulgaris Arising from a Bacillus Calmette-Guérin Vaccination Site

    Directory of Open Access Journals (Sweden)

    Yota Sato

    2016-07-01

    Full Text Available Since bacillus Calmette-Guérin (BCG is an attenuated strain of Mycobacterium bovis, lupus vulgaris (LV is reported as one of the rare complications after BCG vaccination, correlating with immunosuppression in the lesional skin. In this report, we describe a case of LV arising from the BCG vaccination site 22 years after vaccination. Interestingly, in the present case, granuloma cells were composed of M2-polarized macrophages. Our case might explain the contribution of M2-polarized macrophages to the biology of LV arising from a BCG vaccination site.

  17. M2-Polarized Macrophages Compose Lupus Vulgaris Arising from a Bacillus Calmette-Guérin Vaccination Site.

    Science.gov (United States)

    Sato, Yota; Fujimura, Taku; Furudate, Sadanori; Kakizaki, Aya; Iizawa, Osamu; Aiba, Setsuya

    2016-01-01

    Since bacillus Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis , lupus vulgaris (LV) is reported as one of the rare complications after BCG vaccination, correlating with immunosuppression in the lesional skin. In this report, we describe a case of LV arising from the BCG vaccination site 22 years after vaccination. Interestingly, in the present case, granuloma cells were composed of M2-polarized macrophages. Our case might explain the contribution of M2-polarized macrophages to the biology of LV arising from a BCG vaccination site.

  18. Substitution of the transmembrane domain of Vpu in simian-human immunodeficiency virus (SHIVKU1bMC33) with that of M2 of influenza A results in a virus that is sensitive to inhibitors of the M2 ion channel and is pathogenic for pig-tailed macaques

    International Nuclear Information System (INIS)

    Hout, David R.; Gomez, Melissa L.; Pacyniak, Erik; Gomez, Lisa M.; Fegley, Barbara; Mulcahy, Ellyn R.; Hill, M. Sarah; Culley, Nathan; Pinson, David M.; Nothnick, Warren; Powers, Michael F.; Wong, Scott W.; Stephens, Edward B.

    2006-01-01

    The Vpu protein of human immunodeficiency virus type 1 has been shown to shunt the CD4 receptor molecule to the proteasome for degradation and to enhance virus release from infected cells. The exact mechanism by which the Vpu protein enhances virus release is currently unknown but some investigators have shown that this function is associated with the transmembrane domain and potential ion channel properties. In this study, we determined if the transmembrane domain of Vpu could be functionally substituted with that of the prototypical viroporin, the M2 protein of influenza A virus. We constructed chimeric vpu gene in which the transmembrane domain of Vpu was replaced with that of the M2 protein of influenza. This chimeric vpu gene was substituted for the vpu gene in the genome of a pathogenic simian human immunodeficiency virus, SHIV KU-1bMC33 . The resulting virus, SHIV M2 , synthesized a Vpu protein that had a slightly different M r compared to the parental SHIV KU-1bMC33 , reflecting the different sizes of the two Vpu proteins. The SHIV M2 was shown to replicate with slightly reduced kinetics when compared to the parental SHIV KU-1bMC33 but electron microscopy revealed that the site of maturation was similar to the parental virus SHIV KU1bMC33 . We show that the replication and spread of SHIV M2 could be blocked with the antiviral drug rimantadine, which is known to target the M2 ion channel. Our results indicate a dose dependent inhibition of SHIV M2 with 100 μM rimantadine resulting in a >95% decrease in p27 released into the culture medium. Rimantadine did not affect the replication of the parental SHIV KU-1bMC33 . Examination of SHIV M2 -infected cells treated with 50 μM rimantadine revealed numerous viral particles associated with the cell plasma membrane and within intracytoplasmic vesicles, which is similar to HIV-1 mutants lacking a functional vpu. To determine if SHIV M2 was as pathogenic as the parental SHIV KU-1bMC33 virus, two pig-tailed macaques

  19. Multimeric recombinant M2e protein-based ELISA: a significant improvement in differentiating avian influenza infected chickens from vaccinated ones.

    Directory of Open Access Journals (Sweden)

    Farshid Hadifar

    Full Text Available Killed avian influenza virus (AIV vaccines have been used to control H5N1 infections in countries where the virus is endemic. Distinguishing vaccinated from naturally infected birds (DIVA in such situations however, has become a major challenge. Recently, we introduced the recombinant ectodomain of the M2 protein (M2e of H5N1 subtype as a novel tool for an ELISA based DIVA test. Despite being antigenic in natural infection the monomer form of the M2e used in ELISA had limited antigenicity and consequently poor diagnostic capability. To address this shortcoming, we evaluated the use of four tandem copies of M2e (tM2e for increased efficiency of M2e antibody detection. The tM2e gene of H5N1 strain from Indonesia (A/Indonesia/CDC540/2006 was cloned into a pMAL- p4x expression vector and expressed in E.coli as a recombinant tM2e-MBP or M2e-MBP proteins. Both of these, M2e and tM2e antigens reacted with sera obtained from chickens following live H5N1 infection but not with sera from vaccinated birds. A significantly stronger M2e antibody reaction was observed with the tM2e compared to M2e antigen. Western blotting also supported the superiority of tM2e over M2e in detection of specific M2e antibodies against live H5N1 infection. Results from this study demonstrate that M2e tetramer is a better antigen than single M2e and could be more suitable for an ELISA based DIVA test.

  20. Emerging roles of the ribonucleotide reductase M2 in colorectal cancer and ultraviolet-induced DNA damage repair.

    Science.gov (United States)

    Lu, Ai-Guo; Feng, Hao; Wang, Pu-Xiong-Zhi; Han, Ding-Pei; Chen, Xue-Hua; Zheng, Min-Hua

    2012-09-14

    To investigate the roles of the ribonucleotide reductase M2 (RRM2) subunit in colorectal cancer (CRC) and ultraviolet (UV)-induced DNA damage repair. Immunohistochemical staining of tissue microarray was performed to detect the expression of RRM2. Seven CRC cell lines were cultured and three human colon cancer cell lines, i.e., HCT116, SW480 and SW620, were used. Reverse transcription polymerase chain reaction and Western blotting were performed to determine the mRNA and protein expression levels of RRM2, respectively. Cell proliferation assay, cell cycle analysis were performed. Cell apoptosis was evaluated by double staining with fluorescein isothiocyanate-conjugated Annexin V and propidium iodide (PI) using Annexin V/PI apoptosis kit. The motility and invasion of CRC cells were assessed by the Transwell chamber assay. Cells were irradiated with a 254 nm UV-C lamp to detect the UV sensitivity after RRM2 depletion. Immunohistochemical staining revealed elevated RRM2 levels in CRC tissues. RRM2 overexpression was positively correlated with invasion depth (P < 0.05), poorly differentiated type (P = 0.0051), and tumor node metastasis stage (P = 0.0015). The expression of RRM2 in HCT116 cells was downregulated after transfection, and HCT116 cell proliferation was obviously suppressed compared to control groups (P < 0.05). In the invasion test, the number of cells that passed through the chambers in the RRM2-siRNA group was 81 ± 3, which was lower than that in the negative control (289 ± 7) and blank control groups (301 ± 7.2). These differences were statistically significant (P < 0.01). Our data suggest that RRM2 overexpression may be associated with CRC progression. RRM2 silencing by siRNA may inhibit the hyperplasia and invasiveness of CRC cells, suggesting that RRM2 may play an important role in the infiltration and metastasis of CRC, which is a potential therapeutic strategy in CRC. In addition, RRM2 depletion increased UV sensitivity. These findings suggest

  1. Simulations of the Pore Structures for a M2GlyR Derived Channel Forming Peptide in Different Membrane Environments

    Science.gov (United States)

    Al-Rawi, A.; Herrera, A.; Tomich, J.; Rahman, T.

    2007-03-01

    As part of an effort to develop a peptide-based compound suitable for clinical use as a channel replacement therapeutic for treating channelopathies such as cystic fibrosis, we present a reductionist model that appears to grasp the characteristics of ion channeling peptides. In particular we present the observed changes in the functional characteristics of NK4-M2GlyR p22 (KKKKPARVGLGITTVLTMTTQS), a M2 GlyR derived channel forming peptide. Starting with a structure determined by multidimensional NMR (800 MHz) in SDS, a potential from CHARMM force-field was used to relax the structure of NK4-M2GlyR p22. Following the relaxation, numerous pore structures were generated for the symmetric five-helix assembly with geometries varying from cylindrical to conical. As it is difficult a priori to assign accurately the orientation of the hydrophilic portion of M2GlyR derived amphipath towards the inside of the pore, we tilted and rotated the helical structure by five different angles about the backbone axis before forming the pore. Energy minimization of the channel was performed in vacuum, in phosphotidylcholine (POPC) membrane, and 60% POPC 30% phosphotidylethanolamine (POPE) in order to determine the effect of the environment surrounding on the structure on its energy minimization. We will present the various pore assemblies, in the different membrane environments, used to predict the most probably membrane bound structure.

  2. Cardiosphere-Derived Cells Facilitate Heart Repair by Modulating M1/M2 Macrophage Polarization and Neutrophil Recruitment.

    Directory of Open Access Journals (Sweden)

    Al Shaimaa Hasan

    Full Text Available Cardiosphere-derived cells (CDCs, one of the promising stem cell sources for myocardial repair, have been tested in clinical trials and resulted in beneficial effects; however, the relevant mechanisms are not fully understood. In this study, we examined the hypothesis that CDCs favor heart repair by switching the macrophages from a pro-inflammatory phenotype (M1 into a regulatory anti-inflammatory phenotype (M2. Macrophages from mice were cultured with CDCs-conditioned medium or with fibroblasts-conditioned medium as a control. Immunostaining showed that CDCs-conditioned medium significantly enhanced the expression of CD206 (a marker for M2 macrophages, but decreased the expression of CD86 (a marker for M1 macrophages 3 days after culture. For animal studies, we used an acute myocardial infarction model of mice. We injected CDCs, fibroblasts, or saline only into the border zone of infarction. Then we collected the heart tissues for histological analysis 5 and 14 days after treatment. Compared with control animals, CDCs treatment significantly decreased M1 macrophages and neutrophils but increased M2 macrophages in the infarcted heart. Furthermore, CDCs-treated mice had reduced infarct size and fewer apoptotic cells compared to the controls. Our data suggest that CDCs facilitate heart repair by modulating M1/M2 macrophage polarization and neutrophil recruitment, which may provide a new insight into the mechanisms of stem cell-based myocardial repair.

  3. Microwave & Magnetic (M2) Proteomics Reveals CNS-Specific Protein Expression Waves that Precede Clinical Symptoms of Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Raphael, Itay; Mahesula, Swetha; Purkar, Anjali; Black, David; Catala, Alexis; Gelfond, Jonathon A. L.; Forsthuber, Thomas G.; Haskins, William E.

    2014-09-01

    Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave & magnetic (M2) proteomics of CSPs in brain tissue might be an effective means to prioritize putative CSP biomarkers for future immunoassays in serum. To test this hypothesis, we used M2 proteomics to longitudinally assess CSP expression in brain tissue from mice during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Confirmation of central nervous system (CNS)-infiltrating inflammatory cell response and CSP expression in serum was achieved with cytokine ELISPOT and ELISA immunoassays, respectively, for selected CSPs. M2 proteomics (and ELISA) revealed characteristic CSP expression waves, including synapsin-1 and α-II-spectrin, which peaked at day 7 in brain tissue (and serum) and preceded clinical EAE symptoms that began at day 10 and peaked at day 20. Moreover, M2 proteomics supports the concept that relatively few CNS-infiltrating inflammatory cells can have a disproportionally large impact on CSP expression prior to clinical manifestation of EAE.

  4. A Collaboration-Oriented M2M Messaging Mechanism for the Collaborative Automation between Machines in Future Industrial Networks.

    Science.gov (United States)

    Meng, Zhaozong; Wu, Zhipeng; Gray, John

    2017-11-22

    Machine-to-machine (M2M) communication is a key enabling technology for industrial internet of things (IIoT)-empowered industrial networks, where machines communicate with one another for collaborative automation and intelligent optimisation. This new industrial computing paradigm features high-quality connectivity, ubiquitous messaging, and interoperable interactions between machines. However, manufacturing IIoT applications have specificities that distinguish them from many other internet of things (IoT) scenarios in machine communications. By highlighting the key requirements and the major technical gaps of M2M in industrial applications, this article describes a collaboration-oriented M2M (CoM2M) messaging mechanism focusing on flexible connectivity and discovery, ubiquitous messaging, and semantic interoperability that are well suited for the production line-scale interoperability of manufacturing applications. The designs toward machine collaboration and data interoperability at both the communication and semantic level are presented. Then, the application scenarios of the presented methods are illustrated with a proof-of-concept implementation in the PicknPack food packaging line. Eventually, the advantages and some potential issues are discussed based on the PicknPack practice.

  5. Detection of Nuclear Protein Profile Changes by Human Metapneumovirus M2-2 Protein Using Quantitative Differential Proteomics

    Directory of Open Access Journals (Sweden)

    Yuping Ren

    2017-12-01

    Full Text Available Human metapneumovirus (hMPV is a leading cause of lower respiratory infection in pediatric populations globally. This study examined proteomic profile changes in A549 cells infected with hMPV and two attenuated mutants with deleted PDZ domain-binding motif(s in the M2-2 protein. These motifs are involved in the interruption of antiviral signaling, namely the interaction between the TNF receptor associated factor (TRAF and mitochondrial antiviral-signaling (MAVS proteins. The aim of this study was to provide insight into the overall and novel impact of M2-2 motifs on cellular responses via an unbiased comparison. Tandem mass tagging, stable isotope labeling, and high-resolution mass spectrometry were used for quantitative proteomic analysis. Using quantitative proteomics and Venn analysis, 1248 common proteins were detected in all infected samples of both technical sets. Hierarchical clustering of the differentiated proteome displayed distinct proteomic signatures that were controlled by the motif(s. Bioinformatics and experimental analysis confirmed the differentiated proteomes, revealed novel cellular biological events, and implicated key pathways controlled by hMPV M2-2 PDZ domain-binding motif(s. This provides further insight for evaluating M2-2 mutants as potent vaccine candidates.

  6. Population pharmacokinetics of oxaliplatin (85 mg/m(2)) in combination with 5-fluorouracil in patients with advanced colorectal cancer

    NARCIS (Netherlands)

    Kho, Y.H.; Jansman, F.G.A.; Prins, N.H.; Neef, C.; Brouwers, J.R.B.J.

    Pharmacokinetic (PK) studies of oxaliplatin, using a dose regimen of 85mg/m(2) are lacking. A PK model may be used in future studies to investigate the relationship between pharmacokinetics and dose limiting toxicity. The purpose of this study was to construct a population PK model to describe

  7. The flux distribution from a 1.25m2 target aligned heliostat: comparison of ray tracing and experimental results

    CSIR Research Space (South Africa)

    Maliage, M

    2012-05-01

    Full Text Available The purpose of this paper is to validate SolTrace for concentrating solar investigations at CSIR by means of a test case: the comparison of the flux distribution in the focal spot of a 1.25 m2 target aligned heliostat predicted by the ray tracing...

  8. A Collaboration-Oriented M2M Messaging Mechanism for the Collaborative Automation between Machines in Future Industrial Networks

    Directory of Open Access Journals (Sweden)

    Zhaozong Meng

    2017-11-01

    Full Text Available Machine-to-machine (M2M communication is a key enabling technology for industrial internet of things (IIoT-empowered industrial networks, where machines communicate with one another for collaborative automation and intelligent optimisation. This new industrial computing paradigm features high-quality connectivity, ubiquitous messaging, and interoperable interactions between machines. However, manufacturing IIoT applications have specificities that distinguish them from many other internet of things (IoT scenarios in machine communications. By highlighting the key requirements and the major technical gaps of M2M in industrial applications, this article describes a collaboration-oriented M2M (CoM2M messaging mechanism focusing on flexible connectivity and discovery, ubiquitous messaging, and semantic interoperability that are well suited for the production line-scale interoperability of manufacturing applications. The designs toward machine collaboration and data interoperability at both the communication and semantic level are presented. Then, the application scenarios of the presented methods are illustrated with a proof-of-concept implementation in the PicknPack food packaging line. Eventually, the advantages and some potential issues are discussed based on the PicknPack practice.

  9. EspO1-2 regulates EspM2-mediated RhoA activity to stabilize formation of focal adhesions in enterohemorrhagic Escherichia coli-infected host cells.

    Science.gov (United States)

    Morita-Ishihara, Tomoko; Miura, Masashi; Iyoda, Sunao; Izumiya, Hidemasa; Watanabe, Haruo; Ohnishi, Makoto; Terajima, Jun

    2013-01-01

    Enterohemorrhagic Escherichia coli (EHEC) Sakai strain encodes two homologous type III effectors, EspO1-1 and EspO1-2. These EspO1s have amino acid sequence homology with Shigella OspE, which targets integrin-linked kinase to stabilize formation of focal adhesions (FAs). Like OspE, EspO1-1 was localized to FAs in EHEC-infected cells, but EspO1-2 was localized in the cytoplasm. An EHEC ΔespO1-1ΔespO1-2 double mutant induced cell rounding and FA loss in most of infected cells, but neither the ΔespO1-1 nor ΔespO1-2 single mutant did. These results suggested that EspO1-2 functioned in the cytoplasm by a different mechanism from EspO1-1 and OspE. Since several type III effectors modulate Rho GTPase, which contributes to FA formation, we investigated whether EspO1-2 modulates the function of these type III effectors. We identified a direct interaction between EspO1-2 and EspM2, which acts as a RhoA guanine nucleotide exchange factor. Upon ectopic co-expression, EspO1-2 co-localized with EspM2 in the cytoplasm and suppressed EspM2-mediated stress fiber formation. Consistent with these findings, an ΔespO1-1ΔespO1-2ΔespM2 triple mutant did not induce cell rounding in epithelial cells. These results indicated that EspO1-2 interacted with EspM2 to regulate EspM2-mediated RhoA activity and stabilize FA formation during EHEC infection.

  10. Effects of xenoestrogens in human M1 and M2 macrophage migration, cytokine release, and estrogen-related signaling pathways.

    Science.gov (United States)

    Teixeira, Diana; Marques, Cláudia; Pestana, Diogo; Faria, Ana; Norberto, Sónia; Calhau, Conceição; Monteiro, Rosário

    2016-11-01

    Bisphenol A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and di(n-butyl)phthalate (DBP) are environmental estrogens that have been associated with a wide range of adverse health outcomes for which inflammation has also been hypothesized as a potentially involved mechanism and where macrophages play a central role. This study was carried out to evaluate if xenoestrogen (XE) treatment of classically (M1) or alternatively (M2) activated macrophages could affect their behavior. For this purpose, human peripheral blood monocyte-derived macrophages either unstimulated or activated with lipopolysaccharide (100 ng/mL, M1) or with interleukin (IL) 4 (15 ng/mL, M2) were treated with 17β-estradiol (E 2 ), BPA, DEHP and DBP alone or in combination with selective ERα or ERβ antagonists. Migratory capability, cytokine release, and estrogen-associated signaling pathways were evaluated to assess macrophage function. All tested XEs had a tendency to stimulate M2 migration, an effect that followed the same direction than E 2 . Moreover, all XEs significantly induced IL10 in M1 and decreased IL6 and globally decreased IL10, IL6, TNFα, and IL1β release by M2 macrophages. However, DEHP and DBP significantly increased IL1β release in M1 and M2 macrophages, respectively. Some of the effects described above were shown to be mediated by either ERα or ERβ and were simultaneous to modulation of NF-κB, AP1, JNK, or ERK signaling pathways. We provide new evidence of the effect of XE on macrophage behavior and their mechanisms with relevance to the understanding of the action of environmental chemicals on the immune system and inflammation-associated diseases. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1496-1509, 2016. © 2015 Wiley Periodicals, Inc.

  11. Gating at the mouth of the acetylcholine receptor channel: energetic consequences of mutations in the alphaM2-cap.

    Directory of Open Access Journals (Sweden)

    Pallavi A Bafna

    2008-06-01

    Full Text Available Gating of nicotinic acetylcholine receptors from a C(losed to an O(pen conformation is the initial event in the postsynaptic signaling cascade at the vertebrate nerve-muscle junction. Studies of receptor structure and function show that many residues in this large, five-subunit membrane protein contribute to the energy difference between C and O. Of special interest are amino acids located at the two transmitter binding sites and in the narrow region of the channel, where CO gating motions generate a lowhigh change in the affinity for agonists and in the ionic conductance, respectively. We have measured the energy changes and relative timing of gating movements for residues that lie between these two locations, in the C-terminus of the pore-lining M2 helix of the alpha subunit ('alphaM2-cap'. This region contains a binding site for non-competitive inhibitors and a charged ring that influences the conductance of the open pore. alphaM2-cap mutations have large effects on gating but much smaller effects on agonist binding, channel conductance, channel block and desensitization. Three alphaM2-cap residues (alphaI260, alphaP265 and alphaS268 appear to move at the outset of channel-opening, about at the same time as those at the transmitter binding site. The results suggest that the alphaM2-cap changes its secondary structure to link gating motions in the extracellular domain with those in the channel that regulate ionic conductance.

  12. Exploring the MIS M2 glaciation occurring during a warm and high atmospheric CO2 Pliocene background climate

    Science.gov (United States)

    Tan, Ning; Ramstein, Gilles; Dumas, Christophe; Contoux, Camille; Ladant, Jean-Baptiste; Sepulchre, Pierre; Zhang, Zhongshi; De Schepper, Stijn

    2017-08-01

    Prior to the Northern Hemisphere glaciation around ∼2.7 Ma, a large global glaciation corresponding to a 20 to 60 m sea-level drop occurred during Marine Isotope Stage (MIS) M2 (3.312-3.264 Ma), interrupted the period of global warmth and high CO2 concentration (350-450 ppmv) of the mid Piacenzian. Unlike the late Quaternary glaciations, the M2 glaciation only lasted 50 kyrs and occurred under uncertain CO2 concentration (220-390 ppmv). The mechanisms causing the onset and termination of the M2 glaciation remain enigmatic, but a recent geological hypothesis suggests that the re-opening and closing of the shallow Central American Seaway (CAS) might have played a key role. In this article, thanks to a series of climate simulations carried out using a fully coupled Atmosphere Ocean General Circulation Model (GCM) and a dynamic ice sheet model, we show that re-opening of the shallow CAS helps precondition the low-latitude oceanic circulation and affects the related northward energy transport, but cannot alone explain the onset of the M2 glaciation. The presence of a shallow open CAS, together with favourable orbital parameters, 220 ppmv of CO2 concentration, and the related vegetation and ice sheet feedback, led to a global ice sheet build-up producing a global sea-level drop in the lowest range of proxy-derived estimates. More importantly, our results show that the simulated closure of the CAS has a negligible impact on the NH ice sheet melt and cannot explain the MIS M2 termination.

  13. Experimental study of the MHD activity associated to the mode m=2, n=1 in the Tore Supra tokamak; Etude experimentale de l`activite MHD associee au mode m=2, n=1 dans le tokamak Tore Supra

    Energy Technology Data Exchange (ETDEWEB)

    Turlur, S.

    1996-09-20

    In tokamaks such as Tore Supra, the plasma confinement magnetic structure can be severely affected when Magnetohydrodynamic (M.H.D.) instabilities are destabilized. Experimentally, these instabilities are detected as magnetic fluctuations with captors located against the inner wall of the vacuum vessel. Fourier analysis provides amplitude, frequency and wave numbers of magnetic modes. In case of fast or transient phenomena, the analysis of magnetic fluctuations is completed using the singular value decomposition. In this dissertation, these analysis techniques are used to study two specific examples of M.H.D. activity related to the m = 2, n = 1 mode. On Tore Supra, the onset of this mode have strong consequences on the stability of partially or fully non inductive discharges. A regular and persistent sawtooth-like regime is observed on the electronic temperature leading to a significant degradation of the central confinement. Heat exhaust and particle balance are also essential parameters to achieve stationary discharges. On Tore Supra, these are studied with the ergodic divertor which produces stochastic magnetic field lines at the plasma edge. For optimal operating conditions of the ergodic divertor, the growth of the m = 2, N = 1 mode can lead to sudden destruction of magnetic equilibrium. For both cases, understanding and characterization of mechanisms leading to the observed m = 2, n = 1 M.H.D. activity are fundamental to obtain stationary discharges. (author). 115 refs.

  14. Der Wettbewerb "Lesefücshse International" - Bücher für Jugendliche / Sybille Deselaers

    Index Scriptorium Estoniae

    Deselaers, Sybille

    2011-01-01

    Raamatututvustused: Behrens, Katja. Der kleine Mausche aus Dessau. München : Hanser, 2009, Linker, Christian. Blitzlichtgewitter. München : Deutsche Taschenbuch Verlag, 2010, Hammer, Agnes. Herz, Klopf! Bindlach : Script5, 2009, Höra, Daniel. Gedisst. Berlin : Berlin Verlag, 2009, Röder, Marlene. Zebraland. [Ravensburg] : Ravensburger, 2010

  15. Ethyl methane sulfonate induced mutations in M2 generation and physiological variations in M1 generation of peppers (Capsicum annuum L.

    Directory of Open Access Journals (Sweden)

    Mohamed Hamed Arisha

    2015-06-01

    Full Text Available This study was conducted to enhance genetic variability in peppers (Capsicum annuum, cv B12 using ethyl methansulphonate (EMS. Exposure to an EMS concentration of 0.6%, v/v for 12 hours was used to mutagenize 2000 seeds for the first generation (M1. It was observed that the growth behaviors including plant height, flowering date and number of seeds per first fruit were different in the M1 generation than in wild type plants. In addition one phenotypic mutation (leaf shape and plant architecture was observed during the M1 generation. During the seedling stage in the M2 generation, the observed changes were in the form of slow growth or chlorophyll defect (e.g., albino, pale green and yellow seedlings. At maturity, there were three kinds of phenotypic mutations observed in three different families of the mutant population. The first observed change was a plant with yellow leaf color, and the leaves of this mutant plant contained 62.19% less chlorophyll a and 64.06% less chlorophyll b as compared to the wild-type. The second mutation resulted in one dwarf plant with a very short stature (6 cm, compact internodes and the leaves and stem were rough and thick. The third type of mutation occurred in four plants and resulted in the leaves of these plants being very thick and longer than those of wild type plants. Furthermore, anatomical observations of the leaf blade section of this mutant plant type contained more xylem and collenchyma tissue in the leaf midrib of the mutant plant than wild type. In addition, its leaf blade contained thicker palisade and spongy tissue than the wild type.

  16. A latency analysis for M2M and OG-like traffic patterns in different HSPA core network configurations

    Directory of Open Access Journals (Sweden)

    M. V. Popović

    2014-11-01

    Full Text Available In this paper we present an analysis intended to reveal possible impacts of core network features on latency for modelled M2M and Online Gaming traffic. Simulations were performed in a live 3G/HSPA network. Test traffic simulating multiplayer real-time games and M2M applications was generated on 10 mobile phones in parallel, sending data to a remote server. APNs with different combinations of hardware and features (proxy server, different GGSNs and firewalls, usage of Service Awareness feature were chosen. The traffic was recorded on the Gn interface in the mobile core. The goal of experiments was to evaluate any eventually significant variation of average recorded RTTs in the core part of mobile network that would clearly indicate either the impact of used APN on delay for a specific traffic pattern, or selectivity of the APN towards different traffic patterns.

  17. Preserving Smart Objects Privacy through Anonymous and Accountable Access Control for a M2M-Enabled Internet of Things

    Directory of Open Access Journals (Sweden)

    José L. Hernández-Ramos

    2015-07-01

    Full Text Available As we get into the Internet of Things era, security and privacy concerns remain as the main obstacles in the development of innovative and valuable services to be exploited by society. Given the Machine-to-Machine (M2M nature of these emerging scenarios, the application of current privacy-friendly technologies needs to be reconsidered and adapted to be deployed in such global ecosystem. This work proposes different privacy-preserving mechanisms through the application of anonymous credential systems and certificateless public key cryptography. The resulting alternatives are intended to enable an anonymous and accountable access control approach to be deployed on large-scale scenarios, such as Smart Cities. Furthermore, the proposed mechanisms have been deployed on constrained devices, in order to assess their suitability for a secure and privacy-preserving M2M-enabled Internet of Things.

  18. Preserving Smart Objects Privacy through Anonymous and Accountable Access Control for a M2M-Enabled Internet of Things.

    Science.gov (United States)

    Hernández-Ramos, José L; Bernabe, Jorge Bernal; Moreno, M Victoria; Skarmeta, Antonio F

    2015-07-01

    As we get into the Internet of Things era, security and privacy concerns remain as the main obstacles in the development of innovative and valuable services to be exploited by society. Given the Machine-to-Machine (M2M) nature of these emerging scenarios, the application of current privacy-friendly technologies needs to be reconsidered and adapted to be deployed in such global ecosystem. This work proposes different privacy-preserving mechanisms through the application of anonymous credential systems and certificateless public key cryptography. The resulting alternatives are intended to enable an anonymous and accountable access control approach to be deployed on large-scale scenarios, such as Smart Cities. Furthermore, the proposed mechanisms have been deployed on constrained devices, in order to assess their suitability for a secure and privacy-preserving M2M-enabled Internet of Things.

  19. On the simultaneous Pell equations x 2 - (4m 2 - 1)y 2 = y 2 - pz 2 ...

    African Journals Online (AJOL)

    Let m be a positive integer, and let p be an odd prime. By using certain properties of Pell and quartic diophantine equations with some elementary number theory methods, we prove that the system of equations x2 - (4m2 - 1)y2 = 1 and y2 - pz2 = 1 has positive integer solutions (x, y, z) if and only if p ≡ 7(mod 8) and m = 1/4 ...

  20. Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model12

    Science.gov (United States)

    Gabrusiewicz, Konrad; Hossain, Mohammad B.; Cortes-Santiago, Nahir; Fan, Xuejun; Kaminska, Bozena; Marini, Frank C.; Fueyo, Juan; Gomez-Manzano, Candelaria

    2015-01-01

    Monocytes/macrophages are an influential component of the glioma microenvironment. However, understanding their diversity and plasticity constitute one of the most challenging areas of research due to the paucity of models to study these cells' inherent complexity. Herein, we analyzed the role of monocytes/macrophages in glioma growth by using a transgenic model that allows for conditional ablation of this cell population. We modeled glioma using intracranial GL261-bearing CSF-1R–GFP+ macrophage Fas-induced apoptosis (MAFIA) transgenic mice. Conditional macrophage ablation was achieved by exposure to the dimerizer AP20187. Double immunofluorescence was used to characterize M1- and M2-like monocytes/macrophages during tumor growth and after conditional ablation. During glioma growth, the monocyte/macrophage population consisted predominantly of M2 macrophages. Conditional temporal depletion of macrophages reduced the number of GFP+ cells, targeting mainly the repopulation of M2-polarized cells, and altered the appearance of M1-like monocytes/macrophages, which suggested a shift in the M1/M2 macrophage balance. Of interest, compared with control-treated mice, macrophage-depleted mice had a lower tumor mitotic index, microvascular density, and reduced tumor growth. These results demonstrated the possibility of studying in vivo the role and phenotype of macrophages in gliomas and suggested that transitory depletion of CSF-1R+ population influences the reconstitutive phenotypic pool of these cells, ultimately suppressing tumor growth. The MAFIA model provides a much needed advance in defining the role of macrophages in gliomas. PMID:25925380

  1. Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model.

    Science.gov (United States)

    Gabrusiewicz, Konrad; Hossain, Mohammad B; Cortes-Santiago, Nahir; Fan, Xuejun; Kaminska, Bozena; Marini, Frank C; Fueyo, Juan; Gomez-Manzano, Candelaria

    2015-04-01

    Monocytes/macrophages are an influential component of the glioma microenvironment. However, understanding their diversity and plasticity constitute one of the most challenging areas of research due to the paucity of models to study these cells' inherent complexity. Herein, we analyzed the role of monocytes/macrophages in glioma growth by using a transgenic model that allows for conditional ablation of this cell population. We modeled glioma using intracranial GL261-bearing CSF-1R-GFP(+) macrophage Fas-induced apoptosis (MAFIA) transgenic mice. Conditional macrophage ablation was achieved by exposure to the dimerizer AP20187. Double immunofluorescence was used to characterize M1- and M2-like monocytes/macrophages during tumor growth and after conditional ablation. During glioma growth, the monocyte/macrophage population consisted predominantly of M2 macrophages. Conditional temporal depletion of macrophages reduced the number of GFP(+) cells, targeting mainly the repopulation of M2-polarized cells, and altered the appearance of M1-like monocytes/macrophages, which suggested a shift in the M1/M2 macrophage balance. Of interest, compared with control-treated mice, macrophage-depleted mice had a lower tumor mitotic index, microvascular density, and reduced tumor growth. These results demonstrated the possibility of studying in vivo the role and phenotype of macrophages in gliomas and suggested that transitory depletion of CSF-1R(+) population influences the reconstitutive phenotypic pool of these cells, ultimately suppressing tumor growth. The MAFIA model provides a much needed advance in defining the role of macrophages in gliomas. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  2. ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization.

    Science.gov (United States)

    Li, Junjie; Xie, Jiangang; Liu, Shanshou; Li, Xiao; Zhang, Dongliang; Wang, Xianqi; Jiang, Jinquan; Hu, Wei; Zhang, Yuan; Jin, Boquan; Zhuang, Ran; Yin, Wen

    2018-04-25

    ADAR1 (adenosine deaminase acting on double-stranded RNA 1) is an RNA-editing enzyme that mediates adenosine-to-inosine RNA editing events, an important post-transcriptional modification mechanism that can alter the coding properties of mRNA or regulate microRNA biogenesis. ADAR1 also regulates the innate immune response. Here, we have demonstrated that ADAR1 expression increased in LPS-stimulated macrophages. Silencing ADAR1 by using small interfering RNA in macrophages resulted in the pronounced polarization of macrophages to M1, whereas ADAR1 overexpression promoted M2 polarization, which indicated that ADAR1 can inhibit macrophage hyperpolarization and prevent immune hyperactivity. The RNA-RNP immunoprecipitation binding assay demonstrated a direct interaction between ADAR1 and miR-21 precursor. Significant up-regulation in IL-10 and down-regulation in miR-21 were observed in ADAR1-overexpressing macrophages. We evaluated miR-21 target mRNAs and macrophage polarization signaling pathways and found that forkhead box protein O1 (Foxo1) was up-regulated in cells that overexpressed ADAR1. In a mouse allogeneic skin transplantation model, grafts in the ADAR1-overexpressed group survived longer and suffered less immune cell infiltration. In ADAR1-overexpressed recipients, splenic macrophages were significantly polarized to M2, and levels of sera IL-10 were markedly higher than those in the control group. In summary, ADAR1 modulates macrophage M2 polarization via the ADAR1-miR-21-Foxo1-IL-10 axis, thereby suppressing allogeneic graft rejection.-Li, J., Xie, J., Liu, S., Li, X., Zhang, D., Wang, X., Jiang, J., Hu, W., Zhang, Y., Jin, B., Zhuang, R., Yin, W. ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization.

  3. Corneal flap thickness with the Moria M2 single-use head 90 microkeratome in 72 consecutive LASIK procedures

    OpenAIRE

    Karabela,Yunus; Muftuoglu,Orkun; Kaya,Faruk

    2017-01-01

    Yunus Karabela,1 Orkun Muftuoglu,2 Faruk Kaya1 1Department of Ophthalmology, Medipol University, 2Department of Ophthalmology, Vehbi Koç Vakfi Amerikan Hospital, Istanbul, Turkey Purpose: This study aimed to evaluate the accuracy and consistency of corneal flap thickness in laser-assisted in situ keratomileusis (LASIK) with the Moria M2 single-use head 90 microkeratome. Methods: The central corneal thickness of 72 (37 right, 35 left) eyes of 37 patients was measured by ultrasonic...

  4. Security Aspects of Smart Cards vs. Embedded Security in Machine-to-Machine (M2M) Advanced Mobile Network Applications

    Science.gov (United States)

    Meyerstein, Mike; Cha, Inhyok; Shah, Yogendra

    The Third Generation Partnership Project (3GPP) standardisation group currently discusses advanced applications of mobile networks such as Machine-to-Machine (M2M) communication. Several security issues arise in these contexts which warrant a fresh look at mobile networks’ security foundations, resting on smart cards. This paper contributes a security/efficiency analysis to this discussion and highlights the role of trusted platform technology to approach these issues.

  5. Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Tian; Wang, Chenlong; Chen, Xuewei; Duan, Chenfan; Zhang, Xiaoyan [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Chen, Honglei [Department of Pathology and Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yue, Jiang [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Li, Ying, E-mail: lyying0@163.com [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China)

    2015-07-15

    Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. - Highlights: • Dopamine induces tumor growth inhibition and vascular normalization in rat C6 glioma. • Dopamine switches macrophage phenotype from M2 to M1. • Dopamine-induced vascular normalization is mediated by macrophage polarization. • Dopamine is a promising agent targeting the microvasculature in tumor

  6. EFFECT OF GAMMA RADIATION OF MACRO MUTATIONS, EFFECTIVENESS AND EFFICIENCY UNDER M2 GENERATION IN PEA (Pisum sativum L.

    Directory of Open Access Journals (Sweden)

    Arvind KUMAR

    2016-06-01

    Full Text Available The present investigation was undertaken to study the spectrum of macro mutants, effectiveness and efficiency of different doses of gamma rays in pea variety (Arkel. The seeds were treated with gamma rays viz., 00kR (dry control, 05kR, 10kR, 15kR, 20kR, 25kR, 30kR, 35kR, 40kR (dry seeds and presoaked seeds of the same was exposed to 00kR (wet control, 05kR, 10kR, 15kR, 20kR (kilo Roentgen biological damage was calculated in M1 and M2 generation based on lethality (L and pollen sterility. The irradiated seeds were sown in the M1 field their respective controls and harvested in bulk to raise the M2 generation in Randomized Block Design (RBD with three replications. The spectrum of macro mutants i.e., plant stature (tall, dwarf, small dwarf, maturity (early, late, pod shape (bold, long, short, seed colour (brown, light white, light green and seed shape (small, bold, wrinkled were observed in M2 generation. The usefulness of any mutagen in plant breeding depends not only on its effectiveness but also upon if efficiency. Mutagenic effectiveness is a measure of the frequency of mutations induced by unit mutagen dose, whereas mutagenic efficiency is measure of proportion of mutations in relation of undesirable changes like lethality and sterility are used for gamma rays. A result of the indicated positive relationship in M2 generation with macro mutation, effectiveness and efficiency was found to be highest at lowest doses.

  7. How well do we know the quantum numbers of possible anti p p → M1M2 states

    International Nuclear Information System (INIS)

    Lanou, R.E.

    1979-01-01

    Information is available to completely analyze the p anti p → ππ reaction, allowing more global, large-scale, phenomenological analyses which combine the two experimental data sets in an energy independent, amplitude analysis which also includes pion-nucleon data. It would appear from the preliminary analyses of p anti p → M 1 M 2 angular distributions and polarizations the T-region may indeed contain some very interesting activity

  8. Electronic Structure and Bonding Situation in M2O2 (M=Be,Mg,Ca) Rhombic Clusters.

    Czech Academy of Sciences Publication Activity Database

    Li, W.-L.; Lu, J.-B.; Zhao, L.; Ponec, Robert; Cooper, D.L.; Li, J.; Frenking, G.

    2018-01-01

    Roč. 122, č. 10 (2018), s. 2816-2822 ISSN 1089-5639 Grant - others:NNSFCH(CN) 21590792; NNSFCH(CN) 21433005; NNSFCH(CN) 21703099; JPY NSF(CN) BK20170964; NTU(CN) 39837123 Institutional support: RVO:67985858 Keywords : electronic structures * M2O2n clustery * theoretical isnights Subject RIV: CF - Physical ; Theoretical Chemistry OBOR OECD: Physical chemistry Impact factor: 2.847, year: 2016

  9. Deletion of the M2-2 Gene from Avian Metapneumovirus Subgroup C (aMPV-C) Impairs Virus Replication and Immunogenicity in Turkeys

    Science.gov (United States)

    The second matrix (M2) gene of avian metapneumovirus subgroup C (aMPV-C) virus contains two overlapping open reading frames (ORFs), encoding two putative proteins, M2-1 and M2-2. Both proteins are believed to be involved in either viral RNA transcription or replication. To further characterize the f...

  10. He II Raman Scattered Line by Neutral Hydrogen in the Bipolar Platenary Nebula M2-9

    Directory of Open Access Journals (Sweden)

    Hee-Won Lee

    2001-06-01

    Full Text Available In the spectrum of the young bipolar planetary nebula M2-9 obtained from the 1.5 m telescope at the Cerro Tololo Inter-American Observatory, we detected the He~II feature at 6545 Å that are proposed to be formed via Raman scattering by atomic hydrogen. However, in the same spectrum, the He~II emission lines at 6527 Å and 6560 Å are absent, which implies that the He~II emission region is hidden from our line of sight and that the H~I scattering region is pretty much extended not to be obscured entirely. We performed photoionization computations to estimate the physical size of the He~II emission line region to be 1016 cm, from which the location and dimension of the obscuring circumstellar region are inferred and the temperature of the central star must exceed 105 K. The angular size of the circumstellar region responsible for the obscuration of the He~II emission region is ~ 1'' with the assumption of the distance 01 kpc to M2-9, which is consistent with the recent image of M2-9 obtained with the Hubble Space Telescope.

  11. A Case of Acute Myeloid Leukemia (FAB M2 with Inversion 16 Who Presented with Pelvic Myeloid Sarcoma

    Directory of Open Access Journals (Sweden)

    Mustafa Çakan

    2014-01-01

    Full Text Available Acute leukemias are the most common childhood cancer in all age groups. Acute myeloid leukemias (AML constitute about 15–20% of acute leukemias. Fatigability, pallor, fever, and bleeding are the most common presenting symptoms of AML. Hepatosplenomegaly and lymphadenopathy are commonly encountered during physical examination. In rare instances eruptions due to skin involvement and localized tumor masses (myeloid sarcoma may be found. Myeloid sarcoma is especially seen in AML-M2 subtype. By cytogenetic analysis, in AML-M2 subtype t(8;21 is often seen and it is more probable to find inversion 16 in AML-M4Eos subtype. Herein, we present a 15-year-old girl whose initial symptom was abdominal pain for three days and her pathological sign was a large abdominal mass which was verified by imaging studies and diagnosed as myeloid sarcoma by biopsy. On bone marrow examination, she had diagnosis of AML-M2 and by cytogenetic analysis inversion 16 was positive. She was treated with AML-BFM 2004 protocol and she is being followed up in remission on her ninth month of the maintenance therapy.

  12. A high n-6 polyunsaturated fatty acid diet reduces muscarinic M2/M4 receptor binding in the rat brain.

    Science.gov (United States)

    du Bois, Teresa Marie; Bell, Warren; Deng, Chao; Huang, Xu-Feng

    2005-06-01

    The aim of this study was to examine the influence of different fat diets on muscarinic acetylcholine receptor binding. Nineteen male Sprague-Dawley rats were divided into four groups and fed a diet of either high saturated fat, n-6 polyunsaturated fatty acid (PUFA), n-3 PUFA or low fat (control) for 8 weeks. Using quantitative autoradiography, [(3)H]pirenzepine binding to muscarinic M1/M4 receptors and [(3)H]AF-DX384 binding to M2/M4 receptors were measured throughout the brain in all four groups. The main findings were that compared to the low fat control group, M2/M4 receptor binding was significantly reduced in the dorsolateral, dorsomedial and ventromedial parts of the caudate putamen (61-64%, p cortex (59%, p M4 receptor binding densities between the four groups were observed. These results suggest that a diet high in n-6 PUFA, but not of n-3 PUFAs or saturated fat, may selectively alter M2/M4 receptor-mediated signal transduction in the rat brain.

  13. Effect of Cocoa Polyphenolic Extract on Macrophage Polarization from Proinflammatory M1 to Anti-Inflammatory M2 State

    Directory of Open Access Journals (Sweden)

    Laura Dugo

    2017-01-01

    Full Text Available Polyphenols-rich cocoa has many beneficial effects on human health, such as anti-inflammatory effects. Macrophages function as control switches of the immune system, maintaining the balance between pro- and anti-inflammatory activities. We investigated the hypothesis that cocoa polyphenol extract may affect macrophage proinflammatory phenotype M1 by favoring an alternative M2 anti-inflammatory state on macrophages deriving from THP-1 cells. Chemical composition, total phenolic content, and antioxidant capacity of cocoa polyphenols extracted from roasted cocoa beans were determined. THP-1 cells were activated with both lipopolysaccharides and interferon-γ for M1 or with IL-4 for M2 switch, and specific cytokines were quantified. Cellular metabolism, through mitochondrial oxygen consumption, and ATP levels were evaluated. Here, we will show that cocoa polyphenolic extract attenuated in vitro inflammation decreasing M1 macrophage response as demonstrated by a significantly lowered secretion of proinflammatory cytokines. Moreover, treatment of M1 macrophages with cocoa polyphenols influences macrophage metabolism by promoting oxidative pathways, thus leading to a significant increase in O2 consumption by mitochondrial complexes as well as a higher production of ATP through oxidative phosphorylation. In conclusion, cocoa polyphenolic extract suppresses inflammation mediated by M1 phenotype and influences macrophage metabolism by promoting oxidative pathways and M2 polarization of active macrophages.

  14. Essential Role of the m2R-RGS6-IKACh Pathway in Controlling Intrinsic Heart Rate Variability

    Science.gov (United States)

    Posokhova, Ekaterina; Ng, David; Opel, Aaisha; Masuho, Ikuo; Tinker, Andrew; Biesecker, Leslie G.; Wickman, Kevin; Martemyanov, Kirill A.

    2013-01-01

    Normal heart function requires generation of a regular rhythm by sinoatrial pacemaker cells and the alteration of this spontaneous heart rate by the autonomic input to match physiological demand. However, the molecular mechanisms that ensure consistent periodicity of cardiac contractions and fine tuning of this process by autonomic system are not completely understood. Here we examined the contribution of the m2R-IKACh intracellular signaling pathway, which mediates the negative chronotropic effect of parasympathetic stimulation, to the regulation of the cardiac pacemaking rhythm. Using isolated heart preparations and single-cell recordings we show that the m2R-IKACh signaling pathway controls the excitability and firing pattern of the sinoatrial cardiomyocytes and determines variability of cardiac rhythm in a manner independent from the autonomic input. Ablation of the major regulator of this pathway, Rgs6, in mice results in irregular cardiac rhythmicity and increases susceptibility to atrial fibrillation. We further identify several human subjects with variants in the RGS6 gene and show that the loss of function in RGS6 correlates with increased heart rate variability. These findings identify the essential role of the m2R-IKACh signaling pathway in the regulation of cardiac sinus rhythm and implicate RGS6 in arrhythmia pathogenesis. PMID:24204714

  15. Zinc binding activity of human metapneumovirus M2-1 protein is indispensable for viral replication and pathogenesis in vivo.

    Science.gov (United States)

    Cai, Hui; Zhang, Yu; Ma, Yuanmei; Sun, Jing; Liang, Xueya; Li, Jianrong

    2015-06-01

    Human metapneumovirus (hMPV) is a member of the Pneumovirinae subfamily in the Paramyxoviridae family that causes respiratory tract infections in humans. Unlike members of the Paramyxovirinae subfamily, the polymerase complex of pneumoviruses requires an additional cofactor, the M2-1 protein, which functions as a transcriptional antitermination factor. The M2-1 protein was found to incorporate zinc ions, although the specific role(s) of the zinc binding activity in viral replication and pathogenesis remains unknown. In this study, we found that the third cysteine (C21) and the last histidine (H25) in the zinc binding motif (CCCH) of hMPV M2-1 were essential for zinc binding activity, whereas the first two cysteines (C7 and C15) play only minor or redundant roles in zinc binding. In addition, the zinc binding motif is essential for the oligomerization of M2-1. Subsequently, recombinant hMPVs (rhMPVs) carrying mutations in the zinc binding motif were recovered. Interestingly, rhMPV-C21S and -H25L mutants, which lacked zinc binding activity, had delayed replication in cell culture and were highly attenuated in cotton rats. In contrast, rhMPV-C7S and -C15S strains, which retained 60% of the zinc binding activity, replicated as efficiently as rhMPV in cotton rats. Importantly, rhMPVs that lacked zinc binding activity triggered high levels of neutralizing antibody and provided complete protection against challenge with rhMPV. Taken together, these results demonstrate that zinc binding activity is indispensable for viral replication and pathogenesis in vivo. These results also suggest that inhibition of zinc binding activity may serve as a novel approach to rationally attenuate hMPV and perhaps other pneumoviruses for vaccine purposes. The pneumoviruses include many important human and animal pathogens, such as human respiratory syncytial virus (hRSV), hMPV, bovine RSV, and avian metapneumovirus (aMPV). Among these viruses, hRSV and hMPV are the leading causes of acute

  16. Protection against Multiple Influenza A Virus Strains Induced by Candidate Recombinant Vaccine Based on Heterologous M2e Peptides Linked to Flagellin

    Science.gov (United States)

    Kovaleva, Anna A.; Potapchuk, Marina V.; Korotkov, Alexandr V.; Sergeeva, Mariia V.; Kasianenko, Marina A.; Kuprianov, Victor V.; Ravin, Nikolai V.; Tsybalova, Liudmila M.; Skryabin, Konstantin G.; Kiselev, Oleg I.

    2015-01-01

    Matrix 2 protein ectodomain (M2e) is considered a promising candidate for a broadly protective influenza vaccine. M2e-based vaccines against human influenza A provide only partial protection against avian influenza viruses because of differences in the M2e sequences. In this work, we evaluated the possibility of obtaining equal protection and immune response by using recombinant protein on the basis of flagellin as a carrier of the M2e peptides of human and avian influenza A viruses. Recombinant protein was generated by the fusion of two tandem copies of consensus M2e sequence from human influenza A and two copies of M2e from avian A/H5N1 viruses to flagellin (Flg-2M2eh2M2ek). Intranasal immunisation of Balb/c mice with recombinant protein significantly elicited anti-M2e IgG in serum, IgG and sIgA in BAL. Antibodies induced by the fusion protein Flg-2M2eh2M2ek bound efficiently to synthetic peptides corresponding to the human consensus M2e sequence as well as to the M2e sequence of A/Chicken/Kurgan/05/05 RG (H5N1) and recognised native M2e epitopes exposed on the surface of the MDCK cells infected with A/PR/8/34 (H1N1) and A/Chicken/Kurgan/05/05 RG (H5N1) to an equal degree. Immunisation led to both anti-M2e IgG1 and IgG2a response with IgG1 prevalence. We observed a significant intracellular production of IL-4, but not IFN-γ, by CD4+ T-cells in spleen of mice following immunisation with Flg-2M2eh2M2ek. Immunisation with the Flg-2M2eh2M2ek fusion protein provided similar protection from lethal challenge with human influenza A viruses (H1N1, H3N2) and avian influenza virus (H5N1). Immunised mice experienced significantly less weight loss and decreased lung viral titres compared to control mice. The data obtained show the potential for the development of an M2e-flagellin candidate influenza vaccine with broad spectrum protection against influenza A viruses of various origins. PMID:25799221

  17. Protection against multiple influenza A virus strains induced by candidate recombinant vaccine based on heterologous M2e peptides linked to flagellin.

    Directory of Open Access Journals (Sweden)

    Liudmila A Stepanova

    Full Text Available Matrix 2 protein ectodomain (M2e is considered a promising candidate for a broadly protective influenza vaccine. M2e-based vaccines against human influenza A provide only partial protection against avian influenza viruses because of differences in the M2e sequences. In this work, we evaluated the possibility of obtaining equal protection and immune response by using recombinant protein on the basis of flagellin as a carrier of the M2e peptides of human and avian influenza A viruses. Recombinant protein was generated by the fusion of two tandem copies of consensus M2e sequence from human influenza A and two copies of M2e from avian A/H5N1 viruses to flagellin (Flg-2M2eh2M2ek. Intranasal immunisation of Balb/c mice with recombinant protein significantly elicited anti-M2e IgG in serum, IgG and sIgA in BAL. Antibodies induced by the fusion protein Flg-2M2eh2M2ek bound efficiently to synthetic peptides corresponding to the human consensus M2e sequence as well as to the M2e sequence of A/Chicken/Kurgan/05/05 RG (H5N1 and recognised native M2e epitopes exposed on the surface of the MDCK cells infected with A/PR/8/34 (H1N1 and A/Chicken/Kurgan/05/05 RG (H5N1 to an equal degree. Immunisation led to both anti-M2e IgG1 and IgG2a response with IgG1 prevalence. We observed a significant intracellular production of IL-4, but not IFN-γ, by CD4+ T-cells in spleen of mice following immunisation with Flg-2M2eh2M2ek. Immunisation with the Flg-2M2eh2M2ek fusion protein provided similar protection from lethal challenge with human influenza A viruses (H1N1, H3N2 and avian influenza virus (H5N1. Immunised mice experienced significantly less weight loss and decreased lung viral titres compared to control mice. The data obtained show the potential for the development of an M2e-flagellin candidate influenza vaccine with broad spectrum protection against influenza A viruses of various origins.

  18. Protection against influenza A virus by vaccination with a recombinant fusion protein linking influenza M2e to human serum albumin (HSA).

    Science.gov (United States)

    Mu, Xupeng; Hu, Kebang; Shen, Mohan; Kong, Ning; Fu, Changhao; Yan, Weiqun; Wei, Anhui

    2016-02-01

    The highly conserved extracellular domain of M2 protein (M2e) of influenza A viruses has limited immunogenicity on its own. Hence, aiming to enhance immunogenicity of M2e protein, optimal approaches remain to be established. In this study, we created recombinant fusion protein vaccines by linking M2e consensus sequence of influenza A viruses with C-terminal domain of human serum albumin (HSA). Then HSA/M2e recombinant fusion protein was studied. Our results showed that HSA/M2e could induce strong anti-M2e specific humoral immune responses in the established mice model. Administration of HSA/M2e with Freund's adjuvant resulted in a higher number of IFN-γ-producing cells compared to HSA/M2e or M2e peptide emulsified in Freund's adjuvant. Furthermore, HSA/M2e was able to reduce viral load in the mice lungs and provide significant protection against lethal challenge with an H1N1 or an H3N2 virus compared to controls. In conclusion, this study has demonstrated a potential vaccine that could provide protection in preventing the threat of influenza outbreak because of rapid variation of the influenza virus. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. M2-polarized tumor-associated macrophages facilitated migration and epithelial-mesenchymal transition of HCC cells via the TLR4/STAT3 signaling pathway.

    Science.gov (United States)

    Yao, Rong-Rong; Li, Jing-Huan; Zhang, Rui; Chen, Rong-Xin; Wang, Yan-Hong

    2018-01-16

    M2-polarized macrophages are tumor-associated-macrophages (TAMs), which are important contents of tumor-infiltrating immune cells. Toll-like receptor 4 (TLR4) is a molecular biomarker of tumor aggressiveness and poor prognosis. Toll-like receptors (TLRs) have important roles in the immune system and M2-polarized macrophages. However, the effects of TLR4 on M2-polarized macrophages in hepatocellular carcinoma (HCC) are unknown. Here, TLR4 expressed on HCC cells mediates the pro-tumor effects and mechanisms of M2-polarized macrophages. THP-1 cells were induced to differentiate into M2-like macrophages through treatments with IL-4, IL-13, and phorbol myristate acetate (PMA). We used the HCC cell lines SMMC-7721 and MHCC97-H cultured in conditioned medium from M2-like macrophages (M2-CM) to investigate the migration potential of HCC cells and epithelial-mesenchymal transition (EMT)-associated molecular genetics. Signaling pathways that mediated M2-CM-promoted HCC migration were detected using western blotting. HCC cells cultured with M2-CM displayed a fibroblast-like morphology, an increased metastatic capability, and expression of EMT markers. TLR4 expression was markedly increased in M2-CM-treated HCC cells. TLR4 overexpression promoted HCC cell migration, and a TLR4-neutralizing antibody markedly inhibited HCC EMT in cells cultured with M2-CM. Furthermore, the TLR4/(signal transducer and activator of transcription 3 (STAT3) signaling pathway contributed to the effects of M2-CM on HCC cells. Taken together, M2-polarized macrophages facilitated the migration and EMT of HCC cells via the TLR4/STAT3 signaling pathway, suggesting that TLR4 may be a novel therapeutic target. These results improve our understanding of M2-polarized macrophages.

  20. From WSN towards WoT: Open API Scheme Based on oneM2M Platforms

    Directory of Open Access Journals (Sweden)

    Jaeho Kim

    2016-10-01

    Full Text Available Conventional computing systems have been able to be integrated into daily objects and connected to each other due to advances in computing and network technologies, such as wireless sensor networks (WSNs, forming a global network infrastructure, called the Internet of Things (IoT. To support the interconnection and interoperability between heterogeneous IoT systems, the availability of standardized, open application programming interfaces (APIs is one of the key features of common software platforms for IoT devices, gateways, and servers. In this paper, we present a standardized way of extending previously-existing WSNs towards IoT systems, building the world of the Web of Things (WoT. Based on the oneM2M software platforms developed in the previous project, we introduce a well-designed open API scheme and device-specific thing adaptation software (TAS enabling WSN elements, such as a wireless sensor node, to be accessed in a standardized way on a global scale. Three pilot services are implemented (i.e., a WiFi-enabled smart flowerpot, voice-based control for ZigBee-connected home appliances, and WiFi-connected AR.Drone control to demonstrate the practical usability of the open API scheme and TAS modules. Full details on the method of integrating WSN elements into three example systems are described at the programming code level, which is expected to help future researchers in integrating their WSN systems in IoT platforms, such as oneM2M. We hope that the flexibly-deployable, easily-reusable common open API scheme and TAS-based integration method working with the oneM2M platforms will help the conventional WSNs in diverse industries evolve into the emerging WoT solutions.

  1. Structure and Mechanism of Proton Transport Through the Transmembrane Tetrameric M2 Protein Bundle of the Influenza A Virus

    Energy Technology Data Exchange (ETDEWEB)

    R Acharya; V Carnevale; G Fiorin; B Levine; A Polishchuk; V Balannick; I Samish; R Lamb; L Pinto; et al.

    2011-12-31

    The M2 proton channel from influenza A virus is an essential protein that mediates transport of protons across the viral envelope. This protein has a single transmembrane helix, which tetramerizes into the active channel. At the heart of the conduction mechanism is the exchange of protons between the His37 imidazole moieties of M2 and waters confined to the M2 bundle interior. Protons are conducted as the total charge of the four His37 side chains passes through 2{sup +} and 3{sup +} with a pK{sub a} near 6. A 1.65 {angstrom} resolution X-ray structure of the transmembrane protein (residues 25-46), crystallized at pH 6.5, reveals a pore that is lined by alternating layers of sidechains and well-ordered water clusters, which offer a pathway for proton conduction. The His37 residues form a box-like structure, bounded on either side by water clusters with well-ordered oxygen atoms at close distance. The conformation of the protein, which is intermediate between structures previously solved at higher and lower pH, suggests a mechanism by which conformational changes might facilitate asymmetric diffusion through the channel in the presence of a proton gradient. Moreover, protons diffusing through the channel need not be localized to a single His37 imidazole, but instead may be delocalized over the entire His-box and associated water clusters. Thus, the new crystal structure provides a possible unification of the discrete site versus continuum conduction models.

  2. From WSN towards WoT: Open API Scheme Based on oneM2M Platforms.

    Science.gov (United States)

    Kim, Jaeho; Choi, Sung-Chan; Ahn, Il-Yeup; Sung, Nak-Myoung; Yun, Jaeseok

    2016-10-06

    Conventional computing systems have been able to be integrated into daily objects and connected to each other due to advances in computing and network technologies, such as wireless sensor networks (WSNs), forming a global network infrastructure, called the Internet of Things (IoT). To support the interconnection and interoperability between heterogeneous IoT systems, the availability of standardized, open application programming interfaces (APIs) is one of the key features of common software platforms for IoT devices, gateways, and servers. In this paper, we present a standardized way of extending previously-existing WSNs towards IoT systems, building the world of the Web of Things (WoT). Based on the oneM2M software platforms developed in the previous project, we introduce a well-designed open API scheme and device-specific thing adaptation software (TAS) enabling WSN elements, such as a wireless sensor node, to be accessed in a standardized way on a global scale. Three pilot services are implemented (i.e., a WiFi-enabled smart flowerpot, voice-based control for ZigBee-connected home appliances, and WiFi-connected AR.Drone control) to demonstrate the practical usability of the open API scheme and TAS modules. Full details on the method of integrating WSN elements into three example systems are described at the programming code level, which is expected to help future researchers in integrating their WSN systems in IoT platforms, such as oneM2M. We hope that the flexibly-deployable, easily-reusable common open API scheme and TAS-based integration method working with the oneM2M platforms will help the conventional WSNs in diverse industries evolve into the emerging WoT solutions.

  3. M2/M4 muscarinic receptor binding in the anterior cingulate cortex in schizophrenia and mood disorders.

    Science.gov (United States)

    Zavitsanou, Katerina; Katsifis, Andrew; Yu, Yinghua; Huang, Xu Feng

    2005-05-15

    We have previously shown a decrease in [(3)H]pirenzepine binding to M1/M4 muscarinic receptors in the anterior cingulate cortex in schizophrenia but not in major depression or bipolar disorder. The present study aimed to extend these findings by examining the binding of [(3)H]AF-DX 384 to M2/M4 receptors in the same cohort of subjects. Using quantitative autoradiography we measured [(3)H]AF-DX 384 binding in the anterior cingulate cortex of 15 schizophrenia, 15 bipolar, 15 major depression and 15 control cases. Post-mortem tissue was obtained from the Stanley Foundation Brain Bank. [(3)H]AF-DX 384 binding had a homogenous distribution amongst the layers of the anterior cingulate cortex, was higher in males than in females and declined with prolonged storage of tissue. An inverse correlation between [(3)H]AF-DX384 binding and age of onset of the disease was observed in the schizophrenia group suggesting that the earlier the age at onset the higher the binding was. In the depression group, there was a significant effect of gender on [(3)H]AF-DX 384 binding with females having lower binding in comparison to males. In the bipolar group, there was a significant inverse correlation between antipsychotic medication and [(3)H]AF-DX 384 binding, suggesting that the higher the dose of medication the lower the binding was. No differences in [(3)H]AF-DX 384 binding were seen between the four groups. The present results provide no evidence of M2/M4 receptor alterations in the anterior cingulate cortex in schizophrenia and affective disorders and extend the body of evidence implicating cortical M1 but not M2 involvement in the pathology and pharmacotherapy of schizophrenia.

  4. From WSN towards WoT: Open API Scheme Based on oneM2M Platforms

    Science.gov (United States)

    Kim, Jaeho; Choi, Sung-Chan; Ahn, Il-Yeup; Sung, Nak-Myoung; Yun, Jaeseok

    2016-01-01

    Conventional computing systems have been able to be integrated into daily objects and connected to each other due to advances in computing and network technologies, such as wireless sensor networks (WSNs), forming a global network infrastructure, called the Internet of Things (IoT). To support the interconnection and interoperability between heterogeneous IoT systems, the availability of standardized, open application programming interfaces (APIs) is one of the key features of common software platforms for IoT devices, gateways, and servers. In this paper, we present a standardized way of extending previously-existing WSNs towards IoT systems, building the world of the Web of Things (WoT). Based on the oneM2M software platforms developed in the previous project, we introduce a well-designed open API scheme and device-specific thing adaptation software (TAS) enabling WSN elements, such as a wireless sensor node, to be accessed in a standardized way on a global scale. Three pilot services are implemented (i.e., a WiFi-enabled smart flowerpot, voice-based control for ZigBee-connected home appliances, and WiFi-connected AR.Drone control) to demonstrate the practical usability of the open API scheme and TAS modules. Full details on the method of integrating WSN elements into three example systems are described at the programming code level, which is expected to help future researchers in integrating their WSN systems in IoT platforms, such as oneM2M. We hope that the flexibly-deployable, easily-reusable common open API scheme and TAS-based integration method working with the oneM2M platforms will help the conventional WSNs in diverse industries evolve into the emerging WoT solutions. PMID:27782058

  5. Promotion of activity and thermal stability of chloroperoxidase by trace amount of metal ions (M2+/M3+).

    Science.gov (United States)

    Li, Haiyun; Gao, Jinwei; Wang, Limin; Li, Xiaohong; Jiang, Yucheng; Hu, Mancheng; Li, Shuni; Zhai, Quanguo

    2014-03-01

    The effect of M(2+) (Zn(2+), Cu(2+), Cd(2+), Mn(2+), Pb(2+)) and M(3+) (Cr(3+), La(3+), Fe(3+), Ce(3+), Y(3+), Al(3+)) metal ions on the activity and thermal stability of chloroperoxidase (CPO) was investigated in this work. It was found that the lower concentration of metal ions was favorable to CPO activity whereas the higher concentration reversed the results. CPO activity could be increased to 116.4-127.1% in the presence of a trace amount of these M(2+)/M(3+) metal ions at a concentration range of 0-25 μmol L(-1) after 2 h of incubation at 25 °C. The activating effect of M(3+) is better than that of M(2+), and Cr(3+) was mostly efficient. The thermal stability of the enzyme was also improved significantly. Only 30.3% of CPO activity was retained at 50 °C whereas 82.6% of CPO activity was maintained in the presence of Cr(3+) after 2 h of incubation at the same temperature. The activation of CPO by metal ions at their low concentration was studied through intrinsic fluorescence, circular dichroism (CD), and UV-Vis spectra assay. A favorable environment around the active site was achieved in the presence of metal ions. Intrinsic fluorescence and CD spectra indicated that the α-helix structure of CPO was strengthened in metal ion-contained media. More exposure of the heme ring was achieved for easy access of the substrate, which was suggested by UV-Vis spectrum analysis. This strategy for enhancing CPO activity is very simple and useful. It will be favorable to the practical application of this enzyme.

  6. Xanomeline quasi-irreversibly bound to an ectopic site can stimulate presynaptic M2 receptors via the orthosteric binding site

    Czech Academy of Sciences Publication Activity Database

    Machová, Eva; El-Fakahany, E. E.; Doležal, Vladimír

    2005-01-01

    Roč. 94, č. S2 (2005), s. 90-90 ISSN 0022-3042. [Biennial Meeting of the International Society for Neurochemistry and the European Society for Neurochemistry /20./. 21.08.2005-26.08.2005, Innsbruck] R&D Projects: GA AV ČR(CZ) IAA5011206; GA ČR(CZ) GA305/05/0452 Institutional research plan: CEZ:AV0Z50110509 Keywords : xanomeline * presynaptic M2 receptor * acetylcholine release * brain cortex * wash-resistant binding Subject RIV: ED - Physiology

  7. Solution NMR structure of the V27A drug resistant mutant of influenza A M2 channel

    International Nuclear Information System (INIS)

    Pielak, Rafal M.; Chou, James J.

    2010-01-01

    Research highlights: → This paper reports the structure of the V27A drug resistant mutant of the M2 channel of influenza A virus. → High quality NMR data allowed a better-defined structure for the C-terminal region of the M2 channel. → Using the structure, we propose a proton transfer pathway during M2 proton conduction. → Structural comparison between the wildtype, V27A and S31N variants allowed an in-depth analysis of possible modes of drug resistance. → Distinct feature of the V27A channel pore also provides an explanation for its faster rate of proton conduction. -- Abstract: The M2 protein of influenza A virus forms a proton-selective channel that is required for viral replication. It is the target of the anti-influenza drugs, amantadine and rimantadine. Widespread drug resistant mutants, however, has greatly compromised the effectiveness of these drugs. Here, we report the solution NMR structure of the highly pathogenic, drug resistant mutant V27A. The structure reveals subtle structural differences from wildtype that maybe linked to drug resistance. The V27A mutation significantly decreases hydrophobic packing between the N-terminal ends of the transmembrane helices, which explains the looser, more dynamic tetrameric assembly. The weakened channel assembly can resist drug binding either by destabilizing the rimantadine-binding pocket at Asp44, in the case of the allosteric inhibition model, or by reducing hydrophobic contacts with amantadine in the pore, in the case of the pore-blocking model. Moreover, the V27A structure shows a substantially increased channel opening at the N-terminal end, which may explain the faster proton conduction observed for this mutant. Furthermore, due to the high quality NMR data recorded for the V27A mutant, we were able to determine the structured region connecting the channel domain to the C-terminal amphipathic helices that was not determined in the wildtype structure. The new structural data show that the

  8. Photocatalytic Water Splitting for Hydrogen Production with Novel M2YbSbO7 (M = In, Gd, Y by Using Visible Light Photoenergy

    Directory of Open Access Journals (Sweden)

    Jingfei Luan

    2012-01-01

    Full Text Available Novel photocatalysts M2YbSbO7 (M=In, Gd, Y were synthesized by solid state reaction method for the first time. A comparative study on the structural and photocatalytic properties of M2YbSbO7 M2YbSbO7 (M=In, Gd, Y was reported. The results showed that In2YbSbO7, Gd2YbSbO7, and Y2YbSbO7 crystallized with the pyrochlore-type structure, cubic crystal system and space group Fd3m. For the photocatalytic water splitting reaction, H2 or O2 evolution was observed from pure water with In2YbSbO7, Gd2YbSbO7, or Y2YbSbO7 as the photocatalyst under visible light irradiation. (wavelength>420 nm. Moreover, under visible light irradiation (>420 nm, H2 and O2 were also evolved by using In2YbSbO7, Gd2YbSbO7, or Y2YbSbO7 as catalyst from CH3OH/H2O and AgNO3/H2O solutions respectively. The In2YbSbO7 photocatalyst showed the highest activity compared with Gd2YbSbO7 or Y2YbSbO7. At the same time, The Y2YbSbO7 photocatalyst showed higher activity compared with Gd2YbSbO7. The photocatalytic activities were further improved under visible light irradiation with In2YbSbO7, Gd2YbSbO7, or Y2YbSbO7 being loaded by Pt, NiO, or RuO2. The effect of Pt was better than that of NiO or RuO2 for improving the photocatalytic activity of In2YbSbO7, Gd2YbSbO7, or Y2YbSbO7.

  9. Simulations of the pore structures for a M2G1yR derived channel forming peptide in membrane

    Science.gov (United States)

    Al-Rawi, Ahlam N.; Al-Rawi, Asma; Chen, Jianhan; Herrera, Alvaro; Tomich, John; Rahman, Talat S.

    2008-03-01

    In an effort to develop a peptide-based compound suitable for clinical use as a channel replacement therapeutic for treating channelopathies such as cystic fibrosis, we present a reductionist model that appears to capture many of the biophysical properties of an intact ion channel using short channel-forming peptides. We have developed two anion selective channel-forming peptides with near native and altered properties from the peptides derived from the glycine receptor: NK4-M2GlyR-p22 WT (KKKKPAR-VGLGITTVLTMTTQS) and NK4-M2GlyR-p22 S22W (KKKKPARVGLGITTVLTMTTQW), respectively. Starting with the two structures determined by solution multidimensional NMR (800 MHz) in SDS, we used CHARMM and NAMD to perform molecular dynamics simulations on the monomers. Using the existing experimental data, we then built an initial 5- helix assembly by altering the tilted angle, rotational angle and pore radius. We investigated the impact of the single mutation at position 22 on the structure and dynamics of the pore formed in a membrane build in a hydrated POPC lipid bilayer. Probable structures for both assemblies are presented.

  10. M2 priority screening system for near-term activities: Project documentation. Final report December 11, 1992--May 31, 1994

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-08-12

    From May through August, 1993, the M-2 Group within M Division at LANL conducted with the support of the LANL Integration and Coordination Office (ICO) and Applied Decision Analysis, Inc. (ADA), whose purpose was to develop a system for setting priorities among activities. This phase of the project concentrated on prioritizing near-tenn activities (i.e., activities that must be conducted in the next six months) necessary for setting up this new group. Potential future project phases will concentrate on developing a tool for setting priorities and developing annual budgets for the group`s operations. The priority screening system designed to address the near-term problem was developed, applied in a series of meeting with the group managers, and used as an aid in the assignment of tasks to group members. The model was intended and used as a practical tool for documenting and explaining decisions about near-term priorities, and not as a substitute for M-2 management judgment and decision-making processes.

  11. Computer simulation of ion channel gating: the M(2) channel of influenza A virus in a lipid bilayer

    Science.gov (United States)

    Schweighofer, K. J.; Pohorille, A.

    2000-01-01

    The transmembrane fragment of the influenza virus M(2) protein forms a homotetrameric channel that transports protons. In this paper, we use molecular dynamics simulations to help elucidate the mechanism of channel gating by four histidines that occlude the channel lumen in the closed state. We test two competing hypotheses. In the "shuttle" mechanism, the delta nitrogen atom on the extracellular side of one histidine is protonated by the incoming proton, and, subsequently, the proton on the epsilon nitrogen atom is released on the opposite side. In the "water-wire" mechanism, the gate opens because of electrostatic repulsion between four simultaneously biprotonated histidines. This allows for proton transport along the water wire that penetrates the gate. For each system, composed of the channel embedded in a hydrated phospholipid bilayer, a 1.3-ns trajectory was obtained. It is found that the states involved in the shuttle mechanism, which contain either single-protonated histidines or a mixture of single-protonated histidines plus one biprotonated residue, are stable during the simulations. Furthermore, the orientations and dynamics of water molecules near the gate are conducive to proton transfer. In contrast, the fully biprotonated state is not stable. Additional simulations show that if only two histidines are biprotonated, the channel deforms but the gate remains closed. These results support the shuttle mechanism but not the gate-opening mechanism of proton gating in M(2).

  12. Organophosphorus compounds preferentially affect second messenger systems coupled to M2/M4 receptors in rat frontal cortex.

    Science.gov (United States)

    Ward, T R; Mundy, W R

    1996-01-01

    Recent reports indicate that organophosphate insecticides, in addition to inhibiting acetylcholinesterase activity, can bind directly at a subset of muscarinic receptors, which also bind cis-methyldioxolane with high affinity. Muscarinic receptors are known to act through at least two second messenger systems, either the stimulation of phosphoinositide turnover (mediated through the M1 and M3 receptor subtypes) or the inhibition of cAMP formation (mediated through the M2 and M4 receptor subtypes). We have investigated the action of the active forms of parathion, malathion, and chlorpyrifos (paraoxon, malaoxon, and chlorpyrifos oxon, respectively) on these second messenger systems in cortical slices from adult male Long-Evans rats. Paraoxon, malaoxon, and chlorpyrifos oxon (10(-8) to 10(-4) M) inhibited forskolin-stimulated cAMP formation in a concentration-dependent manner. The effect on cAMP formation was blocked by the muscarinic antagonist atropine (10 microM). These results suggest that paraoxon, malaoxon, and chlorpyrifos oxon can act as agonists at the M2 and/or M4 subset of muscarinic receptors. In addition, chlorpyrifos may have another site of action. In contrast, none of the organophosphates had any effect on basal or carbachol-stimulated phosphoinositide hydrolysis. The differential activity on these two second messenger systems make it unlikely that the observed effects on cAMP formation are due to increases in endogenous acetylcholine resulting from inhibition of acetylcholinesterase.

  13. Lactobacillus plantarum CLP-0611 ameliorates colitis in mice by polarizing M1 to M2-like macrophages.

    Science.gov (United States)

    Jang, Se-Eun; Han, Myung Joo; Kim, Se-Young; Kim, Dong-Hyun

    2014-07-01

    The TNF-α expression-inhibitory effect of lactic acid bacteria (LAB) isolated from kimchi were measured in lipopolysaccharide (LPS)-stimulated peritoneal macrophages. Among the LAB evaluated, Lactobacillus plantarum CLP-0611 inhibited the IL-1β and IL-6 expression, as well as the NF-κB and AP1 activation in LPS-stimulated peritoneal macrophages. Therefore, we investigated its inhibitory effect on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. TNBS significantly induced colon shortening, as well as myeloperoxidase activity and macroscopic score. Oral administration of CLP-0611 significantly reduced TNBS-induced body weight loss, colon shortening, myeloperoxidase activity, IRAK-1 phosphorylation, NF-κB and MAP kinase (p38, ERK, JNK) activation, and iNOS and COX-2 expression. CLP-0611 also inhibited TNBS-induced expression of TNF-α, IL-1β, and IL-6. However, IL-10 expression was induced. CLP-0611 also induced the production of M2 macrophage markers (IL-10, arginase I and CD206). Based on these findings, CLP-0611 inhibits TLR-4-linked NF-κB and MAPK signaling pathways and polarizes M1 to M2-like macrophages, thus ameliorating colitis. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. The development and testing of the thermal break divertor monoblock target design delivering 20 MW m-2 heat load capability

    Science.gov (United States)

    Fursdon, M.; Barrett, T.; Domptail, F.; Evans, Ll M.; Luzginova, N.; Greuner, N. H.; You, J.-H.; Li, M.; Richou, M.; Gallay, F.; Visca, E.

    2017-12-01

    The design and development of a novel plasma facing component (for fusion power plants) is described. The component uses the existing ‘monoblock’ construction which consists of a tungsten ‘block’ joined via a copper interlayer to a through CuCrZr cooling pipe. In the new concept the interlayer stiffness and conductivity properties are tuned so that stress in the principal structural element of the component (the cooling pipe) is reduced. Following initial trials with off-the-shelf materials, the concept was realized by machined features in an otherwise solid copper interlayer. The shape and distribution of the features were tuned by finite element analyses subject to ITER structural design criterion in-vessel components (SDC-IC) design rules. Proof of concept mock-ups were manufactured using a two stage brazing process verified by tomography and micrographic inspection. Full assemblies were inspected using ultrasound and thermographic (SATIR) test methods at ENEA and CEA respectively. High heat flux tests using IPP’s GLADIS facility showed that 200 cycles at 20 MW m-2 and five cycles at 25 MW m-2 could be sustained without apparent component damage. Further testing and component development is planned.

  15. Multidrug resistance genes, including bla(KPC) and bla(CTX)-M-2, among Klebsiella pneumoniae isolated in Recife, Brazil.

    Science.gov (United States)

    Cabral, Adriane Borges; Melo, Rita de Cássia de Andrade; Maciel, Maria Amélia Vieira; Lopes, Ana Catarina Souza

    2012-10-01

    The prevalence of cephalosporins and carbapenem-resistant Klebsiella pneumoniae strains is rising in Brazil, with potential serious consequences in terms of patients' outcomes and general care. This study characterized 24 clinical isolates of K. pneumoniae from two hospitals in Recife, Brazil, through the antimicrobial susceptibility profile, analyses of β-lactamase genes (bla(TEM), bla(SHV),bla(CTX-M), bla(KPC), bla(VIM), bla(IMP), and bla(SPM), plasmidial profile and ERIC-PCR (Enterobacterial repetitive intergenic consensus-polymerase chain reaction). ERIC-PCR and plasmidial analysis grouped the isolates in 17 and 19 patterns, respectively. Six isolates from one hospital presented the same pattern by ERIC-PCR, indicating clonal dissemination. All isolates presented bla(SHV), 62.5% presented bla(CTX)-M-2, 29% bla(TEM), and 41.7% bla(KPC). Metallo-β-lactamase genes bla(VIM), bla(IMP), and bla(SPM) not detected. Eleven isolates were identified carrying at least 3 β-lactamase studied genes, and 2 isolates carried bla(SHV), bla(TEM), bla (CTX-M-2) and bla(KPC) simultaneously. The accumulation of resistance genes in some strains, observed in this study, imposes limitations in the therapeutic options available for the treatment of infections caused by K. pneumoniae in Recife, Brazil. These results should alert the Brazilian medical authorities to establish rigorous methods for more efficiently control the dissemination of antimicrobial resistance genes in the hospital environment.

  16. Proinflammatory-Activated Glioma Cells Induce a Switch in Microglial Polarization and Activation Status, From a Predominant M2b Phenotype to a Mixture of M1 and M2a/B Polarized Cells

    Directory of Open Access Journals (Sweden)

    Lucia Lisi

    2014-04-01

    Full Text Available Malignant gliomas are primary brain tumors characterized by morphological and genetic complexities, as well as diffuse infiltration into normal brain parenchyma. Within gliomas, microglia/macrophages represent the largest tumor-infiltrating cell population, contributing by at least one-third to the total tumor mass. Bi-directional interactions between glioma cells and microglia may therefore play an important role on tumor growth and biology. In the present study, we have characterized the influence of glioma-soluble factors on microglial function, comparing the effects of media harvested under basal conditions with those of media obtained after inducing a pro-inflammatory activation state in glioma cells. We found that microglial cells undergo a different pattern of activation depending on the stimulus; in the presence of activated glioma-derived factors, i.e. a condition mimicking the late stage of pathology, microglia presents as a mixture of polarization phenotypes (M1 and M2a/b, with up-regulation of iNOS (inducible nitric oxide synthase, ARG (arginase and IL (interleukine-10. At variance, microglia exposed to basal glioma-derived factors, i.e. a condition resembling the early stage of pathology, shows a more specific pattern of activation, with increased M2b polarization status and up-regulation of IL-10 only. As far as viability and cell proliferation are concerned, both LI-CM [LPS (lipopolysaccharide—IFNγ (interferon γ conditioned media] and C-CM (control-conditioned media induce similar effects on microglial morphology. Finally, in human glioma tissue obtained from surgical resection of patients with IV grade glioblastoma, we detected a significant amount of CD68 positive cells, which is a marker of macrophage/microglial phagocytic activity, suggesting that in vitro findings presented here might have a relevance in the human pathology as well.

  17. The response to climate factors for the different specificity in M2 physiology of 60Co γ-ray irradiated flowers

    International Nuclear Information System (INIS)

    Qiang Jiye; Chen Zongyu; Guo Shichang

    2004-01-01

    Physiology and climate factor of different M 2 flower (Begonia tuberhybrida Voss and Dahlia pinnata Cav root) after 60 Co γ-ray irradiated were determined. The result showed that transpiration rate, stoma conductance, intercellular CO 2 concentration of M 2 of Dahlia pinnata Cav are affected obviously with climate factors, however, effect on the photosynthetic speed was not found, and M 2 of Begonia tuberhybrida Voss was not significant for physiology to climate

  18. SF3M 2.0: improvement of 3D photo-reconstruction interface based on freely available software

    Science.gov (United States)

    Castillo, Carlos; James, Michael R.; Pérez, Rafael; Gómez, Jose A.

    2016-04-01

    During recent years, a number of tools based on Structure-from-Motion algorithms have been released for full image-based 3D reconstruction either freely (e.g. Bundler, PMVS2, VisualSFM, MicMac) or commercially (e.g. Agisoft PhotoScan). The SF3M interface was developed in Matlab® to use link software developments (VisualSFM, CloudCompare) and new applications to create a semi-automated workflow including reconstruction, georeferencing and point-cloud filtering, and has been tested for gully erosion assessment with terrestrial images (Castillo et al., 2015). The main aim of this work to provide an improved freely-available and easy-to-use alternative for 3D reconstruction intended for public agencies, non-profit organisations, researchers and other stakeholders interested in 3D modelling. In this communication we present SF3M 2.0, a new version of the graphical user interface. In this case, the SfM module is based on MicMac, an open-software tool (Pierrot-Deseilligny and Cléry, 2011) which provides advanced features such as camera calibration and constrained bundle adjustment using ground control points. SF3M 2.0 will be tested in two scenarios: a) using the same ground-based image set tested in Castillo et al. (2015) to compare the performance of both versions and b) using aerial images taken from a helium balloon to assess a gully network in a 40-hectares catchment. In this study we explore the advantages of SF3M 2.0, explain its operation and evaluate its accuracy and performance. This tool will be also available for free download. References Castillo, C., James, M.R., Redel-Macías, M. D., Pérez, R., and Gómez, J.A.: SF3M software: 3-D photo-reconstruction for non-expert users and its application to a gully network, SOIL, 1, 583-594. Pierrot-Deseilligny, M and Cléry, I. APERO, an Open Source Bundle Adjusment Software for Automatic Calibration and Orientation of a Set of Images. Proceedings of the ISPRS Commission V Symposium, Image Engineering and Vision

  19. The Role of M1 and M2 Macrophages in Prostate Cancer in relation to Extracapsular Tumor Extension and Biochemical Recurrence after Radical Prostatectomy

    Directory of Open Access Journals (Sweden)

    M. Lanciotti

    2014-01-01

    Full Text Available Introduction. The aim of our work was to investigate the causal connection between M1 and M2 macrophage phenotypes occurrence and prostate cancer, their correlation with tumor extension (ECE, and biochemical recurrence (BR. Patient and Methods. Clinical and pathological data were prospectively gathered from 93 patients treated with radical prostatectomy. Correlations of commonly used variables were evaluated with uni- and multivariate analysis. The relationship between M1 and M2 occurrence and BR was also assessed with Kaplan-Meier survival analysis. Results. Above all in 63.4% there was a M2 prevalence. M1 occurred more frequently in OC disease, while M2 was more represented in ECE. At univariate analysis biopsy and pathologic GS and M2 were statistically correlated with ECE. Only pathologic GS and M2 confirmed to be correlated with ECE. According to macrophage density BCR free survival curves presented a statistically significant difference. When we stratified our population for M1 and M2,we did not find any statistical difference among curves. At univariate analysis GS, pTNM, and positive margins resulted to be significant predictors of BCR, while M1 and M2 did not achieve the statistical significance. At multivariate analysis, only GS and pathologic stage were independent predictors of BR. Conclusion. In our study patients with higher density of M count were associated with poor prognosis; M2 phenotype was significantly associated with ECE.

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

    DEFF Research Database (Denmark)

    Joseph, Lauren; Thomsen, Morgane

    2017-01-01

    Muscarinic M1/M4 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 (SD) effects, but the receptor subtypes mediating those...

  1. Assessment Report Sandia National Laboratories Fuel Cycle Technologies Quality Assurance Evaluation of FY15 SNL FCT M2 Milestone Deliverables

    Energy Technology Data Exchange (ETDEWEB)

    Appel, Gordon John [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2016-05-01

    Sandia National Laboratories (SNL) Fuel Cycle Technologies (FCT) program activities are conducted in accordance with FCT Quality Assurance Program Document (FCT-QAPD) requirements. The FCT-QAPD interfaces with SNL approved Quality Assurance Program Description (SNL-QAPD) as explained in the Sandia National Laboratories QA Program Interface Document for FCT Activities (Interface Document). This plan describes SNL's FY16 assessment of SNL's FY15 FCT M2 milestone deliverable's compliance with program QA requirements, including SNL R&A requirements. The assessment is intended to confirm that SNL's FY15 milestone deliverables contain the appropriate authenticated review documentation and that there is a copy marked with SNL R&A numbers.

  2. Magnetic characteristics of M2FeV3O11 (M = Mg, Zn, Pb, Co, Ni) compounds

    Science.gov (United States)

    Groń, T.; Blonska-Tabero, A.; Filipek, E.; Stokłosa, Z.; Duda, H.; Sawicki, B.

    2018-02-01

    The unusual physical characteristics of the multicomponent oxide systems renewed the interest as the potential cathode materials in high-energy cells. Since the earlier magnetic characteristics were not entirely conclusive, we report the results of dc magnetic measurements including higher harmonics of ac magnetic susceptibility of the M2FeV3O11 (M = Mg, Zn, Pb, Co, Ni) compounds. Ferrimagnetic long-range and antiferromagnetic short-range interactions for all compounds under study at low temperatures as well as superparamagnetic-like behavior with the blocking temperature of 29 K and the freezing parameter of 0.013 were observed. These effects are discussed within the framework of superexchange and double exchange magnetic interactions as well as the mixed valence band of iron ions.

  3. Proto-planetary nebulae. I. The extreme bipolar nebulae M2-9 and M1-91

    International Nuclear Information System (INIS)

    Goodrich, R.W.

    1991-01-01

    Results are presented on a long-slit optical spectroscopy measurements of the prototype bipolar planetary nebula M2-9 and the M1-91 bipolar nebula, performed in order to determine the nature of the morphology of the wings of these two nebulae. It is concluded that the overall bipolar morphologies of these nebulae might be due to the orbital motions of binaries, with the orbital angular momentum vector defining the axis of the nebula. Secondary symmetries in the nebulae, such as the point-symmetric knots in M1-91, could be due to other symmetries, such as the rotation axis of one of the individual stars or the polar axis of the accretion disk. 39 refs

  4. Growth kinetics of boride coatings formed at the surface AISI M2 during dehydrated paste pack boriding

    Energy Technology Data Exchange (ETDEWEB)

    Doñu Ruiz, M.A., E-mail: mdonur0800@alumno.ipn.mx [Universidad Politécnica del Valle de México UPVM, Grupo Ciencia e Ingeniería de Materiales, Av. Mexiquense S/N Esquina Av. Universidad Politécnica, Col Villa Esmeralda, 54910 Tultitlan (Mexico); López Perrusquia, N.; Sánchez Huerta, D. [Universidad Politécnica del Valle de México UPVM, Grupo Ciencia e Ingeniería de Materiales, Av. Mexiquense S/N Esquina Av. Universidad Politécnica, Col Villa Esmeralda, 54910 Tultitlan (Mexico); Torres San Miguel, C.R.; Urriolagoitia Calderón, G.M. [Instituto Politécnico Nacional, SEPI-ESIME, Unidad Profesional Adolfo López Mateos Zacatenco, Edificio 5, 2do. Piso, Col. Lindavista, CP 07738 México, D.F. (Mexico); Cerillo Moreno, E.A. [Universidad Politécnica del Valle de México UPVM, Grupo Ciencia e Ingeniería de Materiales, Av. Mexiquense S/N Esquina Av. Universidad Politécnica, Col Villa Esmeralda, 54910 Tultitlan (Mexico); Cortes Suarez, J.V. [Univerisdad Autónoma Metropolitana Unidad Azcapotzalco, Av. San Pablo 180 Azcapotzalco 02200, Área de Ciencia de los Materiales, México, D.F. (Mexico)

    2015-12-01

    The growth kinetics of the boride coatings (FeB and Fe{sub 2}B) at the surface of AISI M2 high speed steels were studied in this work. Boriding thermochemical treatment was carried out by dehydrated paste pack at three different temperatures 1173, 1223, and 1273 K and four exposure times 1, 3, 5, and 7 h, respectively. The presence of FeB and Fe{sub 2}B phases was identified by scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS) and X-ray diffraction method. In order to obtain the boron diffusion coefficients at the FeB/Fe{sub 2}B boride coatings, a mathematical model based on the mass balance at the growing interfaces was proposed under certain assumptions. Likewise the parabolic growth constants and the boride incubation time were established as a function of the parameters η (T) and ε (T). The activation energy values estimated for the FeB and Fe{sub 2}B layers were 233.42 and 211.89 kJ mol{sup −1} respectively. A good agreement was obtained between the simulated values of boride layer thicknesses and the experimental results. Finally, empirical relationships of boride coating thickness as a function of boriding temperature and time are presented. - Highlights: • Formed boride coatings at the surface of AISI M2 high speed steels by new process dehydrated paste pack boriding. • The model was based on the mass balance equation at the FeB/Fe{sub 2}B and Fe{sub 2}B/Fe interfaces by considering the boride incubation time. • A good agreement was obtained between the simulated values of boride layers coatings and the experimental results.

  5. Evidence That Ly6C(hi) Monocytes are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization.

    Science.gov (United States)

    Chu, Hannah X; Broughton, Brad R S; Kim, Hyun Ah; Lee, Seyoung; Drummond, Grant R; Sobey, Christopher G

    2015-07-01

    Ly6C(hi) monocytes are generally thought to exert a proinflammatory role in acute tissue injury, although their impact after injuries to the central nervous system is poorly defined. CC chemokine receptor 2 is expressed on Ly6C(hi) monocytes and plays an essential role in their extravasation and transmigration into the brain after cerebral ischemia. We used a selective CC chemokine receptor 2 antagonist, INCB3344, to assess the effect of Ly6C(hi) monocytes recruited into the brain early after ischemic stroke. Male C57Bl/6J mice underwent occlusion of the middle cerebral artery for 1 hour followed by 23 hours of reperfusion. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (10, 30 or 100 mg/kg IP) 1 hour before ischemia and at 2 and 6 hours after ischemia. At 24 hours, we assessed functional outcomes, infarct volume, and quantified the immune cells in blood and brain by flow cytometry or immunofluorescence. Gene expression of selected inflammatory markers was assessed by quantitative polymerase chain reaction. Ly6C(hi) monocytes were increased 3-fold in the blood and 10-fold in the brain after stroke, and these increases were selectively prevented by INCB3344 in a dose-dependent manner. Mice treated with INCB3344 exhibited markedly worse functional outcomes and larger infarct volumes, in association with reduced M2 polarization and increased peroxynitrite production in macrophages, compared with vehicle-treated mice. Our data suggest that Ly6C(hi) monocytes exert an acute protective effect after ischemic stroke to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization. © 2015 American Heart Association, Inc.

  6. Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway

    Science.gov (United States)

    Mesquita, Thássio R. R.; de Jesus, Itamar C. G.; dos Santos, Jucilene F.; de Almeida, Grace K. M.; de Vasconcelos, Carla M. L.; Guatimosim, Silvia; Macedo, Fabrício N.; dos Santos, Robervan V.; de Menezes-Filho, José E. R.; Miguel-dos-Santos, Rodrigo; Matos, Paulo T. D.; Scalzo, Sérgio; Santana-Filho, Valter J.; Albuquerque-Júnior, Ricardo L. C.; Pereira-Filho, Rose N.; Lauton-Santos, Sandra

    2017-01-01

    Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M2) and downregulation of β1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba. PMID:28553225

  7. Rapid Evidence Review of Bariatric Surgery in Super Obesity (BMI ≥ 50 kg/m2).

    Science.gov (United States)

    Peterson, Kim; Anderson, Johanna; Boundy, Erin; Ferguson, Lauren; Erickson, Katherine

    2017-04-01

    Despite accumulating evidence of the important health benefits of bariatric surgery in morbidly obese patients in general, bariatric surgery outcomes are less clear in higher-risk, high-priority populations of patients with BMI ≥ 50 kg/m 2 . To help the Department of Veterans Affairs (VA) Health Services Research & Development Service (HSR&D) develop a research agenda, we conducted a rapid evidence review to better understand bariatric surgery outcomes in adults with BMI ≥ 50 kg/m 2 . We searched MEDLINE ® , the Cochrane Database of Systematic Reviews, the Cochrane Central Registry of Controlled Trials, and ClinicalTrials.gov through June 2016. We included trials and observational studies. We used pre-specified criteria to select studies, abstract data, and rate internal validity and strength of the evidence (PROSPERO registration number CRD42015025348). All decisions were completed by one reviewer and checked by another. Among 1892 citations, we included 23 studies in this rapid review. Compared with usual care, one large retrospective VA study provided limited evidence that bariatric surgery can lead to increased mortality in the first year, but decreased mortality long-term among super obese veterans. Studies that compared different bariatric surgical approaches suggested some differences in weight loss and complications. Laparoscopic gastric bypass generally resulted in greater short-term proportion of excess weight loss than did other procedures. Duodenal switch led to greater long-term weight loss than did gastric bypass, but with more complications. The published literature that separates the super obese is insufficient for determining the precise balance of benefits and harms of bariatric surgery in this high-risk subgroup. Future studies should evaluate a more complete set of key outcomes with longer follow-up in larger samples of more broadly representative adults.

  8. Selective activation of heterologously expressed G protein-gated K+ channels by M2 muscarinic receptors in rat sympathetic neurones

    Science.gov (United States)

    Fernandez-Fernandez, Jose M; Wanaverbecq, Nicolas; Halley, Pam; Caulfield, Malcolm P; Brown, David A

    1999-01-01

    G protein-regulated inward rectifier K+ (GIRK) channels were over-expressed in dissociated rat superior cervical sympathetic (SCG) neurones by co-transfecting green fluorescent protein (GFP)-, GIRK1- and GIRK2-expressing plasmids using the biolistic technique. Membrane currents were subsequently recorded with whole-cell patch electrodes.Co-transfected cells had larger Ba2+-sensitive inwardly rectifying currents and 13 mV more negative resting potentials (in 3 mm[K+]o) than non-transfected cells, or cells transfected with GIRK1 or GIRK2 alone.Carbachol (CCh, 1–30 μm) increased the inwardly rectifying current in 70% of GIRK1+ GIRK2-transfected cells by 261 ± 53% (n = 6, CCh 30 μm) at −120 mV, but had no effect in non-transfected cells or in cells transfected with GIRK1 or GIRK2 alone. Pertussis toxin prevented the effect of carbachol but had no effect on basal currents.The effect of CCh was antagonized by 6 nm tripitramine but not by 100 nm pirenzepine, consistent with activation of endogenous M2 muscarinic acetylcholine receptors.In contrast, inhibition of the voltage-activated Ca2+ current by CCh was antagonized by 100 nm pirenzepine but not by 6 nm tripitramine, indicating that it was mediated by M4 muscarinic acetylcholine receptors.We conclude that endogenous M2 and M4 muscarinic receptors selectively couple to GIRK currents and Ca2+ currents respectively, with negligible cross-talk. PMID:10066893

  9. Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway

    Directory of Open Access Journals (Sweden)

    Thássio R. R. Mesquita

    2017-05-01

    Full Text Available Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o. reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.. Moreover, GBE prevented the upregulation of muscarinic receptors (M2 and downregulation of β1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba.

  10. BTB and CNC homolog 1 (Bach1) deficiency ameliorates TNBS colitis in mice: role of M2 macrophages and heme oxygenase-1.

    Science.gov (United States)

    Harusato, Akihito; Naito, Yuji; Takagi, Tomohisa; Uchiyama, Kazuhiko; Mizushima, Katsura; Hirai, Yasuko; Higashimura, Yasuki; Katada, Kazuhiro; Handa, Osamu; Ishikawa, Takeshi; Yagi, Nobuaki; Kokura, Satoshi; Ichikawa, Hiroshi; Muto, Akihiko; Igarashi, Kazuhiko; Yoshikawa, Toshikazu

    2013-01-01

    BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1), which plays an important role in the protection of cells and tissues against acute and chronic inflammation. However, the role of Bach1 in the gastrointestinal mucosal defense system remains little understood. HO-1 supports the suppression of experimental colitis and localizes mainly in macrophages in colonic mucosa. This study was undertaken to elucidate the Bach1/HO-1 system's effects on the pathogenesis of experimental colitis. This study used C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice in which colonic damage was induced by the administration of an enema of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Subsequently, they were evaluated macroscopically, histologically, and biochemically. Peritoneal macrophages from the respective mice were isolated and analyzed. Then, wild-type mice were injected with peritoneal macrophages from the respective mice. Acute colitis was induced similarly. TNBS-induced colitis was inhibited in Bach1-deficient mice. TNBS administration increased the expression of HO-1 messenger RNA and protein in colonic mucosa in Bach1-deficient mice. The expression of HO-1 mainly localized in F4/80-immunopositive and CD11b-immunopositive macrophages. Isolated peritoneal macrophages from Bach1-deficient mice highly expressed HO-1 and also manifested M2 macrophage markers, such as Arginase-1, Fizz-1, Ym1, and MRC1. Furthermore, TNBS-induced colitis was inhibited by the transfer of Bach1-deficient macrophages into wild-type mice. Deficiency of Bach1 ameliorated TNBS-induced colitis. Bach1-deficient macrophages played a key role in protection against colitis. Targeting of this mechanism is applicable to cell therapy for human inflammatory bowel disease.

  11. Machining tools in AISI M2 high-speed steel obtained by spray forming process; Ferramentas de usinagem em aco rapido AISI M2 obtido por conformacao por 'spray'

    Energy Technology Data Exchange (ETDEWEB)

    Jesus, Edilson Rosa Barbosa de. E-mail: erbjesus@usp.br

    2004-07-01

    The aim of the present work was the obtention of AISI M2 high-speed steel by spray forming technique and the material evaluation when used as machining tool. The obtained material was hot rolled at 50% and 72% reduction ratios, and from which it was manufactured inserts for machining tests. The performance of inserts made of the spray formed material was compared to inserts obtained from conventional and powder metallurgy (MP) processed materials. The spray formed material was chemical, physical, mechanical and microstructural characterised. For further characterisation, the materials were submitted to machining tests for performance evaluation under real work condition. The results of material characterisation highlight the potential of the spray forming technique, in the obtention of materials with good characteristics and properties. Under the current processing, hot rolling and heat treatments condition, the analysis of the results of the machining tests revealed a very similar behaviour among the tested materials. Proceeding a criterious analysis of the machining results tests, it was verified that the performance presented by the powder metallurgy material (MP) was slight superior, followed by conventional obtained material (MConv), which presented a insignificant advantage over the spray formed and hot rolled (72% reduction ratio) material. The worst result was encountered for the spray forming and hot rolled (50% reduction ratio) material that presented the highest wear values. (author)

  12. Vaccination with M2e-based multiple antigenic peptides: characterization of the B cell response and protection efficacy in inbred and outbred mice.

    Directory of Open Access Journals (Sweden)

    Amaya I Wolf

    Full Text Available The extracellular domain of the influenza A virus protein matrix protein 2 (M2e is remarkably conserved between various human isolates and thus is a viable target antigen for a universal influenza vaccine. With the goal of inducing protection in multiple mouse haplotypes, M2e-based multiple antigenic peptides (M2e-MAP were synthesized to contain promiscuous T helper determinants from the Plasmodium falciparum circumsporozoite protein, the hepatitis B virus antigen and the influenza virus hemagglutinin. Here, we investigated the nature of the M2e-MAP-induced B cell response in terms of the distribution of antibody (Ab secreting cells (ASCs and Ab isotypes, and tested the protective efficacy in various mouse strains.Immunization of BALB/c mice with M2e-MAPs together with potent adjuvants, CpG 1826 oligonucleotides (ODN and cholera toxin (CT elicited high M2e-specific serum Ab titers that protected mice against viral challenge. Subcutaneous (s.c. and intranasal (i.n. delivery of M2e-MAPs resulted in the induction of IgG in serum and airway secretions, however only i.n. immunization induced anti-M2e IgA ASCs locally in the lungs, correlating with M2-specific IgA in the bronchio-alveolar lavage (BAL. Interestingly, both routes of vaccination resulted in equal protection against viral challenge. Moreover, M2e-MAPs induced cross-reactive and protective responses to diverse M2e peptides and variant influenza viruses. However, in contrast to BALB/c mice, immunization of other inbred and outbred mouse strains did not induce protective Abs. This correlated with a defect in T cell but not B cell responsiveness to the M2e-MAPs.Anti-M2e Abs induced by M2e-MAPs are highly cross-reactive and can mediate protection to variant viruses. Although synthetic MAPs are promising designs for vaccines, future constructs will need to be optimized for use in the genetically heterogeneous human population.

  13. Constant luminance (cd·s/m2) versus constant retinal illuminance (Td·s) stimulation in flicker ERGs.

    Science.gov (United States)

    Davis, C Quentin; Kraszewska, Olga; Manning, Colette

    2017-04-01

    To compare the effect of variable pupil size on the flicker electroretinogram (ERG) between a stimulus having constant luminance and a stimulus having constant retinal illuminance (constant Troland) that compensates for pupil size. Subjects (n = 18) were tested with 12 pairs of the stimuli. The stimulus pair consisted of the ISCEV standard constant luminance stimulus (3 cd·s/m 2 with a 30 cd/m 2 background) and a constant retinal illuminance stimulus (32 Td·s with a 320 Td background) selected to provide the same stimulus and background when the pupil diameter is 3.7 mm. Half the subjects were artificially dilated, and their response was measured before and during the dilation. The natural pupil group was used to assess intra- and inter-subject variability. The artificially dilated group was used to measure the flicker ERG's dependence on pupil size. With natural pupils, intra-subject variability was lower with the constant Troland stimulus, while inter-subject variability was similar between stimuli. During pupil dilation, the constant Troland stimulus did not have a dependence on pupil size up to 6.3 mm and had slightly larger amplitudes with longer implicit times for fully dilated pupils. For the constant luminance stimulus, waveform amplitudes varied by 22% per mm change in pupil diameter, or by 48% over the 2.2 mm diameter range measured in dilated pupil size. There was no difference in inter-subject variability between constant Troland natural pupils and the same subjects with a constant luminance stimulus when dilated (i.e., the ISCEV standard condition). These results suggest that a constant Troland flicker ERG test with natural pupils may be advantageous in clinical testing. Because of its insensitivity to pupil size, constant Troland stimuli should produce smaller reference ranges, which in turn should improve the sensitivity for detection of abnormalities and for monitoring changes. In addition, the test can be administered more efficiently as

  14. Macrophage imbalance (M1 vs. M2 and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results

    Directory of Open Access Journals (Sweden)

    Hasan David

    2012-09-01

    Full Text Available Abstract Background M1 and M2 cells are two major subsets of human macrophages that exert opposite effects on the inflammatory response. This study aims to investigate the role of macrophage M1/M2 imbalance and mast cells in the progression of human cerebral aneurysms to rupture. Methods Ten patients with cerebral aneurysms (five ruptured and five unruptured underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for M1 cells (anti-HLA DR, M2 cells (anti-CD 163, and mast cells (anti-tryptase clone AA. A segment of the superficial temporal artery (STA was also removed and immunostained with monoclonal antibodies for M1, M2, and mast cells. Results All ten aneurysm tissues stained positive for M1, M2, and mast cells. M1 and M2 cells were present in equal proportions in unruptured aneurysms. This contrasted with a marked predominance of M1 over M2 cells in ruptured aneurysms (p = 0.045. Mast cells were also prominently upregulated in ruptured aneurysms (p = 0.001. Few M1 and M2 cells were present in STA samples. Conclusions M1/M2 macrophages and mast cells are found in human cerebral aneurysms; however, M1 and mast cell expression seems to markedly increase in ruptured aneurysms. These findings suggest that macrophage M1/M2 imbalance and upregulation of mast cells may have a role in the progression of cerebral aneurysms to rupture.

  15. Spectroscopic Observation of Water-Mediated Deformation of the CARBOXYLATE-M2+ (M= Mg, Ca) Contact Ion Pair

    Science.gov (United States)

    Kelleher, Patrick J.; DePalma, Joseph W.; Johnson, Mark

    2016-06-01

    The binding of alkaline earth dications to the biologically relevant carboxylate ligand has previously been studied using vibrational sum frequency generation (VSFG) spectroscopy of the air-water interface, infrared multiple photon dissociation (IRMPD) spectroscopy of clusters, and DFT methods. These results suggest the presence of both monodentate and bidentate binding motifs of the M2+ ions to the cayboxyl head groups depending on the extent of solvation. We revisit these systems using vibrational predissociation spectroscopy to measure the gas-phase vibrational spectra of the D2-tagged microhydrated [MgOAc(H2O)n=1-5]+ and [CaOAc(H2O)n=1-6]+ clusters. The spectra show that [MgOAc(H2O)n]+ switches from bidentate to monodentate binding promptly at n = 5, while [CaOAc(H2O)n]+ retains its bidentate attachment such that the sixth water molecule initiates the second solvation shell. The difference in binding behavior between these two divalent metal ions is analyzed in the context of the local acidity of the solvent water molecules and the strength of the metal-carboxylate and metal-water interactions. This cluster study provides insight into the chemical physics underlying the unique and surprising impacts of Mg2+ and Ca2+ on the chemistry mediated by sea spray aerosols. Funding for this work was provided by the NSF's Center for Aerosol Impacts on Climate and the Environment.

  16. Magellan/M2FS Spectroscopy of Galaxy Clusters: Stellar Population Model and Application to Abell 267

    Science.gov (United States)

    Tucker, Evan; Walker, Matthew G.; Mateo, Mario; Olszewski, Edward W.; Bailey, John I., III; Crane, Jeffrey D.; Shectman, Stephen A.

    2017-09-01

    We report the results of a pilot program to use the Magellan/M2FS spectrograph to survey the galactic populations and internal kinematics of galaxy clusters. For this initial study, we present spectroscopic measurements for 223 quiescent galaxies observed along the line of sight of the galaxy cluster Abell 267 (z˜ 0.23). We develop a Bayesian method for modeling the integrated light from each galaxy as a simple stellar population, with free parameters that specify the redshift ({v}{los}/c) and characteristic age, metallicity ([{Fe}/{{H}}]), alpha-abundance ([α /{Fe}]), and internal velocity dispersion ({σ }{int}) for individual galaxies. Parameter estimates derived from our 1.5 hr observation of A267 have median random errors of {σ }{v{los}}=20 {km} {{{s}}}-1, {σ }{Age}=1.2 {Gyr}, {σ }[{Fe/{{H}}]}=0.11 {dex}, {σ }[α /{Fe]}=0.07 {dex}, and {σ }{σ {int}}=20 {km} {{{s}}}-1. In a companion paper, we use these results to model the structure and internal kinematics of A267.

  17. In silico screening, genotyping, molecular dynamics simulation and activity studies of SNPs in pyruvate kinase M2.

    Directory of Open Access Journals (Sweden)

    Ponnusamy Kalaiarasan

    Full Text Available Role of, 29-non-synonymous, 15-intronic, 3-close to UTR, single nucleotide polymorphisms (SNPs and 2 mutations of Human Pyruvate Kinase (PK M2 were investigated by in-silico and in-vitro functional studies. Prediction of deleterious substitutions based on sequence homology and structure based servers, SIFT, PANTHER, SNPs&GO, PhD-SNP, SNAP and PolyPhen, depicted that 19% emerged common between all the mentioned programs. SNPeffect and HOPE showed three substitutions (C31F, Q310P and S437Y in-silico as deleterious and functionally important. In-vitro activity assays showed C31F and S437Y variants of PKM2 with reduced activity, while Q310P variant was catalytically inactive. The allosteric activation due to binding of fructose 1-6 bisphosphate (FBP was compromised in case of S437Y nsSNP variant protein. This was corroborated through molecular dynamics (MD simulation study, which was also carried out in other two variant proteins. The 5 intronic SNPs of PKM2, associated with sporadic breast cancer in a case-control study, when subjected to different computational analyses, indicated that 3 SNPs (rs2856929, rs8192381 and rs8192431 could generate an alternative transcript by influencing splicing factor binding to PKM2. We propose that these, potentially functional and important variations, both within exons and introns, could have a bearing on cancer metabolism, since PKM2 has been implicated in cancer in the recent past.

  18. Autoradiographic distribution of M1, M2, M3, and M4 muscarinic receptor subtypes in Alzheimer's disease.

    Science.gov (United States)

    Rodríguez-Puertas, R; Pascual, J; Vilaró, T; Pazos, A

    1997-08-01

    We studied the autoradiographic densities of all pharmacologically characterised muscarinic receptors (MR) in frontal, temporal, and visual cortex, hippocampal formation, and striatum in autopsied brains from 19 histopathologically verified patients of Alzheimer's disease (AD) and in matched controls. Almost all (16 of 19) of the AD cases were severe. In AD brains, total MR, M1, and M3 MR subtypes were found to be significantly decreased in entorhinal cortex and in most hippocampal strata. Total MR and M1 receptors were also significantly reduced in visual area and in frontal cortex of AD brains, respectively. M2 receptors were significantly reduced over hippocampal formation but increased significantly in striatum of AD brains as compared with controls. M3 receptors in AD were in the range of controls in neocortex and striatum, whereas the M4 receptor subtype was also preserved in all brain regions in AD brains when compared with controls. This is the first autoradiographic study analysing the distribution of all MR subtypes in AD brains. These changes in MR densities concur with the general pattern of neuronal degeneration occurring in AD brains and partly explain the poor response of AD cognitive decline to present cholinergic supplementation therapies. Although M3 and M4 MR were labelled with nonselective approaches, the preservation of M4 and to a lesser degree M3 MR subtypes in AD brains could open an alternative way for the symptomatic therapy of AD dementia.

  19. Sleep During Pregnancy: The nuMoM2b Pregnancy and Sleep Duration and Continuity Study.

    Science.gov (United States)

    Reid, Kathryn J; Facco, Francesca L; Grobman, William A; Parker, Corette B; Herbas, Marcos; Hunter, Shannon; Silver, Robert M; Basner, Robert C; Saade, George R; Pien, Grace W; Manchanda, Shalini; Louis, Judette M; Nhan-Chang, Chia-Lang; Chung, Judith H; Wing, Deborah A; Simhan, Hyagriv N; Haas, David M; Iams, Jay; Parry, Samuel; Zee, Phyllis C

    2017-05-01

    To characterize sleep duration, timing and continuity measures in pregnancy and their association with key demographic variables. Multisite prospective cohort study. Women enrolled in the nuMoM2b study (nulliparous women with a singleton gestation) were recruited at the second study visit (16-21 weeks of gestation) to participate in the Sleep Duration and Continuity substudy. Women sleep log for 7 consecutive days. Time in bed, sleep duration, fragmentation index, sleep efficiency, wake after sleep onset, and sleep midpoint were averaged across valid primary sleep periods for each participant. Valid data were available from 782 women with mean age of 27.3 (5.5) years. Median sleep duration was 7.4 hours. Approximately 27.9% of women had a sleep duration of sleep duration of >9 hours. In multivariable models including age, race/ethnicity, body mass index, insurance status, and recent smoking history, sleep duration was significantly associated with race/ethnicity and insurance status, while time in bed was only associated with insurance status. Sleep continuity measures and sleep midpoint were significantly associated with all covariates in the model, with the exception of age for fragmentation index and smoking for wake after sleep onset. Our results demonstrate the relationship between sleep and important demographic characteristics during pregnancy. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

  20. Hyperhomocysteinemia Promotes Insulin Resistance and Adipose Tissue Inflammation in PCOS Mice Through Modulating M2 Macrophage Polarization via Estrogen Suppression.

    Science.gov (United States)

    Qi, Xinyu; Zhang, Bochun; Zhao, Yue; Li, Rong; Chang, Hsun-Ming; Pang, Yanli; Qiao, Jie

    2017-05-01

    It has been shown that serum homocysteine (Hcy) levels are higher in women with polycystic ovary syndrome (PCOS). However, the specific role of hyperhomocysteinemia (HHcy) in the development of PCOS has never been reported. Adipose tissue inflammation is featured by the infiltration of macrophages, which plays a critical role in the pathogenesis of glucose and insulin intolerance. In this study, C57BL/6 mice were treated with dehydroepiandrosterone (DHEA) and/or a high methionine diet to induce PCOS and HHcy mice models. We showed that DHEA induced a PCOS-like phenotypes, irregular estrous cycles, weight gain, abnormal sex hormone production, glucose and insulin resistance, and polycystic ovaries. HHcy further intensified the effects DHEA on the metabolic, endocrinal, hormonal, and morphological changes in PCOS-like mice. In addition, HHcy attenuated the DHEA-induced increase in serum estrogen levels in mice. Furthermore, HHcy may exacerbate the insulin resistance in PCOS-like mice, most likely through modulating the macrophage M1/M2 polarization pathways via the suppression of estrogen. Most important, our clinical data showed that there were increases in serum Hcy levels in patients with PCOS. These findings deepen our understanding of the pathological roles of HHcy in the development of PCOS and provide a promising target for PCOS therapy in clinical application. Copyright © 2017 Endocrine Society.

  1. Dendrosomal curcumin suppresses metastatic breast cancer in mice by changing m1/m2 macrophage balance in the tumor microenvironment.

    Science.gov (United States)

    Shiri, Sadaf; Alizadeh, Ali Mohammad; Baradaran, Behzad; Farhanghi, Baharak; Shanehbandi, Dariush; Khodayari, Saeed; Khodayari, Hamid; Tavassoli, Abbas

    2015-01-01

    Curcumin, a lipid-soluble compound extracted from the plant Curcuma Longa, has been found to exert immunomodulatory effects via macrophages. However, most studies focus on the low bioavailability issue of curcumin by nano and microparticles, and thus the role of macrophages in the anticancer mechanism of curcumin has received little attention so far. We have previously shown the potential biocompatibility, biodegradability and anti-cancer effects of dendrosomal curcumin (DNC). In this study, twenty-seven BALB/c mice were equally divided into control as well as 40 and 80 mg/kg groups of DNC to investigate the involvement of macrophages in the antitumor effects of curcumin in a typical animal model of metastatic breast cancer. At the end of intervention, the tumor volume and weight were significantly reduced in DNC groups compared to control (PDNC increased the expression of STAT4 and IL-12 genes in tumor and spleen tissues in comparison with control (PDNC decreased STAT3, IL-10 and arginase I gene expression (P<0.05), indicating low levels of M2 macrophage. The results confirm the role of macrophages in the protective effects of dendrosomal curcumin against metastatic breast cancer in mice.

  2. Assessment of Aflatoxin M1 and M2 exposure risk through Oaxaca cheese consumption in southeastern Mexico.

    Science.gov (United States)

    Ramírez-Martínez, Alejandra; Camarillo-Hernández, Estela; Carvajal-Moreno, Magda; Vargas-Ortíz, Manuel; Wesolek, Nathalie; Rodriguez Jimenes, Guadalupe Del Carmen; Garcia Alvarado, Miguel Ángel; Roudot, Alain-Claude; Salgado Cervantes, Marco Antonio; Robles-Olvera, Victor J

    2018-03-21

    The present study evaluated the exposure of Southeast Mexican population to Aflatoxin M1 (AFM1) and M2 (AFM2) through the consumption of Oaxaca cheese. The intake of Oaxaca cheese was assessed via a food 7-day dairy questionnaire (N = 1100, 2014 and 2015). Thirty Oaxaca cheeses were randomly sampled, and the origin of the samples was also investigated. AFM1 and AFM2 were quantified by HPLC-FD. The exposure was assessed through the combination of the Probabilistic Density Functions (probabilistic approach). The percentage of the population at risk was calculated through the population exceeding the toxicological reference values (TDI). The risk assessment revealed that the population at higher risk to AFM1 and AFM2 was the children, followed by the adolescents and adult women. To our knowledge, the present study is the first to assess the exposure risk of different age groups of a population to AFM1 and AFM2 through the consumption of cheese.

  3. Spacially confined M2 centers (M = Fe, Co, Ni, Zn) on a sterically bulky binucleating support: synthesis, structures and ethylene oligomerization studies.

    Science.gov (United States)

    Champouret, Yohan D M; Fawcett, John; Nodes, William J; Singh, Kuldip; Solan, Gregory A

    2006-11-27

    Two new bulky aryl-bridged pyridyl-imine compartmental (pro)ligands, 2,6-{(2,6-i-Pr(2)C6H3)N=C(Me)C5H3N}2C6H3Y (Y = H L1, OH L2-H), have been prepared in moderate to good overall yields via a Stille-type cross-coupling approach. The molecular structure of L2-H reveals a transoid configuration within the pyridyl-imine units with a hydrogen-bonding interaction maintaining the phenol coplanar with one of the adjacent pyridine rings. The interaction of 2 equiv of MX2 with L1 in n-BuOH at 110 degrees C gives the binuclear complexes, [(L1)M2X4] (M = Fe, X = Cl (1a); M = Co, X = Cl (1b); M = Ni, X = Br (1c); M = Zn, X = Cl (1d)), in which the metal centers adopt distorted tetrahedral geometries and occupy the two pyridyl-imine cavities in L1. In contrast, deprotonation of L2-H occurs upon reaction with 2 equiv of MX2 to afford the phenolate-bridged species [(L2)M2(mu-X)X2] (M = Fe, X = Cl (2a); M = Co, X = Cl (2b); M = Ni, X = Br (2c); M = Zn, X = Cl (2d)). 1H NMR studies of diamagnetic 1d and 2d reveal that the limited rotation of the N-aryl groups in 1d is further impeded in 2d by steric interactions imparted by the two closely located N-aryl groups. Partial displacement of the bridging bromide in 2c results upon its treatment with acetonitrile to afford [(L2)Ni2Br3(NCMe)] [2c(MeCN)]; no such reaction occurs for 2a, 2b, or 2d. Upon activation with excess methylalumoxane (MAO), 1b, 1c, 2b, and 2c show some activity for alkene oligomerization forming low molecular-weight materials with methyl-branched products predominating for the nickel systems. Single-crystal X-ray diffraction studies have been performed on L2-H, 1c, 2b, 2c, 2c(NCMe), and 2d.

  4. Pyruvate kinase isoenzyme M2 is a glycolytic sensor differentially regulating cell proliferation, cell size and apoptotic cell death dependent on glucose supply

    International Nuclear Information System (INIS)

    Spoden, Gilles A.; Rostek, Ursula; Lechner, Stefan; Mitterberger, Maria; Mazurek, Sybille; Zwerschke, Werner

    2009-01-01

    The glycolytic key regulator pyruvate kinase M2 (M2-PK or PKM2) can switch between a highly active tetrameric and an inactive dimeric form. The transition between the two conformations regulates the glycolytic flux in tumor cells. We developed specific M2-PK-binding peptide aptamers which inhibit M2-PK, but not the 96% homologous M1-PK isoenzyme. In this study we demonstrate that, at normal blood glucose concentrations, peptide aptamer-mediated inhibition of M2-PK induces a significant decrease of the population doubling (PDL rate) and cell proliferation rate as well as an increase in cell size, whereas under glucose restriction an increase in PDL and cell proliferation rates but a decrease in cell size was observed. Moreover, M2-PK inhibition rescues cells from glucose starvation-induced apoptotic cell death by increasing the metabolic activity. These findings suggest that M2-PK is a metabolic sensor which regulates cell proliferation, cell growth and apoptotic cell death in a glucose supply-dependent manner.

  5. Influenza M2 virus-like particles confer a broader range of cross protection to the strain-specific pre-existing immunity.

    Science.gov (United States)

    Kim, Min-Chul; Lee, Yu-Na; Hwang, Hye Suk; Lee, Young-Tae; Ko, Eun-Ju; Jung, Yu-Jin; Cho, Min Kyoung; Kim, Yu-Jin; Lee, Jong Seok; Ha, Suk-Hoon; Kang, Sang-Moo

    2014-10-07

    Immunity in humans with annual vaccination does not provide effective protection against antigenically distinct strains. As an approach to improve cross-protection in the presence of pre-existing strain-specific immunity, we investigated the efficacy of heterologous and heterosubtypic protection in previously vaccinated mice at earlier times after subsequent immunization with conserved-antigenic target influenza M2 ectodomain (M2e) virus-like particle vaccine (M2e5× VLP). Immunization of mice with H1N1 split vaccine induced virus specific antibodies to homologous influenza virus but did not provide heterosubtypic hemagglutination inhibiting antibody responses and cross-protection. However, subsequent M2e5× VLP immunization induced an M2e specific antibody response as well as interferon-γ (IFN-γ) producing cells in systemic and mucosal sites. Upon lethal challenge with H3N2 or H5N1 subtype influenza viruses, subsequently immunized mice with M2e5× VLP were well protected against heterosubtypic influenza viruses. These results provide evidence that non-seasonal immunization with M2e5× VLP, an experimental candidate for universal vaccine, is a promising approach for broadening the cross-protection even in the presence of strain-specific immunity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Vaccination potential of B and T epitope-enriched NP and M2 against Influenza A viruses from different clades and hosts.

    Directory of Open Access Journals (Sweden)

    Irina Tutykhina

    Full Text Available To avoid outbreaks of influenza virus epidemics and pandemics among human populations, modern medicine requires the development of new universal vaccines that are able to provide protection from a wide range of influenza A virus strains. In the course of development of a universal vaccine, it is necessary to consider that immunity must be generated even against viruses from different hosts because new human epidemic virus strains have their origins in viruses of birds and other animals. We have enriched conserved viral proteins-nucleoprotein (NP and matrix protein 2 (M2-by B and T-cell epitopes not only human origin but also swine and avian origin. For this purpose, we analyzed M2 and NP sequences with respect to changes in the sequences of known T and B-cell epitopes and chose conserved and evolutionarily significant epitopes. Eventually, we found consensus sequences of M2 and NP that have the maximum quantity of epitopes that are 100% coincident with them. Consensus epitope-enriched amino acid sequences of M2 and NP proteins were included in a recombinant adenoviral vector. Immunization with Ad5-tet-M2NP induced strong CD8 and CD4 T cells responses, specific to each of the encoded antigens, i.e. M2 and NP. Eight months after immunization with Ad5-tet-M2NP, high numbers of M2- and NP-responding "effector memory" CD44posCD62neg T cells were found in the mouse spleens, which revealed a long-term T cell immune memory conferred by the immunization. In all, the challenge experiments showed an extraordinarily wide-ranging efficacy of protection by the Ad5-tet-M2NP vaccine, covering 5 different heterosubtypes of influenza A virus (2 human, 2 avian and 1 swine.

  7. The effects of irradiation to 8x1026m-2 on the mechanical properties of 6061-T651 aluminum

    International Nuclear Information System (INIS)

    Alexander, D.J.

    1995-01-01

    The effects of irradiation on the mechanical properties of candidate structural materials are being examined. A key to the generation of useful neutron beams is allowing the neutrons produced in the core to escape. Therefore, an aluminum alloy has been selected for the first wall containment adjacent to the core, the Core Pressure Boundary Tube (CPBT), Alloy (6061 J651 Al 1.0Mg-0.6Si-0.3Cu-0.2Cr) with acceptable mechanical properties in unirradiated condition, low neutron cross-section, high thermal conductivity for heat removal. This alloy may also be used for the beam tubes and reflector tank. An irradiation program is underway to determine the effects of irradiation on the mechanical properties of 6061-T651 aluminium in particular the fracture toughness. This data will allow the operating lifetime of the CPBT to determined which will in turn determine its replacement schedule in the ANS. The first two capsules for the ANS Irradiation Effects program have been successfully irradiated to 10 26 and 8x10 26 m -2 (thermal flux), respectively, at a nominal irradiation temperature of 95 deg. C. The testing of the specimens of 6061-T651 aluminum has shown: 1. The yield and ultimate tensile strengths are increased by irradiation; 2. The uniform and total elongations are reduced, but useful ductility remains, even at the higher irradiation level; 3. The fracture toughness at 25 deg. C and 95 deg. C is unaffected by irradiation, but at 150 deg. C, it decreases with an increase in irradiation; 4. The tearing modulus of 6061-T651 is low in the unirradiated condition, and is reduced to very low values by irradiation. This alloy also shows a tendency for sudden unstable crack extension

  8. Bone marrow-derived and peritoneal macrophages have different inflammatory response to oxLDL and M1/M2 marker expression

    DEFF Research Database (Denmark)

    Bisgaard, Line S; Mogensen, Christina K; Rosendahl, Alexander

    2016-01-01

    -like CD206(high)CD11c(low) macrophages in advanced versus early atherosclerotic disease in ApoE-/- mice. In isolated lesions, mRNA levels of the M2 markers Socs2, CD206, Retnla, and IL4 were downregulated with increasing disease severity. Likewise, mRNA expression of lipid metabolism genes (SREBP2......, ACSL1, SRB1, DGAT1, and cpt1a) was decreased in advanced versus early lesions. In conclusion, PEMs and BMDMs are phenotypically distinct and differ from macrophages in lesions with respect to expression of M1/M2 markers and lipid metabolism genes.......Macrophages are heterogeneous and can polarize into specific subsets, e.g. pro-inflammatory M1-like and re-modelling M2-like macrophages. To determine if peritoneal macrophages (PEMs) or bone marrow derived macrophages (BMDMs) resembled aortic macrophages from ApoE-/- mice, their M1/M2 phenotype...

  9. BMI > or = 50 kg/m2 is associated with a younger age of onset of overweight and a high prevalence of adverse metabolic profiles.

    LENUS (Irish Health Repository)

    O'Connell, Jean

    2010-07-01

    To study the demographic and clinical parameters of three different categories of obesity, with particular focus on a cohort of individuals with BMI > or = 50 kg\\/m2, the fastest growing category of obesity.

  10. An H5N1 M2e-based multiple antigenic peptide vaccine confers heterosubtypic protection from lethal infection with pandemic 2009 H1N1 virus

    Directory of Open Access Journals (Sweden)

    Yu Hong

    2010-07-01

    Full Text Available Abstract Background A 2009 global influenza pandemic caused by a novel swine-origin H1N1 influenza A virus has posted an increasing threat of a potential pandemic by the highly pathogenic avian influenza (HPAI H5N1 virus, driving us to develop an influenza vaccine which confers cross-protection against both H5N1 and H1N1 viruses. Previously, we have shown that a tetra-branched multiple antigenic peptide (MAP vaccine based on the extracellular domain of M2 protein (M2e from H5N1 virus (H5N1-M2e-MAP induced strong immune responses and cross-protection against different clades of HPAI H5N1 viruses. In this report, we investigated whether such M2e-MAP presenting the H5N1-M2e consensus sequence can afford heterosubtypic protection from lethal challenge with the pandemic 2009 H1N1 virus. Results Our results demonstrated that H5N1-M2e-MAP plus Freund's or aluminum adjuvant induced strong cross-reactive IgG antibody responses against M2e of the pandemic H1N1 virus which contains one amino acid variation with M2e of H5N1 at position 13. These cross-reactive antibodies may maintain for 6 months and bounced back quickly to the previous high level after the 2nd boost administered 2 weeks before virus challenge. H5N1-M2e-MAP could afford heterosubtypic protection against lethal challenge with pandemic H1N1 virus, showing significant decrease of viral replications and obvious alleviation of histopathological damages in the challenged mouse lungs. 100% and 80% of the H5N1-M2e-MAP-vaccinated mice with Freund's and aluminum adjuvant, respectively, survived the lethal challenge with pandemic H1N1 virus. Conclusions Our results suggest that H5N1-M2e-MAP has a great potential to prevent the threat from re-emergence of pandemic H1N1 influenza and possible novel influenza pandemic due to the reassortment of HPAI H5N1 virus with the 2009 swine-origin H1N1 influenza virus.

  11. MD SIMULATION STUDIES TO INVESTIGATE ISO-ENERGETIC CONFORMATIONAL BEHAVIOUR OF MODIFIED NUCLEOSIDES M2G AND M22G PRESENT IN tRNA

    Directory of Open Access Journals (Sweden)

    Rohit S Bavi

    2013-02-01

    Full Text Available Modified nucleic acid bases are most commonly found in tRNA. These may contain modifications from simple methylation to addition of bulky groups. Methylation of the four canonical nucleotide bases at a wide variety of positions is particularly prominent among the known modification. Methylation of N2 group of guanine is a relatively common modification in tRNA and rRNA. N2-methylguanosine (m2G is the second most often encountered nucleoside in E. coli tRNAs. N2, N2-dimethylguanosine (m22G is found in the majority of eukaryotic tRNAs and involved in forming base pair interactions with adjacent bases. Hence, in order to understand the structural significance of these methylated nucleic acid bases we have carried out molecular dynamics simulation to see the salvation effect. The results obtained shows iso-energetic conformational behaviors for m2G and m22G. The simulation trajectory of m2G shows regular periodical fluctuations suggesting that m2G is equally stable as either s-cis or s-trans rotamers. The two rotamers of m2G may interact canonically or non-canonically with opposite base as s-trans m2G26:C/A/U44 and s-cis m2G26:A/U44. The free rotations around the C-N bond could be the possible reason for these iso-energetic conformations. Dimethylation of G has almost no influence on base pairing with either A or U. Thus, these results reveal that modified nucleosides m2G and m22G may play an important role to prevent tRNA from adopting the unusual mitochondrial like conformation.

  12. Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain.

    Directory of Open Access Journals (Sweden)

    Helen M Wise

    Full Text Available Segment 7 of influenza A virus produces up to four mRNAs. Unspliced transcripts encode M1, spliced mRNA2 encodes the M2 ion channel, while protein products from spliced mRNAs 3 and 4 have not previously been identified. The M2 protein plays important roles in virus entry and assembly, and is a target for antiviral drugs and vaccination. Surprisingly, M2 is not essential for virus replication in a laboratory setting, although its loss attenuates the virus. To better understand how IAV might replicate without M2, we studied the reversion mechanism of an M2-null virus. Serial passage of a virus lacking the mRNA2 splice donor site identified a single nucleotide pseudoreverting mutation, which restored growth in cell culture and virulence in mice by upregulating mRNA4 synthesis rather than by reinstating mRNA2 production. We show that mRNA4 encodes a novel M2-related protein (designated M42 with an antigenically distinct ectodomain that can functionally replace M2 despite showing clear differences in intracellular localisation, being largely retained in the Golgi compartment. We also show that the expression of two distinct ion channel proteins is not unique to laboratory-adapted viruses but, most notably, was also a feature of the 1983 North American outbreak of H5N2 highly pathogenic avian influenza virus. In identifying a 14th influenza A polypeptide, our data reinforce the unexpectedly high coding capacity of the viral genome and have implications for virus evolution, as well as for understanding the role of M2 in the virus life cycle.

  13. E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Zejun [Sanmen People' s Hospital of Zhejiang, Sanmen, Zhejiang, 317100 (China); Gong, Chaoju [Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058 (China); Liu, Hong [Zhejiang Normal University – Jinhua People' s Hospital Joint Center for Biomedical Research, Jinhua, Zhejiang, 321004 (China); Zhang, Xiaomin; Mei, Lingming [Sanmen People' s Hospital of Zhejiang, Sanmen, Zhejiang, 317100 (China); Song, Mintao [Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS), School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, 100005 (China); Qiu, Lanlan; Luo, Shuchai; Zhu, Zhihua; Zhang, Ronghui; Gu, Hongqian [Sanmen People' s Hospital of Zhejiang, Sanmen, Zhejiang, 317100 (China); Chen, Xiang, E-mail: sychenxiang@126.com [Sanmen People' s Hospital of Zhejiang, Sanmen, Zhejiang, 317100 (China)

    2015-08-21

    As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression of E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease. - Highlights: • E2F1 promotes RRM2 transactivation in CRC cells. • E2F1 promotes the proliferation of CRC cells by activating RRM2. • E2F1 promotes the migration and

  14. The effect of flap thickness on corneal biomechanics after myopic laser in situ keratomileusis using the M-2 microkeratome

    Directory of Open Access Journals (Sweden)

    Goussous IA

    2017-11-01

    Full Text Available Iyad A Goussous,1 Mohamed-Sameh El-Agha,1 Ahmed Awadein,1 Mohamed H Hosny,1 Alaa A Ghaith,2 Ahmed L Khattab2 1Department of Ophthalmology, Faculty of Medicine, Cairo University, Cairo, 2Faculty of Medicine, Alexandria University, Alexandria, Egypt Purpose: The purpose of this study was to determine the effect of flap thickness on corneal biomechanics after myopic laser in situ keratomileusis (LASIK.Methods: This is a prospective controlled non-randomized, institutional study. Patients underwent either epi-LASIK with mitomycin (advanced surface ablation [ASA], thin-flap LASIK (90 µm head, or thick-flap LASIK (130 µm head. In ASA, the Moria Epi-K hydroseparator was used. LASIK flaps were created using the Moria M-2 mechanical microkeratome. The corneal hysteresis (CH and corneal resistance factor (CRF were measured preoperatively and 3 months after surgery, using the Ocular Response Analyzer®.Results: Ten patients (19 eyes underwent ASA, 11 patients (16 eyes underwent thin-flap LASIK, and 11 patients (16 eyes underwent thick-flap LASIK. The mean preoperative CH was 10.47±0.88, 10.52±1.4, and 11.28±1.4 mmHg (p=0.043, respectively, decreasing after surgery by 1.75±1.02, 1.66±1.00, and 2.62±1.03 mmHg (p=0.017. The mean reduction of CH per micron of central corneal ablation was 0.031, 0.023, and 0.049 mmHg/µm (p=0.005. Mean preoperative CRF was 10.11±1.28, 10.34±1.87, and 10.62±1.76 mmHg (p=0.66, decreasing after surgery by 2.33±1.35, 2.77±1.03, and 2.92±1.10 mmHg (p=0.308. The mean reduction of CRF per micron of central corneal ablation was 0.039, 0.040, and 0.051 mmHg/µm (p=0.112.Conclusion: Thick-flap LASIK caused a greater reduction of CH and CRF than thin-flap LASIK and ASA, although this was statistically significant only for CH. ASA and thin-flap LASIK were found to be biomechanically similar. Keywords: flap thickness ectasia, hysteresis, LASIK, surface ablation

  15. Molecular association of glucose-6-phosphate isomerase and pyruvate kinase M2 with glyceraldehyde-3-phosphate dehydrogenase in cancer cells.

    Science.gov (United States)

    Das, Mahua R; Bag, Arup K; Saha, Shekhar; Ghosh, Alok; Dey, Sumit K; Das, Provas; Mandal, Chitra; Ray, Subhankar; Chakrabarti, Saikat; Ray, Manju; Jana, Siddhartha S

    2016-02-24

    For a long time cancer cells are known for increased uptake of glucose and its metabolization through glycolysis. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key regulatory enzyme of this pathway and can produce ATP through oxidative level of phosphorylation. Previously, we reported that GAPDH purified from a variety of malignant tissues, but not from normal tissues, was strongly inactivated by a normal metabolite, methylglyoxal (MG). Molecular mechanism behind MG mediated GAPDH inhibition in cancer cells is not well understood. GAPDH was purified from Ehrlich ascites carcinoma (EAC) cells based on its enzymatic activity. GAPDH associated proteins in EAC cells and 3-methylcholanthrene (3MC) induced mouse tumor tissue were detected by mass spectrometry analysis and immunoprecipitation (IP) experiment, respectively. Interacting domains of GAPDH and its associated proteins were assessed by in silico molecular docking analysis. Mechanism of MG mediated GAPDH inactivation in cancer cells was evaluated by measuring enzyme activity, Circular dichroism (CD) spectroscopy, IP and mass spectrometry analyses. Here, we report that GAPDH is associated with glucose-6-phosphate isomerase (GPI) and pyruvate kinase M2 (PKM2) in Ehrlich ascites carcinoma (EAC) cells and also in 3-methylcholanthrene (3MC) induced mouse tumor tissue. Molecular docking analyses suggest C-terminal domain preference for the interaction between GAPDH and GPI. However, both C and N termini of PKM2 might be interacting with the C terminal domain of GAPDH. Expression of both PKM2 and GPI is increased in 3MC induced tumor compared with the normal tissue. In presence of 1 mM MG, association of GAPDH with PKM2 or GPI is not perturbed, but the enzymatic activity of GAPDH is reduced to 26.8 ± 5 % in 3MC induced tumor and 57.8 ± 2.3 % in EAC cells. Treatment of MG to purified GAPDH complex leads to glycation at R399 residue of PKM2 only, and changes the secondary structure of the protein complex. PKM2

  16. Molecular association of glucose-6-phosphate isomerase and pyruvate kinase M2 with glyceraldehyde-3-phosphate dehydrogenase in cancer cells

    International Nuclear Information System (INIS)

    Das, Mahua R.; Bag, Arup K.; Saha, Shekhar; Ghosh, Alok; Dey, Sumit K.; Das, Provas; Mandal, Chitra; Ray, Subhankar; Chakrabarti, Saikat; Ray, Manju; Jana, Siddhartha S.

    2016-01-01

    For a long time cancer cells are known for increased uptake of glucose and its metabolization through glycolysis. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key regulatory enzyme of this pathway and can produce ATP through oxidative level of phosphorylation. Previously, we reported that GAPDH purified from a variety of malignant tissues, but not from normal tissues, was strongly inactivated by a normal metabolite, methylglyoxal (MG). Molecular mechanism behind MG mediated GAPDH inhibition in cancer cells is not well understood. GAPDH was purified from Ehrlich ascites carcinoma (EAC) cells based on its enzymatic activity. GAPDH associated proteins in EAC cells and 3-methylcholanthrene (3MC) induced mouse tumor tissue were detected by mass spectrometry analysis and immunoprecipitation (IP) experiment, respectively. Interacting domains of GAPDH and its associated proteins were assessed by in silico molecular docking analysis. Mechanism of MG mediated GAPDH inactivation in cancer cells was evaluated by measuring enzyme activity, Circular dichroism (CD) spectroscopy, IP and mass spectrometry analyses. Here, we report that GAPDH is associated with glucose-6-phosphate isomerase (GPI) and pyruvate kinase M2 (PKM2) in Ehrlich ascites carcinoma (EAC) cells and also in 3-methylcholanthrene (3MC) induced mouse tumor tissue. Molecular docking analyses suggest C-terminal domain preference for the interaction between GAPDH and GPI. However, both C and N termini of PKM2 might be interacting with the C terminal domain of GAPDH. Expression of both PKM2 and GPI is increased in 3MC induced tumor compared with the normal tissue. In presence of 1 mM MG, association of GAPDH with PKM2 or GPI is not perturbed, but the enzymatic activity of GAPDH is reduced to 26.8 ± 5 % in 3MC induced tumor and 57.8 ± 2.3 % in EAC cells. Treatment of MG to purified GAPDH complex leads to glycation at R399 residue of PKM2 only, and changes the secondary structure of the protein complex. PKM2

  17. A systematic review and meta-analysis of the diagnostic accuracy of pyruvate kinase M2 isoenzymatic assay in diagnosing colorectal cancer.

    Science.gov (United States)

    Uppara, Mallikarjuna; Adaba, Franklin; Askari, Alan; Clark, Susan; Hanna, George; Athanasiou, Thanos; Faiz, Omar

    2015-02-13

    Screening programmes exist in many countries for colorectal cancer. In recent years, there has been a drive for a non-invasive screening marker of higher sensitivity and specificity. Stool-based pyruvate kinase isoenzyme M2 (M2-PK) is one such biomarker under investigation. The aim of this systematic review and meta-analysis is to determine the diagnostic accuracy, sensitivity and specificity of M2-PK as a screening tool in colorectal cancer. A literature search of Ovid Medline, EMBASE and Google Scholar was carried out. The search strategy was restricted to human subjects and studies published in English. Data on sensitivity and specificity were extracted and pooled. Statistical analysis was conducted using summary receiver operating characteristic (SROC) curve methodology. A total of eight studies were suitable for data synthesis and analysis. Our analysis showed a pooled sensitivity and specificity for M2-PK to be 79% (CI 73%-83%) and 80% (CI 73%-86%), respectively. The accuracy of M2-PK was 0.85(0.82-0.88). Faecal M2-PK assay has a relatively good sensitivity and specificity and high accuracy for screening colorectal cancer.

  18. Comparison of weekly administration of cisplatin versus three courses of cisplatin 100 mg/m2 for definitive radiochemotherapy of locally advanced head-and-neck cancers

    International Nuclear Information System (INIS)

    Rades, Dirk; Seidl, Daniel; Janssen, Stefan; Bajrovic, Amira; Karner, Katarina; Strojan, Primoz; Schild, Steven E

    2016-01-01

    To compare definitive radiochemotherapy with weekly administration of 30–40 mg/m 2 of cisplatin to 100 mg/m 2 of cisplatin on days 1, 22 and 43 for outcomes and toxicity in patients with squamous cell carcinoma of the head-and-neck. Seventy-five patients receiving radiochemotherapy with weekly cisplatin (30–40 mg/m 2 ) were compared to 58 patients receiving radiochemotherapy with 100 mg/m 2 cisplatin on days 1, 22 and 43. Radiochemotherapy regimen plus seven characteristics (age, gender, performance score, tumor site, T-/N-category, histologic grading) were evaluated for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Radiochemotherapy groups were compared for toxicity. On multivariate analysis, improved LRC was associated with cisplatin 100 mg/m 2 (hazard ratio [HR] 1.57; p = 0.008) and female gender (HR 4.37; p = 0.003). Radiochemotherapy regimen was not significantly associated with MFS on univariate analysis (p = 0.66). On multivariate analysis, better MFS was associated with ECOG performance score 0–1 (HR 5.63; p < 0.001) and histological grade 1–2 (HR 1.81; p = 0.002). On multivariate analysis, improved OS was associated with cisplatin 100 mg/m 2 (HR 1.33; p = 0.023), ECOG performance score 0–1 (HR 2.15; p = 0.029) and female gender (HR 1.98; p = 0.026). Cisplatin 100 mg/m 2 was associated with higher rates of grade ≥3 hematotoxicity (p = 0.004), grade ≥2 renal failure (p = 0.004) and pneumonia/sepsis (p = 0.033). Radiochemotherapy with 100 mg/m 2 of cisplatin every 3 weeks resulted in better LRC and OS than weekly doses of 30–40 mg/m 2 . Given the limitations of a retrospective study, 100 mg/m 2 of cisplatin appears preferable. Since this regimen was associated with considerable acute toxicity, patients require close monitoring

  19. γδ T Cells Are Required for M2 Macrophage Polarization and Resolution of Ozone-Induced Pulmonary Inflammation in Mice.

    Science.gov (United States)

    Mathews, Joel A; Kasahara, David I; Ribeiro, Luiza; Wurmbrand, Allison P; Ninin, Fernanda M C; Shore, Stephanie A

    2015-01-01

    We examined the role of γδ T cells in the induction of alternatively activated M2 macrophages and the resolution of inflammation after ozone exposure. Wildtype (WT) mice and mice deficient in γδ T cells (TCRδ-/- mice) were exposed to air or to ozone (0.3 ppm for up to 72h) and euthanized immediately or 1, 3, or 5 days after cessation of exposure. In WT mice, M2 macrophages accumulated in the lungs over the course of ozone exposure. Pulmonary mRNA abundance of the M2 genes, Arg1, Retnla, and Clec10a, also increased after ozone. In contrast, no evidence of M2 polarization was observed in TCRδ-/- mice. WT but not TCRδ-/- mice expressed the M2c polarizing cytokine, IL-17A, after ozone exposure and WT mice treated with an IL-17A neutralizing antibody exhibited attenuated ozone-induced M2 gene expression. In WT mice, ozone-induced increases in bronchoalveolar lavage neutrophils and macrophages resolved quickly after cessation of ozone exposure returning to air exposed levels within 3 days. However, lack of M2 macrophages in TCRδ-/- mice was associated with delayed clearance of inflammatory cells after cessation of ozone and increased accumulation of apoptotic macrophages in the lungs. Delayed restoration of normal lung architecture was also observed in TCRδ-/- mice. In summary, our data indicate that γδ T cells are required for the resolution of ozone-induced inflammation, likely because γδ T cells, through their secretion of IL-17A, contribute to changes in macrophage polarization that promote clearance of apoptotic cells.

  20. Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE{sub 2} and IL-6

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Haixia [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zhang, Xinhua [Department of Liver, Biliary And Pancreatic Tumors, Hubei Cancer Hospital, Wuhan 430079 (China); Chen, Xuewei; Li, Ying; Ke, Zunqiong [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Guo, Austin M. [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Department of Pharmacology, New York Medical College, Valhalla, NY 10595 (United States); Chen, Honglei, E-mail: hl-chen@whu.edu.cn [Department of Pathology and Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)

    2014-09-15

    M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75 mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12 weeks significantly decreased colon cancer incidence, multiplicity and tumor size by 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE{sub 2} and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE{sub 2}/PPARδ and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE{sub 2} or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis-associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE{sub 2} and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer. - Highlights: • Isoliquiritigenin (ISL) prevents colitis-associated tumorigenesis. • ISL inhibits M2 macrophage polarization in vivo and in vitro. • ISL inhibits PGE{sub 2} and IL-6 signaling in colitis-associated tumorigenesis. • ISL may be an attractive candidate agent for

  1. Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6

    International Nuclear Information System (INIS)

    Zhao, Haixia; Zhang, Xinhua; Chen, Xuewei; Li, Ying; Ke, Zunqiong; Tang, Tian; Chai, Hongyan; Guo, Austin M.; Chen, Honglei; Yang, Jing

    2014-01-01

    M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75 mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12 weeks significantly decreased colon cancer incidence, multiplicity and tumor size by 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE 2 and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE 2 /PPARδ and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE 2 or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis-associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE 2 and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer. - Highlights: • Isoliquiritigenin (ISL) prevents colitis-associated tumorigenesis. • ISL inhibits M2 macrophage polarization in vivo and in vitro. • ISL inhibits PGE 2 and IL-6 signaling in colitis-associated tumorigenesis. • ISL may be an attractive candidate agent for chemoprevention of

  2. High Frequency of vacA s1m2 Genotypes Among Helicobacter pylori Isolates From Patients With Gastroduodenal Disorders in Kermanshah, Iran.

    Science.gov (United States)

    Pajavand, Hamid; Alvandi, Amirhooshang; Mohajeri, Parviz; Bakhtyari, Somaye; Bashiri, Homayoon; Kalali, Behnam; Gerhard, Markus; Najafi, Farid; Abiri, Ramin

    2015-11-01

    Helicobacter pylori infection and related diseases outcome are mediated by a complex interplay between bacterial, host and environmental factors. Several distinct virulence factors of H. pylori have been shown to be associated with different clinical outcomes. Here we focused on vacA and cagA genotypes of H. pylori strains isolated from patients with gastric disorder. The aim of this study was to determine the frequency of two toxins and genotypes of VacA toxin in patients referred to a central hospital in the west of Iran (Imam Reza hospital, Kermanshah) during 2011 - 2012. Samples were collected from patients infected with H. pylori. Gastric biopsy specimens from the stomach antrum and corpus were cultured. PCR analysis was performed for genotyping H. pylori vacA and cagA genes. Helicobacter pylori was isolated from 48% (96/200) of patients with gastroduodenal disorders. In 81/96 (84%) cases, the cagA gene was present. Among different genotypes of vacA, two s1m2 and s2m2 genotypes were dominant with frequency of 39.5% and 50%, respectively. The frequency of the s1m1 genotype was 7.2% (7/96), which is much lower than elsewhere. H. pylori isolates with positive results for cagA gene and vacA s1m2 genotypes showed statistically significant correlation with peptic ulcer (s1m2 13/34 [38.2%] P = 0.003). However, isolates of H. pylori infection with cagA gene and vacA s2m2 genotypes were significantly associated with development of gastritis (s2m2 41/42 [97.6%] P = 0.000). About 90% of H. pylori strains potentially contained vacA s2m2 and s1m2 genotypes. Infection with H. pylori strain containing the cagA gene or the vacA s1m1 and s1m2 genotypes was associated with increased incidence of peptic ulcer disease (PUD).

  3. Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells

    Directory of Open Access Journals (Sweden)

    An S

    2018-04-01

    Full Text Available Shuxian An,1,* Liangqian Huang,2,3,* Ping Miao,1 Liang Shi,1 Mengqin Shen,1 Xiaoping Zhao,1 Jianjun Liu,1 Gang Huang1,3,4 1Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 2Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; 3Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; 4Shanghai University of Medicine and Health Sciences, Shanghai, China *These authors contributed equally to this work Objective: Lung cancer is the leading cause of cancer-related death worldwide. Aerobic glycolysis is considered the seventh hallmark of cancer. The M2 isoform of pyruvate kinase (PKM2 is an important rate-limiting enzyme in glycolytic pathway, and is strongly expressed in several types of cancer. Thus, understanding the underlying mechanisms of regulation of PKM2 is of great value for targeted therapy for lung cancer.Patients and methods: Seventy-three lung adenocarcinoma patients were analyzed in our study. The expression levels of PKM2 were analyzed by immunohistochemistry on tissues. The effect of small ubiquitin-like modifier 1 (SUMO1 on PKM2 expression was investigated using Western blot assay and quantitative polymerase chain reaction. PKM2 SUMO1 modification was determined by in vitro and in vivo SUMOylation assays. 18F-deoxyglucose uptake and lactate production measurements were conducted to research the levels of glycolysis. The level of oxidative phosphorylation in cells was determined by cellular oxygen consumption rate measurements. Cell proliferation assays were carried out to confirm the growth ability of tumor cells.Results: PKM2 was overexpressed in lung adenocarcinoma patients based on immunohistochemical staining. Patients with high PKM2 expression had reduced

  4. Does Small Size Matter With Continuous Flow Devices?: Analysis of the INTERMACS Database of Adults With BSA ≤1.5 m2.

    Science.gov (United States)

    Zafar, Farhan; Villa, Chet R; Morales, David L; Blume, Elizabeth D; Rosenthal, David N; Kirklin, James K; Lorts, Angela

    2017-02-01

    This study investigated how small patient size affects clinical outcomes in patients implanted with a continuous flow left ventricular assist device (CFLVAD). The development of smaller CFLVADs has allowed ventricular assist device (VAD) use in anatomically smaller patients; however, limited outcome data exist regarding CFLVAD use in patients with a body surface area (BSA) ≤1.5 m 2 . All CFLVAD patients entered in the Interagency Registry for Mechanically Assisted Circulatory Support registry April 2008 to September 2013 and with BSA data were included. Biventricular VAD patients were excluded. Patient characteristics and clinical outcomes were compared between patients with BSA ≤1.5 m 2 (small patients) and those >1.5 m 2 . Of 10,813 CFLVAD recipients, 231 had a BSA ≤1.5 m 2 . Small patients were more commonly female patients (68% vs. 20%; p  0.05), overall survival (p > 0.05), and 1-year competing outcomes (p > 0.05) were similar between BSA groups. Patients with a BSA ≤1.5 m 2 supported with a CFLVAD have similar survival to larger patients. These data support the use of CFLVAD in anatomically small patients. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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).

  6. Recent progress in computational approaches to studying the M2 proton channel and its implication to drug design against influenza viruses.

    Science.gov (United States)

    Du, Qi-Shi; Huang, Ri-Bo

    2012-05-01

    For quite a long period of time in history, many intense efforts have been made to determine the 3D (three-dimensional) structure of the M2 proton channel. The reason why the M2 proton channel has attracted so many attentions is because (1) it is the key for really understanding the life cycle of influenza viruses, and (2) it is indispensable for conducting rational drug design against the flu viruses. Recently, the long-sough 3D structures of the M2 proton channels for both influenza A and B viruses were consecutively successfully determined by the high-resolution NMR spectroscopy (Schnell J.R. and Chou, J.J., Nature, 2008, 451: 591-595; Wang, J., Pielak, R.M., McClintock, M.A., and Chou, J.J., Nature Structural & Molecular Biology, 2009,16: 1267-1271). Such a milestone work has provided a solid structural basis for in-depth understanding the action mechanism of the M2 channel and rationally designing effective drugs against influenza viruses. This review is devoted to, with the focus on the M2 proton channel of influenza A, addressing a series of relevant problems, such as how to correctly understand the novel allosteric inhibition mechanism inferred from the NMR structure that is completely different from the traditional view, what the possible impacts are to the previous functional studies in this area, and what kind of new strategy can be stimulated for drug development against influenza.

  7. Thermodynamics of formation of double salts M2SO4 · M'SO4 · 6H2O and M2SeO4 · M'SeO4 · 6H2O where M denotes Rb, or Cs and M' denote Co, Ni, or Zn

    International Nuclear Information System (INIS)

    Christov, Christomir.

    2003-01-01

    This paper describes a chemical model that calculates (solid + liquid) equilibria in the (m 1 Rb 2 SO 4 + m 2 CoSO 4 )(aq), (m 1 Rb 2 SeO 4 + m 2 CoSeO 4 )(aq), (m 1 Rb 2 SO 4 + m 2 NiSO 4 )(aq), (m 1 Rb 2 SO 4 + m 2 ZnSO 4 )(aq), (m 1 Rb 2 SeO 4 + m 2 ZnSeO 4 )(aq), (m 1 Cs 2 SO 4 + m 2 CoSO 4 )(aq), (m 1 Cs 2 SeO 4 + m 2 CoSeO 4 )(aq), (m 1 Cs 2 SO 4 + m 2 NiSO 4 )(aq), (m 1 Cs 2 SeO 4 + m 2 NiSeO 4 )(aq), (m 1 Cs 2 SO 4 + m 2 ZnSO 4 )(aq), and (m 1 Cs 2 SeO 4 + m 2 ZnSeO 4 )(aq) systems, where m denotes molality at the temperature T=298.15 K. The Pitzer ion-interaction model has been used for thermodynamic analysis of the experimental osmotic and solubility data presented in the literature. The thermodynamic functions needed (binary and ternary parameters of ionic interaction, thermodynamic solubility products) have been calculated and the theoretical solubility isotherm has been plotted. The mixing parameters {θ(MN) and ψ(MNX)} have been chosen on the basis of the compositions of saturated ternary solutions and data on the binary solubility of the sulfate M 2 SO 4 . M ' SO 4 · 6H 2 O double salts in water. To validate the mixing solutions model two different approaches have been used in evaluation of the ternary parameters: (I) preserving the same value of the binary mixing θ(MN) for the corresponding chloride, bromide, sulfate, and selenate systems with the same cations, and (II) with constant θ(MN) value (set equal to -0.05) for the all 11 sulfate and selenate systems. Very good agreement between experimentally determined and model predicted solubilities has been found. Important thermodynamic characteristics (thermodynamic solubility products, standard molar Gibbs free energy of formation) of the solid phases (simple salts, six sulfate - M 2 SO 4 · M ' SO 4 · 6H 2 O, and five selenate - M 2 SeO 4 · M ' SeO 4 · 6H 2 O - double salts) crystallizing in the systems under consideration are determined

  8. Structural changes of carbides in a high-speed steel - M2 - after hardness and drawing back

    International Nuclear Information System (INIS)

    Santos, D.B.; Luz Ferreira, O. da; Ribeiro, O.L.R.

    1984-01-01

    The microstructure of a high-speed steel was studied through the scanning electron microscope. The carbide chemical composition was determined by the X-ray energy spectroscopy. The analyses were done in situ and in precipitate extracted from carbon replica. The phases were shown through the X-ray diffraction in the wastes from electrolytic use. In the annealed structure, some carbides as M 6 C, MC and M 23 C 6 and in the annealed and drawing back structure, carbide as M 6 C and MC were seen. The volumetric fraction of each type was calculated by quantitative metalography. The utilization of the replica technique allows the analysis of carbides smaller than 1 μm without the matrix interference. (E.G.) [pt

  9. Probing topology and dynamics of the second transmembrane domain (M2δ) of the acetyl choline receptor using magnetically aligned lipid bilayers (bicelles) and EPR spectroscopy.

    Science.gov (United States)

    Sahu, Indra D; Mayo, Daniel J; Subbaraman, Nidhi; Inbaraj, Johnson J; McCarrick, Robert M; Lorigan, Gary A

    2017-08-01

    Characterizing membrane protein structure and dynamics in the lipid bilayer membrane is very important but experimentally challenging. EPR spectroscopy offers a unique set of techniques to investigate a membrane protein structure, dynamics, topology, and distance constraints in lipid bilayers. Previously our lab demonstrated the use of magnetically aligned phospholipid bilayers (bicelles) for probing topology and dynamics of the membrane peptide M2δ of the acetyl choline receptor (AchR) as a proof of concept. In this study, magnetically aligned phospholipid bilayers and rigid spin labels were further utilized to provide improved dynamic information and topology of M2δ peptide. Seven TOAC-labeled AchR M2δ peptides were synthesized to demonstrate the utility of a multi-labeling amino acid substitution alignment strategy. Our data revealed the helical tilts to be 11°, 17°, 9°, 17°, 16°, 11°, 9°±4° for residues I7TOAC, Q13TOAC, A14TOAC, V15TOAC, C16TOAC, L17TOAC, and L18TOAC, respectively. The average helical tilt of the M2δ peptide was determined to be ∼13°. This study also revealed that the TOAC labels were attached to the M2δ peptide with different dynamics suggesting that the sites towards the C-terminal end are more rigid when compared to the sites towards the N-terminus. The dynamics of the TOAC labeled sites were more resolved in the aligned samples when compared to the randomly disordered samples. This study highlights the use of magnetically aligned lipid bilayer EPR technique to determine a more accurate helical tilt and more resolved local dynamics of AchR M2δ peptide. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Cholinergic Neurotransmission in the Posterior Insular Cortex Is Altered in Preclinical Models of Neuropathic Pain: Key Role of Muscarinic M2 Receptors in Donepezil-Induced Antinociception

    Science.gov (United States)

    Ferrier, Jérémy; Bayet-Robert, Mathilde; Dalmann, Romain; El Guerrab, Abderrahim; Aissouni, Youssef; Graveron-Demilly, Danielle; Chalus, Maryse; Pinguet, Jérémy; Eschalier, Alain; Richard, Damien; Daulhac, Laurence; Balayssac, David

    2015-01-01

    Neuropathic pain is one of the most debilitating pain conditions, yet no therapeutic strategy has been really effective for its treatment. Hence, a better understanding of its pathophysiological mechanisms is necessary to identify new pharmacological targets. Here, we report important metabolic variations in brain areas involved in pain processing in a rat model of oxaliplatin-induced neuropathy using HRMAS 1H-NMR spectroscopy. An increased concentration of choline has been evidenced in the posterior insular cortex (pIC) of neuropathic animal, which was significantly correlated with animals' pain thresholds. The screening of 34 genes mRNA involved in the pIC cholinergic system showed an increased expression of the high-affinity choline transporter and especially the muscarinic M2 receptors, which was confirmed by Western blot analysis in oxaliplatin-treated rats and the spared nerve injury model (SNI). Furthermore, pharmacological activation of M2 receptors in the pIC using oxotremorine completely reversed oxaliplatin-induced mechanical allodynia. Consistently, systemic treatment with donepezil, a centrally active acetylcholinesterase inhibitor, prevented and reversed oxaliplatin-induced cold and mechanical allodynia as well as social interaction impairment. Intracerebral microdialysis revealed a lower level of acetylcholine in the pIC of oxaliplatin-treated rats, which was significantly increased by donepezil. Finally, the analgesic effect of donepezil was markedly reduced by a microinjection of the M2 antagonist, methoctramine, within the pIC, in both oxaliplatin-treated rats and spared nerve injury rats. These findings highlight the crucial role of cortical cholinergic neurotransmission as a critical mechanism of neuropathic pain, and suggest that targeting insular M2 receptors using central cholinomimetics could be used for neuropathic pain treatment. SIGNIFICANCE STATEMENT Our study describes a decrease in cholinergic neurotransmission in the posterior insular

  11. Initial transient accumulation of M2 macrophage-associated molecule-expressing cells after pulpotomy with mineral trioxide aggregate in rat molars.

    Science.gov (United States)

    Takei, Erika; Shigetani, Yoshimi; Yoshiba, Kunihiko; Hinata, Go; Yoshiba, Nagako; Okiji, Takashi

    2014-12-01

    M2 (alternatively activated) macrophages are known to participate in wound healing and tissue repair. This study aimed to analyze the temporospatial changes in the distribution and density of M2 macrophage-associated molecule-expressing cells after pulpotomy with mineral trioxide aggregate (MTA) in rat molars to ascertain the role played by M2 macrophages in the healing of MTA-capped pulp tissue. The maxillary first molars of 8-week-old Wistar rats were pulpotomized and capped with MTA. After 1-14 days, the teeth were examined after hematoxylin-eosin staining or immunoperoxidase staining of CD68 (a general macrophage marker) and M2 macrophage markers (CD163 and CD204). The density of positively stained cells was enumerated in the surface and inner regions (0-100 μm and 300-400 μm, respectively, from the wound surface). MTA capping initially caused mild inflammatory changes and the formation of a degenerative layer followed by progressive new matrix formation and calcified bridging. At 1-2 days, CD68-, CD163-, and CD204-positive cells started to accumulate beneath the degenerative layer, and the density of these cells was significantly higher in the surface region than in the inner region (P MTA, M2 macrophage-associated molecule-expressing cells transiently accumulated beneath the degenerative layer under the MTA. This suggests that M2 macrophages participate in the initial phases of the healing of MTA-capped pulp tissue. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  12. Accuracies of fecal calprotectin, lactoferrin, M2-pyruvate kinase, neopterin and zonulin to predict the response to infliximab in ulcerative colitis.

    Science.gov (United States)

    Frin, Anne-Claire; Filippi, Jérôme; Boschetti, Gilles; Flourie, Bernard; Drai, Jocelyne; Ferrari, Patricia; Hebuterne, Xavier; Nancey, Stéphane

    2017-01-01

    Fecal markers might predict the response to anti-TNFα in ulcerative colitis (UC). To compare the performance of fecal calprotectin (fCal), lactoferrin (fLact), M2-PK (fM2-PK), neopterin (fNeo), and zonulin (fZon) to predict the response to therapy in active UC patients. Disease activity from 31 consecutive patients with an active UC, treated with infliximab (IFX) was assessed by the Mayo score at baseline and at week 14 and by the partial Mayo score at W52 and stool samples collected for fecal marker measurements at W0, W2, and W14. At W14, 19 patients (61%) were responders to IFX induction. The median levels of fCal, fLact and fM2-PK drop dramatically from baseline to W14 in clinical responders. At W2, fM2-PK, fLact and fCal levels predicted accurately the response to IFX induction. At W14, fLact, fCal, and fM2-PK were individually reliable markers to predict sustained response at W52. The performances of fNeo and fZon were weaker in this setting. The performance of fM2-PK at W2 to predict response to induction therapy with IFX was superior to that of fLact and fCal, whereas monitoring fLact was the best tool to predict adequately the course of the disease at one year under maintenance IFX in UC. Copyright © 2016. Published by Elsevier Ltd.

  13. A boosting skin vaccination with dissolving microneedle patch encapsulating M2e vaccine broadens the protective efficacy of conventional influenza vaccines.

    Science.gov (United States)

    Zhu, Wandi; Pewin, Winston; Wang, Chao; Luo, Yuan; Gonzalez, Gilbert X; Mohan, Teena; Prausnitz, Mark R; Wang, Bao-Zhong

    2017-09-10

    The biodegradable microneedle patch (MNP) is a novel technology for vaccine delivery that could improve the immunogenicity of vaccines. To broaden the protective efficiency of conventional influenza vaccines, a new 4M2e-tFliC fusion protein construct containing M2e sequences from different subtypes was generated. Purified fusion protein was encapsulate into MNPs with a biocompatible polymer for use as a boosting vaccine. The results demonstrated that mice receiving a conventional inactivated vaccine followed by a skin-applied dissolving 4M2e-tFliC MNP boost could better maintain the humoral antibody response than that by the conventional vaccine-prime alone. Compared with an intramuscular injection boost, mice receiving the MNP boost showed significantly enhanced cellular immune responses, hemagglutination-inhibition (HAI) titers, and neutralization titers. Increased frequency of antigen-specific plasma cells and long-lived bone marrow plasma cells was detected in the MNP boosted group as well, indicating that skin vaccination with 4M2e-tFliC facilitated a long-term antibody-mediated immunity. The 4M2e-tFliC MNP-boosted group also possessed enhanced protection against high lethal dose challenges against homologous A/PR/8/34 and A/Aichi/2/68 viruses and protection for a majority of immunized mice against a heterologous A/California/07/2009 H1N1 virus. High levels of M2e specific immune responses were observed in the 4M2e-tFliC MNP-boosted group as well. These results demonstrate that a skin-applied 4M2e-tFliC MNP boosting immunization to seasonal vaccine recipients may be a rapid approach for increasing the protective efficacy of seasonal vaccines in response to a significant drift seen in circulating viruses. The results also provide a new perspective for future exploration of universal influenza vaccines. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Reliable and Efficient Access for Alarm-initiated and Regular M2M Traffic in IEEE 802.11ah Systems

    DEFF Research Database (Denmark)

    Madueño, Germán Corrales; Stefanovic, Cedomir; Popovski, Petar

    2016-01-01

    IEEE 802.11ah is a novel WiFi-based protocol, aiming to provide an access solution for the machine-to-machine (M2M) communications. In this paper, we propose an adaptive access mechanism that can be seamlessly incorporated into IEEE 802.11ah protocol operation and that supports all potential M2M...... reporting regimes, which are periodic, on-demand and alarm reporting. The proposed access method is based a periodically re- occurring pool of time slots, whose size is proactively determined on the basis of the reporting activity in the cell. We show that it is possible to both efficiently and reliably...

  15. Murine gammaherpesvirus M2 protein induction of IRF4 via the NFAT pathway leads to IL-10 expression in B cells.

    Directory of Open Access Journals (Sweden)

    Udaya S Rangaswamy

    2014-01-01

    Full Text Available Reactivation of the gammaherpesviruses Epstein-Barr virus (EBV, Kaposi's sarcoma-associated herpesvirus (KSHV and murine gammaherpesvirus 68 (MHV68 from latently infected B cells has been linked to plasma cell differentiation. We have previously shown that the MHV68 M2 protein is important for virus reactivation from B cells and, when expressed alone in primary murine B cells, can drive B cell differentiation towards a pre-plasma cell phenotype. In addition, expression of M2 in primary murine B cells leads to secretion of high levels of IL-10 along with enhanced proliferation and survival. Furthermore, the absence of M2 in vivo leads to a defect in the appearance of MHV68 infected plasma cells in the spleen at the peak of MHV68 latency. Here, employing an inducible B cell expression system, we have determined that M2 activates the NFAT pathway in a Src kinase-dependent manner--leading to induction of the plasma cell-associated transcription factor, Interferon Regulatory Factor-4 (IRF4. Furthermore, we show that expression of IRF4 alone in a B cell line up-regulates IL-10 expression in culture supernatants, revealing a novel role for IRF4 in B cell induced IL-10. Consistent with the latter observation, we show that IRF4 can regulate the IL-10 promoter in B cells. In primary murine B cells, addition of cyclosporine (CsA resulted in a significant decrease in M2-induced IL-10 levels as well as IRF4 expression, emphasizing the importance of the NFAT pathway in M2- -mediated induction of IL-10. Together, these studies argue in favor of a model wherein M2 activation of the NFAT pathway initiates events leading to increased levels of IRF4--a key player in plasma cell differentiation--which in turn triggers IL-10 expression. In the context of previous findings, the data presented here provides insights into how M2 facilitates plasma cell differentiation and subsequent virus reactivation.

  16. Studies on some quantitative characters in the M2 generation in jute (Corchorus olitorius L.) originating after pre-irradiation treatments with hydroxylamine and pre- and post-irradiation treatments with colchicine

    International Nuclear Information System (INIS)

    Bose, S.; Chakrabarti, C.C.; Banerjee, B.

    1977-01-01

    Studies on quantitative characters have been made on M 2 mutants like - slender plants with many branches and oval shaped leaves, plants with bifurcation at the base of the stem, stout dwarf plants with many branches, slender plants with many branches, small, slender plants with lesser number of branches, slender, tall plants with many branches, tall plants with crincked leaves and many branches and in the bulk type having many branches and tall habit. The bulk types originated after pre-irradiation treatment with hydroxylamine, colchicine and post-irradiation treatment with colchicine and the mutants originated after pre-irradiation treatment with hydroxylamine and distilled water. The quantitative characters taken into consideration were plant height, basal diameter, number of nodes per plant, number pods per plant, number of seeds per pod and 100 seed weight. (author)

  17. Luminescent Afterglow Behavior in the M2Si5N8: Eu Family (M = Ca, Sr, Ba

    Directory of Open Access Journals (Sweden)

    Koen Van den Eeckhout

    2011-05-01

    Full Text Available Persistent luminescent materials are able to emit light for hours after being excited. The majority of persistent phosphors emit in the blue or green region of the visible spectrum. Orange- or red-emitting phosphors, strongly desired for emergency signage and medical imaging, are scarce. We prepared the nitrido-silicates Ca2Si5N8:Eu (orange, Sr2Si5N8:Eu (reddish, Ba2Si5N8:Eu (yellowish orange, and their rare-earth codoped variants (R = Nd, Dy, Sm, Tm through a solid state reaction, and investigated their luminescence and afterglow properties. In this paper, we describe how the persistent luminescence is affected by the type of codopant and the choice and ratio of the starting products. All the materials exhibit some form of persistent luminescence, but for Sr2Si5N8:Eu,R this is very weak. In Ba2Si5N8:Eu the afterglow remains visible for about 400 s, and Ca2Si5N8:Eu,Tm shows the brightest and longest afterglow, lasting about 2,500 s. For optimal persistent luminescence, the dopant and codopant should be added in their fluoride form, in concentrations below 1 mol%. A Ca3N2 deficiency of about 5% triples the afterglow intensity. Our results show that Ba2Si5N8:Eu(,R and Ca2Si5N8:Eu(,R are promising persistent phosphors for applications requiring orange or red light.